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Dementia – a National Health Priority Helping Australians with dementia and their carers Dementia Research Mapping Project Final Report
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Page 1: Dementia – a National Health Prioritylibrary.bsl.org.au/jspui/bitstream/1/2716/1... · 3.3.1 Alzheimer’s Disease and Vascular Dementia 41 3.3.2 Mixed Dementia 43 3.3.3 Dementia

Dementia – a National Health Priority

Helping Australians with dementia and their carers

Dementia Research Mapping ProjectFinal Report

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Final Report Australian Government Dementia Health Priority Initiative Dementia Research Mapping Project Prepared for the Commonwealth Department of Health and Ageing by: Professor Helen Bartlett Australasian Centre on Ageing The University of Queensland Professor Len Gray Academic Unit in Geriatric Medicine The University of Queensland Associate Professor Gerard Byrne Department of Psychiatry The University of Queensland Dr Catherine Travers Australasian Centre on Ageing The University of Queensland Dr Chi-Wai Lui Australasian Centre on Ageing The University of Queensland

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Acknowledgements We would like to acknowledge the valuable assistance of the Panel of Experts in the field of dementia who assisted with this project. They provided guidance regarding key areas of research to be included in the final document as well as critiquing sections of the report. Members of the Panel included: Dr Jonathon Chalk Centre for Magnetic Resonance Imaging The University of Queensland Brisbane Associate Professor George Mellick Institute for Cell and Molecular Therapies Griffith University Brisbane Associate Professor Peteris Darzins Associate Professor of Geriatric Medicine Monash Ageing Research Centre Monash University Melbourne Professor Murna Downs Chair Bradford Dementia Group University of Bradford UK In addition, we are grateful for the valuable comments regarding the genetics of dementia provided by: Dr Corinne Lendon Head, Molecular Psychiatry Laboratory Queensland Institute of Molecular Research Brisbane We would also like to acknowledge the invaluable assistance of Kate Suridge from the Australasian Centre on Ageing at The University of Queensland, in the compilation of the final report. Finally, the helpful comments received by the Office for An Ageing Australia, Commonwealth Department of Health and Ageing and the project’s Reference Group are also acknowledged.

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Contents 1.0 Background to the Project and Methodology 1 1.1 Project Aim 1 1.2 Introduction 1 1.3 Scope of the Project 2 1.4 Literature Review - General Strategy 2 1.5 Review of the literature by Panel of Experts 3 1.6 General Inclusion Criteria 5 1.7 General Exclusion Criteria 5 References 10 2.0 What is Dementia: Definitions and Diagnostic Criteria 11 2.1 Classification of Dementia 11 2.2 Alzheimer’s Dementia 12

2.2.1 NINCDS-ADRDA Criteria 132.2.2 Clinical Presentation 13

2.3 Vascular Dementia 14

2.3.1 Clinical presentation of VaD 17 2.4 Mixed Dementia 17

2.4.1 Clinical Presentation of Mixed dementia 17 2.5 Dementia with Lewy bodies (DLB) 18 2.5.1 Clinical Presentation of DLB 18 2.6 Parkinson’s Disease 20

2.6.1 Clinical Presentation of Parkinson’s Disease 202.6.2 Dementia in Parkinson’s Disease 20

2.7 Frontotemporal Lobar Degeneration (FTLD) 22

2.7.1 Clinical Presentation 26 2.8 Mild Cognitive Impairment 26 References 27 3.0 Epidemiology 32 3.1 Literature Search 32 3.2 Incidence of Dementia - all causes 33

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3.2.1 Australian studies 333.2.2 Indigenous Australians 373.2.3 European studies 373.2.4 Global Prevalence of Dementia 37

3.3 Dementia Variants 41

3.3.1 Alzheimer’s Disease and Vascular Dementia 413.3.2 Mixed Dementia 433.3.3 Dementia with Lewy bodies 443.3.4 The Prevalence of Dementia in Parkinson’s disease 453.3.5 Frontotemporal Dementia 453.3.6 Early Onset Dementia 463.3.7 Mild Cognitive Impairment 473.3.8 Rare causes of Dementia 47

3.4 Summary 48 References 50 4.0 Aetiology and Pathophysiology of dementia 55 4.1 Literature Search 55 4.2 Classification of dementia 56 4.3 Genetic Factors in dementia 57

4.3.1 Alzheimer’s disease 574.3.1.1 Apolipoprotein E isoform ε4 (APOE- ε4) 574.3.1.2 Susceptibility Genes 584.3.1.3 Alzgene 58

4.4 Genetic studies in dementia with Lewy bodies 59 4.5 Genetic studies in Parkinson Disease (PD) 59 4.6 Genetics of Frontotemporal Lobar Degeneration 59 4.7 Genetic forms of Vascular dementia 60 4.8 Neuropathology of Dementia 61

4.8.1 Alzheimer’s Disease 614.8.1.1 Amyloid Plaques 614.8.1.2 Neurofibrillary Tangles 624.8.1.3 Aetiological Hypothesis 64

4.8.1.3.1 The Amyloid Hypothesis 644.8.1.3.2 The Vascular Hypothesis 664.8.1.3.3 The Cholinergic Hypothesis 67

4.9 Vascular Dementia: Pathophysiology 67 4.10 Frontotemporal Lobar Degeneration (FTLD) 69

4.10.1 Neuropathology 704.10.2 Neurotransmitter studies in FTD 70

4.11 Dementia with Lewy bodies (DLB) 70

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4.11.1 Neuropathology 704.11.2 Neurotransmitter studies in DLB 71

4.12 Dementia in Parkinson’s disease (PDD) 72

4.12.1 Neurotransmitter studies in PDD 73 4.13 Infectious Causes of Dementia: Prion disease 73 4.14 Summary 73 References 75 5.0 Risk and Protective factors 82 5.1 Literature Search 82 5.2 Risk Factors 83

5.2.1 Age 835.2.2 Family history of Dementia 845.2.3 Down Syndrome 845.2.4 Apolipoprotein E isoform ε4 (APOE-E4) 855.2.5 Cerebrovascular Risk Factors 86

5.2.5.1 Stroke 865.2.5.2 Diabetes Mellitus 865.2.5.3 Hypertension 875.2.5.4 Homocysteine 89

5.2.6 Mild Cognitive Impairment 895.2.7 Subjective Memory Complaints 895.2.8 Depression 905.2.9 Head Trauma 905.2.10 Obesity and Dietary Factors 915.2.11 Exposure to Environmental Toxins 92

5.3 Probable Protective Factors 92

5.3.1 Education and Intelligence 925.3.2 Occupation 925.3.3 Physical Activity 935.3.4 Social Integration/Cognitive Activity/Leisure 935.3.5 Brain Reserve Hypothesis 945.3.6 Alcohol Consumption 94

5.4 Factors for which the evidence is inconclusive 95

5.4.1 Cholesterol and Cholesterol lowering medications (Statins) 955.4.2 Non-Steroidal Anti-Inflammatory Medications (NSAIDS)/Aspirin 965.4.3 Omega-3 Fatty Acids 975.4.4 Race and Regional Variation 975.4.5 Gender 985.4.6 Smoking 985.4.7 Hormone Replacement Therapy 99

5.5 Factors that appear to offer little benefit 100

5.5.1 Anti-Oxidants – Vitamins C and E 1005.5.2 Folic Acid with or without Vitamin B12; Vitamin B6 100

5.6 Summary 101

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References 102 6.0 Diagnosis and Assessment 113 6.1 Literature Search 113 6.2 Diagnosis of Dementia 114

6.2.1 Medical History and Physical Examination 115 6.3 Brief Screening Tests 116

6.3.1 Mental State Examination 1166.3.2 The Rowland Universal Dementia Assessment Scale (RUDAS) 1166.3.3 The Kimberley Indigenous Cognitive Assessment (KICA) 117

6.4 Neuropsychological Assessment 117

6.4.1 Neuropsychological Profiles 1186.4.2 Neuropsychological Assessment in Preclinical AD 120

6.5 Neuroimaging Techniques 121

6.5.1 Structural Neuroimaging 1216.5.2 Functional Imaging 1226.5.3 Other Neuroimaging Techniques 1246.5.4 The National Institute of Health Neuroimaging Initiative 124

6.6 Biomarkers 125 6.7 Electroencephalogram (EEG) 126 6.8 Brain Biopsy 126 6.9 Genetic Tests 126 6.10 Summary 127 References

128

7.0 Treatment 135 7.1 Literature Search 135 7.2 Pharmacological Treatments 137

7.2.1 Cholinesterase Inhibitors 1377.2.1.1 Donepezil (Aricept) – Clinical Efficacy 1377.2.1.2 Donepezil for Mild Cognitive Impairment 1387.2.1.3 Donepezil for Vascular Cognitive Impairment 1387.2.1.4 Donepezil – Current Clinical Trials 1397.2.1.5 Galantamine (Reminyl) – Clinical Efficacy 1397.2.1.6 Galantamine for Vascular Cognitive Impairment 1407.2.1.7 Galantamine – Current Clinical Trials 1407.2.1.8 Rivastigmine (Exelon) – Clinical Efficacy 1417.2.1.9 Rivastigmine Transdermal Patch 1417.2.1.10 Rivastigmine for Vascular Cognitive Impairment 1427.2.1.11 Cholinesterase Inhibitors for Parkinson’s Disease 142

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dementia 7.2.1.12 Cholinesterase Inhibitors for dementia with Lewy bodies and Frontotemporal dementia 1437.2.1.13 Donepezil, galantamine, Rivastigmine – Comparative Studies 143

7.3 Memantine 144

7.3.1 Memantine – Current Clinical Trials 145 7.4 Cost Effectiveness of Donezepil, Galantamine, Rivastigmine and Memantine

145

7.5 Medications specifically for the treatment of Psychological and Behavioural Symptoms of Dementia (BPSD)

146

7.5.1 Atypical Antipsychotics 1467.5.2 Antipsychotics in patients with dementia with Lewy bodies 1477.5.3 Atypical Antipsychotics – Current Clinical Trials 1477.5.4 Antidepressants 1487.5.5 Antidepressants – Current Clinical Trials 1487.5.6 Mood Stabilisers 1497.5.7 Mood Stabilisers – Current Clinical Trials 149

7.6 Treatment of risk factors and concurrent physical conditions in patients with Vascular Dementia

149

7.6.1 Aspirin for Vascular Dementia 1507.6.2 Ibuprofen for Alzheimer’s disease 1507.6.3 NSAIDs – Current Clinical Trials 1507.6.4 Pentoxifylline for Vascular Dementia 1507.6.5 Calcium Channel Blockers 1517.6.6 Calcium Channel Blockers – Current Clinical Trials 1517.6.7 Antihypertensive medications – Current Clinical Trials 1517.6.8 Medications for cholesterol lowering drugs – Current Clinical Trials

152

7.6.9 Medications for glucose control – Current Clinical Trials 152 7.7 Other Pharmacological Treatments 152

7.7.1 Hormone Therapy 1527.7.2 Hormone Therapy – Current Clinical Trials 1527.7.3 A Vaccine for AD 1537.7.4 Vaccines – Current Clinical Trials 1537.7.5 Other 153

7.8 Complementary Therapies 154

7.8.1 Ginkgo Biloba 1547.8.2 Acupuncture for the treatment of Vascular dementia 1547.8.3 Homeopathy 1557.8.4 Aromatherapy 1557.8.5 Vitamin E for Alzheimer’s disease 1557.8.6 Vitamin E – Current Clinical Trials 1557.8.7 Melantonin 156

7.8.8 Complementary Therapies – Current Clinical Trials 156 7.9 Psychosocial Interventions to promote health, cognitive functioning and well-being 156

7.9.1 Physical Exercise 156

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7.9.2 Cognitive Rehabilitation/Cognitive Training 1577.9.3 Cognitive Stimulation 1577.9.4 Reminiscence Therapy 1587.9.5 Behaviour Management 1587.9.6 Validation Therapy 1597.9.7 Reality Orientation 1597.9.8 Bright Light Therapy for managing sleep, behaviour and mood disturbances in dementia

159

7.9.9 Snoezelen 1607.9.10 Music Therapy 1607.9.11 Transcutaneous Electrical Nerve Stimulation (TENS) 160

7.10 Miscellaneous Clinical Trials 160 7.11 Summary 161 References 163 8.0 Care and support for people with dementia and their carers

178

8.1 Introduction 1788.2 Literature Search

178

8.3 Palliative Care

180

8.4 Activities of Daily Living

181

8.4.1 Feeding 1828.4.2 Ambulation 1838.4.3 Hygiene and Personal Care 185

8.4.4 Driving 186 8.5 Behavioural and Psychological Symptoms of Dementia 187 8.6 Accessing the Perspective of People with Dementia 190 8.7 Support for Carers 192

8.7.1 Prevalence and Nature of Caregiver Burden 1928.7.2 Interventions to Reduce Caregiver Burden

193

8.8 Housing Provision and Environmental Design 196 8.8.1 Housing Provision 196

8.8.2 Environmental design

197

8.9 Cultural differences in Carer Experience

197

8.10 Ethical Issues in Dementia Care 2008.10.1 Overview 2008.10.2 Disclosure of a Diagnosis of Dementia 2008.10.3 Decision-Making Ability of People with Dementia

202

8.11 Summary 203

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References

205

9.0 Gaps in the Evidence and Recommendations for Future Research

212

9.1 Epidemiology

212

9.2 Aetiology and Pathophysiology of Dementia

212

9.3 Diagnosis and Assessment

214

9.4 Risk and Prevention of Dementia

215

9.5 Treatments

215

9.6 Care and Support for People with Dementia and their Carers 217 9.7 Summary

218

References 220

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List of Tables Table 1.1 Specific Literature Search Strategies…………………………........7 Table 2.1 NINCDS-ADRDA Criteria for the diagnosis of Alzheimer’s

Disease……………………………………………………………….14 Table 2.2 NINDS-AIREN diagnostic criteria for definite, probable

and possible Vascular dementia ……………………………….....15 Table 2.3 The Hachinski Ischemic Index criteria………………………........16 Table 2.4 Revised consensus criteria for the clinical diagnosis of

dementia with Lewy bodies (DLB)………………………………..19 Table 2.5 UK PDS Brain Bank criteria for the diagnosis of

Parkinson’s disease…………………………………………………21 Table 2.6 Consensus criteria for the diagnosis of Frontotemporal

dementia…………………………………………………………......23 . Table 2.7 Consensus criteria for the diagnosis of progressive

nonfluent aphasia………………………………………….………..24 Table 2.8 Consensus criteria for the diagnosis of semantic dementia……25 Table 3.1 Prevalence rates according to Meta-analyses:

All dementias (%)…………………….………………….……….....34 Table 3.2 Incidence rates according to Meta-analyses:

All dementias (%)…………………….…………………….…….....35 Table 3.3 Access Economics projections: Prevalence of dementia

in Australia by age and gender 2001 - 2050……….…….………35 Table 3.4 Access Economics projections: Incidence of dementia by

by age and gender 2001 – 2050……...……….…………………..36 . Table 3.5 Consensus estimates of the prevalence and incidence of

dementia by world region and projected numbers of people with dementia……………………………………………….40

Table 3.6 Prevalence rates according to Meta-analyses: Alzheimer’s

dementia (%)…………………………………………………………41 Table 3.7 Incidence rates according to Meta-analyses: Alzheimer’s

dementia (%)……………………………….………………………..41 Table 3.8 Prevalence of dementia in Europe …………….………….…..….42 Table 3.9 Prevalence and Incidence of Vascular dementia

in Europe………………...…………………………………………..43

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Table 3.10 Prevalence of Mixed dementia in Epidemiological studies….....................................................................................44 Table 4.1 Pathological deficits in patients with dementia……….….………57 .. Table 4.2 Pathological lesions capable of producing Vascular

dementia……………………………………………….…………….68

Table 7.1 Summary of included Cochrane reviews of dementia treatments……………………………………….………….……..169 Table 7.2 Summary of Cochrane reviews of dementia treatments

not included……………...…………………………….……..…..175

Table 8.1 Search Strategy…………………………………………….…......178 . Table 8.2 Systematic review of palliative care in dementia………………181 Table 8.3 Systematic review of strategies to assist eating in people

with dementia……………………………………………………...182 Table 8.4 Systematic review of gait disturbance in dementia……………183 Table 8.5 Systematic review of oral hygiene in dementia………………..185 Table 8.6 Systematic review of driving in dementia………………………186 Table 8.7 Systematic reviews of interventions for BPSD…………………188 Table 8.8 Interventions used with patients with BPSD………………… 189 Table 8.9 Systematic reviews of instruments to ascertain the

perspective of people with dementia………………………… 191 Table 8.10 Systematic reviews of caregiver burden……………………....192 Table 8.11 Systematic reviews of interventions to reduce

caregiver burden………………………………………………....194 Table 8.12 Meta-Analyses of interventions for carers of people with

dementia.................................................................................195 Table 8.13 Systematic review of housing provision and environmental

design for people with dementia……………………………….196 Table 8.14 Systematic reviews of cultural factors in dementia…………..198 Table 8.15 Meta-analysis of cultural factors in dementia…………….…...199 Table 8.16 Systematic review of the disclosure of a diagnosis

of dementia…………………………………………………….....201

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List of Figures Figure 1.1 Types of research included in the report…………………….........3 Figure 3.1 Flowchart of identification of large-scale pooled analyses

for inclusion in the review of epidemiology………………………33

Figure 3.2 Worldwide prevalence studies of dementia……………………...39 Figure 4.1 Flowchart of identification of systematic reviews and

meta-analytic studies for inclusion in the review of aetiology and pathophysiology of dementia………………………………...56

Figure 4.2 Amyloid Cascade Hypothesis Diagram………………….………65 Figure 5.1 Flowchart of identification of systematic studies and

meta-analytic studies for inclusion in the review of risk and protective factors……………………………………………...83

Figure 6.1 Flowchart of identification of systematic reviews and

meta-analytic studies for inclusion in the review of diagnosis and assessment of dementia………………………..114

Figure 7.1 Flowchart of identification of systematic reviews and

meta-analytic studies for inclusion in the treatment of dementia …………………………………………………………..136

Figure 8.1 Flowchart of literature search process for dementia care …...180

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1.0 Background to the Project and Methodology The Dementia Research Mapping Project was one of a number of projects sponsored by Commonwealth Government under the Dementia Initiative: Helping Australians with dementia, and their carers – making dementia a National Health Priority announced in the 2005 federal Budget. 1.1 Project Aim The aim of the dementia research mapping project was to map published national and international dementia research with a view to developing a resource for stakeholders and identifying gaps in dementia research. The objective of the project was to develop a publication that provided a summary and catalogue of key dementia research for stakeholders that will underpin further research by identifying gaps in dementia research and support future systematic reviews of dementia research. The Dementia Research Mapping Project will also inform the Dementia Collaborative research Centres, the Dementia Research Grants and the Dementia Research Website. 1.2 Introduction Dementia is not a single, specific disease. It is a term used to describe a group of diseases that affect the brain and cause a progressive decline in the ability to think, remember and learn. Although dementia is a condition that primarily affects older people, it is not a normal part of ageing. The World Health Organization’s International Classification of Disease (1992-1994) describes dementia as:

‘dementia is a syndrome due to disease of the brain, usually of a chronic or progressive nature, in which there is disturbance of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement. Consciousness is not clouded. The impairments of cognitive function are commonly accompanied, and occasionally preceded by deterioration in emotional control, social behaviour, or motivation. The syndrome occurs in Alzheimer’s disease, in cerebrovascular disease, and in other conditions primarily or secondarily affecting the brain’ (World Health Organisation, 1992-1994)

While projected estimates of dementia in Australia vary, it is clear that the number of people diagnosed with dementia will increase markedly over the next two decades alongside the ageing of the population. It was estimated that 171,220 Australians had dementia (0.89% of total population) in 2000 and the number was around 197,000 in 2004 (0.98% of total population) and it has been projected that the total number of dementia cases will exceed 730,000 (2.8% of the projected population) by 2050. This represents a fourfold increase in the number of cases since 2000 (Access Economics, 2005). Dementia has been found to be the greatest single contributor to burden of disease due to disability at older ages as well as the greatest single contributor to the cost of care in nursing homes (Australian Institute of Health and Welfare, 2004).

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In 2002, the total direct costs of dementia in Australia were estimated to be $6.5 billion of which $42.8 million was for the residential care sector and $174 million for home and community care sectors. Indirect financial costs included a loss of around $490 million in potential taxation from carers of those with dementia (Hogan, 2004) as well as welfare payments to patients and their carers. The total direct and indirect costs of dementia are expected to rise from 0.91 % of gross domestic product (GDP) in 2002 to 3.3% of GDP in 2051. This is without consideration of the enormous emotional burden of caring for someone with dementia. 1.3 Scope of the Project There are numerous subtypes of dementia, of which the most common variants are:

1. Alzheimer’s disease (AD) is the most common type of dementia, and accounts for approximately 50% of dementia cases1. It is characterised by short-term memory loss and difficulties with language in the early stages, and gradually becomes more severe over several years.

2. Vascular dementia (VaD) – this is a form of dementia caused by

cerebrovascular conditions including multi-infarct disease and stroke. It is estimated to account for approximately 20% of all cases of dementia.1

3. Mixed dementia – the coexistence of AD and VaD is referred to as mixed

dementia. Accurate prevalence and incidence data are not available.

4. Dementia with Lewy bodies – this is estimated to account for up to 15% of dementia cases and is characterised by symptoms similar to Parkinson’s disease as well as hallucinations and a tendency to fall.

5. Frontotemporal Dementia – dementia that affects the frontal and temporal

regions of the brain and is estimated to account for approximately 5% of cases.

6. Dementia in Parkinson’s disease – Parkinson’s disease is the most

common neurodegenerative adult-onset movement disorder. It has been estimated that dementia secondary to Parkinson’s disease accounts for approximately 3 - 4% of dementia cases (Aarsland, Zaccai, & Brayne, 2005).

Numerous other dementia subtypes exist including HIV complex and alcohol related dementia, demyelination, human prion disease including Creutzfeldt-Jacob dementia, Huntington’s disease, progressive supranuclear palsy and dementia due to other infectious or metabolic cause. This report will focus on the most common variants of dementia, which together account for the majority (approximately 95%) of all cases. 1.4 Literature Review - General Strategy The principal project consultants, in consultation with the panel of experts, developed specific inclusion criteria (see below) and the literature was searched for additional consensus criteria. A stepwise, hierarchical approach to the literature search was adopted with the published and ‘grey’ literature being searched backwards from 2006.

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The search included both national and international literature, but was limited to English language publications. The most recently published research was given precedence over older research on the grounds that the more recently conducted studies are generally of a higher methodological standard and are more likely to include the use of standardised instruments; use more rigorously and clearly defined diagnostic criteria; and make more use of neuroimaging techniques and autopsy results. Systematic reviews, meta-analyses and large-scale pooled analyses were identified and retrieved in the first instance. In areas that had not been systematically reviewed, review articles were obtained. Additional articles were identified by reviewing the reference lists of retrieved papers and primary research was obtained in instances where systematic and review articles for a particular topic were limited. For instance, no systematic reviews of acupuncture as a treatment for dementia have been published to date (although a Cochrane protocol exists) and thus primary research articles relating to acupuncture were obtained. Similarly, research into a vaccine for dementia is in its infancy and only primary research articles have been published. The types of research included in the final report are shown in the following diagram:

Figure 1.1 Types of Research included in the Report

Primary Research

Systematic Reviews/Meta-Analysis

Literature Review

Government/OrganizationalReports

Consensus Statements/Reports

Books/Book Chapter

Clinical Guidelines

Other - includes editorials, pressreleases, etc

1.5 Review of the Literature by Panel of Experts The literature review was guided by a panel of experts comprised of leading researchers with national and international reputations in the field of dementia research. They identified key areas of research and relevant references for inclusion in the review document. A preliminary document was then drafted and selected sections were submitted to each member of the panel for a critical appraisal depending on his or her particular area of expertise.

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The document was evaluated for its completeness and thoroughness and subsequently revised on the basis of the feedback received. The process of critiquing the draft document was guided by a list of criteria specifically developed for the purpose by the principal consultants. A separate literature search was conducted for each of the following topics included in the report: Epidemiology Evidence of the prevalence and incidence of the most frequently occurring dementia subtypes - including Alzheimer’s disease, Vascular dementia, Mixed dementia, Lewy body dementia, dementia secondary to Parkinson’s disease, Frontotemporal dementia, Mild Cognitive Impairment and early-onset dementia - was identified and retrieved. Both Australian and international epidemiological data are reported. Aetiology and Pathophysiology The key neuropathological changes characteristic of the most frequently occurring dementia subtypes are summarised as is the role of genetic factors thought to be causative in dementia. Key theories regarding the development and progression of Alzheimer’s disease are also summarised Risk and Protective Factors Risk factors that are considered to increase an individual’s risk of dementia as well as factors that may be protective against the disease are summarised. This includes a review of genetic risk factors, cerebrovascular disease as well as environmental risk factors. Diagnosis and Assessment The literature regarding the currently available instruments that are considered to be the best diagnostic aids for dementia - including neuropsychological assessments, structural imaging techniques including computed tomography and magnetic resonance imaging (MRI) and scanning techniques positron emission tomography (PET) and single photon emission computed tomography (SPECT) - are summarised. Research into potential biomarkers of the disease is also documented. Treatment Treatments and therapies for dementia that have demonstrated evidence of their effectiveness are summarised. Included are treatments designed to slow the progression of the disease as well as treatments that target psychological and behavioural symptoms of the disease. Both pharmacological therapies (e.g. cholinesterase inhibitors) and psychosocial interventions are reviewed as well as the use of aids and interventions aimed at secondary prevention such as the early identification and treatment of risk factors including hypertension. Details of promising clinical trials that are currently in progress are also documented. Care and Support for People with Dementia and their Carers Interventions that have demonstrated evidence of their effectiveness are summarised.

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This includes information and education for patients and their carers, the use of respite care to reduce carer stress, the provision of practical and emotional support to carers and dementia friendly housing. Important cross-cultural differences that may influence the recognition of dementia, treatment and management of dementia, in particular attitudes to help-seeking, are also included. Gaps in the Evidence and Recommendations for Future Research Currently, there are gaps in the knowledge base regarding almost every aspect of dementia. For example, there are gaps in epidemiological studies in many areas of the world, including parts of Australia, the cellular-molecular mechanisms that lead to the development of brain pathology are not understood, the treatments that are currently available are limited in their effectiveness and a definitive diagnostic tool does not currently exist. These gaps are documented and a number of recommendations for future research are made. The list, however, is not intended to be exhaustive nor definitive and the proposed questions are not listed in order of priority – rather its purpose is to highlight important areas for future research in dementia. The following general inclusion and exclusion criteria were adopted for each search conducted. Additional criteria adopted in relation to specific topics are listed in Table 1 below: 1.6 General Inclusion Criteria The review/study was required to relate specifically to one of the most frequently occurring subtypes of dementia in humans (i.e. Alzheimer's disease, Vascular dementia, Mixed dementia, Lewy Body dementia, Parkinson’s disease, Frontotemporal dementia, Mild Cognitive Impairment, early onset dementia). An adequate description of the methodology was required, including an adequate description of the design, study population, sampling procedures and diagnostic criteria.

In the case of meta-analyses, an adequate description of the included studies, the pooling method and analytic technique were required. There was no restriction on the methodology employed and both observational (epidemiological) and experimental studies were included. 1.7 General Exclusion Criteria All animal studies were excluded from this review. Articles were excluded if they repeated what was already reported, failed to add any new knowledge or had been superseded by more recent work. Therefore, general review studies or overviews were generally not included. Publications relating to cognitive ageing or cognitive decline in healthy older people or in the general older population were not included. Single case-studies were not included in the review, nor were treatments that were not evidence-based or the results of expert consultation/consensus. Evidence based guidelines were evaluated on the quality and level of supporting evidence.

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For all searches, the following computer-based databases were searched:

• Ageline • Cumulative Index to Nursing and Allied Health Literature (CINAHL), • MEDLINE, • PubMed, • PsycINFO,

In addition, abstracts were searched from the 10th International Conference on Alzheimer’s Disease and Related Disorders (Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 2006, 2: S1) Additional databases and websites were accessed for research specifically relating to each topic and these are listed in Table 1. Six primary keywords were used in all computer searches and included dementia, Alzheimer's disease, Vascular dementia, Lewy body dementia, Frontotemporal dementia and Mixed dementia. The primary keywords were used in conjunction with a number of secondary keywords, also identified in Table 1.1. The results of the literature search for each topic are summarised in this report accompanied by a list of references that may be cross-referenced to an Endnote file. A section describing the most frequently occurring subtypes of dementia with a listing of the most commonly used diagnostic criteria for each is also included. This provides background information for the report.

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Table 1.1 Specific Literature Search Strategies Topic Additional Databases/Websites

Accessed Secondary Keywords

Inclusion/Exclusion Criteria

Epidemiology

Alzheimer’s Australia (including state offices) Alzheimer’s Organization, US Commonwealth Department of Health and Ageing (Australia) Australian Institute of Health and Welfare National Aged Care Alliance (Australia) National Institute of Neurological Disorders and Stroke (US) National Institute for Health and Clinical Excellence (UK) The National Creutzfeldt-Jakob Disease Surveillance Unit The Queensland Institute of Medical Research The World Health Organization

epidemiology, prevalence, incidence, mild cognitive impairment and Indigenous Australians.

The review/study was required to relate specifically to the prevalence and incidence of one of the most frequently occurring subtypes of dementia. Epidemiological studies of some of the rarer forms of dementia (Creutzfeldt-Jakob Disease; alcohol related dementia) were also included for illustrative purposes. Large-scale pooled analyses and meta-analyses were selected for inclusion in the first instance. These were limited in some cases (e.g. frontotemporal dementia) and primary research studies were included in those instances.

Aetiology and Pathophysiology

Alzheimer’s Organization, US Alzheimer Research Forum Alzheimer’s Society UK Australian Neuroscience Society Centre for Neuroscience, Flinders University, Adelaide Society for Neuroscience The Association for Frontotemporal

aetiology, cause, pathology, pathogenesis, pathophysiology, tau, inflammation, beta-amyloid, neurological, neurotransmitter, neurodegenerative, neuropathology, biological markers, genetics, development and course.

Only aetiological and pathophysiological factors for which there is some evidence, are included. Hypothetical factors are not included.

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Dementias

Diagnosis and Assessment

Neurosciences Abstracts PsycARTICLES Alzheimer’s Australia Alzheimer Research Forum The Hammond Care Group UK NHS National Institute for Health and Clinical Excellence Alzheimer Research Forum NHS Health Technology Assessment Programme

diagnosis, diagnostic, diagnostic criteria, diagnostic tool, symptoms, assessment, prognosis, clinical assessment, biomarkers, neuropsychological, MRI, imaging, structural imaging, scanning, PET, SPECT, test, brain biopsy and EEG.

Only diagnostic tools and techniques that have demonstrated evidence of their effectiveness were included. Experimental methods were not included.

Risk and protective factors

Cochrane Database of Systematic Reviews

mild cognitive impairment, age, risk factor, protective, gender, sex, apolipoprotein E isoform ε4 (APO-ε4), Down syndrome, diabetes mellitus, hypertension, blood pressure, cerebrovascular disease, stroke, head injury, cholesterol, lipids, homocysteine, depression, obesity, fat intake, diet, family history, familial, first-degree relative, genetic, folic acid, hormone replacement therapy, smoking, education, intelligence, activity, exercise, non-steroidal anti-inflammatory medications (NSAIDs), aspirin, statins, antioxidant, alcohol, infection, toxins, regional, omega-3 fatty acids and vitamins B12, C, and E.

A review/study was required to specifically relate to risk and protective factors for any of the subtypes of dementia listed above. Reviews/studies relating to cognitive decline or cognitive impairment only without reference to dementia.

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Treatment

AMED (Allied and Complementary Medicine) Clinical Trials.gov Cochrane Database of Systematic Reviews MIMS Online Alzheimer’s Australia Australian Clinical Trials Registry Alzheimer Research Forum Commonwealth Department of Health and Ageing, Australia Mental Health Institute of Victoria UK NHS National Institute for Health and Clinical Excellence NHMRC Clinical Trials Centre

dementia, Alzheimer's disease, Vascular dementia, Mixed dementia, Lewy body dementia, Parkinson’s disease, Frontotemporal dementia, early onset dementia and mild cognitive impairment in conjunction with treatment, pharmacotherapy, drug treatment, intervention, cholinesterase inhibitor, antidepressant, antipsychotic, behaviour therapy, prevention, psychological, therapy, acupuncture, ginkgo biloba, vitamin E, exercise and physical activity.

The review/study was required to relate to treatments specifically relevant to the treatment of any of the most frequently occurring dementia subtypes in humans. Reviews/studies relating to cognitive impairment only.

Care and support for people with dementia and their carers

Cochrane Database of Systematic Reviews PsycINFO Social Health: Nursing/Academic Edition Social Services Abstracts Sociological Abstracts GreyNet Joanna Briggs Institute Social Care Online UK NHS National Institute for Health and Clinical Excellence

dementia, Alzheimer’s disease, care, carer, caregiver, support, service, palliative, feeding, mobility, hygiene, driving, behavioural and psychological symptoms, BPSD, housing, environment, quality of life, evaluation, race, ethnic, ethics.

Systematic review was required to address clearly defined question plus a rigorous and reproducible search methodology. Only interventional or treatment studies from peer-reviewed journals with clear descriptions of research design, sampling method, analytical procedures and ethics were considered. Priority was given to studies that adopted a RCT design.

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References Aarsland, D., Zaccai, J., & Brayne, C. (2005). A systematic review of prevalence studies

of dementia in Parkinson's disease. Mov Disord, 20(10), 1255-1263. [Link] Access Economics. (2005). Dementia Estimates & Projections, Australia States &

Territories: Alzheimer's Australia. [Link] Australian Institute of Health and Welfare. (2004). The impact of Dementia on the health

and aged care systems. (No. AIHW Cat. No. AGE 37). Canberra: Commonwealth Government. [Link]

Hogan, W. P. (2004). Review of pricing arrangements in residential aged care.

Canberra: Commonwealth of Australia. [Link] World Health Organisation. (1992-1994). ICD-10: international statistical classification of

diseases and related health problems. Geneva, Switzerland: WHO. [Link]

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2.0 What is Dementia: Definitions and Diagnostic Criteria The World Health Organization (WHO) defines dementia as a syndrome caused by disease of the brain, usually of a chronic or progressive nature, in which there is a disturbance of multiple cortical functions, calculation, learning capacity, language and judgement. Consciousness is not clouded. Impairments of cognitive function are commonly preceded by deterioration in emotional control, social behaviour or motivation (Mega, Cummings, Fiorello, & Gornbein, 1996). While dementia is associated with old age, it is not a normal part of aging. Dementia shortens life expectancy, although there is wide variability in rates of decline from person to person. The hallmark of dementia is one of decreased ability to conduct everyday activities compared with past performance as a consequence of diminished cognitive ability. 2.1 Classification of Dementia There are many ways in which dementia may be classified, of which one is the system suggested by the National Institute of Neurological Disorders and Stroke:

• Cortical dementia - dementia where the brain damage primarily affects the

brain's cortex, or outer layer. Cortical dementias tend to cause problems with memory, language, thinking, and social behaviour.

• Subcortical dementia - dementia that affects parts of the brain below the cortex.

Subcortical dementia tends to cause changes in emotions and movement in addition to problems with memory.

• Progressive dementia - dementia that gets worse over time, gradually

interfering with more and more cognitive abilities.

• Primary dementia - dementia such as AD that does not result from any other disease.

• Secondary dementia - dementia that occurs as a result of a physical disease or

injury. (National Institute of Neurological Disorders and Stroke, 2004) Sub-types of Dementia There are numerous causes of dementia. The most common are:

• Alzheimer’s dementia – the most common form of dementia, estimated to account for 50 - 70% of all dementias (World Health Organisation, 1993). Onset is usually insidious.

• Vascular dementia – dementia caused by cerebrovascular conditions including

multi-infarct disease and stroke. Onset may be sudden, following a stroke, or gradual.

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• Mixed dementia - The coexistence of AD and VaD pathology is often termed

mixed dementia.

• Dementia with Lewy bodies, in which abnormal brain cells (Lewy bodies) form in parts of the brain.

• Dementia in Parkinson’s disease (PD) - PD is the most common

neurodegenerative adult-onset movement disorder affecting approximately 1% of people over the age of 60 years. Estimates vary, however, it has been reported that between 24.5% (Aarsland, Zaccai, & Brayne, 2005) to 80% of patients with PD (Aarsland, Andersen, Larsen, Lolk, & Kragh-Sorensen, 2003) will develop dementia at some point in the course of their illness. It has also been estimated that dementia secondary to Parkinson’s disease accounts for approximately 3 - 4% of dementia cases (Aarsland et al., 2005).

• Frontotemporal dementia – dementia that affects the frontal and temporal

regions of the brain giving rise to a common set of clinical symptoms; the average age of onset is 50-60 years.

• Mild Cognitive Impairment (MCI) is a clinical label that includes aged persons

without dementia, but with memory impairment and no significant disability. It is considered by many to being a prodromal stage of dementia (Almkvist et al., 1998).

There are numerous other causes of dementia including dementia secondary to HIV complex and alcohol related dementia, Huntington’s chorea, human prion disease including Creutzfeldt-Jacob dementia and dementia due to other infection or metabolic cause. These are uncommon causes of dementia which together account for a minority of cases (1 - 5% of dementias). This section summarises the most commonly used diagnostic criteria for each of the dementias listed above as well as a description of the clinical manifestations of each condition. 2.2 Alzheimer’s Dementia (AD) Several sets of diagnostic criteria are available, of which the criteria of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA ; see Table 2.1) are the most commonly used (van der Flier & Scheltens, 2005). Their use is recommended by the UK NHS National Institute for Health and Clinical Excellence in their draft guidelines (National Institute for Health and Clinical Excellence, 2006) and by the American Academy of Neurology (Knopman et al, 2001). Reliable alternatives include the ICD-10 (WHO, 1992-1994) and the DSM-IV criteria (APA, 1994).

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2.2.1 NINCDS-ADRDA Criteria (McKhann et al., 1984) A diagnosis of definite AD requires that the patient meet clinical criteria for probable AD while living and have histopathologic evidence of AD at autopsy or from a cerebral biopsy. Probable AD requires that the dementia syndrome is established by clinical criteria, documented by mental status questionnaire and confirmed by neuropsychological testing. There must be deficits in memory and at least one other cognitive function. The memory and cognitive deficit must worsen over time and be present for a minimum of 6 months. The patient must not be delirious at the time of the assessment. Possible AD is diagnosed when there is a systemic disease or second brain disease capable of producing a dementia, but not thought to be the cause of the current dementia. Alternately, possible AD is diagnosed when there is a progressive decline in a single intellectual function (e.g. loss of memory or language) in the absence of any other identifiable cause. Studies of the diagnostic accuracy of the NINCDS/ADRDA criteria for probable AD have reported a high level of sensitivity (mean = 81%) with a mean specificity of 70% while the diagnosis of possible AD has achieved a very high level of sensitivity (mean = 93%) although a lower level of specificity (mean = 48%) (Knopman et al, 2001). The inter-rater reliability of the NINCDS-ADRDA criteria is acceptable with 65 - 75% agreement (Farrer et al., 1994). 2.2.2 Clinical Presentation Onset of AD is between 40 and 90 years of age and it has been estimated that the median survival time from the onset of the disease to death is 7.1 years (Fitzpatrick, Kuller, Lopez, Kawas, & Jagust, 2005) although ranges of between three and nine years have also been reported. The disorder usually begins with episodic memory impairment and encompasses language, visuospatial and behavioural dysfunction. The characteristic memory disturbance of AD is an amnestic type of storage abnormality in which patients have difficulty learning and recalling new information. Language abnormalities in AD begin with subtle word finding difficulties and as the disease progresses, the patient develops difficulty with naming objects (anomia) and eventually deficits in comprehension appear. Alzheimer’s disease also features a complex array of psychiatric symptoms including prominent apathy, agitation, depression, anxiety, delusions and irritability. It is believed that the clinical symptoms of AD are preceded by a period of unknown duration, during which neuropathologic alterations may accumulate in the brain without detectable changes in cognition (Goldman et al., 2001). Motor and sensory abnormalities are usually absent until the final phases of the disease when rigidity, dysphagia and incontinence appear. Patients lose the ability to walk and become bedridden in the final stages, often dying from dementia/failure to thrive or from coronary heart disease (Fitzpatrick et al., 2005). Three variants of the disease have been identified – one group of patients is characterised by few behavioural abnormalities, a second group has prominent symptoms of psychosis while the third group has a prominent mood disorder syndrome (Lyketsos et al., 2001). Agitation and apathy may be seen in combination with the other symptoms.

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Table 2.1 NINCDS-ADRDA Criteria for the diagnosis of Alzheimer’s disease Criteria for definite AD Clinical criteria for probable AD Histopathological evidence of AD (autopsy or biopsy) Criteria for Probable AD Dementia established by clinical examination and documented by mental status questionnaire Dementia confirmed by neuropsychological testing Deficits in two or more areas of cognition Progressive worsening of memory and other cognitive functions No disturbance of consciousness Onset between ages 40 and 90 Absence of systemic disorders or other brain diseases capable of producing a dementia syndrome Criteria for Possible AD Presence of a systemic disorder or other brain disease capable of producing dementia but not thought to be the cause of the dementia Gradually progressive decline in a single intellectual function in the absence of any other identifiable cause (e.g. memory loss or aphasia) Unlikely AD Sudden onset Focal neurologic signs Seizures or gait disturbance early in the course of the illness 2.3 Vascular Dementia (VaD) VaD can be defined as a syndrome of acquired cognitive impairment due to cerebrovascular disorder. It is considered to be the second most common cause of non-reversible dementia, accounting for between 15 – 20% of cases (Lobo et al., 2000). VaD frequently coexists with AD with as many as 45% of AD patients exhibiting significant vascular pathology (Lim et al., 1999). Similarly, patients diagnosed with VaD frequently show pathological features of AD at autopsy (Nolan, Lino, Seligmann, & Blass, 1998). The criteria developed by the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l”Enseignement en Neurosciences (NINCDS-AIREN, Roman et al., 1993) have had widespread application (Stewart, 2004) and are recommended for use by the UK NHS National Institute of Health and Clinical Excellence in their draft guidelines (2006). The criteria have modest sensitivity (0.58) and fair specificity (0.80), (Gold et al., 1997) with moderately good inter-rater reliability (Lopez et al., 1994) and are presented in Table 2.2. They are more circumspect than either the DSM-4 (American Psychiatric Association, 1994) or the ICD-10 (World Health Organisation, 1993) criteria and may result in the under-diagnosis of VaD (Wetterling, Kanitz, & Borgis, 1996).

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The American Academy of Neurology suggests that the Hachinski Ischemic Index criteria (Haschinski et al, 1974), which has been shown to have higher sensitivity and specificity (both 89%, Moroney et al, 1997) may be more suitable for identifying patients with VaD (Knopman et al, 2001). The Hachinski Ischemic criteria are presented in Table 2.3. Table 2.2 NINDS-AIREN diagnostic criteria for definite, probable and possible VaD Definite VaD Clinical criteria for probable VaD Autopsy demonstration of appropriate ischemic or hemorrhagic brain injury and no other cause of dementia Probable VaD Decline from a previously higher level of cognitive functioning Impairment in two or more cognitive domains Deficits severe enough to interfere with activities of daily living and not due to the physical effects of stroke alone Absence of delirium, absence of psychosis, aphasia or sensorimotor impairment that precludes neuropsychological testing; and absence of any other disorder capable of producing a dementia syndrome Cerebrovascular disease: Focal neurological signs consistent with stroke, and Neuroimaging evidence of extensive vascular lesions Relationship between dementia and cerebrovascular disease as evidenced by one or more of the following: (1) onset of dementia within three months of a recognised stroke, (2) abrupt deterioration or fluctuating or stepwise progression of the cognitive deficit Supporting features Subtle onset and variable course of cognitive deficits Early presence of gait disturbance History of unsteadiness, frequent and unprovoked falls, Early urinary frequency, urgency, and other urinary symptoms not explained by urologic disease Pseudobulbar palsy Personality and mood changes, abulia, depression, emotional incontinence, and subcortical deficits, including psychomotor retardation and abnormal executive function Possible VaD Dementia with focal neurological signs but without neuroimaging confirmation of definite cerebrovascular disease Dementia with focal neurological signs but without a clear temporal relationship between dementia and stroke Dementia with focal neurological signs but with subtle onset and variable course of cognitive deficits.

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Table 2.3 The Hachinski Ischemic Index criteria Item Score Abrupt onset Stepwise deterioration Fluctuating course Nocturnal confusion Preservation of personality Depression Somatic complaints Emotional incontinence History of hypertension History of stroke Associated atherosclerosis Focal neurological symptoms Focal neurological signs

2 1 2 1 1 1 1 1 1 2 1 2 2

The NINDS-AIREN criteria describe a number of categories of VaD including multi-infarct dementia, strategic single infarct dementia, excessive white matter disease, hypoperfusion and hemorrhagic dementia. These categories are discussed in greater detail in Section 4. In comparison to the NINDS-AIREN criteria the Diagnostic and Statistical Manual of Mental Disorders – 4th edition (American Psychiatric Association, 1994), uses the following criteria to diagnose VaD: DSM-4 Diagnostic Criteria for Vascular Dementia: A. The development of multiple cognitive deficits manifested by both:

(1) memory impairment (impaired ability to learn new information or to recall previously learned information)

(2) one (or more) of the following: (a) aphasia – language disturbance (b) apraxia impaired ability to carry out motor activities despite intact motor

function (c) agnosia – failure to recognise or identify objects despite intact sensory

function (d) disturbance in executive functioning (i.e. planning, organising,

sequencing, abstracting) B. The cognitive deficits cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning. C. Focal neurological signs and symptoms or laboratory evidence indicative of cerebrovascular disease that are judged to be etiologically related to the disturbance.

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2.3.1 Clinical Presentation of VaD Although decline is usual in VaD, the course of the condition is less predictable than AD, since in some cases relative stability may be seen for a period, if the underlying vascular disease is stabilised. Alternatively, a subsequent vascular event can cause a sudden and ‘stepwise’ deterioration in cognitive function. The clinical picture of VaD varies depending on the location and volume of the brain injury. The most common lesions associated with VaD are subcortical ischemic infarctions or areas of ischemic injury occurring in subcortical white matter. Lacunar state refers to the occurrence of multiple lesions in the basal ganglia, thalami, and subcortical white matter. Gait disturbance is a common sign of ischemic injury to the subcortical white matter (Briley, Wasay, Sergent, & Thomas, 1997) with hesitation, diminished stride length, and diminished stride height characteristic. Binswager’s disease refers to extensive ischemic injury of subcortical white matter. Symptoms typically include prominent executive dysfunction with diminished motivation, loss of insight, apathy and abulia. Cortical VaD is related to atherothrombotic strokes, cardiac embolic strokes and infarcts in cortical watershed areas. Typical clinical features are lateralised sensorimotor changes and abrupt onset of cognitive impairment and aphasia. Focal infarcts in the cortical area usually cause restricted focal behavioural syndromes or dementia. Subcortical vascular dementia relates to lacunar infarcts and deep white matter lesions and deficits in executive functioning, attention and psychomotor speed are typically evident. Anomia may be present and articulation abnormalities are common (Powell, Cummings, Hill, & Benson, 1988). Affective disorder including impaired emotional control, depression, changes in personality and psychosis are all associated with VaD although, as for motor and cognitive symptoms, the symptoms vary according to the location and severity of the injury (Gustafson & Passant, 2004). 2.4 Mixed Dementia (MD) Community, clinic-based, and experimental studies have provided converging evidence for a link between AD and vascular injury in the brain. AD and vascular dementia, once seen as mutually exclusive disorders, are now recognised as coexisting processes that contribute to the expression of dementia. There is also evidence to indicate that clinical dementia is more likely to occur when AD is accompanied by strokes and cerebrovascular brain changes (Riekse et al., 2004). There is, however, a lack of consensus regarding the definition and diagnostic criteria for mixed dementia. The NINDS-AIREN diagnostic criteria for VaD do not include a category for mixed dementia, recommending instead that the term ‘AD with cerebrovascular disease’ be used. Alternatively, the International Classification of Diseases and Health Related Problems, 10th Revision (ICD-10) uses the term MD for patients who met criteria for both VaD and AD (World Health Organisation, 1993) while the DSM-4 criteria includes patients who meet the criteria for primary degenerative dementia of the Alzheimer type together with clinical or neuroimagery features of VaD. The criteria, however, have not been well validated by neuropathological studies (Zekry, Hauw, & Gold, 2002). 2.4.1 Clinical Presentation of Mixed Dementia Mixed dementia lies on a spectrum between AD and VaD and it has been reported that the combination of AD and VaD exaggerates the cognitive deficits associated with each disorder (Snowdon et al., 1997).

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It has also been reported that patients with MD had a much higher frequency of depressed mood, focal motor or sensory findings, and gait disorder than patients with a diagnosis of AD (Corey-Bloom, Galasko, Hofstetter, Jackson, & Thal, 1993). Another study reported that the neuropsychological characteristics of MD are more closely related to those of VaD than AD, suggesting an important role for the ischemic component of MD (Bowler et al., 1997). 2.5 Dementia with Lewy Bodies (DLB) DLB is a common cause of dementia and accounts for approximately 20% of cases. It is thought by some that DLB is the second most common type of degenerative dementia in older people (McKeith, 2002). The pathologic hallmark of DLB is the presence of Lewy bodies in the cerebral cortex. Consensus criteria for the diagnosis of DLB were originally agreed upon in 1995 (McKeith et al., 1996) and were determined to be highly specific (79 to >95%), however, much less sensitive (22-75%; Mega et al, 1996). The criteria were subsequently revised in 2003 (see Table 2.4) to incorporate new information regarding DLB (McKeith et al, 2005) which, it is believed, should improve diagnostic accuracy. The original criteria have been almost universally adopted for use in all clinical research and are recommended for use by the UK NHS National Institute of Health and Clinical Excellence in their draft guidelines (2006). 2.5.1 Clinical Presentation of DLB The average age of onset of DLB is around 69 years and cognitive impairment is the presenting feature of DLB in most, but not all, cases. Cognitive deficits in attention and visuospatial ability are prominent and while memory impairment may not necessarily occur in the early stages, it is usually evident with progression of the disease. There may be pronounced fluctuations in attention and cognition with cognitive impairment ranging from near-to-normal performance to severe confusion within periods ranging from minutes to days and weeks (Ballard et al., 2001). Patients with DLB may also exhibit significant difficulty with frontal lobe associated cognitive skills such as the loss of the ability to solve problems or to plan and successfully execute a task (Leverenz & McKeith, 2002). Recurrent, complex visual hallucinations are present in up to 80% of patients with DLB and are accompanied by illusions in many cases (Collerton, Burn, McKeith, & O'Brien, 2003). Typical themes are of animals and people intruding into the patient’s home (McKeith, 2002). Approximately 40% of patients with DLB have severe depressive episodes while up to 70% of patients also present with Parkinsonian symptoms that may either precede or follow the manifestation of DLB. Postural instability, gait disturbance and bradykinesia are common symptoms while tremor is rare (McKeith, 2002). The duration of the disease varies between six and ten years – similar to or of slightly shorter duration than AD (Papka, Rubio, & Schiffer, 1998).

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Table 2.4 Revised consensus criteria for the clinical diagnosis of dementia with Lewy bodies (DLB) Central feature (essential for a diagnosis of possible or probable DLB) Dementia defined as progressive cognitive decline of sufficient magnitude to interfere with normal social and occupational function. Prominent or persistent memory impairment does not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention, executive function, and visuospatial ability may be especially prominent. Core features (two core features are sufficient for a diagnosis of probable DLB, one for possible DLB) Fluctuating cognition with pronounced variations in attention and alertness Recurrent visual hallucinations that are typically well formed and detailed Spontaneous features of parkinsonism Suggestive features (If one or more of these is present in the presence of one or more core features, a diagnosis of probable DLB can be made. In the absence of any core features, one or more suggestive features is sufficient for possible DLB. Probable DLB should not be diagnosed on the basis of suggestive features alone) REM sleep behaviour disorder Severe neuroleptic sensitivity Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging Supportive features (commonly present but not proven to have diagnostic specificity) Repeated falls and syncope Transient, unexplained loss of consciousness Severe autonomic dysfunction , eg orthostatic hypotension, urinary incontinence Hallucinations in modalities other than visual (auditory, olfactory and tactile) Systematised delusions Depression Relative preservation of medial temporal lobe structures on CT/MRI scan Generalised low uptake on SPECT/PET perfusion scan with reduced occipital activity Prominent slow wave activity on EEG with temporal lobe transient sharp waves A diagnosis of DLB is less likely In the presence of cerebrovascular disease evident as focal neurological signs or on brain imaging In the presence of any other physical illness or brain disorder sufficient to account in part or in total for the clinical picture If parkinsonism only appears for the first time at a stage of severe dementia Temporal sequence of symptoms DLB should be diagnosed when dementia occurs before or concurrently with parkinsonism (if it is present). The term Parkinson disease dementia (PDD) should be used to describe dementia that occurs in the context of well-established Parkinson disease. In a practice setting the term that is most appropriate to the clinical situation should be used and generic terms such as LB disease are often helpful. In research studies in which distinction needs to be made between DLB and PDD, the existing one-year rule between the onset of dementia and parkinsonism DLB continues to be recommended.

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The majority of DLB cases exhibit some pathologic features of AD, particularly senile plaques (Mark, 2001) while approximately one-third of AD patients display the presence of Lewy bodies at autopsy (Gibb, Luthert, Janota, & Lantos, 1989). 2.6 Parkinson’s Disease (PD) Parkinson's disease is a progressive neurological disorder that results from degeneration of neurons in the substantia nigra - a region of the brain that controls movement. This degeneration creates a shortage of the neurotransmitter dopamine, causing the movement impairments that characterise the disease. Although there are many manifestations of PD, the classical diagnostic symptoms include slowness and poverty of movement, stiffness and shaking (National Collaborating Centre for Chronic Conditions, 2006). There is considerable overlap in the symptom and pathological profiles of DLB and in dementia in Parkinson’s disease (Emre, 2003) and the presence of Lewy bodies are a common diagnostic feature of both conditions at autopsy. The most widely accepted clinical criteria for the diagnosis of PD are those introduced by the UK PDS Brain Bank Criteria (Table 2.5). 2.6.1 Clinical Presentation of Parkinson’s Disease Often, the first symptom of Parkinson's disease is tremor (trembling or shaking) of a limb, especially when the body is at rest. The tremor often begins on one side of the body, frequently in one hand. Other common symptoms include slow movement (bradykinesia), an inability to move (akinesia), rigid limbs, a shuffling gait, and a stooped posture. People with Parkinson's disease often show reduced facial expressions and speech changes are common – hypophonia with reduced speech volume is the most frequently observed abnormality. Neuropsychiatric symptoms are also common including depression, personality changes, hallucinations, delusions, dementia, sleep disturbances and sexual difficulties (National Collaborating Centre for Chronic Conditions, 2006). Parkinson's disease is a progressive condition that results in significant disability and reduced quality of life for the patient. The average age of onset is about 60. 2.6.2 Dementia in Parkinson’s Disease Estimates vary, however, it has been reported that between 24.5% (Aarsland et al., 2005) to 80% of patients with PD (Aarsland et al., 2003) will develop dementia at some point in the course of their illness. It has also been estimated that dementia secondary to Parkinson’s disease accounts for approximately 3 - 4% of dementia cases (Aarsland et al., 2005). The profile of dementia seems to be similar to that of dementia with Lewy bodies and is characterised by a dysexecutive syndrome although deficits in visuospatial ability and attention are also common as is decreased verbal fluency (Emre, 2003, 2004). Memory is also impaired although the storage of information appears to be relatively preserved with patients displaying better performance in recognition tasks compared with free recall. Dementia in PD is associated with increased mortality and risk factors for the onset of dementia include older age at onset of PD, reduced verbal fluency, more advanced Parkinson’s disease and cognitive impairment (Emre, 2003).

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Table 2.5 UK PDS Brain Bank criteria for the diagnosis of Parkinson’s disease Step 1. Diagnosis of a Parkinsonian syndrome Bradykinesia and at least one of the following:

• Muscular rigidity • Rest tremor (4-6 Hz) • Postural instability unrelated to primary visual, cerebellar, vestibular or

proprioceptive dysfunction Step 2. Exclusion criteria for PD History of:

• Repeated strokes with stepwise progression • Repeated head injury • Antipsychotic or dopamine-depleting drugs • Definite encephalitis and/or oculogyric crises on no drug treatment • More than one affected relative • Sustained remission • Negative response to large doses of levodopa (if malabsorption excluded) • Strictly unilateral features after three years • Other neurological features: supranuclear gaze palsy, cerebellar signs, early

severe autonomic involvement, Babinski sign, early severe dementia with disturbances of language, memory or praxis

• Exposure to known neurotoxin • Presence of cerebral tumour or communicating hydrocephalus on

neuroimaging Step 3. Supportive criteria for PD Three or more required for diagnosis of definite PD:

• Unilateral onset • Rest tremor present • Progressive disorder • Persistent asymmetry affecting the side of onset most • Excellent response to levodopa • Severe levodopa-induced chorea • Levodopa response for over five years • Clinical course of over ten years

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2.7 Frontotemporal Lobar Degeneration (FTLD) FTLD is comprised of a spectrum of dementing disorders with degeneration of the frontal lobes, anterior temporal lobes or both. FTLD has a high familial incidence and it has been reported that approximately 40% of patients with FTLD have a positive family history of a similar disorder in a first degree-relative (Chow, Miller, Hayashi, & Geschwind, 1999). Frontotemporal dementia (FTD) is the main FTLD syndrome and manifests as prominent personality and behavioural disturbances. FTD is characterised by early and progressive changes in personality and social conduct, inertia and loss of volition or social inhibition and distractibility, with relative preservation of memory function (Neary, Snowden, Northen, & Goulding, 1988). It corresponds to an involvement of the frontal lobes. The second syndrome: progressive non-fluent aphasia (PA) is a disorder of expressive language, corresponding to an involvement of the language area, most often on the left hemisphere. PA is characterised by effortful speech production, phonologic and grammatical errors, and word retrieval difficulties. Difficulties in reading and writing also occur while comprehension of word meaning remains relatively well preserved. The disorder of language occurs in the absence of impairment in other cognitive domains, although behavioural changes may emerge later in the course of the disease. The third syndrome: semantic dementia (SD) involves the anterior and inferior part of the temporal cortices, usually more on the left side. In SD, a severe naming and word comprehension impairment occurs in the context of fluent, effortless, and grammatical speech output. There is also an inability to recognise the meaning of visual concepts while visuospatial skills and memory are preserved. There can be substantial overlap among the three syndromes. The length of illness is variable, ranging from two to twenty years, with an average duration of eight years and mild, moderate and severe stages of FTD have been identified (Farmer & Grossberg, 2005). Consensus criteria (presented below) for the three subtypes were developed by members of an international workshop on FTLD – the Lund-Manchester criteria (Neary et al., 1998) and are presented in Tables 2.6 – 2.8. Good pre-mortem diagnostic accuracy, with a sensitivity of 85% and specificity of 99% has been reported (Knopman et al., 2005). Another set of diagnostic criteria has been proposed by the NINDS Work Group on Frontotemporal Dementia and Pick’s Disease that recognises two main presentations, frontal (behavioural) and temporal (language) (McKhann et al., 2001). Both sets of criteria are recommended by the UK NHS National Institute for Health and Clinical Excellence in their draft guidelines (2006).

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Table 2.6 Consensus criteria for the diagnosis of Frontotemporal dementia Clinical Profile Character change and disordered social conduct are the dominant features initially and throughout the disease course. Instrumental functions of perception, spatial skills, praxis and memory are intact or relatively well preserved

Core Diagnostic features Insidious onset and gradual progression; Early decline in interpersonal conduct; Early impairment in regulation of personal conduct Early emotional blunting; Early loss of insight Supportive Diagnostic features Behavioural Disorder Decline in personal hygiene and grooming; Mental rigidity and inflexibility; Distractibility and impersistence; Hyperorality and dietary changes Perseverative and stereotyped behaviour; Utilisation behaviour Speech and Language Altered speech output; Aspontaneity and economy of speech Press of speech; Stereotype of speech; Echolalia; Perseveration Mutism Physical Signs Primitive reflexes; Incontinence; Akinesia, rigidity, and tremor Low and labile blood pressure Investigations Neuropsychology: significant impairment on frontal lobe tests in the absence of severe amnesia, aphasia, or perceptuospatial disorder. Electroencephalography: normal on conventional EEG despite clinically evident dementia Brain imaging (structural and/or functional): predominant frontal and/or anterior temporal abnormality

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Table 2.7 Consensus criteria for the diagnosis of progressive nonfluent aphasia Clinical Profile Disorder of expressive language is the dominant feature initially and throughout the disease course. Other aspects of cognition are intact or relatively well preserved.

Core Diagnostic features Insidious onset and gradual progression Non-fluent spontaneous speech with at least one of the following: agrammatism, phonemic paraphasias, anomia Supportive Diagnostic features Speech and language Stuttering or oral apraxia; Impaired repetition; Alexia, agraphia; Early preservation of word meaning; Late mutism Behaviour Early preservation of social skills Late behavioural changes similar to FTD Physical signs Late contralateral primitive reflexes, akinesia, rigidity and tremor

Investigations Neuropsychology: non-fluent aphasia in the absence of severe amnesia or perceptuospatial disorder Electroencephalography: normal or minor asymmetric slowing Brain imaging (structural and/or functional): asymmetric abnormality predominantly affecting dominant (usually left) hemisphere

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Table 2.8 Consensus criteria for the diagnosis of semantic dementia Clinical Profile Semantic disorder (impaired understanding of word meaning and/or object identity) is the dominant feature initially and throughout the disease course. Other aspects of cognition, including autobiographical memory, are intact or relatively well preserved.

Core Diagnostic features Insidious onset and gradual progression Language Disorder characterised by Progressive, fluent, empty spontaneous speech Loss of word meaning, manifest by naming and comprehension Semantic paraphasias, and/or Perceptual disorder characterised by Prosopagnosia: impaired recognition of identity of familiar faces and/or Associative agnosia: impaired recognition of object identity Preserved perceptual matching and drawing reproduction Preserved single-word repetition Preserved ability to read aloud and write to dictation orthographically regular words Supportive Diagnostic features Speech and language Press of speech; Idiosyncratic word usage; Absence of phonemic paraphasias; Surface dyslexia and dysgraphia Preserved calculation Behavior Loss of sympathy and empathy; Narrowed preoccupations Parsimony Physical signs Absent or late primitive reflexes; Akinesia, rigidity, and tremor

Investigations Neuropsychology: Profound semantic loss, manifest in failure of word comprehension and naming and/or face and object recognition Preserved phonology and syntax, and elementary perceptual processing, spatial skills and day-to-day memorising Electroencephalography: normal Brain imaging (structural and/or functional): predominant anterior temporal abnormality (symmetric or asymmetric)

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2.7.1 Clinical Presentation FTD usually commences before the age of 65 years and survival is approximately eight years (Neary, Snowden, & Mann, 2005). The clinical presentation is variable with more than half of FTD patients exhibiting sociopathic behaviour including unsolicited sexual acts, traffic violations, physical assaults and other unacceptable behaviours. On interview, FTD patients who engage in sociopathic behaviour report that they are aware of their behaviour and know it is wrong but are unable to prevent themselves from acting impulsively (Mendez, Chen, Shapira, & Miller, 2005). Loss of insight is a core diagnostic criterion for FTD. Patients with a behavioural variant of FTD have difficulty recognising facial emotions, particularly negative emotion. As the disease advances, behavioural rigidity, disinhibition, loss of social skills, fatuousness, emotional lability and impulsivity often develop. Hyperorality and the development of a sweet tooth are characteristic (Sampson, Warren, & Rossor, 2004). Semantic dementia resembles a progressive fluent aphasia with increasingly empty and circumlocutory (but grammatically correct) speech due to a loss of semantic knowledge about the meanings of words and objects. Other cognitive functions are generally well preserved at presentation although generalised cognitive decline tends to occur at later stages of the illness (Garrard & Hodges, 2000). 2.8 Mild Cognitive Impairment (MCI) MCI generally refers to a transitional zone between normal cognitive function and clinically probable AD. Consensus criteria for the diagnosis of MCI have recently been published and include objective evidence of cognitive impairment that represents a decline in functioning from a previous level, but which does not qualify, in degree, to dementia (Winblad et al, 2004). The ability to undertake activities of daily living, however, is not compromised or at least, the impairment is minimal (Winblad et al, 2004). The clinical presentations of MCI can be classified according to three subtypes: amnestic, single non-memory domain or multiple cognitive domains. Several authors have demonstrated that those with amnestic MCI are at an increased risk for subsequently developing dementia, most usually of the Alzheimer type (10-15% per annum) (Bischkopf et al, 2002). Similarly, those with MCI due to cerebrovascular disease also appear to be at an increased risk of subsequently developing dementia (Wentzel et al, 2001).

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3.0 Epidemiology Epidemiology refers to the medical science that studies frequencies of disease (Rothman & Greenland, 1998) and measures both the prevalence - the proportion of people who have the condition at a specific point in time (frequency of current cases), and the incidence of disease - the number of new cases over time. Although information regarding the prevalence and incidence of a health condition is important for health care planning, the goal of epidemiology is to gain insight into predisposing risk factors for disease that may suggest fruitful avenues for treatment and/or prevention. 3.1 Literature Search This section summarises the results of a comprehensive literature search of the most recent epidemiological studies of the most frequently occurring dementias. The following computerised databases were searched for relevant published research:

• Ageline • Cochrane Library. • Cumulative Index to Nursing and Allied Health Literature (CINAHL) • MEDLINE, • PubMeD, • PsycINFO,

Additional websites that were searched included:

• Alzheimer’s Australia (including state offices), Alzheimer’s Organization, US • Commonwealth Department of Health and Ageing (Australia) • Australian Institute of Health and Welfare • National Aged Care Alliance (Australia) • National Institute of Neurological Disorders and Stroke (US) • National Institute for Health and Clinical Excellence (UK) • The National Creutzfeldt-Jakob Disease Surveillance Unit • The World Health Organization

Keywords used in the searches included dementia, Alzheimer’s disease, Vascular dementia, Mixed dementia, Lewy body dementia, Parkinson’s disease, Frontotemporal dementia, early onset dementia and mild cognitive impairment in conjunction with epidemiology, prevalence, incidence and Indigenous Australians. Meta-analyses and large-scale pooled analyses were identified and retrieved initially. For topics that had not been systematically reviewed, review articles were obtained. Additional articles were identified by reviewing the reference lists of retrieved papers and primary research was obtained in instances where systematic and review articles for a particular topic were limited. A flowchart of the literature search process is shown in Figure 3.1.

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Figure 3.1 Flowchart of identification of meta-analyses and large-scale pooled analyses for inclusion in the review of epidemiology 3.2 Incidence of Dementia – all causes 3.2.1 Australian Studies In an endeavour to provide the most reliable projections of dementia in Australia, Alzheimer’s Australia commissioned Access Economics to compile a report (2005) estimating the current and projected future prevalence and incidence of dementia in Australia. Access Economics estimated prevalence and incidence data for people aged 60 years and older by averaging age and gender specific prevalence rates derived from the latest meta-analyses of studies conducted in Europe including studies by Jorm et al (1987), Hofman et al (1991), Ritchie & Kildea (1995) and Lobo et al (2000). These data are presented in Tables 3.1 and 3.2. All of the meta-analyses showed an increase in both the prevalence and incidence of dementia from all causes with older age.

Titles Identified n = 129

Included: 14 Meta-Analyses/Large-scale pooled analyses [In addition, 4 review articles, 12 Government/Commissioned reports, 21 primary research articles, 1 Consensus statement & 1 book chapter were included]

Abstracts inspected n = 44

Full copies retrieved n = 30

Excluded n = 16

Excluded at title stage n = 85

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These rates were applied to revised Australian demographic projections (Australian Bureau of Statistics, 2003) and it was estimated that 171,220 Australians had dementia in 2000 (0.89% of total population) while the number was around 197,000 in 2004 (0.98% of total population). There was no significant difference between State prevalence rates after standardising for age and gender distributions for the population aged 60 years and older. It was projected that by 2050 the total number of dementia cases will exceed 730,000 (2.8% of the projected population) – a fourfold increase since 2000. Of that number, it is expected that 420,000 will be female (3.2% of all females) while over 310,000 will be Australian males (2.4% of all males) or 2.8% of the overall population. The projections are shown in Tables 3.3 and 3.4 and it is evident that both the prevalence and incidence increase with older age with a slightly greater prevalence in females from the age of 75 years, compared to males. These predictions were based on the assumption that current demographic trends will continue and that there will be minimal advances in the prevention or treatment of certain dementias, such as Alzheimer’s disease (AD). Incidence rates were also reported. In 2005, it was projected that there would be nearly 52,000 new cases of dementia in Australia, of which a quarter will be aged 80-84 years. By 2050, there are projected to be over 175,000 new cases of dementia diagnosed each year, more than the total number of cases in Australia in 2000. Table 3.1 Prevalence rates according to Meta-analyses: All dementias (%) Adapted from (Wancata, Musalek, Alexandrowicz, & Krautgartner, 2003) Age group (years)

(Jorm et al., 1987)

F & M

(Hofman et al., 1991) Female Male

(Ritchie & Kildea, 1995)

F & M

(Lobo et al., 2000) Female Male

Average Female Male

60 – 64 0.7 0.5 1.6 - - - 0.6 1.2 65 – 69 1.4 1.1 2.2 1.5 1.0 1.6 1.3 1.7 70 – 74 2.8 3.9 4.6 3.5 3.1 2.9 3.3 3.5 75 – 79 5.6 6.7 5.0 6.8 6.0 5.6 6.3 5.8 80 – 84 10.5 13.5 12.1 13.6 12.6 11 12.6 11.8 85 – 89 20.8 22.8 18.5 22.3 20.2 12.8 21.5 18.6 90 – 94 38.6 32.2 32.1 31.5 30.8 22.1 33.3 31.1 95+ - 36.0 41.6 44.5 - - 40.3 38.1

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Table 3.2 Incidence rates according to Meta-analyses: All dementias (%) Adapted from (Wancata et al., 2003) Age group (years)

(Jorm & Jolley, 1998)

F & M

(Gao, Hendrie, Hall, & Hui, 1998)

F&M

(Launer et al., 1999)

F & M

(Fratiglioni et al., 2000) Female Male

Average Female Male

60 – 64

- 0.11 - - - 0.1 0.1

65 – 69 0.91 0.33 0.2 0.25 0.24 0.4 0.4 70 – 74 1.76 0.84 0.49 0.47 0.64 0.9 0.9 75 – 79 3.33 1.82 1.62 1.75 1.37 2.1 2.0 80 – 84 5.99 3.36 2.97 3.41 2.76 3.9 3.8 85 – 89 10.41 5.33 5.36 5.38 3.88 6.6 6.2 90 – 94 17.98 7.29 9.14 8.17 4.01 10.6 9.6 95+ - 8.68 - - - 8.7 8.7

Table 3.3 Access Economics projections: Prevalence of dementia in Australia by age and gender 2001 – 2050 Age group (years)

2001 Females Males

2006 Females Males

2050 Females Males

0-59

0.80

0.81

0.84

0.85

0.87

0.89

60-64 2.45 4.76 2.95 5.76 4.91 9.41 65-69 4.34 5.62 4.99 6.61 10.03 13.24 70-74 11.13 10.47 10.94 10.49 24.08 24.25 75-79 18.32 13.07 18.99 14.60 45.31 38.3 80-84 25.33 15.13 30.44 19.88 76.23 62.17 85-89 26.03 11.06 30.46 14.27 102.91 69.05 90-94 16.14 5.57 21.23 7.97 93.01 57.65 95+ 5.58 1.73 8.62 2.64 63.39 35.32 % of total F Population

1.1%

1.3%

3.2%

% of total M Population

0.7%

0.8%

2.4%

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Table 3.4 Access Economics projections: Incidence of dementia by age and gender 2001 – 2050 Age group (years)

2001 Females Males

2006 Females Males

2050 Females Males

0-59

0.02

0.01

0.01

0.01

0.00

0.00

60-64 0.45 0.45 0.54 0.54 0.89 0.89 65-69 1.45 1.39 1.67 1.63 3.35 3.26 70-74 2.88 2.73 2.83 2.74 6.23 6.33 75-79 5.83 4.36 6.04 4.87 14.42 12.78 80-84 6.94 4.26 8.34 5.60 20.89 17.52 85-89 6.28 3.02 7.35 3.90 24.84 18.87 90-94 3.45 1.19 4.53 1.70 19.85 12.28 95+ 0.72 0.24 1.11 0.37 8.17 4.99 % of total F Population

0.29%

0.31%

0.74%

% of total M Population

0.18%

0.21%

0.59%

Using the same meta-analytic data as Access Economics, Jorm and his colleagues (2005) also estimated prevalence and incidence rates of dementia for the Australian population. Rather than computing the prevalence and incidence rates by averaging results across all studies, Jorm and his colleagues adopted the method developed by Wancata and his colleagues (2003) and calculated mean age-and gender-adjusted rates. A prevalence projection for each meta-analysis was determined by multiplying the population projection for each five-year age group separated by gender with the corresponding age-specific prevalence rate from each meta-analysis. The mean for age group and gender across all studies was then calculated and summed. Those estimates were applied to population projections developed for Australia by the United Nations for 2000 – 2050 (United Nations Population Division, 2001). They reported that there were 172,000 people with dementia in Australia in 2000 and projected that the number would increase by 241% to 588,000 cases in 2050. The prevalence of dementia is projected to increase at a much greater rate than both the total population and the older population. The reason is that the old–old are the fastest growing age group and also have the highest prevalence rate. The annual number of new (incident) cases in Australia was estimated to rise from 43,170 new cases of dementia in 2000 to 142,910 new cases in the year 2050. This rise represents an estimated 231% increase in new dementia cases per year in the next 50 years. While the estimated number of cases for 2000 was very similar to the figure produced, the projected number of cases for 2050 was considerably fewer. Methodological differences between the studies are likely to account for the discrepancy in the findings. Nevertheless, the results of both studies indicate that the number of cases of dementia will increase substantially over the next four decades constituting a major health problem.

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3.2.2 Indigenous Australians The Aboriginal and Torres Strait Islander population was estimated to be 458,500 or 2.4% of the total population in 2001. Of those, only 3% were aged 65 years and over in comparison to 13% of the total Australian population (Australian Bureau of Statistics, 2001). Data regarding the prevalence and incidence of dementia within the Aboriginal and Torres Strait Islander communities are very limited. A prevalence study conducted in North Queensland in 1994 reported a prevalence rate of 20% for dementia or suspected dementia in Indigenous Australians aged 65 years and older (Zann, 1994). Alcohol related dementia was the main diagnosis in that study. The Indigenous Dementia Project report commissioned by Alzheimer’s Australia, Northern Territory (NT) (Alzheimer's Australia, 2002) concluded that there was no Australian–wide data regarding the prevalence and incidence of dementia in Indigenous people nor were data specific for Indigenous dementia status in the NT available for the report. It was, however, reported that dementia was the fourth highest reason for hospital admission for Aboriginal people in the NT, by principal diagnosis. Thus, it appears that dementia is a problem of considerable magnitude within the Indigenous community and there is a clear need for adequate dementia prevalence data for this population. 3.2.3 European Studies Wancata et al (2003) provided estimations of the current and projected number of cases of dementia (all causes) for the entire European region for the period 2000 – 2050. Mean age-and gender-adjusted prevalence data were calculated using data from previously published meta-analyses (based on a MEDLINE search) of studies conducted in Europe (see Tables 3.1 & 3.2). These figures were then applied to the most recent population estimates for the year 2000 for Europe and the most recent population projections of the United Nations for the period 2010–2050 (United Nations Population Division, 2001). The age- and gender-adjusted mean number of prevalent dementia cases in the year 2000 was 7.1 million. Within the next 50 years, this number is projected to rise to about 16.2 million dementia sufferers. Similarly, the number of new dementia cases per year will increase from about 1.9 million in 2000 to about 4.1 million in the year 2050. 3.2.4 Global Prevalence of Dementia In 2005, Ferri and colleagues reported prevalence estimates of dementia for every region of the world where epidemiological data were available. Firstly, they conducted a systematic review of published work from around the world on the prevalence of dementia. This review consisted of a MEDLINE search covering the period from 1980 to 2004. Studies were identified using the terms: dementia, Alzheimer’s disease, prevalence, and cross-sectional. Secondary references and review papers were also examined. Consensus panel members were asked to identify any omissions. The only inclusion criterion was that the study should be population-based. Twelve international experts in the epidemiology of dementia were provided with the review and were asked to prepare prevalence estimates for every WHO world region, for men and women combined, in five-year age bands from 60 to 84 years, and for those aged 85 years and older.

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The sexes were aggregated and the focus was on the overall prevalence of dementia rather than subtypes such as Alzheimer’s disease because most prevalence data were neither gender-specific nor distinguished by subtype. WHO has divided the countries of the world into fourteen regions based on geography (AMRO [the Americas], EURO [Europe], EMRO [north Africa and the middle east], AFRO [Africa], SEARO [south Asia] and WPRO [western Pacific]) and patterns of child and adult mortality, from A (lowest) to E (highest). Figure 3.2 shows the extent of the global research evidence on the prevalence of dementia. The world regions coloured in red (North America, Europe, Japan, and Australia) are well covered with several studies of good methodological quality. Some epidemiological studies have been undertaken in the regions coloured in pink, but they are insufficient in quality or quantity to provide representative estimates of the regional prevalence of dementia. Regions marked in white are completely or almost completely lacking in epidemiological studies; in these regions sites of single studies are marked with a red dot (Ferri et al., 2005). The lowest prevalence and incidence estimates for all age groups were for the AFRO D region followed by SEARO B (Indonesia, Thailand and Sri Lanka) and AFRO E. Prevalence estimates of dementia in North American and Western Europe were similar for most age groups and ranged from 0.8 – 0.9% in the 60-64 year age group to approximately 12% in the 80-84 year age group. For people aged 85 years and older living in North America, however, the estimate increased to around 30% while it was approximately 25% in Western Europe. Applying the prevalence figures from Table 5 to the 2001 world population, it was estimated that 24.3 million people had dementia in 2001 with an estimated 4.6 million new cases every year (one new case every seven seconds). It is projected that the number of people affected will double every twenty years to 81.1 million by 2040. China and its developing western-Pacific neighbours had the highest number of people with dementia (six million), followed by western Europe (4.9 million), and North America with 3.4 million. Of those with dementia, 60% live in developing countries, with this number rising to 71% by 2040. Rates of increase are not uniform across countries: numbers in developed countries are forecast to increase by 100% between 2001 and 2040, but by more than 300% in India and China. Table 3.5 shows the number of people with dementia in 2001 and projected increases for 2020 and 2040. The estimate of 24.3 million was similar to an estimate by Wimo et al (2003), who estimated there to be 25 million people with dementia worldwide in 2000 rising to 63 million by 2040 and 114 million by 2050. They, however, assumed the age-specific prevalence to be the same worldwide and hence some of their prevalence estimates for some regions differed considerably to those of Ferri and his colleagues, who argued that their estimates should be more sensitive to regional variation. It was not possible to compare the estimates from this study to the estimates calculated by Access Economics for Australia as the region WPRO A including Australia also included Japan and Singapore, precluding a direct comparison. For China and nearby areas (WPRO B), the consensus prevalence estimates were similar to prevalence data published since completion of the consensus exercise. Zhang et al (2005) conducted a large-scale population based prevalence study (n = 34,807) in four Chinese cites in 1997 using the NINCDS-AIREN classification system to diagnose AD and the NINDS criteria for VaD. Their results indicated that the overall prevalence of AD was 4.8% and the prevalence of VaD was 1.1%. It was concluded that the prevalence of dementia subtypes in China is comparable to Western countries. This result is a considerably higher estimate of the prevalence of dementia in China than previously reported (Liu, Guo, Zhou, & Xia, 2003).

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Liu and his colleagues reviewed population-based epidemiological studies of dementia published in Chinese journals between 1990–1999 and identified seventeen studies for inclusion in a meta-analysis. The results indicated an overall prevalence rate of 1.26% for AD for people aged 60 years and older while the overall prevalence rate for VaD was 0.74%. The prevalence of dementia increased with age, approximately doubling every 5 years and AD was found to be greater in women (2.1%) than in men (0.76%) while there was no difference in the prevalence of VaD between women (0.71) and men (0.69). Those results, however, were based on a number of relatively small scale studies (with one exception, all sample sizes were less than 5500) which Zhang and his colleagues suggested may have yielded relatively few dementia cases upon screening. The use of different diagnostic criteria in the studies is also likely to contribute to the differing results.

Figure 3.2 Worldwide prevalence studies of dementia (Source: Ferri et al, 2005)

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Table 3.5 Consensus estimates of the prevalence and incidence of dementia by world region and projected numbers of people with dementia. Adapted from (Ferri et al., 2005) Region

Population (millions)

age 60 years+

Prevalence estimate (%)

age 60 years+

Estimated annual

incidence per 1000

Projected number of people with

dementia >60 years (millions)

2001 2020 2040 Western Europe

89.6

5.4

8.8

4.9

6.9

9.9 Eastern Europe (EURO B)*

27.4

3.8

7.7

1.0

1.6

2.8

Eastern Europe (EURO C)**

44.6

3.9

8.1

1.8

2.3

3.2

North America

53.1

6.4

10.5

3.4

5.1

9.2

Latin America

40.1

4.6

9.2

1.8

4.1

9.1

North Africa & Middle Eastern Crescent

27.5

3.6

7.6

1.0

1.9

4.7

Developed West Pacific

34.5

4.3

7.0

1.5

2.9

4.3

China and developing West Pacific

151.1

4.0

8.0

6.0

11.7

26.1

Indonesia, Thailand and Sri Lanka

23.7

2.7

5.9

0.6

1.3

2.7

India and South Asia

93.1

1.9

4.3

1.8

3.6

7.5

Africa

31.5

1.6

3.5

0.5

0.9

1.6

TOTAL

616.2

3.9

7.5

24.3

42.3

81.1

*region with low rate of adult mortality; **region with high rate of adult mortality

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3.3 Dementia Variants 3.3.1 Alzheimer’s Dementia (AD) and Vascular Dementia (VaD) Alzheimer’s disease is the most common type of dementia, and accounts for more than 50% of dementia cases (WHO 2006) while Vascular dementia is considered to be the second most common form, accounting for 5-10% of dementias (Alva & Potkin, 2003). Summaries of the prevalence and incidence data for Alzheimer’s disease based on meta-analyses of studies conducted in Europe appear in Tables 3.6 and 3.7 from (Wancata et al., 2003). Table 3.6 Prevalence Rates according to Meta-analyses: Alzheimer’s Dementia (%) Adapted from (Wancata et al., 2003) Age group (years)

(Rocca et al., 1991) Female Male

(Lobo et al., 2000) Female Male

(Hy & Keller, 2000) Female Male

60 – 64 0.4 0.3 - - - - 65 – 69 - - 0.7 0.6 1.0 0.7 70 – 74 3.6 2.5 2.3 1.5 2.1 1.5 75 – 79 - - 4.3 1.8 4.5 3.1 80 – 84 11.2 10.0 8.4 6.3 9.0 6.4 85 – 89 - - 14.2 8.8 17.4 12.8 90 – 94 24.7 40.9 23.6 17.6 31.0 23.7 95+ - - 48.9 39.8 Table 3.7 Incidence Rates according to Meta-analyses: Alzheimer Dementia (%) Adapted from (Wancata et al., 2003) Age group (years)

(Jorm & Jolley, 1998) Female & Male

(Gao et al., 1998) Female & Male

(Launer et al., 1999) Female & Male

(Fratiglioni et al., 2000) Female Male

60 – 64 - 0.06 - - - 65 – 69 0.25 0.19 0.11 0.22 0.09 70 – 74 0.52 0.51 0.27 0.38 0.30 75 – 79 1.07 1.17 0.97 1.03 0.69 80 – 84 2.21 2.31 2.16 2.73 1.48 85 – 89 4.61 3.86 3.80 4.15 2.42 90 – 94 9.66 5.49 6.56 6.97 2.0 95+ 6.68 6.56 In an earlier meta-analysis, (Lobo et al., 2000) combined data from eleven population-based studies in Europe to estimate the prevalence of dementia and dementia subtypes in Europe. The primary studies were conducted in the 1990’s in eight European countries including Finland, Sweden, Denmark, the Netherlands, the United Kingdom (two studies), France, Spain (three studies), and Italy. A total of 2,346 cases of mild to severe dementia were identified in eleven cohorts. Overall, the age-standardised prevalence was 6.4% for dementia (all causes), 4.4% for AD, and 1.6% for VaD. Alzheimer’s disease accounted for 53.7% of cases while VaD accounted for 15.8% of cases.

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The pooled age-specific rates of prevalence for male and females are presented in Table 3.8 and it is evident from the results that the prevalence of dementia increases with older age. The age-standardised prevalence of AD was 4.4% in persons age 65 years or more with variation in the prevalence of AD being greatest for men across studies. The sample size for men was smaller, however, in each separate study, particularly in the older age groups. The results indicated that the prevalence of dementia nearly doubles every five years and AD is the main contributor to the steep increase of prevalence with age. The prevalence of dementia was higher in women than men across most studies with the difference being particularly apparent in the older age groups. This finding has also been reported by Jorm et al (1987) and should be interpreted cautiously as the difference may reflect differences in the survival between men and women. The pooled prevalence of VaD was 1.6% in subjects aged 65 years or older with increasing prevalence in the oldest subjects (Table 3.9). In contrast to AD, the difference in prevalence between men and women was age dependent: under 85 years of age, the prevalence of VaD was higher in men compared to women; thereafter, the prevalence in women was higher. This finding may, however, be attributed to differences in survival between men and women. There was considerable variation in the prevalence estimates of both AD and VaD across studies and in the case of AD ranged from 38.5 - 78%. Prevalence and incidence data, however, are highly sensitive to the study design and variations in sample selection and the diagnostic criteria used can materially influence the results (Erkinjuntti et al., 1997). Thus, it can be misleading to compare epidemiological data across regions on the basis of studies that have employed different methodologies. A recently published study overcame this limitation by using identical methodology to ascertain the incidence of dementia in five diverse sites across the United Kingdom (Matthews & Brayne, 2005). The results indicated that incidence figures did not vary according to site although the incidence in women tended to be higher than in men older than 80 years. Thus, while there may be real differences in the prevalence and incidence of dementia across some regions, this cannot be known with any degree of certainty until comparable studies are conducted in each of those regions. Table 3.8 Prevalence of Dementia in Europe Adapted from (Lobo et al., 2000) Age Group (years)

All types Dementia

Females Males

Alzheimer’s Dementia

Females Males 65-69

1.0%

1.6%

0.7%

0.6%

70-74

3.1%

2.9%

2.3%

1.5%

75-79

6%

5.6%

4.3%

1.8%

80-84

12.6%

11%

8.4%

6.3%

85-89

20.2%

12.8%

14.2%

8.8%

90+

30.8%

22.1%

23.6%

17.6%

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Table 3.9 Prevalence and Incidence of Vascular Dementia in Europe Adapted from (Lobo et al., 2000) Age Group (years)

Prevalence (%) (Lobo et al., 2000)

Females Males

Incidence (%) (Fratiglioni et al., 2000)

Females Males

65-69

0.1

0.5

0.03

0.12

70-74

0.6

0.8

0.08

0.16

75-79

0.9

1.9

0.32

0.39

80-84

2.3

2.4

0.45

0.83

85-89

3.5

2.4

0.61

0.62

90+

5.8

3.6

0.70

1.09

Fratiglioni et al (2000) conducted a meta-analysis of incidence data that were available from eight studies carried out in seven European countries: five from northwest Europe (Finland, Sweden, Denmark, the Netherlands, and the United Kingdom and three from southern Europe (France and Spain). The pooled data included 835 cases of mild to severe dementia and 42, 996 person-years of follow-up. In all studies a higher proportion of cases was diagnosed with AD (60 to 70% of all cases) than VaD (15 to 20% of cases), confirming that AD is the most frequent dementing disorder in all ages and that there is a higher incidence of dementia, specifically AD, in women than in men. The incidence of dementia and AD increased with age up to the age of 85 years after which rates continued to increase in women but not men. There was a large variation in the incidence of VaD across studies suggesting that there may be some regional differences as seven out of the eight studies employed the same diagnostic criteria (DSM-III-R). In the pooled analysis, the incidence rates of VaD increased with age without any substantial difference between males and females (Table 3.9). In comparison to the finding that VaD accounted for 15 - 20% of dementia cases in Europe, reports from Japan suggest that VaD accounts for a higher proportion of total dementia cases in that country. Estimates of the proportion of dementias classifiable as VaD range from 32% (Fujishima & Kiyohara, 2002) to 47% (Yamada et al., 1999). 3.3.2 Mixed Dementia Mixed dementia (MD) refers to the co-existence of AD and VaD (Zekry, Hauw, & Gold, 2002) and there is emerging evidence from autopsy studies that a substantial proportion of patients show evidence of both pathologies at autopsy (Nolan, Lino, Seligmann, & Blass, 1998).

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Most epidemiological studies, however, report the prevalence and incidence of AD and VaD as separate entities, the evidence regarding the prevalence and incidence of mixed dementia is very limited. Zekry and his colleagues (2002) summarised the results of epidemiological studies that had reported these data – see table 3.10. They concluded that the prevalence rates varied across the studies due to a number of factors including differences in data collection and differences in the diagnostic criteria and assessment procedure. Only three studies had reported incidence data ranging from 0.2 cases per 100 in people aged 75 years and older after an interval of three years follow-up to 1.0 case per 100 in people aged 75-85 years after an eight year follow-up. Table 3.10 Prevalence of Mixed Dementia in Epidemiological Studies Adapted from (Zekry et al., 2002) Study Age (years) Prevalence (%) London, UK (Livingston, Sax, Willison, Blizard, & Mann, 1990)

≥ 65

0.7

Stockholm, Sweden (Fratiglioni et al., 1997)

> 75

0.2

Honolulu, Hawaii (White et al., 1996)

71-93 Males

1.4

Framingham, US (Bachman et al., 1992)

61-93

0.2

Similarly, the results of autopsy studies show considerable variation in the prevalence of mixed dementia - from 0 - 55 %, most likely due to methodological differences in the studies (Zekry et al., 2002). 3.3.3 Dementia with Lewy Bodies (DLB) Although there is limited evidence regarding the prevalence and incidence of DLB, some researchers consider that it is the second commonest form of dementia, accounting for 15 - 25% of cases (McKeith, 2002). Zaccai and her colleagues conducted a systematic literature review of the prevalence and incidence of dementia with Lewy bodies in the total population in December 2004 using PubMed (Zaccai, McCracken, & Brayne, 2005). Although 221 articles were initially identified, only six studies reporting the prevalence of DLB and one study reporting the incidence of DLB met their inclusion criteria. Overall, prevalence estimates ranged from 0 - 5% for the general population and from 0 - 30.5% of all dementia cases. The only estimate for the incidence of DBL is 0.1% per year for the general population and 3.2% per year for all new dementia cases.

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There were too few cases to draw any conclusion regarding any relationship between DLB and gender although case reports have reported DLB to be more common in males than in females (Rosenberg et al., 2001). Prevalence estimates were not reported by age group although the prevalence appeared to increase with older age. Three of the included studies using the same diagnostic criteria for DLB (McKeith et al., 1996) in cohorts aged over 65 years showed a similar prevalence of DLB (0.1%). The three studies were conducted in widely differing locations (Brazil, Sri Lanka, Japan) which suggests that there may not be any dramatic environmental influences that may influence development of the disease. 3.3.4 The Prevalence of Dementia in Parkinson’s Disease (PDD) Parkinson’s disease (PD) is recognised as one of the most common neurological disorders, affecting approximately 1% of individuals older than 60 years. It affects more than 500,000 Americans and about 50,000 new cases are reported each year (National Institute of Neurological Disorders and Stroke, 2004; Siderowf & Stern, 2003). Internationally, the incidence rate for PD approximates 17 per 100,000 per year, although this is probably an underestimate (Twelves, Perkins, & Counsell, 2003). Both prevalence and incidence increase with advancing age - the rates are very low in people under 40 and rise among people in their 70s and 80s. A systematic review of prevalence studies of dementia in Parkinson’s disease (PDD) was undertaken by Aarsland and his colleagues (Aarsland, Zaccai, & Brayne, 2005). They searched PubMed for all published studies of the prevalence of PDD as well as studies that examined the epidemiology of dementia subtypes until December 2003. Twelve studies of the prevalence of PD or PDD (1,767 patients) and 24 prevalence studies of dementia subtypes (4, 711 patients) were included. There was marked variation in the methodology of the first group of studies which yielded a proportion of dementia in PD of 25 - 30%. There was less methodological variation in the second group of studies and results indicated that 3 - 4% of dementia cases could be accounted for by PDD. On the basis of these data, the prevalence of PDD in the general population aged 65 and over is estimated to be 0.2-0.5% or around 150 to 500 per 100,000 persons. 3.3.5 Frontotemporal Dementia (FTD) There have been few epidemiologic studies examining the prevalence of frontotemporal lobar degeneration (FTD), including Pick's disease. Two community based studies in the UK have recently examined the prevalence of early-onset dementia. Of 108 dementia cases with onset prior to the age of 65 in the Cambridge area, 15.7% had FTD while 25% had AD. This translated to a prevalence of fifteen cases of FTD per 100, 000 (95% CI, 8.4 – 27.0) in people aged 45 to 64 years – equivalent to the prevalence of AD in that age group (Ratnavalli et al., 2004). The mean age at onset was 52.8 years and there was a striking male preponderance (14:3). The second study revealed that 12% of cases in the same age group fulfilled the Lund-Manchester FTD criteria (Harvey, Skelton-Robinson, & Rossor, 2003). Another study in the Netherlands (245 cases), however, reported a much lower prevalence of 3.6 per 100 000 in the age group 50-59 years; 9.4 per 100 000 in ages 60-69 and 3.8 per 100 000 in ages 70-79 with an equal distribution of cases among males and females (Rosso et al., 2003). Prevalence estimates in the United States range from 9.4 to 53.4 per 1001000 in the 60-69 year old population (Knopman, Petersen, Edland, Cha, & Rocca, 2004).

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Authors of a Japanese study recently reported that, of 330 consecutive hospital outpatients with dementia (all ages), 42 (12.7%) had FTLD and 215 (65.1%) had AD (Ikeda, Ishikawa, & Tanabe, 2004). Gislason et al (2003) investigated the prevalence of Frontotemporal dementia in a population based cohort of 85 year olds in Sweden. Of a total sample of 451 subjects, fourteen fulfilled the Lund-Manchester criteria for FTD and it was concluded that the prevalence of FTD was 3% in 85 year olds with there being no difference in the prevalence for males and females. Thus, estimates of the prevalence of FTD range from 3% - 15.7% of the cohort studied and it is likely that differences in cohort size and diagnostic criteria contribute to the differing results. 3.3.6 Early Onset Dementia Young or early onset dementia refers to dementia that occurs in individuals younger than 65 years of age. Few studies have estimated the prevalence of young onset dementia. A recent study in a large catchment area (total population 567,500) in the United Kingdom determined that the prevalence of dementia in those aged 30-64 years was 54 per 100 000 (95% CI 45.1 to 64.1 per 100 000). For those aged 45-64 years, the prevalence was 98.1 per 100,000 (95% CI 81.1 to 118.0 per 100,000). From the age of 35 onwards, the prevalence of dementia approximately doubled with every five year increase in age (Harvey et al., 2003). Extrapolating these figures nationally suggested that there are approximately 18 319 (15,296 – 21,758) people under the age of 65 with dementia in the UK. Fifty-eight percent of cases were male and 42% were females, suggesting a trend towards a higher prevalence in males than in females. In Australia, (Access Economics, 2005) estimated that 1,700 Australian aged less than 60 years had dementia in 2003 (0.01% of Australians aged less than 60 years), albeit with a very high standard error. Prevalence estimates for people aged less than 60 years were based on age specific prevalence rates derived from the Australian Bureau of Statistics (ABS) Survey of Disability Ageing and Carers (DAC Survey) that was conducted between June to November 2003 (Australian Bureau of Statistics, 2004).This figure is estimated to increase to around 14,220 in 2020, assuming that current demographic trends continue and there are minimal advances in the prevention, delay or reversal of dementia. A recently released study (2006) commissioned by Alzheimer’s Association, America, has indicated that the prevalence of early onset dementia is much greater than previously thought. Using data from the Health and Retirement study, a large, longitudinal study, it was estimated that 480,000 people under the age of 65 years (2% of the US population in that age group) had dementia in 2000 and an additional 590,000 (2.5% of the population aged 55-64 years) had borderline cognitive impairment. In the United Kingdom study, AD was the most frequent diagnosis of the confirmed cases and accounted for 34% of cases while the relative prevalence of VaD was 18% - roughly equal to the prevalence at old age. Frontotemporal dementia (12%) and alcohol related dementia (10%) were relatively more prevalent among this population than among older populations (Harvey et al., 2003).

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Another recent study has confirmed the finding of a higher prevalence of frontotemporal dementia in patients with early-onset dementia. McMurtray et al (2006) reviewed medical records, including a neurological evaluation, of all patients seen at a large Veteran’s Affairs Medical Centre Memory Disorders Clinic and assessed demographic variables, final diagnoses and presence of dementia. Among 1683 patients who had presented for an evaluation of a decline in memory or cognitive performance, 948 (56%) met established criteria for a dementing illness. Of those, about 30 % (n = 278) had an age of onset of less than 65 years. The early-onset group had significantly more dementia attributed to traumatic brain injury, alcohol, human immunodeficiency virus (HIV) and frontotemporal lobar degeneration compared to patients with later onset. 3.3.7 Mild Cognitive Impairment (MCI) MCI is a clinical label that includes aged persons without dementia, but with memory impairment and no significant disability (Winblad et al., 2004). Panza et al (2005) conducted a review of the literature and reported that the prevalence of MCI and predementia syndromes varies between studies as a result of different diagnostic criteria, sampling and assessment procedures. They reported a range of prevalence estimates of MCI from 3% - 53.8% in population studies based on people aged 60 years and older. The incidence rates of all predementia syndromes increase with age and are higher in subjects with less education; but age, educational background, and gender are not consistently related to prevalence rates. Thus, there is no consensus regarding the prevalence or incidence of MCI and there is a need for epidemiological studies using standardised diagnostic criteria. 3.3.8 Rare Causes of Dementia In addition to the main subtypes of dementia already discussed in this Section, numerous other dementia subtypes exist including Huntington’s disease, HIV complex and alcohol related dementia, demyelination, human prion disease including Creutzfeldt-Jacob dementia, amyotrophic lateral sclerosis (ALS) with dementia, progressive supranuclear palsy and dementia due to other infectious or metabolic cause. These are uncommon causes of dementia which together account for a minority of cases (1-5% of dementias). Epidemiological data for all rare causes are not presented, as in many cases, only limited data are available - rather, a selection is presented for illustrative purposes. Huntington’s Disease (HD) HD is a fatal neurodegenerative disorder that involves the extrapyramidal system and is characterised by uncontrolled movement (chorea), progressive dementia and behavioural change. HD is genetically transmitted with an estimated prevalence of 1/10,000 (Davies & Ramsden, 2001). Creutzfeldt-Jakob Disease (CJD) Creutzfeldt-Jakob disease (CJD) is a rapidly progressive disease causing damage to the brain and is characterised by dementia. It is one of a group of rare diseases that affects humans and animals, known as the transmissible spongiform encephalopathies or prion diseases. Sporadic CJD (vCJD) affects approximately one in every million people each year which in the Australian population of about twenty million, translates to approximately twenty cases per year (Commonwealth

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Department of Health and Ageing, 2004). In Australia, cases of CJD are monitored by The Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). The average annual age-adjusted mortality rate during the period from 1970 to 2003 was 0.83 deaths per million per year. During the prospective period of ANCJDR surveillance from 1993 to 2003, the average annual rate of mortality was 1.19 deaths per million population. Currently, Australia remains free of vCJD. From October 1996 to November 2002, 129 cases of vCJD were reported in the United Kingdom (UK), six in France and one each in Canada, Ireland, Italy and the United States of America (World Health Organisation, 2006). Amyotrophic lateral sclerosis (ALS) with dementia ALS with dementia is characterised by both frontotemporal degeneration and motor neuron disease, causing progressive muscular atrophy and a frontotemporal type of dementia. The prevalence of ALS is between four and six per 100 000 with males more commonly affected than females (Kurz, 2005). Alcohol-related Dementia Although it has been reported that alcohol-related dementia is a common cause of dementia among Indigenous Australians (Zann, 1994), there are no Australian-wide prevalence data for dementia in Australian Aboriginal and Torres Strait Islander people. 3.4 Summary While there is considerable variation in the estimates of the prevalence and incidence of dementia, epidemiological studies of dementia conducted in European countries agree that Alzheimer’s disease (AD) is the most common reason for dementia, followed by Vascular dementia (VaD). This, however, may not be the case in all regions of the world as reports from Japan suggest that VaD accounts for a higher proportion of total dementia cases in that country. While this finding hints that different risk factors may be operative, epidemiological data are highly sensitive to methodological variations and as different diagnostic criteria and sampling procedures have been employed across studies, it can be misleading to compare these data. Whether there are real differences in the prevalence and incidence of dementia across regions remains to be confirmed by studies that use comparable methodologies across regions. Also unknown are the rates of prevalence and incidence of dementia and dementia variants in many parts of the world. Few epidemiological studies have been undertaken in developing countries including among Indigenous Australians and with the exception of AD and VaD, few studies have examined the prevalence and incidence of other frequent dementia variants.

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The studies that have been conducted, however, indicate that variants including mixed dementia, dementia with Lewy bodies and Frontotemporal dementia account for a considerable proportion of cases. Nevertheless, a number of studies agree that the numbers of people diagnosed with dementia will increase substantially over the next two to three decades. For example, it has been predicted that there will be a four-fold increase in the number of cases between 2000 and 2050 in Australia and that Alzheimer’s disease will be the most common diagnosis with the oldest old being the most affected. Global studies of the prevalence and incidence of dementia suggest that the greatest increase will occur in developing countries including India and China.

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Liu, L., Guo, X. E., Zhou, Y. Q., & Xia, J. L. (2003). Prevalence of dementia in China.

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Zekry, D., Hauw, J. J., & Gold, G. (2002). Mixed dementia: epidemiology, diagnosis,

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4.0 Aetiology and Pathophysiology of Dementia 4.1 Literature Search This section summarises the most recent research regarding the aetiology and pathophysiology of the most frequently occurring dementias. Research into genetic factors that are thought to play a role in the aetiology of these variants is presented, followed by a synopsis of the key neuropathological changes characteristic of these variants and key theories regarding the development and progression of Alzheimer’s disease are also reviewed. The following computer-based databases were searched for studies relevant to the aetiology and pathophysiology of dementia:

• Ageline • MEDLINE • PubMed

Keywords used in the searches included dementia, Alzheimer’s disease, Vascular dementia, Mixed dementia, Lewy body dementia, Parkinson’s disease and Frontotemporal dementia in conjunction with aetiology, cause, risk factor, pathology, pathophysiology, pathogenesis, tau, neurological, neurotransmitter, neuropathology, genetic factors, genetics, neurodegenerative, biological markers, development and course. Additional websites that were searched included:

• Alzheimer’s Organization, US • Alzheimer Research Forum • Alzheimer’s Society UK • Australian Neuroscience Society • Centre for Neuroscience, Flinders University, Adelaide • Society for Neuroscience • The Association for Frontotemporal Dementias

Systematic reviews and meta-analyses were retrieved initially. For topics that had not been systematically reviewed, review articles were obtained. Additional articles were identified by reviewing the reference lists of retrieved papers and primary research was obtained in instances where systematic and review articles for a particular topic were limited. A flowchart of the literature search process is shown in Figure 4.1.

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Figure 4.1 Flowchart of identification of systematic reviews and meta-analytic studies for inclusion in the review of aetiology and pathophysiology of dementia 4.2 Classification of Dementia An alternative system of classifying dementia to that proposed by the National Institute of Neurological Disorders and Stroke (see Section 2) is a classification system based broadly on the underlying pathology. Three core groups are identified within this system. The first is dementias characterised by the amyloid plaques and neurofibrillary tangles that are characteristic of Alzheimer’s disease. The second group is referred to as tauopathies in which the most common histological feature is tau pathology. Examples include Frontotemporal dementia (FTD) and Pick’s disease. α-synucleinopathies constitute the third group and include dementia with Lewy bodies (DLB) and dementia in Parkinson’s disease (PDD), while Vascular dementia (VaD) and rare forms of dementia stand alone.

Titles Identified n = 164

Abstracts inspected n = 38

Full copies retrieved n = 16

Included: 3 Systematic Reviews/Meta-Analyses [In addition, 22 Review articles, 51 primary research articles, 3 book chapters & 4 other types of documents were included]

Excluded n = 13

Excluded at title stage n = 126

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The primary pathological characteristics of the most frequently occurring dementia variants are listed in Table 4.1. Table 4.1 Pathological deficits in patients with dementia Diagnosis Pathology Protein

Neurotransmitter Deficit

Alzheimer’s disease Amyloid plaques and tangles

Abeta, tau Cholinergic Serontonergic Noradrenergic

Dementia with Lewy bodies Parkinson’s disease with dementia

Lewy bodies α-synuclein PARKIN

Cholinergic Serontonergic Noradrenergic Dopaminergic

Frontotemporal Lobar Degeneration

Neurofibrillary tangles

Tau Progranulin

Serotonergic

Mad cow disease, CJD Prion plaques Prion protein (PrP)

Variable

Vascular dementia Vascular lesions

N/A Variable Cholinergic Variable Dopaminergic Variable Serontonergic

4.3 Genetic Factors in Dementia 4.3.1 Genetic Factors in Alzheimer’s disease (AD) Familial AD is rare, accounting for up to 5% of all cases of AD (Rocchi, Pellegrini, Siciliano, & Murri, 2003). Three genes have been identified as responsible for the early-onset familial form of the disease and are fully penetrant with autosomal dominant inheritance (Imbimbo, Lombard, & Pomara, 2005). These genes are the Aβ precursor protein (APP) on chromosome 21, the presenilin 1 (PS1) on chromosome 14, and presenilin 2 (PS2) gene on chromosome 1. All these mutations seem to result from the overproduction of the β-amyloid protein (Aβ), which is generated by cleavage of the APP by the enzymes β- and y-secretase. The remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic features of the individual. 4.3.1.1 Apolipoprotein E isoform ε4 (APOE- ε4) APOE is a cholesterol protein carrier that is encoded on chromosome 19. APOE-ε4 is a variant of the APOE gene and has been identified as a biological risk modifier for both Alzheimer’s disease (Higgins, Large, Rupniak, & Barnes, 1997; Roses, 1995), preclinical cognitive decline (DeCarli et al., 2001) and VaD (Davidson et al., 2006). APOE-ε4 is neither necessary nor sufficient to cause AD but operates as a genetic risk modifier as the age of onset is lower in those positive for APOE-ε4 (Miech et al.,

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2002). In the population of patients who have AD, approximately 30 - 45% of APOE alleles are of the ε4 type. 4.3.1.2 Susceptibility Genes While numerous genetic linkage and association investigations aimed at identifying additional susceptibility genes for dementia have been conducted and several potential candidates, including genes located on chromosomes 6, 9 ,10,12 and 19, have been detected (Kamboh, 2004), none apart from APOE-ε4 have been fully confirmed. Nevertheless, it is estimated that there are at least six additional susceptibility genes that may influence the age at onset and the risk for sporadic AD (Tanzi & Bertram, 2005). For example, genomic screenings of patients with late-onset AD have identified a susceptibility locus on chromosome 10 that modifies the risk for AD by elevating Aβ42 plasma levels and acts independently of the APOE genotype (Myers et al., 2000). Similarly, a susceptibility locus on chromosome 12, not linked to the presence of APOE-ε4, has also been identified (Scott et al., 2000). Other genes implicated in AD include the gene that encodes neprilysin (NEP) that is located on chromosome 3. A number of nucleotide polymorphisms in NEP have also been found to be associated with sporadic AD, suggesting that genetic variations within or extremely close to NEP might influence the susceptibility to AD (Helisalmi et al., 2004). Similarly, the gene encoding Ubiquilin 1(UBQLN1) is another candidate gene for AD located on chromosome 9 and UBQLN1 is also considered a candidate (Bertram et al., 2005). The gene that encodes β-secretase (BACE1), the enzyme the starts the first cleavage of APP to generate Aβ, located on chromosome 11 may also be a genetic risk factor for sporadic AD (Imbimbo et al., 2005). α1-antichymotrypsin (ACT), a major component of senile plaques, is also considered a suspect as increased levels of ACT have been found in the brain and peripheral blood of patients who have AD (DeKosky et al., 2003). Microtubule-associated protein tau is a major component of the intracellular neurofibrillar tangles that histologically define AD and a number of other degenerative diseases. Currently 32 different mutations have been identified and approximately half of these reduce the ability of protein tau to interact with microtubules and increase its propensity to assemble into abnormal filaments. Although no mutations in protein tau have yet been associated with AD, the abundance of NFTs correlates with the degree of neurodegeneration in the disease (Imbimbo et al., 2005). Further, it has recently been reported that tau glycosylation is an early abnormality of neurofibrillary degeneration and that it facilitates tau abnormal hyper-phosphorylation in the AD brain (Liu et al., 2002). None of these polymorphisms, however, have demonstrated consistent evidence of association from study to study and possible reasons for the lack of replication include small sample size and genetic heterogeneity. 4.3.1.3 Alzgene Bertram and his colleagues recently presented the results of a number of systematic meta-analyses of genetic association studies in AD, at the 10th International Conference on Alzheimer’s disease and Related Disorders in Madrid in 2006 (Bertram et al 2006).

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Included in the analyses were the results of almost 1000 studies of over 300 different candidate genes, the results of which are stored on a publicly accessible database (“Alzgene”; hosted by the Alzheimer research Forum, available at www.alzgene.org) that systematically collects and summarises the results of genetic association studies in AD. Results of the analyses indicated that thirteen genes with twenty variants in total have more supporting evidence than non-supporting evidence with Odds Ratios of 1.25 (95%CI 1.09-2.07). These include ACE, MTHFR, TNFa, TFAM, Psen1, PRNP, NCSTN, IDE, GAPDHS, ESRI, CST3 and CHRNB2 that collectively may account for a population attributable risk of approximately 37% (in comparison to APOE-ε4 alone which accounts for approximately 25%). 4.4 Genetic studies in Dementia with Lewy bodies (DLB) Genetic investigations of DLB have been complicated by the substantial overlap between the condition with both AD and PD. However, a few cases of familial DLB have been identified with an autosomal-dominant inheritance pattern, although generally with low penetrance (Brett, Henson, & Staunton, 2002); Galvin et al., 2002). In a recent study, the causative mutation, E46K in the α-synuclein gene on chromosome 4, was identified (Zarranz et al., 2004). This mutation seems to interfere with the normal function of the presynaptic α-synuclein protein. 4.5 Genetic Studies in Parkinson Disease (PD) PD is one of the most common neurological disorders and while rates are low in people under 40 years of age, the majority of individuals with early-onset PD show typical Mendelian inheritance although it is predominantly an autosomal-recessive mode of inheritance (Bertram & Tanzi, 2005). Mutations in at least five genes have been shown to cause familial early-onset Parkinsonism including �-synuclein [SNCA or PARK1; Polymeropoulos et al, 1997]); and parkin [PRKN or PARK2; Kitada et al, 1998]. Recently, mutations in a second gene with dominant inheritance have also been identified [LRRK2; Zimprich et al, 2004]. 4.6 Genetics of Frontotemporal Lobar Degeneration (FTLD) Frontotemporal dementia (FTD) is the most common of a group of clinical syndromes associated with circumscribed degeneration of the prefrontal and anterior temporal lobes and non-Alzheimer disease type pathology, which has been called frontotemporal lobar degeneration (FTLD). FTLD has a high familial incidence and research has shown that familial FTD with Parkinsonism is linked to mutations in the gene encoding the microtubule-associated protein tau (MAPT) localised to chromosome 17q21 (Hutton et al., 1998). The neuropathology of patients with defined MAPT mutations is characterised by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. Mutations in the gene have been detected in 25 to 40% of families with FTD that have autosomal dominant inheritance (Hosler et al., 2000). Since then, further mutations in tau have been identified – around 35 different mutations in approximately 100 families in total (Neary et al., 2005). Many of the mutations exist as missense mutations that generate mutated proteins that fail to promote microtubule assembly or facilitate axonal transport. Rare cases of FTD have also been linked to chromosomes 3p 11.1-q11.2 (Gydesen et al., 2002) and another locus on chromosome 9q21-q22 was identified for amyotrophic lateral sclerosis with FTD (Hosler et al., 2000).

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In 2006, it has been reported that mutations in another gene (progranulin, PGRN), also located on chromosome 17 (17q21.31), are responsible for some cases of tau-negative FTD-17 (Baker et al., 2006). The genetics of non-monogenic FTD have been less studied, although several groups have examined the potential association of FTD with the APOE gene, with inconsistent results. For instance, while several studies have reported an increased risk of FTLD in carriers of the ε4-allele (e.g. Gustafson, Abrahamson, Grubb, Nilsson, & Fex, 1997), a number of studies have failed to replicate this association (Verpillat et al., 2002). More recently, it has been reported that the APOE-ε4 allele roughly doubles the risk of FTLD not associated with mutations in the tau gene, in males but not in females (Srinivasan et al., 2006). An increased risk of FTLD has also been reported among carriers of the ε2-allele (Gustafson et al., 1997; Verpillat et al., 2002). Verpillat and her associates concluded that the presence of the ε2-allele may be associated with an increased risk of FTD, although further replication is required. 4.7 Genetic Forms of Vascular Dementia VaD can be defined as a syndrome of acquired cognitive impairment due to cerebrovascular disorder. A very small group of VaD cases are due to underlying genetic conditions that increase the risk of strokes including Cerebral Autosomal Dominant Arteriopathy with subcortical infarcts and leukoenecephalopathy (CADASIL) and Cerebral Amyloid Angiopathy (CAA). CADASIL is an uncommon inherited nonamyloid systemic angiopathy caused by mutations in the notch 3 gene on chromosome 19 (Tournier-Lasserve et al., 1993). It has been only recently identified as an uncommon cause of familial VaD, with some 100 families identified worldwide (Dichgans, 2004; Tournier-Lasserve et al., 1993). The clinical phenoType 1s highly variable, with age at onset as early as the twenties or as late as the seventies, and includes migraine with aura, epileptic seizures, transient ischemic attacks (TIAs), strokes and vascular cognitive impairment and dementia (Dichgans et al., 1998). The dementia is slow in onset, subcortical, frontal in type, and accompanied by gait and urinary disturbances and pseudobulbar palsy. MRI reveals a combination of small lacunar lesions and diffuse white matter abnormalities (Chabriat, Bousser, & Pappata, 1995). Age at onset does not correlate with progression or severity of illness and mean age of death is around age 60 years (Desmond et al., 1999). It is, however, unclear how mutations in notch 3 cause angiopathy and how this results in VaD. Cerebral Amyloid Angiopathy (CAA) CAA comprises a heterogeneous group of disorders characterised by deposition of amyloid in the walls of leptomeningeal and cerebral cortical blood vessels and demonstrated clinically by recurrent or multiple lobar haemorrhages, cognitive deterioration, and ischemic strokes. MRI displays diffuse white matter abnormalities along with ischemic or hemorrhagic focal brain lesions. On histologic examination, the vessels show amyloid deposition, microaneurysms, and fibrinoid necrosis (Roman, 2002).

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Several autosomal dominant forms of CAA have been identified, although with differences in their clinical, genetic, biochemical, and pathologic findings. Familial British dementia with amyloid angiopathy (FBD) is an autosomal dominant condition characterised by VaD and a point mutation in the BRI gene has been shown to be the genetic abnormality. On brain MRI, Binswanger-type deep white matter hyperintensities and lacunar infarcts are seen, but no intracerebral hemorrhages are apparent. The corpus callosum is severely affected and atrophic plaques and tangles are present, but the amyloid subunit found in FBD brains is entirely different and unrelated to other amyloid proteins (Ghiso et al., 2001). 4.8 Neuropathology of Dementia 4.8.1 Alzheimer’s Disease (AD) Cortical atrophy is the characteristic gross abnormality identified in the brain of a patient with AD. The surface manifestations of cortical atrophy include narrowing of the gyri and widening of the sulci and prominent atrophy of the hippocampal formation. The subcortical nuclei, including the caudate, putamen, and globus pallidus, are typically normal in appearance. The brain stem and cerebellum are also typically uninvolved, although up to one third of cases may show pallor of the substantia nigra (Mirra, Hart, & Terry, 1993). The two key histopathologic lesions identified in brains that have AD include amyloid plaques and neurofibrillary tangles (NFTs) although associated features include neuronal loss, inflammation and cerebral amyloid angiopathy (CAA). Several additional abnormalities are found at increased frequency in brains of patients who have AD, such as Hirano bodies and granulovacuolar degeneration. The pathologic changes seen in AD begin in the entorhinal cortex, then develop in the hippocampal area and finally spread to the neocortex, eventually involving the entire brain (E. Braak & Braak, 1997). 4.8.1.1 Amyloid Plaques Amyloid plaques, which are found in the tissue between the nerve cells, are unusual clumps of a protein called amyloid- (A ) along with degenerating remains of neurons, other cells and molecules believed to be attracted to or entrapped in the lesions. There are two primary plaque types characteristic of the brain with AD, including neuritic (dense-core) and diffuse plaques. Neuritic plaques contain a central core of amyloid material with radially oriented bands of fibrils and are associated with a glial response, including astrocytes and microglia. The second primary plaque Type 1s the diffuse plaque, which is an amorphous localised collection of Aß peptides that lacks a dense core, dystrophic neurites, or a glial reaction. Amyloid- is derived from a larger protein called the amyloid precursor protein (APP) which is thought to play a fundamental role in cellular physiology (Imbimbo et al., 2005). Although it remains unclear whether Aβ has any normal physiologic role in the brain, it is widely believed that increased production of the Aß peptides together with the deposition of amyloid in the form of plaques is thought to trigger the cascade of events leading to Alzheimer's pathology. Evidence that amyloid causes the disease comes from genetic studies in which mutations of APP, PS1, PS2 and APOE e4 have been shown to facilitate amyloid accumulation. Further evidence derives from studies that have demonstrated that levels of Aβ40 and Aβ42 are elevated early in patients who have AD.

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Higher plasma levels of Aβ42 have been reported in healthy individuals who subsequently develop symptoms of the disease and receive a diagnosis of AD, relative to matched controls (Mayeux et al., 1999) and it has been demonstrated that Aβ is elevated in the frontal cortex, before the occurrence of significant tau pathology (Naslund et al., 2000). In addition, it has been shown that levels of both peptides, especially Aβ42, correlate strongly with cognitive decline. Significantly lower cerebrospinal fluid concentrations of Aβ42 have been found in patients with AD in comparison to controls, suggesting a diminished clearance of the toxic peptide from central nervous system (Motter et al, 1995). Finally, expression and activity of β-secretase, the enzyme that initiates the amyloidogenic metabolic pathway, seem to be increased in the brain of sporadic AD (Li et al., 2004). While these findings are consistent with the notion that dysregulation of Aβ production is a primary factor in the pathogenesis of familial AD, strong evidence for the overproduction of Aβ does not exist in late-onset AD (95% of cases) (Bateman et al, 2006). The distribution of neuritic plaques has been mapped in the brains of patients who have had AD. Arnold and colleagues reported that neuritic plaques were more evenly distributed throughout the cortex than were NFTs, with the exception of the entorhinal cortex and hippocampus, which had consistently fewer plaques than any other region (Arnold, Hyman, Flory, Damasio, & Van Hoesen, 1991). Braak and Braak (1991) also examined AD-related changes in 83 brains from patients both with and without dementia and reported that amyloid plaques had a characteristic pattern of anatomic distribution, which they categorised into three pathologic stages (stages A–C). Stage A was characterised by low densities of amyloid deposits in the basal portions of the frontal, temporal, and occipital lobes. With this stage, the entorhinal cortex and hippocampus remained largely devoid of amyloid. Stage B was characterised by moderate densities of amyloid deposits in most of the neocortical regions, sparing only the primary sensory areas and primary motor field. During this stage, the hippocampal formation remained only mildly involved. Stage C was largely similar to stage B, with the additional involvement of the primary sensory and motor areas. Similar to Arnold and colleagues, they found relatively little involvement of the entorhinal cortex and hippocampus, regardless of stage. 4.8.1.2 Neurofibrillary Tangles (NFTs) Neurofibrillary tangles (NFTs) are bundles of twisted filaments found within neurons. These tangles are largely made up of a protein called hyperphosphorylated tau and ubiquitin. In healthy neurons, the tau protein helps the functioning of microtubules, which are part of the cell's structural support and deliver substances throughout the nerve cell. However, in AD, tau twists into pairs of helical filaments that collect into tangles. When this happens, the microtubules cannot function correctly and they disintegrate. This collapse of the neuron's transport system may impair communication between nerve cells and cause them to die. Reports attempting to correlate specific histopathologic findings with the degree of dementia have been conflicting although a number of studies have shown that the severity of dementia was positively correlated to the number of NFTs in the neocortex but not to the number of amyloid plaques (Mott & Hulette, 2005).

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NFTs are most likely to form in large pyramidal cells, and cortical areas that have been shown to be most affected included the entorhinal cortex, periamygdaloid cortex, hippocampal formation, accessory basal nucleus of the amygdala, and nucleus basalis of Meynert. In comparison, the least affected areas were the primary sensory cortex, agranular cortex, and the primary sensory association cortex - findings that suggest that certain brain regions might be more susceptible to neurofibrillary pathology (Arnold et al., 1991). Braak and Braak (1991) also reported that NFTs had a characteristic pattern of distribution which they classified into six stages believed to be related to the temporal progression of AD pathology. The six stages could be further categorised on the basis of anatomical location, which includes transentorhinal (stages I-II), limbic (stages III-IV), and neocortical (stages V-VI). The transentorhinal category is believed to represent the preclinical period of AD, in which patients are yet to display overt signs of dementia. This category is characterised by neurofibrillary pathology that is confined to the transentorhinal region, which consists of the transition zone between the entorhinal cortex and the temporal neocortex. Stage 1 is designated when a mild degree of neurofibrillary pathology is present within the region, whereas stage II is designated when these changes are moderate to severe in extent. During these stages the neocortex is largely free of NFTs and neuropil threads, whereas the entorhinal cortex proper and layer CA1 of the hippocampus show minimal changes at the most. Progression to the limbic category (stages III-IV) is believed to coincide with clinically incipient AD. With stage III, the NFTs and neuropil threads engulf the transentorhinal region and entorhinal cortex, with early involvement of the amygdala and thalamus. Within the hippocampal formation, NFTs and neuropil threads remain confined to layer CA1 of Ammon's horn. The last two stages belong to the neocortical category, which is believed to coincide with fully developed AD. With stage V, there is general progression of pathologic changes in the aforementioned sites. The hallmark of this stage is significant involvement of the neocortex which is evident first in the temporal, frontal and parietal lobes, particularly in the association areas. The primary sensory regions, especially the primary visual cortex of the occipital lobe, remain the most resistant to neurofibrillary pathology until stage VI. Although the model has found not to be exact and order violations have been reported (Gertz et al., 1998), the model validly approximates the progression of neurofibrillary pathology in AD. Both NFTs and Amyloid- plaques can be seen in the cerebral cortices of cognitively normal aged individuals, but it is their number and widespread distribution (Esiri, Lee, & Trojanowski, 2004), the occurrence of neuritic plaques, the level of soluble Amyloid- (Lue et al., 1999) and the severity of CAA (Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), 2001) that distinguish the pathology of Alzheimer’s disease from the cognitively normal. CAA refers to the deposition of Aß peptides in the walls of arteries and arterioles in the leptomeninges and cerebral cortex. Although CAA occurs in older people without dementia, it tends to be more common and more severe in patients who have AD. Areas that tend to be more severely affected include midfrontal, occipital, inferior temporal, middle temporal, entorhinal, and hippocampal regions (Ellis et al., 1996), although the role of CAA in the pathogenesis of dementia in AD remains unclear.

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4.8.1.3 Aetiological Hypotheses Although plaques and tangles generally increase in the brain with the progression of AD, it is not known if amyloid plaques and neurofibrillary tangles are harmful or if they are merely side effects of the disease process that damages neurons and leads to the symptoms of AD. Neither is it known whether the inflammatory responses associated with A promotes or counterbalances neurological damage. A number of pathological and epidemiological studies have suggested that inflammation is a key step in the pathogenesis of AD although it has alternately been suggested that inflammation may serve to clear Aβ (Wyss-Coray et al., 2001). Evidence that inflammation may be a factor in the pathogenesis of AD derives from findings that proteins involved in inflammatory reactions in the brain have been associated with AD brain lesions (Hull, Strauss, Berger, Volk, & Bauer, 1996). There is also epidemiological evidence of a protective effect of anti-inflammatory agents (Etminan, Gill, & Samii, 2003) and evidence of elevated levels of markers of inflammation including cytokines and cytokine receptors in AD brains (Fillit et al., 1991). A multitude of hypotheses have been proposed for AD including abnormalities in proteins regulating the cell cycle, mitochondrial dysfunction and oxidative stress. However, the theory that has generated the most research, to date, is the Aβ hypothesis. 4.8.1.3.1 The Amyloid Hypothesis The hypothesis, first conceptualised by Hardy and Allsop (1991) and updated by Hardy and Selkoe (2002) states that AD is a clinicopathological syndrome in which different gene defects can lead—directly or indirectly—to altered APP expression or proteolytic processing or to changes in Aβ stability or aggregation (see Figure 2). These result in a chronic imbalance between Aβ production and clearance. Gradual accumulation of aggregated Aβ initiates a complex, multistep cascade that includes gliosis, inflammatory changes, neuritic/synaptic change, tangles and transmitter loss. The hypothesised steps are depicted in the Amyloid Cascade Hypothesis Diagram in Figure 2. Evidence in favour of the β-amyloid hypothesis The following observations support the hypothesis that β-amyloid is the common initiating factor in AD: (Selkoe, 2005)

• All AD patients have many amyloid plaques containing degenerating nerve endings; their plaque count far exceeds that found in normal ageing.

• All four genes now known to cause AD have been shown to increase Aβ

production (APP, PS1, PS2) or Aß deposition (ApoE4).

• Down syndrome patients, who invariably develop classical AD pathology by age 50, produce too much Aß from birth and begin to get amyloid plaques as early as age twelve, long before the appearance of tangles and other AD lesions.

• ApoE4, the major genetic risk factor for AD, leads to excess amyloid

accumulation in the brain before AD symptoms arise. Thus, Aß deposition precedes clinical AD.

• Aβ fibrils reproducibly damage cultured neurons and activate brain

inflammatory cells (microglia). Blocking Aß fibril formation prevents this

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toxicity. For example: transgenic mice over expressing a mutant human APP gene develop first diffuse and then fibrillar Aß plaques, associated with neuronal and microglial damage.

• The disease severity correlates much better with Aβ assayed biochemically

than with histologically determined plaque counts, and the concentration of soluble Aβ species seems to correlate with cognitive impairment (Mclean et al, 1999).

• Recently, it was shown that soluble oligomers of Aβ, but not monomers or insoluble amyloid fibrils, may be responsible for synaptic dysfunction in the brains of patients who have AD and in AD animal models. Thus, it may be that large polymeric aggregates (such as amyloid plaques) represent inactive reservoirs of species that are in equilibrium with smaller, putatively neurotoxic assemblies (Aβ oligomers) (Imbimbo et al., 2005).

Figure 4.2 Amyloid Cascade Hypothesis Diagram (adapted from Selkoe 2005)

Dominantly inherited AD Non-Dominant (sporadic) AD

Missense mutations in the APP or Presenilin 1 or 2 genes

Failure of Aß clearance mechanism (eg. APOE-ε4

positive)

Increased Aß42 production throughout

life

Gradually increasing Aß42 levels in the brain

Accumulation and oligomerisation of Aß42 in limbic and association cortices

Subtle effects of Aß oligomers on synaptic efficacy

Gradual deposition of Aß42 oligomers as diffuse plaques

Microglial and astrocytic activation and attendant inflammatory

responses

Altered neuronal ionic homeostasis; oxidative injury

Altered kinase/phosphatise activities lead to tangles

Widespread neuronal/synaptic dysfunction and selective neuronal loss, with associated neurotransmitter deficits

DEMENTIA

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Evidence against the β-amyloid hypothesis The following evidence has been cited to refute the amyloid hypothesis:

• The number of amyloid deposits in the brain do not correlate well with the degree of cognitive impairment experienced by patients in life (Hyman, 1997).

• The histopathologic work of Braak and Braak (1991) shows that the

distribution pattern and packing density of amyloid deposits are of limited significance for differentiation of neuropathologic stages.

A number of mechanisms have been hypothesised to explain the pathway by which Aβ induces neuronal cell death. Those formulated from in vivo experiments include intracellular calcium accumulation, reactive oxygen species (ROS) and nitric oxide production, inflammatory processes, and increased sensitivity to apoptosis (Imbimbo et al., 2005). Although the debate surrounding the amyloid hypothesis has not yet been resolved and the mechanism underlying Aβ toxicity is unclear, the debate has undeniably led to a greatly improved understanding of the cellular and molecular processes that underlie AD. Alternative hypotheses include the Vascular Hypothesis (de la Torre & Mussivand, 1993) and the Cholinergic Hypothesis (Davies and Maloney, 1976). 4.8.1.3.2 The Vascular Hypothesis de La Torre and his colleagues have proposed a Vascular Hypothesis to account for the development of non-mendelian inherited forms of AD and suggest that rather than causing AD, excess Aβ production is a product of the disease process. They propose that AD results from a dysfunctional cerebrovasculature that begins with chronic suboptimal blood flow to the brain and results in chronic brain hypoperfusion (de la Torre & Mussivand, 1993). This, in turn, leads to a crisis among glia and neurons that eventually culminates in neurodegeneration and cognitive impairment. The hypothesis was initially based on findings that reduced cerebral blood flow (CBF) in ageing rats resulted in metabolic, memory and neurodegenerative abnormalities reminiscent of AD pathology although the following evidence from human studies supports the hypothesis (de la Torre, 2004, 2005).

• Epidemiologic studies link vascular risk factors to cerebrovascular pathology that can set in motion metabolic, neurodegenerative, and cognitive changes in Alzheimer brains;

• AD and Vascular dementia (VaD) share many similar risk factors;

• Pharmacotherapy that improves cerebrovascular insufficiency also improves

AD symptoms;

• The preclinical detection of potential AD is possible from direct or indirect regional cerebral perfusion measurements;

• There are overlapping clinical symptoms in AD and VaD;

• There is evidence of parallel cerebrovascular and neurodegenerative

pathology in AD and VaD;

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• Evidence that cerebral hypoperfusion can trigger hypometabolic, cognitive,

and degenerative changes; and

• There is evidence that AD clinical symptoms arise from cerebromicrovascular pathology.

• Recent evidence that the vascular gene MEOX2 is linked to dysfunctional

brain vasculature in AD (Wu et al., 2005). It was reported that expression of MEOX2, a homeobox gene that is upregulated during vascular differentiation, is significantly reduced in late-stage AD, and MEOX2 is required for optimal clearance of amyloid-β (Aβ) from the brains of mice. It is, however, not clear from the data whether low expression of MEOX2 is a genetic risk factor for AD or is triggered by the neurodegenerative process.

While de la Torre argues that there is a causal relation between vascular mechanisms and the development of non-genetic AD, most of the evidence is correlational and as such does not imply causation. Thus, the question of whether hypoperfusion and other vascular factors play a role in the aetiology of AD remain unanswered. 4.8.1.3.3 The Cholinergic Hypothesis The cholinergic hypothesis of Alzheimer’s disease (AD) states that cholinergic neurons in the basal forebrain are severely affected in the course of disease and that the resulting cerebral cholinergic deficit leads to memory loss and other cognitive and non-cognitive symptoms. The hypothesis was based on findings of deficits of cortical cholinergic activity in the brains of patients who had advanced dementia (Davies & Maloney, 1976). The deficits correlated with the degree of mental impairment to a greater extent than other neurotransmitter abnormalities (Wilcock, Esiri, Bowen, & Smith, 1982) and the cholinergic deficits were found to occur primarily in brain areas which are concerned with memory and cognition, i.e. the hippocampus and adjacent temporal lobe and some frontal cortical areas. Further, the extent of the cholinergic deficits correlated with the clinical severity of AD before death and the deposition of neurofibrillary tangles and to some extent with the deposition of amyloid plaques (Bierer et al., 1995). More recently, however the hypothesis has fallen out of favour owing to the lack of supportive data and the finding that cholinergic deficits occur late in the disease (de la Torre, 2005; Frolich, 2002). Additionally, it has been demonstrated that there is an upregulation of cholinergic activity in the brain in the earliest stages of the disease suggesting that there is a plasticity of the central cholinergic system in AD (Frolich, 2002) challenging the cholinergic hypothesis in its present form. 4.9 Vascular Dementia (VaD): Pathophysiology VaD can be defined as a syndrome of acquired cognitive impairment due to cerebrovascular disorder, although pure VaD is relatively rare and patients clinically diagnosed with VaD commonly have concomitant AD type pathology at autopsy (Nolan, Lino, Seligmann, & Blass, 1998). VaD may be caused by a number of vascular lesions and pathogenetic mechanisms listed in Table 4.2 (Roman, 2002). In addition to acute ischemia from embolic and artherothrombotic large vessel occlusions, older people are also susceptible to ischemic lesions of small vessels

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resulting in lacunes, cortical microinfarcts (granular atrophy) and white matter ischemic lesions. Repeated episodes of ischemia from chronic hypoperfusion affect the deep white matter territories that are perfused by small vessels (medullary arterioles). These ischemic lesions may interrupt the frontal cortical-subcortical circuits that underlie executive functions, motivation, and socially responsive behaviours. Table 4.2 Pathological lesions capable of producing Vascular dementia Multi-Infarct dementia Multiple large complete infarcts, cortico-subcortical in location, usually with perifocal incomplete infarction involving the white matter Strategic infarct dementia A single brain infarct, often lacunar in size, damages functionally critical areas of the brain (angular gyrus, thalamus, basal forebrain, posterior cerebral artery and anterior cerebral artery territories) Small vessel disease with dementia Subcortical Binswager’s disease CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoenecephalopathy) Lacunar dementia or lacunar state Cortical and Subcortical Hypertensive and arteriolosclerotic angiopathy Amyloid angiopathies (including British dementia) Collagen-vascular disease with dementia Ischemic-hypoxic dementia (hypoperfusive) Diffuse anoxic-ischemic encephalopathy Restricted injury due to selective vulnerability Incomplete white-matter infarction Border-zone infarction Hemorrhagic dementia Traumatic subdural hematoma Subarachnoid hemorrhage Cerebral hematoma Venous thrombosis Other mechanisms

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Although the relationship between the volume of infarcted tissue and the presence and severity of cognitive deterioration and neuropsychiatric symptoms is imprecise, the pathological changes relate to the corresponding type of VaD. When VaD is the clinical diagnosis, there are typically extensive and multi-focal vascular lesions, while infarctions of the cerebral cortex and underlying white matter are characteristic of multi-infarct dementia, multiple cortical infarctions, borderzone infarctions and strategic infarct dementia. Patients with lacunar state have multiple subcortical lacunar infarctions involving the thalamus and basal ganglia while those with Binswanger’s disease (BD) show widespread ischemic injury of the cerebral white matter, particularly in the frontal region while the cortex and u-fibers are spared. Complete infarctions are characterised pathologically by gliosis, absence of neurons and oligodendroglial cells while less severe anoxic ischemic injury results in laminar necrosis of the neocortex, hippocampal degeneration, and deep white matter demyelination. When areas of increased signal intensity on MRI are examined pathologically, the associated regions are areas of pallor with ill-defined margins and sparing the subcortical U-fibres. There is depletion of both myelin and axons, diffuse vacuolization, and significant reduction in the density of the glial cells and associated pathology of the cerebral arteries and arterioles. Compared with AD, patients with VaD have significantly more white matter involvement including vacuolization and myelin loss. U-fibres immediately beneath the cortical ribbon tend to be least affected and periventricular white matter areas have the greatest abnormalities (Cummings, Vinters, & Felix, 2003). Subcortical vascular dementia is one of the more common forms of VaD and results from small vessel disease with lacunes and white matter lesions that damage structures (caudate nucleus, globus pallidus, thalamus, and connecting fibers) of the prefrontal subcortical circuits (Roman, 2002). It is characterised by pure motor hemiparesis, bulbar signs and dysarthria, depression and emotional lability. Other features are a slowing of mental processing, executive dysfunction, inattention and apathy. 4.10 Frontotemporal Lobar Degeneration (FTLD) Frontotemporal dementia (FTD) is the most common of a group of clinical syndromes associated with circumscribed degeneration of the prefrontal and anterior temporal lobes and non-Alzheimer disease type pathology, which has been called frontotemporal lobar degeneration (FTLD). Two clinically associated syndromes include progressive non-fluent aphasia (PA) and semantic dementia (SD). Differences in the topographical distribution of neurodegeneration determine the clinical manifestation of FTD, PA and SD although there may be some overlapping of the symptoms. The degree of cerebral atrophy correlates with duration of disease and severity of dementia (Kril & Halliday, 2004). In FTD, there is prominent bilateral and usually symmetric involvement of the frontal lobes. In PA, atrophy is asymmetric, involving mainly the left frontotemporal lobe, while in SD, atrophy is typically bilateral and is most marked in the anterior temporal neocortex, with inferior and middle temporal gyri being predominantly affected. Asymmetries in the involvement of the left and right temporal lobes in SD mirror the relative severity of impairment for verbal and visual concepts (word meaning versus object recognition) (Neary et al., 1998).

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4.10.1 Neuropathology Frontotemporal dementia (FTD) is pathologically heterogeneous although immunohistochemical analysis has defined four major types of pathological features: (1) Microvacuolation without neuronal inclusions, that is, dementia lacking distinctive histological features. (2) FTLD-ubiquitinated (FTLD-U) type – characterised by microvacuolation with ubiquitinated rounded intraneuronal inclusions and dystrophic neuritis within layer 2 of the frontal and temporal neocortex and hippocampal dentate gyrus cells. (3) Pick’s type – characterised by transcortical gliosis with tau-reactive rounded intraneuronal inclusions (Pick's bodies) and (usually) swollen achromatic neurons (Pick's cells). (4) Microvacuolation and tau-positive neurofibrillary tangles or Pick-like bodies in neurons, and sometimes tangles in glial cells of the cerebral cortica white matter. This is associated with familial FTD because of mutations in the tau gene. Types 3 and 4 are referred to as tauopathies (Neary, Snowden, & Mann, 2005). In individual cases of FTD, PA or SD, the underlying histological changes cannot be precisely inferred on the basis of the clinical syndrome. It has, however, been reported that, in cases that fulfill the strict criteria for FTD, the most common histological feature is tau pathology while patients with SD and PA show a preponderance of non-tau features (Neary et al., 2005). 4.10.2 Neurotransmitter Studies in FTD Huey and his colleagues (Huey, Putnam, & Grafman, 2006) recently conducted a systematic review of studies that had examined neurotransmitter deficits in, and treatments for patients with FTD. In total, six studies were included in the review and it was reported that the majority of studies that had examined the serotonergic and dopaminergic systems in patients with FTD revealed deficiencies in the two systems using a variety of assessment methods. They further concluded that the serotonergic deficit appears to be more postsynaptic rather than presynaptic, and that the anatomical and clinical presentation of FTD corresponds well to serontonergic dysfunction. This finding is, however, not universal, as concentrations of serontonin and its metabolites have been found to be high in some patients with FTLD (Francis et al., 1993) and some studies have failed to show abnormalities of dopamine concentrations in the brain (Sjogren, Wikkelso, Ostling, Wallin, & Blennow, 2002). In comparison to possible serontonergic and dopaminergic dysfunction in FTD, a majority of studies have demonstrated a relatively intact cholingeric system in FTD including intact acetylcholinesterase levels and preservation of cortical choline acetyltransferase in patients. 4.11 Dementia with Lewy bodies (DLB) 4.11.1 Neuropathology Pathologically, DLB can be characterised as a Lewy body disorder and/or as an α-synucleinopathy. The hallmark of DLB is the presence of Lewy bodies in the brain stem and cortical (frontotemporal) structures.

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In the brain stem, Lewy bodies are found in the substantia nigra and the locus ceruleus although the extent of the pathology is highly variable (McKeith et al, 2005). They are also common in the basalis of Meynert. Subcortical Lewy bodies consist of a dense amorphous core surrounded by a filamentous halo. They are typically round and one or two may occur in the cytoplasm of the neuron. Cortical Lewy bodies are smaller, less well-defined, and rarely have a definite core. Lewy bodies are neuronal inclusions composed of abnormally phosphorated neural filament proteins aggregated with ubiquitin and α-synuclein. DLB is also accompanied by the appearance of ‘Lewy neurites’, degenerating neurites showing ubiquitin and α-synuclein immunoreactivity similar to Lewy bodies, in the substantia nigra, hippocampal region CA2/3, dorsal vagal nucleus, basal nucleus of Meynert and transentorhinal cortex. The mechanism by which cortical Lewy body formation leads to the clinical syndrome of dementia is yet to be determined although the severity of dementia in DLB has been shown to be significantly associated with the abundance of cortical Lewy bodies. In DLB, Lewy bodies are common in the limbic system (transitional form of DLB) or the limbic system and the neocortex (neocortical form of DLB) while in Parkinson’s disease, they are prominent in the brain stem structures and rare in the cortex. Approximately half of all cases have neurofibrillary tangles although the abundance of tangle formation is less severe than in AD. Amyloid deposits in blood vessels are common in DLB. Patients with typical DLB (onset over age 60) have β-amyloid plaques in addition to cortical Lewy bodies. The presence of both Lewy bodies and amyloid plaques suggests that DLB represents the mid-point of a spectrum of diseases ranging from AD to Parkinson’s disease. While there has been considerable debate as to whether DLB is more closely related to AD or Parkinson’s disease, the emerging consensus is that DLB is a distinct pathologic entity somewhere between the two (Chartier-Harlin et al., 2004). Studies with magnetic resonance imaging (MRI) reveal that medial temporal and hippocampal atrophy is significantly greater in DLB than in normal control patients but less severe than in patients with AD (Barber et al., 1999). Studies with single photon emission tomography (SPECT) or flurodeoxyglucose (FDG) positron emission tomography (PET) reveal diminished cortical perfusion or metabolism sparing the primary somatomotor cortex. Unlike patients with AD, patients with DLB have marked hypoperfusion or hypometabolism of the primary occipital cortex (Higuchi et al, 2000). Neuroimaging studies also reveals diminished dopaminergic activity in the basal ganglia of patients with DLB. 4.11.2 Neurotransmitter Studies in DLB Neurochemical studies reveal that patients with DLB have reductions in basal ganglia dopamine similar to that observed in Parkinson’s disease. Markers of cholinergic functions are reduced in DLB although cholinergic deficits are less severe than in AD. Cholinergic activity is more markedly reduced in DLB patients with visual hallucinations than in those without. In comparison, serotonergic receptor binding and both dopaminergic and serontonergic metabolites are significantly more reduced in cases without hallucinations when compared with patients who report hallucinations. Thus, a ratio of reduced cholinergic activity compared with relatively preserved dopaminergic and serotonergic activity is characteristic of DLB patients with hallucinations. Increased muscarinic receptor binding (M1 receptor) and increased D3 receptor density have both been associated with the occurrence of psychosis in patients with DLB.

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4.12 Dementia in Parkinson’s disease (PDD) Histopathologically, Parkinson’s disease (PD) is characterised by a severe loss of dopaminergic neurons in the substantia nigra together with the presence of Lewy bodies. Neuropathological studies of PDD suggest that the disease can be broadly classified into three groups according to the suggested cause of the dementia: subcortical pathology, limbic or cortical Lewy body-type degeneration and those suggesting coincident AD type pathology. Evidence of subcortical involvement derives from studies that have reported an association between cellular loss in the medial substantia nigra and dementia, even after accounting for amyloid burden (Rinne, Rummukainen, Paljarvi, & Rinne, 1989). Other studies have reported that AD-type pathology may underlie the manifestation of dementia in patients with PD (Emre, 2003). For instance, one autopsy study showed that all of the patients with severe PDD examined had evidence of AD-type pathology in the cerebral cortices, but the pathology was evident in only a small proportion of non-demented patients with PD (Boller, Mizutani, Roessmann, & Gambetti, 1980). In addition, a more recent study has shown PDD to be significantly correlated with AD pathology (Jellinger, Seppi, Wenning, & Poewe, 2002). A third group of studies suggest cortical or limbic Lewy body type degeneration to be the main cause of dementia in PD. Recent evidence using �-synuclein antibodies to detect Lewy bodies supports the view that PDD best correlates with the presence of Lewy bodies in the limbic and cortical areas, although AD-type pathology frequently co-exists (Emre, 2003). A recent autopsy study of 22 older PD patients in whom Parkinsonism preceded cognitive decline by at least three years revealed a highly significant correlation between clinical dementia rating scores and regional Lewy bodies in the entorhinal cortex and area 24. While there was also some correlation between senile plague density in the entorhinal cortex, NFT densities did not predict cognitive status (Kovari et al., 2003). The presence of limbic or cortical Lewy bodies may not, however, always be associated with dementia in PD. Another autopsy study has shown that not all patients with Lewy bodies in the limbic areas and cerebral cortex, some in sufficient numbers to justify a pathological diagnosis of DLB, are clinically demented, implying that factors other than the number of Lewy bodies may be important for the development of dementia in PD (Colosimo, Hughes, Kilford, & Lees, 2003). It has also recently been suggested that an ascending order of pathological changes occurs in PDD. It has been reported that the lesions in PDD initially occur in certain brainstem nuclei and anterior olfactory nucleus following which limbic and cortical areas gradually become affected. The disease seems to pursue an ascending course, in which ensuing cortical involvement begins with the anteromedial temporal mesocortex and spreads to the neocortex, commencing with high order sensory association and prefrontal areas, areas involved in cognitive functions (H. Braak et al., 2003). This may explain why cognitive changes appear rather late in the course of PD. Structural imaging studies using Magnetic Resonance Imaging (MRI) and volumetry have shown there to be no significant differences in whole brain or caudate volumes between controls, PD and PD dementia patients. Nor were there any significant correlations between the caudate volume and either global cognitive function, executive performance or processing speed. The authors concluded that structural changes in the caudate, as assessed in vivo by MRI, do not appear to contribute to the cognitive impairment observed among patients with PDD (Almeida et al., 2003).

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4.12.1 Neurotransmitter Studies in PDD Although dopaminergic deficit is the main neurochemical impairment in PD and PDD has been shown to be associated with impaired mesolimbic and caudate dopaminergic function, it appears that other neurotransmitter systems are also involved in cognitive dysfunction in patients with PD (Emre, 2003). There is substantial evidence that cholinergic deficits due to degeneration of the ascending cholinergic pathways may significantly contribute to cognitive impairment and dementia in patients with PD. A decrease in cholinergic innervation of the cerebral cortex and severe cellular loss in the basal nucleus of Meynert has been described in patients with PD and has been shown to be correlated with the degree of cognitive impairment and dementia (Emre, 2003). In-vivo imaging of cortical cholinergic function using positron emission tomography has also shown that compared with controls, mean cortical acetylcholinesterase activity was lowest in patients with PD dementia (20%), followed by patients with PD without dementia (13%) and AD (9%). It was concluded that reduced cortical acetylcholinesterase activity seemed to be more characteristic of patients with PD dementia than of patients with mild AD (Bohnen et al., 2003). The involvement of the noradrenergic and serotonergic pathways have also been implicated in PDD although the evidence for this has been inconsistent. 4.13 Infectious Causes of Dementia: Prion Disease Dementia syndromes due to infectious diseases are rare, particularly since effective antibiotic treatment is now widely available. The most frequent infectious causes of dementia include prion diseases (including Creutzfeldt-Jakob disease - CJD) and infections caused by viruses including herpes, human immunodeficiency virus (HIV), toxoplasmosis, cytomegalovirus and syphilis. Six human diseases associated with prions have been described, including kuru, CJD, Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), atypical prion disease, and new variant CJD (Tsuang & Bird, 2002). Some prion diseases (eg, CJD, new variant CJD) can be transmitted both genetically and via infection. The prion protein (PRNP) gene that encodes the prion protein (PrP) was identified in 1996 (Prusiner, 1996) and although some families have mutations in the PRNP gene that are transmitted in an autosomal dominant fashion and other cases are caused by known exposure to contaminated tissue, most sporadic cases have no known cause. The neuropathologic hallmarks of CJD include spongiform degeneration, neuronal loss, and astrocytic gliosis. PrPSc-positive kuru plaques and other PrP-containing amyloid plaques are pathognomic of prion disease and are almost exclusively found in familial CJD cases with PRNP mutations. 4.14 Summary This section provides a summary of the most recent research regarding the aetiology and pathophysiology of the most frequent subtypes of dementia including Alzheimer’s disease, vascular dementia (VaD), frontotemporal dementia, dementia with Lewy bodies and dementia in Parkinson’s disease. In addition, the causes of, and pathological changes evident in prion diseases were briefly described. Only a small minority of all the dementia syndromes are transmitted genetically for which a number of the genes responsible have been identified. Most cases, however, are sporadic and while investigations have identified a number of candidate genes, few have been confirmed.

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Most cases appear to result from a complex aetiology due to interactions between environmental conditions and genetic features of the individual. In particular, the relationship between VaD and cerebrovascular disease has been well-established although the mechanism by which cerebrovascular disease causes dementia remains to be discovered. Three influential hypotheses regarding the development of dementia were also described: the amyloid hypothesis, the vascular hypothesis and the cholinergic hypothesis. All three have generated, and continue to generate, a substantial body of research that has furthered the knowledge and understanding of dementia.

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5.0 Risk and Protective Factors 5.1 Literature Search This section summarises the findings of a comprehensive literature search of the most recent research into risk factors that are considered to increase an individual’s risk of dementia, as well as factors that may be protective against the disease. The evidence for genetic risk factors, cerebrovascular disease and environmental risk factors is also synopsised, although specific genes that have been shown to be causative are included in the ‘Aetiology and Pathophysiology’ section. The following computer-based databases were searched for published research:

• MEDLINE, • PubMed, • PsycINFO, • Cumulative Index to Nursing and Allied Health Literature (CINAHL), • Cochrane Library.

Keywords used in the searches included dementia, Alzheimer’s disease, Vascular dementia, Lewy body dementia, Frontotemporal dementia and Mixed dementia in conjunction with age, risk factor, protective, gender, sex, apolipoprotein E isoform ε4 (APOE-ε4), Down syndrome, diabetes mellitus, hypertension, blood pressure, cerebrovascular disease, stroke, head injury, cholesterol, lipids, homocysteine, depression, obesity, fat intake, diet, family history, familial, first-degree relative, genetic, folic acid, hormone replacement therapy, smoking, education, intelligence, activity, exercise, non-steroidal anti-inflammatory medications (NSAIDs), aspirin, statins, antioxidant, alcohol, infection, toxins, regional, omega-3 fatty acids and vitamins B12, C, and E. Systematic reviews and meta-analyses were retrieved initially. For topics that had not been systematically reviewed, review articles were obtained. Additional articles were identified by reviewing the reference lists of retrieved papers and primary research was obtained in instances where systematic and review articles for a particular topic were limited. A flowchart of the literature search process is shown in Figure 5.1.

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Figure 5.1 Flowchart of identification of systematic analyses and meta-analytic studies for inclusion in the review of risk and protective factors 5.2 Risk Factors 5.2.1 Age Older age is the most important risk factor for dementia (American Psychiatric Association, 1994). The prevalence and incidence of dementia from all causes increases with older age and approximately doubles every five years (Access Economics, 2005; Jorm, Dear, & Burgess, 2005; Wancata, Musalek, Alexandrowicz, & Krautgartner, 2003). Other firmly established risk factors for dementia include family history of AD, Down syndrome and stroke, while the apolipoprotein E isoform ε4 (APOE-ε4) gene has been confirmed as a susceptibility factor for Alzheimer’s disease (McDowell, 2001). No specific environmental risk factor has been definitively identified as being associated with dementia.

Included: 36 Systematic reviews/Meta-Analysis [In addition, 15 Review articles, 81 Primary research articles, 1 Editorial & 1 statement were included)

Titles Identified n = 285

Abstracts inspected n = 235

Full copies retrieved n = 84

Excluded n = 48

Excluded at title stage n = 50

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There are, however, a number of putative risk and protective factors for the disease that have generated a large body of research and recent evidence indicates that there is considerable overlap between Alzheimer’s disease (AD) and Vascular dementia (VaD) in terms of risk factors (de la Torre, 2004). This section summarises the research evidence for each of those factors. Risk factors for the less common variants of dementia are outside the scope of this review. 5.2.2 Family History of Dementia An increased risk of AD has been consistently reported among relatives of patients with AD (Hendrie, 1998; Silverman, Ciresi, Smith, Marin, & Schnaider-Beeri, 2005), although the genetic and shared environmental factors underlying the increased risk remain to be determined. A number of twin studies have been conducted and have reported substantially higher concordance rates for AD in monozygotic than in dizygotic twins (Breitner et al., 1995; Pedersen et al., 1998) indicating that both genetic and shared environmental factors are important in the pathogenesis of the disease. Additionally, clinical and population based studies have consistently shown an increased relative risk for first-degree relatives in both early and late-onset forms of AD (Breitner, Murphy, Silverman, Mohs, & Davis, 1988; Fratiglioni, Ahlbom, Viitanen, & Winblad, 1993; Lautenschlager et al., 1996) although the familial risk appears to be lower with later ages of onset of the disease (Silverman et al., 2005). Silverman and his colleagues examined the proband onset age of dementia and the age of the at-risk relative. The results indicated that the risk of AD for relatives of probands with AD not only increases with increasing age at least until the mid to late 80s, it also varies with the age at onset of the proband with AD, decreasing as the onset age of the proband with AD increases. 5.2.3 Down Syndrome Bush and Beail (2004) summarised the results of a number of key studies that have reported prevalence rates in people with Down syndrome and it is clear that there is an increased prevalence of Alzheimer’s disease in this population. Additionally, there is an increased incidence of early onset AD in people with Down syndrome – a relationship that appears to be modified by the presence of the APOE-ε4 allele. The results of a meta-analysis of studies that had assessed the relationship between APOE and Down syndrome indicated that there was a significantly higher frequency of the APOE-ε4 allele in adults with Down syndrome and dementia (OR = 2.02, 95%CI 1.33 – 3.07) (Deb et al., 2000). It was concluded that the Apo E epsilon 4 allele acts as a risk factor for the age-specific manifestation of Alzheimer’s disease in people with Down syndrome. Conversely, presence of the APOE-ε2 allele appears to be protective (Deb et al., 2000). It is, however, unclear whether other risk and protective factors for AD are the same for people with Down syndrome as for the remainder of the population.

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5.2.4 Apolipoprotein E isoform ε4 (APOE- ε4) The APOE-ε4, a cholesterol protein carrier, has been identified as a biological risk modifier for both Alzheimer’s disease (Higgins, Large, Rupniak, & Barnes, 1997; Roses, 1995), preclinical cognitive decline (DeCarli et al., 2001) and VaD (Davidson et al., 2006), while epsilon ε2 appears to be protective (Farrer et al., 1997). APOE-ε4 itself is neither necessary nor sufficient to cause AD but operates as a genetic risk modifier as the age of onset is lower in those positive for APOE-ε4 (Miech et al., 2002). The affect of the ε4 allele is also ‘dose-dependent’: heterozygous carriers of APOE-ε4 (carriers of one allele) are at between three and four times the risk of developing dementia while homozygous carriers of the ε4 allele (carriers of two alleles) are at between ten to twelve times the risk (Corder et al., 1993; Farrer et al., 1997).

In a meta-analysis of studies that had examined the relationship between the ε4 allele and the risk of developing Alzheimer’s disease, Farrer and his colleagues (1997) determined that an increased risk of developing AD was present in both sexes and in all racial and ethnic groups. The influence of the gene, however, appears to be weaker in Africans, African-Americans, Hispanics and Arabs and its influence diminishes after the age of 70 years (Farrer et al., 1997). The influence of the ε4 allele also appears to vary according to dementia subtype. Bang and his colleagues (Bang, Kwak, Joo, & Huh, 2003) conducted a meta-analysis of studies that had included over 10 000 patients with dementia and reported that the association between APO-ε4 and AD (OR 4.2) was stronger than between APO-ε4 and VaD (OR 1.3) while the association between APO-ε4 and mixed dementia was intermediate (OR 2.6) (Bang et al., 2003).

It has also been observed that Lewy bodies are more frequent in males with APOE-ε4 (Huckvale, Richardson, Mann, & Pickering-Brown, 2003) and the presence of APOE-ε4 also appears to be associated with a higher prevalence of dementia in Parkinson’s disease. Huang et al (2006) reviewed the literature regarding APOE-ε4 and dementia in Parkinson’s disease. Nine studies with a total of 295 PD and 163 PDD cases met the selection criteria and were included in a meta-analysis. The results indicated that the presence of the APOE-ε4 allele appears to be associated with a higher prevalence of dementia in Parkinson’s disease (OR 1.6) although methodological issues including publication bias may compromise this finding. While several studies have also reported an increased risk of frontotemporal lobar degeneration (FTLD) in carriers of the ε4-allele, for example, (Gustafson, Abrahamson, Grubb, Nilsson, & Fex, 1997), a number of studies have failed to replicate this association (Verpillat et al., 2002). An increased risk of FTLD has also been reported among carriers of the ε2-allele (Gustafson et al., 1997). Verpillat and her colleagues (2002) conducted a case-control study of 94 patients with FTLD to determine whether APOE is a risk factor, together with a meta-analysis of case-control studies that had examined the association. The results of their case-control study indicated that patients who were homozygous for the APOE ε2-allele had a greater risk of developing FTLD (odds ratio (OR) = 11.3; p = .033) and the association remained significant in patients with a positive family history of FTLD (OR = 23.8; p = .02). In comparison, the results of the meta-analysis comprising data from ten case-control studies with a total of 364 FTD patients and 2671 controls, failed to reach significance. Due to heterogeneity among the studies, the neuropathologically confirmed cases and clinically confirmed cases were analysed separately. In both analyses, a significant increase in the frequency of the ε2-allele was found while no results were significant for the ε4-allele.

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It was concluded that the presence of the ε2-allele may be associated with an increased risk of FTD although further replication is required. More recently, it has been reported that the APOE-ε4 allele roughly doubles the risk of FTLD not associated with mutations in the tau gene, in males but not in females (Srinivasan et al., 2006). One possibility is that the APOE-ε4 and ε2-allele are differentially associated with certain clinical or pathological subgroups within FTLD. 5.2.5 Cerebrovascular Risk Factors 5.2.5.1 Stroke Stroke has been reported to be the second most common cause of dementia in developed countries (Murray & Lopez, 1997) and VaD is a direct consequence of cerebral infarcts, haemorrhages and white-matter changes although not all patients who have a stroke have VaD. Leys and his colleagues (2005) reviewed published studies that had examined the relationship between stoke and dementia from 1970 to 2005. They reported that, in community-based studies, the prevalence of dementia in stroke survivors is about 30% and the incidence of new onset dementia after stroke increases from 7% after one year to 48% after 25 years. In hospital-based studies, the prevalence of dementia following a stroke ranged from 5.9 to 32% while the incidence ranged from 9% to 16% after one year to 32% after five years. It was concluded that having a stroke doubles the risk of dementia. The major determinant of dementia following stroke was older age. In one study, after a median follow-up of 21 months, 15% of patients aged 60-69 years with stroke developed dementia while 36% of patients aged 80 years developed dementia following a stroke (Pohjasvaara et al., 1998). Other patient-related variables associated with an increased risk of dementia following stroke were lower levels of education, dependency before stroke and pre-stroke cognitive decline without dementia. Health conditions including diabetes mellitus, atrial fibrillation, myocardial infarction, epileptic seizures, sepsis, cardiac arrhythmias and congestive heart failure have also been shown to be independently associated with an elevated risk. Stroke-related variables associated with an increased risk of dementia include the severity of the stroke, its location (location in the left hemisphere is associated with a five-fold increase in the risk of post-stroke dementia) and stroke recurrence (Leys et al., 2005). 5.2.5.2 Diabetes Mellitus Biessels et al (2006) systematically reviewed the incidence of dementia in people with diabetes mellitus. Fourteen eligible longitudinal population-based studies were identified and included in a meta-analysis. The studies did not distinguish between Type 1 and Type 2 diabetes, but the authors thought that, in view of the age of the populations involved, most participants probably had Type 2 diabetes. Overall, the incidence of dementia was increased by 50–100% in people with diabetes relative to people without diabetes. This increased risk included both Alzheimer’s disease and Vascular dementia (seven of eleven studies and six of seven studies respectively), with an increase in risk of Alzheimer’s disease of 50–100%, and an increase in risk of Vascular dementia of 100–150%. The authors concluded that there is convincing evidence to support an increased risk of “any dementia” in individuals with diabetes than in those without diabetes and the increased risk seems to include both Alzheimer’s disease and Vascular dementia.

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This result confirms the results of an earlier literature review that examined the relationship between Type 2 diabetes (non-insulin dependent) and impaired cognitive function (Strachan, Deary, Ewing, & Frier, 1997). Nineteen controlled studies were included in the review although there was wide variation with respect to the nature of the diabetic populations studied and the psychological tests used. Thirteen studies demonstrated that the diabetic individuals performed more poorly in at least one aspect of cognitive function. The most commonly affected cognitive ability was verbal memory. The remaining six studies showed no differences in cognitive ability between subjects with Type 2 diabetes and non-diabetic control subjects, but none had adequate statistical power to detect a between-group difference in cognitive ability of 0.5 of a standard deviation (a medium effect size). The authors concluded that the findings are consistent with Type 2 diabetes being associated with an increased risk of cognitive dysfunction and that the etiology of the cognitive impairment is likely to result from an interaction between metabolic abnormalities intrinsic to diabetes, diabetes-specific complications, and other diabetes-related disorders. Further, the risk of developing AD appears to be higher in diabetics who also carry the APOE-ε4 allele. Results of a recent longitudinal study have shown that people with both diabetes and the ε4 allele have a greatly increased risk of developing AD in comparison to people without either risk factor or only one risk factor. Individuals with both Type 1I diabetes and the ε4 allele had a RR of 4.4 for AD compared with those with neither risk factor, while the risk for incident AD was 1.6 for the presence of diabetes only and 2.0 for the presence of the ε4 allele (Peila, Rodriguez, & Launer, 2002). In comparison to the findings of an increased incidence of dementia in patients with diabetes mellitus, a Cochrane review (Sastre & Evans, 2006) assessed whether there was a relationship between the treatment of Type 1I diabetes and the incidence of cognitive impairment or dementia. They concluded that there were no appropriate randomised controlled trials that addressed this question and thus there was no evidence upon which to draw a conclusion. 5.2.5.3 Hypertension Although there is a clear association between hypertension and stroke (Rodgers et al., 1996) and studies have documented an association between hypertension and the development of both AD and VaD, a direct association between hypertension and dementia has not yet been fully established. Qiu et al (2003) reviewed population–based observational studies and randomised controlled trials that examined the relationship between blood pressure, antihypertensive treatments and dementia including AD. Of five longitudinal studies that had assessed blood pressure during midlife, four reported a positive association between midlife hypertension and an increased risk of late life dementia and cognitive impairment. One study reported an association between midlife hypertension and VaD but not AD (Yamada et al., 2003) while in another study, an association between high blood pressure and dementia was present only among men who had never been treated with antihypertensive medication (Launer et al., 2000). It has also been reported that mid-life hypertension may be a greater risk factor for cognitive impairment in men with the APOE-ε4 allele (Peila et al., 2001).

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There was, however, less evidence for an association between late-life hypertension and dementia with some studies reporting an association between low blood pressure in later life and an increased risk of dementia, some studies reporting no association and other studies reporting an association between high blood pressure and an increased risk of developing dementia. The authors concluded that there was no strong evidence to indicate that raised blood pressure in later life is a risk factor for dementia and that more studies have shown low blood pressure in later life to be a risk factor. There is also uncertainty about the role of blood pressure lowering therapy in the prevention of cognitive decline and dementia. A Cochrane review (McGuinness, Todd, Passmore, & Bullock, 2006) has investigated the effects of blood pressure lowering treatments for the prevention of dementia and cognitive decline in patients with hypertension but no history of cerebrovascular disease. Three trials were identified for inclusion with 12,091 hypertensive subjects with an average age of 72.8 years. All trials instituted a stepped care approach to hypertension treatment, starting with a calcium-channel blocker, a diuretic or an angiotensin receptor blocker. The combined result of the three trials revealed no significant difference between treatment and placebo (Odds Ratio (OR) = 0.89, 95% CI 0.69, 1.16). Blood pressure reduction resulted in a 11% relative risk reduction of dementia in patients with no prior cerebrovascular disease but this effect was not statistically significant (p = 0.38) and there was considerable heterogeneity between the trials. The combined results from the two trials reporting change in Mini Mental State Examination (MMSE) did not indicate a benefit from treatment (Weighted Mean Difference (WMD) = 0.10, 95% CI -0.03, 0.23). Both systolic and diastolic blood pressure levels were reduced significantly in the two trials that assessed this outcome. The authors concluded that there was no convincing evidence from the trials identified that blood pressure lowering prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease. There were significant problems identified with analysing the data, however, due to the number of patients lost to follow-up and the number of placebo patients given active treatment. Feigin and her colleagues (2005) conducted a meta-analysis of four large-scale randomised controlled trials (RCTs) that evaluated the preventive effects of blood pressure lowering treatment on dementia in over 18,500 patients with cardiovascular or cerebrovascular disease. The results indicated a statistically non-significant 20% relative risk reduction of dementia or cognitive decline in patients with vascular disease. The authors reported that there was noticeable heterogeneity among the trials and the lack of a definitive result could be attributed to methodological limitations of the studies. It was concluded that while the results provide some support for the hypothesis that blood pressure lowering treatments reduce the risk of dementia in patients with vascular disease, considerable uncertainly regarding the effects of blood pressure treatments in relation to dementia remains.

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5.2.5.4 Homocysteine Kuo et al (2005) conducted a systematic review of studies that had examined the association between elevated plasma homocysteine levels and age-related problems including AD and VaD. They reported that a number of case-control studies had reported a positive relationship between elevated plasma homocysteine and both AD and VaD. One study reported that patients who had serum homocysteine levels in the upper third of the distribution had a five-fold elevated risk of histologically confirmed AD in comparison to patients in the bottom third of the distribution (Clarke et al., 1998). In addition, authors of the Framingham study, a large longitudinal study that followed 1097 elderly subjects for a median of eight years, concluded that an increased plasma homocysteine level was a strong independent risk factor for the development of dementia and AD (Seshadri et al., 2002). While elevated homocysteine levels may be associated with dementia, the results of intervention studies of dietary supplements aimed at lowering homocysteine levels (folate, vitamins B12 & B6 – reviewed below) have failed to demonstrate evidence of efficacy in reducing risk for dementia. 5.2.6 Mild Cognitive Impairment (MCI) MCI is considered by many to be a prodromal phase of AD or very mild AD (Bruscoli & Lovestone, 2004; J. C. Morris, 2006) and is therefore predictive of subsequent dementia. As for dementia, both older age and less education appear to be risk factors for incident MCI (Panza et al, 2005). Rates of conversion of MCI to AD and dementia, however, vary widely among studies with annual rates ranging from 6 - 25% (Petersen et al., 2001). This is partly due to heterogeneity of the subjects, the use of different diagnostic criteria, sampling and assessment procedures. Bruscoli and Lovestone (2004) conducted a meta-analysis of studies that had addressed the conversion of MCI to dementia and calculated a mean annual conversion rate of 10.24% (95% CI 6.9 – 11.9). They also examined factors that predict conversion from MCI to dementia and found that, in every study examined in the review, the results of cognitive testing at baseline was considerably lower in those who developed dementia than those who did not. There was little effect of the age of the subjects and the length of follow-up on conversion rates. 5.2.7 Subjective Memory Complaints Another finding from the Bruscoli and Lovestone (2004) study was that the conversion rate for subjects who had been recruited from Memory Clinics was twice that of subjects who were recruited from community samples. This suggests that subjective memory complaints are an important predictor of conversion from MCI to dementia, as has previously been suggested (Jonker, Geerlings, & Schmand, 2000). Jonker and colleagues reviewed community based cross-sectional and longitudinal studies that had examined the relationship between subjective memory complaints, defined as difficulty with everyday memory, and subsequent cognitive impairment and/or dementia. The authors concluded that, although there were some inconsistencies in the findings that could be attributable to methodological differences in the studies, there was evidence of a weak association between subjective memory complaints in older people and objective memory impairment, after adjustment for depression. They also concluded that memory complaints were predictive of dementia after a follow-up of two years, in individuals with mild cognitive impairment at baseline, defined as a score of less than 23 on the Mini-Mental State Examination. Thus, it appears that subjective memory complaints in conjunction with mild cognitive impairment may be indicative of subsequent dementia.

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5.2.8 Depression Ownby et al (2006) systematically reviewed the literature in relation to depression and risk for Alzheimer’s disease. Electronic databases were searched and 153 potentially relevant studies were identified, of which twenty studies were included in the analyses. Data were available from an aggregate sample of 102,172 people in eight countries. Results of the meta-analysis showed that individuals with a history of depression were more likely to be diagnosed with AD later in life – a finding that was robust across analyses stratified by study type, retrospective versus prospective data collection, and strictness of diagnostic criteria used for AD and depression. Findings of increased risk were also robust to sensitivity analyses. The meta-analytic evaluation with random-effects models resulted in a pooled odds ratios of 2.03 (95% confidence interval, 1.73–2.38) for case-control and of 1.90 (95% confidence interval, 1.55–2.33) for cohort studies. A secondary purpose of this study was to evaluate whether the observed risk for developing AD was related to the interval between the diagnoses of depression and AD. Results of the metaregression analysis indicated that the interval between the diagnoses was positively and significantly related to an increased risk of developing AD, suggesting that rather than a prodrome, depression may be a risk factor for AD – a finding that is consistent with the results of a large study that specifically examined the issue (Green et al., 2003). Given the small number of studies included in the metaregression, however, this interpretation must be tentative. However, this result further strengthens the observation that depression may be a distinct risk factor for AD. It should be recognised that these findings do not rule out the possibility that depression is both a remote risk factor for AD and a proximal prodromal feature of it. The authors concluded that a history of depression may confer an increased risk for later developing AD and may reflect an independent risk factor for the disease. 5.2.9 Head Trauma The research findings regarding traumatic head injury as a risk factor for the development of dementia is uncertain. Several epidemiological studies have reported an increased risk of dementia in individuals who had suffered head trauma (Plassman et al., 2000; Sundstrom et al., 2006) while other studies have found no association (Launer et al., 2000; Lindsay et al., 2002). Fleminger and his colleagues (2003) recently conducted a meta-analysis of fifteen case-controlled studies that investigated the relationship between prior head injury with loss of consciousness and the risk of developing Alzheimer’s disease. The results of the meta-analysis indicated that a history of prior head injury was associated with an increased risk of developing Alzheimer’s disease (OR 1.58, 95% CI 1.21 – 2.06). The increased risk was, however, only apparent in males (OR 2.26; 95% CI 1.13 to 4.53) and not in females (OR 0.92; 95% CI 0.53 to 1.59). It was concluded that a serious prior head injury in males increases the risk of developing Alzheimer’s dementia. The authors were unable to review the potential interactions between head injury and APOE gene status in relation to the risk for AD as only two of the identified studies had investigated these relationships using a case-control design.

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Mayeux et al (1995) reported that patients with at least one APOE-ε4 and a history of head injury had a ten-fold increased risk of developing Alzheimer’s disease and that there was no association between head injury and Alzheimer’s disease in the absence of the APOE-ε4 allele. O'Meara et al (1997), however, failed to replicate the finding between head injury and an increased risk of developing dementia in carriers of APOE-ε4. A low rate of reported head injury in the control subjects, however, may have compromised the study's power to detect an interaction between head injury and the APOE-ε4 allele. Thus, it is uncertain whether possession of the APOE-ε4 allele further increases the risk of developing Alzheimer’s disease in males who have sustained a traumatic head injury. 5.2.10 Obesity and Dietary Factors Obesity, defined as a body mass index (BMI) of >30 kg/m2, has been established as an independent risk factor for coronary heart disease and is strongly related to several major risk factors for stroke including hypertension and diabetes. Obesity thus places an individual at an increased risk for VaD (Fontaine, Redden, Wang, Westfall, & Allison, 2003; Turcato et al., 2000). Epidemiological studies have reported that both obesity (Kivipelto et al., 2005; Whitmer, Gunderson, Barrett-Connor, Quesenberry, & Yaffe, 2005) and a high intake of saturated fat in mid-life (Luchsinger, Tang, Shea, & Mayeux, 2002; M. C. Morris et al., 2003) is associated with an increased risk of dementia in later life. A population based study of 10,276 men and women, followed up for 27 years showed that those who were obese in mid-life (body mass index ≥ 30) had a 74% increased risk of dementia (hazard ratio 1.74, 95% CI 1.34 – 2.26) while those who were overweight (body mass index 25.0 – 29.9) had a 35% greater risk of developing dementia (1.35, 1.14 -1.60) compared to those who were of normal weight (body mass index 18.6 - 24.9). It was concluded that obesity in mid-life increases the risk of dementia in later life, independently of co-morbid conditions (Whitmer et al., 2005). A recently reported Swedish study generated a similar conclusion and further stated that midlife obesity, high total cholesterol level and high systolic blood pressure were all significantly associated with an increased risk of developing dementia with ORs of around two for each factor and that each factor increased the risk additively (OR, 6.2 for the combination; (Kivipelto et al., 2005)). Several prospective studies have found associations between intake of dietary fats and an increased risk of AD but the mechanisms for these associations are unknown. Among 980 older people studied for four years, the risk of AD was greatest for those in the top quartiles of total fat and calorie intake who were also carriers of the APOE-ε4 allele (Luchsinger et al., 2002). Another study found that high intakes of saturated and transunsaturated fatty acids were associated with a high risk of AD regardless of the APOE genotype (M. C. Morris et al., 2003). In comparison, however, authors for the Rotterdam study, a large, population based study that included 5,395 individuals who were followed up for six years, reported no association between high intake of fat and an increased risk of AD (Engelhart et al., 2002). Thus, the relationship between dietary fat intake and risk of dementia is unclear at present.

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5.2.11 Exposure to Environmental Toxins Some work has been undertaken to explore the potential relationship between neurodegenerative disease and pesticide exposure. In a Canadian study, the relative risk of developing AD was found to be considerably higher (RR 2.39, 95% CI 1.02 – 5.63) in males, but not in females, who had been occupationally exposed to pesticides (Baldi et al., 2003). Similarly, high-dose solvent exposure either in industrial settings or through the abuse of substances that contain toluene, has been associated with the development of a chronic encephalopathy that include cognitive impairment and dementia in varying combinations (Rosenberg, Grigsby, Dreisbach, Busenbark, & Grigsby, 2002). In addition, several studies have demonstrated that exposures to certain synthetic chemicals are associated with an increased incidence of Parkinson’s Disease (PD). The first such study was the description in 1982 of severe Parkinson-like symptoms among a group of drug users in northern California who had taken synthetic heroin contaminated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;(Langston et al., 1999)). Epidemiologic data also suggest a positive dose-response relationship between lifetime cumulative exposure to the herbicide ‘paraquat’ and risk of PD (Liou et al., 1997). More work, however, is needed to fully explore the observed association between environmental toxins and risk of dementia. 5.3 Probable Protective Factors 5.3.1 Education and Intelligence The majority of studies that have investigated the relationship between education and cognitive decline and/or dementia, have found higher levels of education to be protective while fewer years of education have been associated with an increased risk of cognitive decline and/or dementia even after controlling for potential confounding variables including age and occupation (Valenzuela & Sachdev, 2006). Valenzuela and his colleagues conducted a systematic review and meta-analysis of studies that had addressed this relationship and reported that the combined odds ratio (OR) for incident dementia for individuals with high education compared to low was 0.53 (95% CI 0-45 – 0.62) indicating a decreased risk of 47%. They also reported that only two studies had reported on the relationship between high premorbid intelligence (IQ) and the likelihood of developing dementia, with both studies reporting a significant protective effect for premorbid IQ. On the basis of those studies, they computed an overall OR for individuals with high pre-dementia IQ compared to low of 0.58 (95% CI 0.44 – 0.77) indicating a decreased risk of 42%. It was concluded that involvement in complex mental activity in the early, mid and late-life stages is associated with a significant reduction in the incidence of dementia. 5.3.2 Occupation The relationship between occupation and risk of dementia is uncertain. Lifetime occupations characterised by low socioeconomic status have been found to increase the risk of dementia in a number of population-based studies, for example, (Canadian Study of Health and Aging, 1994; Qiu et al., 2003; Smyth et al., 2004). Potential explanations for this relationship include greater mental demands of high-status occupations (Smyth et al., 2004) and a greater likelihood of adverse occupational exposures in low-status occupations (Canadian Study of Health and Aging, 1994). Other studies, however, have found no association between low-status versus high-status occupation and risk of dementia, for example, (Helmer et al., 2001; Ravaglia et al., 2002) leaving the link between occupation and dementia unclear.

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A recently reported study (Andel et al., 2005) examined the association between risk of dementia or Alzheimer’s disease (AD) and occupation by using measures of complexity of work with data, people, and things. The study included 10,079 twins and after controlling for age, gender, and level of education, the authors found that more complex work with people was associated with reduced risk of AD. Greater complexity of work with people and data was protective in twin pairs discordant for AD. Findings suggest that greater complexity of work, and particularly complex work with people, may reduce the risk of AD. Mental exercise provided by frequent engagement in intellectually demanding activity at work may facilitate the maintenance of inherent cognitive reserve (see Brain Reserve Hypothesis below), leading to more sophisticated cerebral networks in old age and allowing ageing individuals to tolerate dementia neuropathology longer into the progression of the disease. 5.3.3 Physical Activity Although a considerable body of evidence exists to demonstrate that physical activity exerts a beneficial effect on multiple cardiovascular disease risk factors, including those for stroke (Lee, Folsom, & Blair, 2003), and hence increasing (Shouldn’t this be decreasing?) the risk of VaD, evidence for a direct association between physical activity and cognition is less clear. Lautenschlager (2006) reviewed the evidence for an association between physical activity and cognition in older age and reported that the results of several large observational studies show that regular physical activity, including walking, is associated with better cognitive function and less cognitive decline in later life - largely consistent with the hypothesis that physical activity reduces the risk of cognitive decline and dementia in later life. However there have been very few randomised clinical trials that have examined this issue and hence data to support this finding are very limited. There is scant evidence to suggest that physical activity may in fact reduce the risk of dementia and Alzheimer’s disease. In addition, data to support the systematic introduction of physical activity programmes to reduce the risk of dementia in later life are not as yet available from randomised clinical trials. At the time of publication, one longitudinal study of the impact of physical exercise on brain ageing is being undertaken in the United States (NCT00267124). The aim of this study is to evaluate the effects of exercise and cardiorespiratory fitness on age-related brain changes in healthy older subjects and in those with mild AD. Measures include cognitive assessments and MRI scans. The study will conclude in 2006 and results should be available in 2007. 5.3.4 Social Integration / Cognitive Activity / Leisure A number of recent studies have examined the effect of current leisure and mental activity on incident dementia, for example, (Fratiglioni et al., 2000; Verghese et al., 2003; Wang, Karp, Winblad, & Fratiglioni, 2002) reported a significant protective effect both before and after controlling for a number of covariates including age, general health, education and occupation. Verghese and colleagues (2003) reported that participation in cognitively demanding leisure activities may protect against dementia. Over a medium follow-up period of 5.1 years the authors found that reading, playing board games, playing musical instruments and dancing were associated with a reduced risk of dementia.

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Fratiglioni et al (2004) conducted a comprehensive review of studies that had examined the relationship between an individual’s social network, physical leisure and cognitive activity on cognition and dementia. The included studies were large population-based, longitudinal studies that had solid internal validity. The authors concluded that all three components appear to have a beneficial effect on cognition and a protective effect against dementia indicating that an active and socially integrated lifestyle in late life protects against dementia. Although it has been suggested that reduced social interaction and activity could be a manifestation of early stage dementia, this issue was addressed and refuted in several studies by controlling for baseline cognition or by excluding cases with diagnoses of dementia. 5.3.5 Brain Reserve Hypothesis One explanation for the observed beneficial effect of social interaction and activity on cognition and dementia could be the ‘Cognitive’ or ‘Brain Reserve’ hypothesis first proposed by Katzman (1993). The hypothesis suggests that there are individual differences in the ability to cope with AD pathology and those with greater reserves are able to tolerate more pathology. This theory could account for the absence of a direct relationship between the degree of brain pathology and clinical manifestations of dementia (Scarmeas & Stern, 2003). Valenzuela et al (2006) conducted a systematic review of studies that had specifically addressed the relationship between brain reserve and incident dementia. The authors examined cohort studies of the effects of education, occupation, premorbid IQ and mentally stimulating activities - all proxy markers of brain reserve. Twenty-two studies met the inclusion criteria and data were extracted through a quantitative random-effects meta-analysis. The results indicated that higher brain reserve was associated with a lower risk of incident dementia (OR 0.54; 95% CI 0.49-0.59) over a median 7.1 years follow-up with data from 29,000 individuals. Importantly, increased complex activity in late life was associated with a lower rate of dementia independent of other risk factors. The authors concluded that there was robust evidence that complex patterns of mental activity in the early, mid and late life stages is associated with a significant reduction in the incidence of dementia. 5.3.6 Alcohol Consumption Although heavy alcohol consumption has been identified as a risk factor for dementia, Alzheimer’s disease and stroke (French et al., 1985; Mazzaglia, Britton, Altmann, & Chenet, 2001; Saunders et al., 1991), mild to moderate alcohol consumption appears to be protective against the development of dementia and stroke (Letenneur, 2004). Recently, a series of population-based studies - the Rotterdam Study (Ruitenberg et al., 2002), the Cardiovascular Health Study (Mukamal et al., 2003) and the Copenhagen City Heart Study (Truelsen, Thudium, & Gronbaek, 2002) - have examined the relationship between alcohol consumption and the risk of dementia. The Rotterdam Study screened 5,395 individuals aged 55 and over who were followed progressively for approximately six years. The Cardiovascular Health Study adopted a case-control design and screened approximately 750 adults aged 65 years and over. Although neither study included large numbers of heavy drinkers, both identified that light to moderate drinking (one to three drinks per day in the Rotterdam Study, one to six drinks per week in the Cardiovascular Health Study) was associated with a lower risk of dementia. The Copenhagen City Health Study screened over 2,700 individuals aged 65 years or older and identified 83 individuals with dementia.

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This study showed no relationship between the alcohol intake and the risk of dementia in univariate or multivariate analysis but recognised that individuals with monthly or weekly intake of wine (by contrast to beer or spirits) had a significantly lower risk of developing dementia. A Stockholm Study of 1,800 eligible participants screened and followed for at least three years, reported that light to moderate alcohol consumption (one – twenty one units/week) was statistically associated with the decreased incidence of dementia (W. Huang, Qiu, Winblad, & Fratiglioni, 2002). Thus, four population-based studies have reported that light to moderate alcohol consumption confers protection against the development of dementia. The association between alcohol consumption and dementia may be modified by the presence of the APOE-ε4 allele. The Epidemiology of Vascular Aging study reported that moderate drinkers who were carriers of the ε4 allele were at an increased risk of developing AD while non-carriers who drank moderate amounts of alcohol had a decreased risk (Dufouil et al., 2000). The Cardiovascular Health Study showed that the risk of developing dementia was more pronounced among heavy drinkers positive for the ε4 allele (Mukamal et al., 2003). 5.4 Factors for which the Evidence is Inconclusive 5.4.1 Cholesterol & Cholesterol Lowering Medications - Statins (coenzyme-A reductase inhibitors) The evidence regarding the role of cholesterol as a risk factor for dementia is equivocal, with several epidemiological studies showing an association between high serum concentrations of cholesterol and an increased susceptibility to AD (Kivipelto et al., 2002; Pappolla et al., 2003), other studies report no association (Tan et al., 2003) or an association between lower total serum cholesterol and AD (Kuusisto et al., 1997). Furthermore, it has been suggested high plasma concentrations of cholesterol in midlife, as opposed to later life, may determine the risk of developing late onset AD (Pappolla et al., 2003). The results of ten studies that had assessed the relationship between total cholesterol levels and triglycerides in patients with Alzheimer’s disease were subjected to a meta-analysis (Knittweis & McMullen, 2000). The results showed that both plasma total cholesterol levels and plasma triglycerides were significantly lower in patients with AD than in control subjects. It has, however, been suggested that the lower plasma total cholesterol observed in patients with AD may be related to preclinical weight loss (Romas, Tang, Berglund, & Mayeux, 1999). Thus, the results are inconclusive regarding the possible role of cholesterol in the pathogenesis of AD and cholesterol may be a risk factor for only some subgroups of individuals. The current literature is also inconclusive with regard to the neuroprotective effects of cholesterol lowering medications (statins) on cognitive function and impairment. While an observational study found that the prevalence of probable Alzheimer’s dementia was 60% to 73% (p<.001) lower in patients taking statins compared to those taking antihypertensive or cardiovascular medications (Wolozin, Kellman, Ruosseau, Celesia, & Siegel, 2000), two large randomised controlled trials with cognitive function as a secondary endpoint found that statins did not show any benefit compared with placebo.

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The PROSPER trial, a randomised controlled trial designed to assess the effect of pravastatin (Pravachol) on coronary heart disease and stroke, assigned 5,804 study participants (2,804 men and 3,000 women) aged 70–82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2,891) or placebo [n=2,913; (Shepherd et al., 2002)]. Cognitive function was measured by four different tests including the Mini-mental Status Examination (MMSE) and the results at three-year follow-up indicated that overall cognitive function declined at the same rate in both groups. The largest randomised controlled trial of a statin – the Heart Protection Study, enrolled more than 20,000 people and randomised them into treatment with simvastatin or placebo. After a median of five years follow-up, the results indicated that there was no difference in cognitive scores or the incidence of dementia between the two groups (Heart Protection Study Collaborative Group, 2004). Thus, a firm conclusion regarding the effects of statins on cognitive function has not been determined although the draft guidelines of the National Institute of Health and Clinical Excellence (National Institute for Health and Clinical Excellence, 2006) state that statins should not be prescribed for the prevention of dementia. 5.4.2 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)/Aspirin Etminan et al (2003) conducted a systematic review of observational studies that had examined the efficacy of NSAIDs and aspirin in reducing the risk of developing Alzheimer’s disease. Three separate analyses were conducted: the first examined studies that had explored the risk of Alzheimer’s disease in users of all NSAIDs; the second included studies that had addressed the risk of Alzheimer’s disease specifically among aspirin users and the third included studies that had looked at the risk of Alzheimer’s disease according to duration of use of NSAIDs. A total of nine studies with over 14,500 subjects were included in the analyses. The results indicated that the use of a NSAID lowers the risk of developing Alzheimer’s disease and the benefit was greater for long term rather than intermediate term use. The meta-analysis also indicated that aspirin has a protective effect, although this result was not significant, possibly because of the small number of studies that specifically evaluated the effects of aspirin. Another meta-analysis of 25 case-control and cohort studies of NSAIDs conducted separate analyses of studies that had reported prevalent dementia cases, studies with incident dementia cases and studies in which cognitive decline was the clinical endpoint (de Craen, Gussekloo, Vrijsen, & Westendorp, 2005). Results of the analyses indicated that the benefit of NSAIDs in preventing dementia or cognitive impairment decreased from 50% in studies that had reported prevalent dementia cases to 20% in studies that reported incident cases and was absent in studies that reported cognitive decline as the endpoint. It was therefore concluded that most of the reported benefits of NSAIDs in preventing cognitive decline may result from various forms of bias - recall bias, prescription bias and publication bias. While observational studies have indicated that the use of NSAIDs and aspirin may confer some benefit in reducing the incidence of dementia, there have been no published randomised, controlled trials that have assessed this relationship. Thus, it is not known whether the use of NSAIDs or aspirin is protective against dementia. Nonetheless, the draft guidelines of the UK NHS National Institute of Health and Clinical Excellence (2006) currently state that NSAIDs should not be prescribed for the prevention of dementia.

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Nevertheless, there is currently one RCT of Ibuprofen in progress that is recruiting patients. The hypothesis to be tested is that the possible role of Ibuprofen in preventing AD in healthy older subjects (≥ 70 years) can be detected in changes in biomarkers of AD (NCT00239746). 5.4.3 Omega-3 Fatty Acids According to two recently published systematic reviews, there is currently insufficient evidence to either confirm or refute the hypothesis that dietary or supplemental omega-3 polyunsaturated fatty acid reduces the risk of cognitive impairment or dementia prevention of dementia (Issa et al., 2006; Lim, Gammack, Van Niekerk, & Dangour, 2006). Issa et al (Issa et al., 2006) searched computerised databases with the intent to conduct a meta-analysis. Of a total of 497 studies, only five studies met their inclusion criteria. A single-cohort study that assessed the effects of omega-3 fatty acids on cognitive function in normal ageing found no association for fish or total omega-3 consumption. In four studies that assessed the effects of Omega-3 fatty acids on the incidence and treatment of dementia, a trend towards reducing the risk of dementia and improving cognitive function was observed. The authors concluded that the limited evidence suggests a possible association between omega-3 fatty acids and reduced risk of dementia although no firm conclusions can be drawn at this stage. Similarly, the authors of a recently published Cochrane Review (Lim et al., 2006) reported that, as no randomised controlled trials have been conducted, there is no evidence upon which to draw a conclusion regarding the efficacy of omega-3 fatty acids for the prevention of dementia and cognitive decline. Results of two clinical trials are expected in 2008. 5.3.4 Race and Regional Variation Prevalence and incidence rates for dementia have been found to vary between studies suggesting that there may be some regional variation in the rates of occurrence of dementia. For example, the incidence of dementia has been reported to be higher in African-American people than in other ethnic groups (Luchsinger, Tang, Stern, Shea, & Mayeux, 2001). In addition, a lower incidence of dementia across all age groups in several developing countries (Africa, South Asia, Nigeria, India) than in developed countries has been reported (Ferri et al., 2005). This result, however, is based on very limited epidemiological data and it may be that mild cases of dementia go undetected in the least developed regions. Further, while AD predominates in Europe and North America, reports from Japan indicate that VaD accounts for a higher proportion of cases than AD in that country (Fujishima & Kiyohara, 2002; Yamada et al., 1999). Prevalence and incidence data, however, are highly sensitive to the study design and variations in sample selection and the diagnostic criteria used can materially influence the results. The effect of different diagnostic criteria on the prevalence of dementia was investigated by Erkinjuntti and his colleagues (1997). They examined the effects of six commonly used classification schemes – DSM-III, DSM-III-R, DSM-IV, ICD-9, ICD-10 and the CAMDEX9 on the prevalence of dementia in a large population-based cohort of older people. The proportion of people diagnosed with dementia varied from 3.1% when the ICD-10 criteria was used to 29.1% with the DSM-III criteria.

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Thus, it can be misleading to compare epidemiological data across regions on the basis of studies that have employed different methodologies. A recently published study overcame this limitation by using identical methodology [the diagnosis of dementia was based on the Geriatric Mental State B3 organicity case level generated by AGECAT (Automated Geriatric Examination Computer Assisted Taxonomy), equivalent to DSM-III-R diagnoses] to ascertain the incidence of dementia in five diverse sites across the United Kingdom (Matthews & Brayne, 2005). The results indicated that incidence figures did not vary according to site although the incidence in women tended to be higher than in men older than 80 years Thus, while there may be real differences in the prevalence and incidence of dementia across some regions this cannot be known with any degree of certainty until comparable studies are conducted in each of those regions. 5.3.5 Gender It appears that gender may be a risk factor for dementia with females at greater risk for AD and males at greater risk for VaD although the results are not entirely conclusive. The majority of studies show that the prevalence and incidence of all causes of dementia and AD is higher in women than men (Access Economics, 2005; Jorm et al., 2005; Wancata et al., 2003) and the risk appears to increase with advancing age. For instance, researchers for the EURODEM Incidence Research Group pooled data from four large population based studies conducted in Europe. They reported significant differences in the rates of AD for men and women after the age of 85 years. At age 90, the rate of AD was 81.7 (95% CI, 63.8 to 104.7) for women and 24.0 (95% CI, 10.3 to 55.6) for men (Andersen et al., 1999). Similarly, authors for the Rotterdam study reported an increased risk of AD in females after age 90 (Ruitenberg, Ott, van Swieten, Hofman, & Breteler, 2001). Thus, it seems that female gender may be a risk factor for AD although this finding should be interpreted cautiously as the difference may reflect differences in the survival rates between men and women. Similarly, the prevalence and incidence of VaD has been reported to be higher in men compared to women (Lobo et al., 2000; Ruitenberg et al., 2001) although findings of no gender differences have also been reported (Andersen et al., 1999;Fratiglioni et al., 2000). Lobo et al (2000) combined data from eleven population-based studies in Europe to estimate the prevalence and incidence of dementia and dementia subtypes in Europe. Analyses of the pooled data indicated that men under the age of 85 years were at greater risk for VaD while women aged 85 years and older were at greater risk than men (Lobo et al., 2000). Thus, it is not entirely clear whether male gender is a risk factor for VaD as differences in survival between men and women may also account for this finding. 5.3.6 Smoking Although there is strong and convincing evidence that cigarette smoking is a major independent risk factor for ischemic stroke (Shinton & Beevers, 1989), and as a consequence, places one at greater risk for VaD, the evidence as to whether smoking is associated with an increased risk of developing Alzheimer’s disease is inconclusive. A recently conducted meta-analysis of studies that had examined this issue reported conflicting findings from case-control and cohort studies (Almeida, Hulse, Lawrence, & Flicker, 2002).

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The results of 21 case-control studies that included data on 5,323 subjects indicated that ever smoking was associated with a reduced risk of developing Alzheimer’s disease, after adjustment for potentially confounding variables. In comparison, the results of eight cohort studies that included data on 43,885 indicated an increased risk of developing AD for ever smokers. The authors suggested that survival bias (ie non-smokers have a longer life-expectancy than non-smokers) and methodological problems associated with case-control studies may partly explain the different results. 5.3.7 Hormone Replacement Therapy (HRT) The evidence regarding whether HRT is protective against the development of dementia in women is inconclusive. The authors of a meta-analysis of twelve observational studies that had addressed this relationship (LeBlanc, Janowsky, Chan, & Nelson, 2001) reported that HRT was associated with a lower risk of developing dementia although most studies had important methodological limitations. More recently, Low L-F and Anstey KJ (2006) reported the results of an updated review that included eighteen studies that investigated the potential relationship between HRT and dementia. Although unable to conduct a meta-analysis due to heterogeneity among the studies, the authors reported that ever use of HRT was associated with a decreased risk of dementia in the observational studies. In comparison, the results of the one large-scale randomised controlled trial that has been conducted reported a two-fold increased risk of dementia in female subjects with the use of oestrogen plus progestin compared to placebo (Shumaker et al., 2003). In that trial, however, the mean age of subjects was 73 at baseline and it has been suggested that HRT was commenced too long post menopause to have a positive effect on either cognition or cardiovascular disease (Naftolin et al., 2004). In women, it may be that HRT only has a positive effect when commenced during the perimenopause or shortly after menopause (Sherwin, 2005). Thus, HRT appears to be related to an increased risk of developing dementia in women aged 65 years and older. This is reflected in the draft guidelines of the National Institute of Health and Clinical Excellence (2006) that state that HRT should not be prescribed for the prevention of dementia. However, it remains unknown whether HRT commenced during the perimenopausal or menopausal period may be protective against the development of dementia. Two RCTs have examined the effects of Raloxifene, a selective oestrogen-receptor modulator, on cognitive functioning in postmenopausal women with osteoporosis (Nickelsen, Lufkin, Riggs, Cox, & Crook, 1999; Yaffe et al., 2005). Nickelsen and his colleagues reported no significant differences on any measure of cognition between the Raloxifene group and the placebo group after twelve months of treatment. In comparison, Yaffe and her colleagues reported that women taking 120mg/day of Raloxifene had a 33% lower risk of mild cognitive impairment compared to women taking placebo and a slightly lower, although statistically non-significant, risk of developing AD. It is not known whether the benefits of Raloxifene apparent in this trial also apply to other than postmenopausal women without osteoporosis and larger-scale RCTS are needed to address this question.

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5.5 Factors that appear to offer little benefit 5.5.1 Antioxidants – Vitamins C and E Several population-based prospective, observational studies have reported a protective effect of the antioxidants – vitamins E and C, in the prevention of cognitive decline and/or dementia in later life, for example, (Masaki et al., 2000; Maxwell, Hicks, Hogan, Basran, & Ebly, 2005; Zandi et al., 2004). In comparison, other population-based studies have reported no association, for example, (Luchsinger, Tang, Shea, & Mayeux, 2003; Mendelsohn, Belle, Stoehr, & Ganguli, 1998). The results of a recent large-scale randomised controlled trial also suggest that vitamin E is of no benefit in patients with mild cognitive impairment (Petersen et al., 2005). Over 750 subjects were randomised to receive either 2000 IU/day of vitamin E, 10 mg/day of Donepezil, or placebo for three years. There were no significant differences in the rate of progression to AD between the vitamin E group and placebo group at any time (Petersen et al., 2005). Also relevant to the use of antioxidants, are recent reports of serious adverse events associated with long-term use of high doses of vitamin E. For instance, the results of a recently conducted meta-analysis of randomised controlled trials of vitamin E suggest that doses of vitamin E of 400 IU or more per day for more than a year is associated with increased all-cause mortality (Miller et al., 2005). Further, the results of a large international, randomised, double-blind, placebo controlled trial of vitamin E indicated that doses of vitamin E of 400 IU or more over a period of 6.9 years in patients with pre-existing vascular disease or diabetes mellitus increase the risk of heart failure with no other outcome benefits reported (Lonn et al., 2005). The authors concluded that, due to the lack of benefit and increased risk of harm, vitamin E should not be used in patients with vascular disease or diabetes mellitus. Thus, although there is some evidence from population based studies that vitamins C and E may confer a slightly decreased risk of cognitive impairment and/or dementia in later life, recent randomised controlled trials have indicated that there is considerable potential for harm associated with the long-term use of high dosage vitamin E. In the light of these findings of adverse events, and the finding that vitamin E was of no benefit in subjects with mild cognitive impairment in a large-scale RCT (Petersen et al, 2005), the use of vitamin E is not recommended as a preventive strategy for the prevention of cognitive impairment and/or dementia (Boothby & Doering, 2005; National Institute for Health and Clinical Excellence, 2006). Nevertheless, a large-scale RCT of the safety and efficacy of vitamin E in preventing AD is currently recruiting subjects in the United States (Prevention of Alzheimer’s disease by Vitamin E and Selenium; NCT00040378). It is anticipated that 10,000 men will take part in the study. 5.5.2 Folic Acid with or without Vitamin B12; Vitamin B6 Deficiencies of folate, vitamins B12 and B6 result in high levels of homocysteine in the brain which has been implicated in the pathogenesis of AD (Seshadri et al., 2002). Malouf et al (M. Malouf, Grimley, & Areosa, 2003) conducted a systematic literature review of the effects of folic acid supplementation, with or without vitamin B12, on both healthy, older people and those with dementia in preventing cognitive impairment or retarding its progress. Four randomised controlled trials fulfilled the inclusion criteria for the review. One trial enrolled healthy women, and three recruited people with mild to moderate cognitive impairment or dementia with or without diagnosed folate deficiency.

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Analysis of the included trials found no benefit from folic acid with or without vitamin B12 in comparison with placebo on any measures of cognition or mood for healthy or cognitively impaired or people with dementia. The authors suggested that further studies are required as the available studies are limited in size and scope. A similar result was reported by the authors of another systematic review (Ellinson, Thomas, & Patterson, 2004) that examined the relationship between serum vitamin B (12), folate and total homocysteine and cognitive function in older people. Sixteen electronic databases and cited articles were searched and yielded 383 potential articles, of which six met the inclusion criteria. On the basis of the review, the authors concluded that the evidence failed to support a relationship between serum vitamin B(12) or folate and cognitive impairment and there was little justification for treating cognitive impairment with vitamin B(12) or folate. A systematic review of studies that had addressed the relationship between vitamin B6 and cognitive function and/or decline in older people was conducted by Malouf and Grimley Evans (2003). No RCTs of vitamin B6 involving people with cognitive decline were identified and only two RCTs of vitamin B6 in healthy older people were identified for inclusion in the review. No adverse events were reported in either trial nor was any benefit from vitamin B6 observed on either mood or cognition. Neither trial measured homocysteine levels. The authors concluded that there is no evidence of any benefit of vitamin B6 on mood or cognition in healthy older people and there is a need for further RCTs to explore the efficacy of vitamin B6 supplementation for both healthy older people and for those with cognitive impairment and dementia. 5.6 Summary Very few factors have been identified as definite risk factors for dementia. These include older age, family history of AD, Down syndrome and stroke, while the presence of the apolipoprotein E isoform ε4 (APOE-ε4) gene has been confirmed as a susceptibility factor for AD. No environmental factor has been definitely identified as a risk for dementia, although a number of factors have been found to be associated with an increased risk of developing dementia. Epidemiological studies have reported a greatly increased risk of dementia for patients with diabetes mellitus, mid-life hypertension, obesity and depression. The evidence also suggests that head trauma, particularly serious injury, a high dietary intake of fat and exposure to environmental toxins may be associated with an increased risk, although the evidence regarding these factors is less clear. The research literature also suggests there are a number of factors that probably protect against developing dementia. These include higher levels of education and intelligence, moderate alcohol consumption and maintaining a physically, socially and cognitively active lifestyle throughout middle-age. Factors that may be protective, but for which the evidence is inconclusive, include high levels of cholesterol, the preventive use of cholesterol lowering medications (Statins) and non-steroidal anti-inflammatory medications (NSAIDS), aspirin and intake of Omega-3 fatty acids. Factors that have been researched and appear to offer little benefit as a preventive measure against dementia include the use of folic acid with or without vitamin B12 and the use of the anti-oxidants – vitamins C and E. Other factors that have been examined but for which the evidence is inconclusive include gender, regional variation, the use of hormone replacement therapy and smoking. Further research is needed to determine the relative degree of risk and protection conferred by each of these factors as well as the mechanisms underlying these associations. It is also unknown whether these factors act in an interactive or additive manner to influence risk.

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6.0 Diagnosis and Assessment 6.1 Literature Search This section summarises the results of a comprehensive literature search of the most recent research relevant to the diagnosis and assessment of the most frequently occurring dementias. While the diagnosis of dementia is made on the basis of a clinical examination and a definitive diagnostic tool does not currently exist, there are nevertheless, a number of clinical tools that are useful in making the diagnosis and in discriminating between the different subtypes of dementia. This review summarises the research regarding the currently available instruments that are considered to be the best diagnostic aids for dementia including neuropsychological assessment, structural imaging techniques including computed tomography and magnetic resonance imaging (MRI) and functional imaging techniques including positron emission tomography (PET) and single photon emission computed tomography

(SPECT). Research into potential biomarkers of the disease is also documented. The following computerised databases were searched for relevant research:

• Ageline • Cochrane Library • MEDLINE • PubMed • PsycINFO

Keywords used in the searches included dementia, Alzheimer's disease, Vascular dementia, Mixed dementia, Lewy body dementia, Parkinson’s disease and Frontotemporal dementia in conjunction with diagnosis, diagnostic, diagnostic criteria, symptoms, assessment, clinical assessment, biomarkers, neuropsychological, MRI, structural imaging, test, imaging, scanning, CT, MRI, PET, SPECT, test, brain biopsy and EEG. Additional websites that were searched included:

• Alzheimer Research Forum • Hammond Care • National Institute for Health and Clinical Excellence • NHS Health Technology Assessment Programme

Systematic reviews and meta-analyses were identified and retrieved initially. For topics that had not been systematically reviewed, review articles were obtained. Additional articles were identified by reviewing the reference lists of retrieved papers and primary research was obtained in instances where systematic and review articles for a particular topic were limited. A flowchart of the literature search process is shown in Figure 6.1.

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Figure 6.1 Flowchart of identification of systematic review and meta-analytic studies for inclusion in the review of the diagnosis and assessment of dementia 6.2 Diagnosis of Dementia There is no single diagnostic test for Alzheimer’s Dementia (AD) or most of the other forms of dementia. The diagnosis is based on clinical criteria and can be graded as possible, probable or definite dementia (see section 2). For people with AD and their families, a definitive diagnosis early in the course of the disease provides an opportunity to plan and to pursue options for treatment while the patient can still play an active role in decision making. There is also some evidence that early recognition and active intervention at an early stage of the disease delays the subsequent need for nursing home care and reduces the risk of misdiagnosis and inappropriate management (Chang & Silverman, 2004).

Titles Identified n = 306

Abstracts inspected n = 60

Full copies retrieved n = 24

Included: 6 Systematic Reviews/Meta-Analysis [In addition, 16 review articles, 51 primary research articles, 1 Clinical guideline, 3 Consensus Statements/Reports, 4 book chapters & 2 other types of documents were included]

Excluded n = 18

Excluded at title stage n = 246

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However, the insidious nature of the condition, the difficulty in detecting the transition between when normal ageing and the onset of dementia and the lack of a definitive diagnostic tool often precludes early diagnosis. A diagnosis of probable AD is made in the absence of other disorders that may contribute to the dementia, and a diagnosis of possible AD is made when there may be other contributing causes for the dementia. A diagnosis of definitive AD is made only when post-mortem confirmation is available. The diagnosis is based on the combination of clinical history, physical and neurological examination, cognitive and mental state examination together with appropriate investigations. These should include blood tests and may also include structural and functional neuroimaging to further define the diagnosis as well as to exclude other conditions such as stroke, metabolic disorders and head injury. The diagnostic accuracy of the clinical diagnosis of both probable and possible AD is quite high when either the NINCDS-ADRDA or DSM-III-R criteria is used. Both sets have been shown to have reasonable sensitivity (mean 81%) and specificity (70%) for the diagnosis of probable AD while the NINCDS/ADRA criteria for possible AD has higher sensitivity (mean 83%) but lower specificity (mean 48%; Knopman et al., 2001). Inter-rater agreement on the diagnosis of dementia and AD with DSM-III-R and NINCDS-ADRDA criteria has also been good [κ = 0.54–0.81 for DSM-III-R (Graham et al, 1996) and κ = 0.51–0.72 for NINCDS-ADRDA criteria (Baldereschi et al., 1994) in population-based studies], providing evidence that DSM-IIIR and NINCDS-ADRDA criteria are reliable for the diagnosis of dementia and AD. In comparison, the diagnostic criteria for Vascular dementia (VaD), dementia with Lewy bodies (DLB) and Frontotemporal dementia (FTD) have lower sensitivities and specificities and are hence less reliable as diagnostic tools (see section 2). 6.2.1 Medical History and Physical Examination A detailed clinical history is required including current and past medical and psychiatric history, medication use, drug and alcohol history, family medical history and a history of changes in personality or behaviour and assessment of the ability to undertake everyday tasks. Information from a relative or someone who knows the person well should also be obtained. A physical examination (including basic neurological examination) can detect evidence of physical disorders that can cause cognitive impairment, as well as other features that are important in making an accurate diagnosis, including the presence of focal neurological signs and motor features such as Parkinsonism. There is no universal consensus on the appropriate diagnostic battery which should be undertaken in those with suspected dementia. However, a review of fourteen guidelines and consensus statements found considerable similarity in recommendations (Beck, Cody, Souder, Zhang, & Small, 2000). The main reason for undertaking investigations in a person with suspected dementia is to exclude a potentially reversible or modifying cause for the dementia, and to help exclude common misdiagnoses including delirium, although the prevalence of reversible dementias is low. Clarfield (2003) reviewed 39 studies of over 7,000 cases and found potentially reversible causes in 9%, though only 0.6% of cases actually reversed. The UK NHS National Institute of Health and Clinical Excellence guidelines (2006) recommend the following tests be routinely performed in the assessment of patients with suspected dementia: haematology, biochemistry (including electrolytes, calcium, glucose, renal and liver function), thyroid function tests, serum vitamin B12 and folate levels and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP).

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In comparison, the American Academy of Neurology recommends that screening for depression, hypothyroidism and vitamin B12 deficiency be routinely performed as these are common co-morbidities in the elderly (Knopman et al., 2001). 6.3 Brief Screening Tests 6.3.1 Mental State Examination The Mini-Mental State Examination (MMSE, Folstein, Folstein, & McHugh, 1975) is probably the most commonly used mental state exam. It is simple, inexpensive and takes approximately five minutes to complete. The MMSE has demonstrated good specificity (96.8%) but somewhat lower sensitivity (71.8%) in detecting AD and other forms of dementia (59.8%). Although the MMSE is less sensitive to mild dementia in highly educated individuals and among those with non-cortical dementias (Rothlind & Brandt, 1993), it appears quite useful as a screening tool and for assessing the degree of cognitive impairment and is recommended for this purpose by the American Academy of Neurology (Petersen et al., 2001). A number of instruments have been developed to overcome the limitations of the MMSE including the 7-minute screen (Solomon & Pendlebury, 1998) and the Rowland Universal Dementia Assessment Scale (RUDAS; Storey, Rowland, Basic, Conforti, & Dickson, 2004). 6.3.2 The Rowland Universal Dementia Assessment Scale (RUDAS): a multicultural cognitive assessment scale. The RUDAS is a six-item cognitive assessment scale that was developed and validated in multi-cultural populations in Australia. It is scored out of 30 with scores below 23 suggesting dementia. It is easy to administer, requiring about ten minutes to complete and can be administered by both skilled and unskilled health-care workers following a short training session. In comparison to the MMSE, several items assess abstraction, executive function, praxis and gnosis. It has been shown to be at least as sensitive as the MMSE in discriminating between community dwelling subjects with and without dementia and unlike the MMSE, the RUDAS does not appear to be influenced by language, education or gender (Rowland, Basic, Storey, & Conforti, 2006; Storey et al., 2004). A recent systematic review of existing dementia screening tools was conducted in Australia with the aim of informing and recommending instruments to General Practitioners (GPs; Brodaty, Low, Gibson, & Burns, 2006). In addition to considerations of test reliability, practical issues relevant to general practice were considered, specifically the ease of administration and time taken. A total of 16 brief, commonly used screening instruments were identified including the MMSE, the 7-minute screen, Abbreviated Mental Test (AMT, Hodkinson, 1972), the Clock Drawing Test, (CDT, (Sunderland et al., 1989), a short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE; Short IQCODE, Jorm, 1994), the General Practitioner Assessment of Cognition (GPCOG, Brodaty et al., 2002), the Memory Impairment Screen (MIS, Buschke et al., 1999), the Mini-Cog, (Borson, Scanlan, Brush, Vitaliano, & Dokmak, 2000) and the RUDAS were included in the review . Five of the instruments (AMT, CDT, GPCOG, Short IQCODE, Mini-Cog, and MIS) had administration times of five minutes or less and each of these had a negative predictive value greater than or equal to the MMSE (0.92).

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The GPCOG, Mini-Cog, and MIS also had high sensitivity and specificity (>=80%) and a misclassification rate less than or equal to the MMSE (15%) and had been validated in studies showing reasonable quality and applicability to general practice. Therefore, the GPCOG, Mini-Cog, and MIS and were selected as the most suitable instruments for use in general practice and it was recommended that GPs consider using these instruments when screening for cognitive impairment. Although suitable for use with the majority of patients who present to GPs in Australia, these tools may not necessarily be appropriate for use with older Indigenous Australians living in remote areas. Hence, a brief, cognitive assessment tool was developed, specifically for use with older Indigenous Australians living in the Kimberley in Western Australia: the Kimberley Indigenous Cognitive assessment tool (KICA; LoGiudice et al., 2006). 6.3.3 Kimberley Indigenous Cognitive Assessment Tool (KICA) The KICA is a newly developed cognitive assessment tool for use with older Indigenous Australians. It was developed in conjunction with Indigenous health and aged care organisations and comprises three sections that gather clinical information about the subject, cognitive data and clinical information from an informant (including functional assessment). The cognitive assessment section comprises 16 questions and the total score can range from zero to 39 with lower scores indicating increasing degrees of cognitive impairment. The KICA-Cog takes approximately 30-40 minutes to administer and predominantly assesses memory and language skills although a number of items assess comprehension and executive function, to a limited extent. The psychometric properties of the KICA-Cog were recently evaluated and the results indicated that it has good inter-rater reliability and internal consistency and importantly, was accepted by participants in the study and appeared to successfully discriminate between people with and without cognitive impairment. It was concluded that the KICA-Cog is a reliable assessment tool for the assessment of cognitive impairment with older Indigenous Australians. 6.4 Neuropsychological Assessment In order to make a clinical diagnosis of a dementia, cognitive assessment is essential. The aim is to determine which cognitive domains are affected and to what extent. The assessment may also provide important information regarding specific sub-type diagnosis and to inform management. Indeed, neuropsychological confirmation is required by the NINCDS-ADRDA criteria for AD. Neuropsychological assessment enables a clinician to analyse a patient's cognitive status, as well as emotional, psychological, motor, and sensory functions. If the diagnosis is unclear, it also provides a baseline against which any future cognitive change can be measured. This may be particularly important in cases where cognitive change has been identified, but this does not meet the diagnostic criteria for dementia, as in MCI. Cognitive assessment includes testing attention and concentration, orientation, immediate and delayed memory, and higher cortical function including praxis, perception, language and executive function. As dementia represents a change from the person’s previous level of function, life-long intellectual and educational attainment provide the context for evaluating current performance. Evidence that neuropsychological assessment improves the reliability of the diagnosis of dementia was provided by Hentschel and his colleagues (2005).

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The individual contribution of neuropsychological assessment (using the CERAD battery of tests, Consortium to Establish a Registry for Alzheimer's disease; Morris (Morris et al., 1989; Morris, Mohs, Rogers, Fillenbaum, & Heyman, 1988)) and magnetic resonance imaging (MRI) to the final clinical diagnosis was quantified in a memory clinic setting. The results indicated that both the neuropsychological assessment and MRI improved the reliability of the diagnosis of dementia and led to a significant change of diagnosis in 26% of cases over a purely clinical diagnosis. The relative contribution of two methods was not significantly different. The sensitivity and specificity of the neuropsychological assessment was highest for the exclusion of non-demented cases while MRI was more accurate in discriminating between AD and VaD. The authors concluded that, as the accuracy of the initial clinical diagnosis was the lowest overall, the inclusion of both neuropsychological assessment and MRI scanning in the diagnostic work-up are complementary and both contribute to improved diagnostic accuracy. Numerous neuropsychological tests with established reliability and validity are available to assess cognitive functioning across a range of domains including global cognitive ability, episodic memory, executive functioning, verbal ability, visuospatial skill, attention, perceptual speed, and primary memory. A recent meta-analysis reported that the individual cognitive tests used in the studies had little influence on the overall result (Backman, Jones, Berger, Laukka, & Small, 2005) suggesting that the specific test used may be less important than other aspects of the assessment. For all neuropsychological assessments, it is important to tailor the assessment to suit the patient’s needs, abilities and limitations by selecting tests appropriate for the client and for their relevancy to the diagnostic question to be addressed. Compendia of neuropsycholgical tests with detailed critiques are available (eg. Spreen & Strauss, 2006; Lezak, Howieson, & Loring, 2004). 6.4.1 Neuropsychological Profiles Although there is no neuropsychological profile specific to AD or any of the dementia variants, there are some patterns of performance on neuropsychological tests that can be useful in assisting with the diagnosis. For instance, AD is characterised by an insidious onset, early memory loss, particularly verbal memory deficits, and visuospatial problems (Harciarek & Jodzio, 2005). The characteristic memory disturbance of AD is an amnestic type of storage abnormality in which patients have difficulty learning and recalling new information. The most sensitive measure is delayed memory and the delayed recall of a word list (CERAD battery) has been shown to best discriminate between patients with AD and normal control subjects in one study (Kaltreider et al., 2000). Another study showed that three memory tests – CERAD Word List Acquisition, WMS-R Logical memory II (ie delayed recall) and Visual Reproduction II were able to distinguish patients with mild dementia from age-matched controls with 100% sensitivity and 92% accuracy (Derrer et al., 2001). Language abnormalities are also typical of AD and deterioration in the quality, quantity and meaningfulness of speech and in verbal comprehension is often apparent in relatively early stages of the condition and worsens with the progression of the disease (Mendez & Cummings, 2003). In the early stages, patients often experience difficulty retrieving words and are poor at generating lists of words, especially for semantic categories (Cerhan et al., 2002) while naming problems are often evident in the mid-stage of AD. Another early manifestation of AD is visuospatial deficits and patients often demonstrate problems with drawing, construction and orientation in their surroundings (Mendez & Cummings, 2003).

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Their performance on simple tasks such as clock drawing is generally impaired as is their performance on more complex copying tasks such as the Rey Complex Figure test (Harciarek & Jodzio, 2005). Subtle deficits are also often apparent on measures of attention although not all patients display such problems, particularly in the early stages. Other deficits are also likely in speeded psychomotor performance, arithmetic and complex reasoning, although there is considerable variability between individual patients (Lezak et al., 2004). Patients with AD generally score highest on tests of over-learned behaviour, presented in a familiar format. Neuropsychological assessment can also be useful is discriminating amongst dementia subtypes. Studies that have compared the performance of patients with AD to that of patients with FTD generally show that patients with AD perform more poorly on memory tests than do patients with FTD, although the finding is not universal (A. J. Walker, Meares, Sachdev, & Brodaty, 2005). Further, the neuropsychological evaluation of patients with FTD often reveals evidence of executive dysfunction with impairments in planning, judgement, problem solving, attention, abstraction and mental flexibility apparent. In comparison, visual perception, spatial skills and memory can be relatively well preserved (Neary et al., 1998). Other studies have reported superior performance by patients with FTD on measures of visuoconstructional ability compared to those with AD (Neary et al., 1998) while some studies have reported no differences in the neuropsychological performance of those with FTD and AD (Pasquier et al,1995). While the features of FTD become more apparent as the disease progresses, it can be difficult to diagnose in the early stages and can be misdiagnosed as a psychiatric disorder or AD (McKhann et al., 2001). A comparison of patients with early FTD with patients with mild AD and healthy controls showed that the FTD group performed below the level of the other two groups on all measures except constructional ability. In keeping with the majority of previous research findings, the FTD group performed significantly more poorly on measures of executive functioning compared to the AD group while their performance on memory tests was significantly better. Importantly, almost 30% of the FTD patients showed no difference on neuropsychological measures in comparison to the healthy control group, consistent with the Lund criteria which note that neuropsychological performance may be intact (Neary et al., 1998). While the test results were able to correctly classify 90% of the patients, only 64% of the patients with FTD were correctly classified, highlighting the difficulty in diagnosing patients in the early stages of FTD. Nevertheless, the neuropsychological profile of patients with FTD, in conjunction (in conjunction with what?) may assist in improving diagnostic accuracy. While quantitative neuropsychological assessment may fail to distinguish FTD from AD, the addition of qualitative features of the patient’s test performance including impulsivity, concrete thought, perseveration, confabulation and poor organisation can improve the accuracy of classification. Thompson and his colleagues (2005) reported that while neuropsychological test scores correctly classified 71% of FTD patients in their study, the combination of test scores together with qualitative aspects of the patient’s performance including error rates increased the classification rate to 96%. It was concluded that qualitative information should be included in the assessment process. Fluctuating cognition with pronounced variation in attention and alertness is one of the core features of the diagnostic criteria for DLB (McKeith et al., 2005). Patients may experience periods of normal performance interspersed with obvious deficits in cognitive function, complicating the assessment process.

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Also, due to the relative recency of the category, few neuropsychological studies have been undertaken with this patient group. Nevertheless, the studies that have been conducted show that patients with DLB usually demonstrate prominent visuospatial deficits early in the course of the disease and show more severe attentional deficits than do patients with AD (Ballard et al., 1999). Patients with DLB have more difficulty copying designs with blocks than do patients with AD and their usually poor performance on the clock drawing task does not improve when allowed to copy from a template (Gnanalingham, Byrne, Thornton, Sambrook, & Bannister, 1997). In comparison, they perform better on memory tests than patients with AD and although memory impairment may not necessarily occur in the early stages, it is usually evident with progression of the disease. Patients with DLB may also exhibit significant difficulty with frontal lobe associated cognitive skills such as the loss of the ability to solve problems or to plan and successfully execute a task (Leverenz & McKeith, 2002). Although the performance of patients with VaD on neuropsychological tests varies according to the location and volume of the brain injury, the features that best distinguish VaD from AD include stepwise progression, a fluctuating course and focal neurological symptoms. The course of disease progression is more varied in patients with VaD than in patients with AD in terms of symptoms, rate of progression and disease outcome. Whereas memory and language function deficits prevail in AD, executive functions including planning, sequencing, speed of mental processing, performance on unstructured task and attention are more impaired in VaD. Patients with VaD also exhibit greater deficits on measures of verbal fluency than do patients with AD while primary language functions are otherwise generally preserved (Desmond et al, 2004). 6.4.2 Neuropsychological Assessment in Preclinical AD Studies of people with amnestic MCI have shown that performance on a range of neuropsychological tests can predict those who will develop dementia. These include episodic memory (such as delayed recall of word lists and paired-associates learning), semantic memory, attention processing, and mental speed (Chong & Sahadevan, 2005). A meta-analysis to determine the size of the impairment across different cognitive domains in preclinical AD was recently reported (Backman et al., 2005). Forty-seven studies were included in the review involving 9,097 controls and 1,207 preclinical AD cases. The studies employed a wide range of neuropsychological tests that were organised into several broad domains of cognitive functioning. Results of the meta-analysis revealed that the incident AD group demonstrated statistically significant deficits in all cognitive domains assessed except primary memory. The largest effect sizes, all above 1.0, were found for global cognitive ability, episodic memory, perceptual speed, and executive functioning although there was considerable overlap in cognitive performance of the control and incident AD groups. Significant group differences were also observed for verbal ability, visuospatial skill, and attention, with d values ranging from 0.62 to 0.79. The authors concluded that there was compelling evidence that impairment in multiple cognitive domains several years before clinical diagnosis is characteristic of AD and cognitive assessment may assist in identifying persons in a preclinical phase of AD. It has further been reported that a combination of neuropsychological testing and neuroimaging improves the diagnostic accuracy of predicting cognitive decline in people in the MCI phase over that achieved with either modality alone.

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For instance, the combination of PET imaging and neuropsychological assessment has been shown to result in a 90% correct classification rate, whereas only PET or neuropsychological assessment alone gave 75% and 65% correct classification, respectively. Of the neuropsychological tests administered, performance on the block design test of the Wechsler Adult Intelligence Scale – Revised (Wechsler, 1981) was found most effectively predict the future development of AD (Arnaiz et al., 2001). 6.5 Neuroimaging Techniques 6.5.1 Structural Neuroimaging The two main forms of structural imaging are computed tomography (CT) and magnetic resonance imaging (MRI). Although MRI is generally regarded as superior to CT in terms of anatomical visualisation of structural lesions and better tissue contrast, MRI is unsuitable for patients with metallic implants or medical devices including pacemakers and can be claustrophobic (Albert et al., 2004). There are two main reasons for undertaking structural imaging in people with suspected dementia. The first is to exclude an intercerebral lesion (e.g., space-occupying lesion, subdural, normal pressure hydrocephalus) as a cause for the cognitive impairment. Systematic reviews have suggested that between 2.2 and 5% of cases with suspected dementia had conditions which required structural neuroimaging to assist with diagnosis (Chui & Zhang, 1997; Clarfield, 2003). The use of structural neuroimaging with either a noncontrast CT or MRI scan to identify structural brain disease that can cause cognitive impairment is recommended by both the American Academy of Neurology (Knopman et al., 2001) and the UK NHS National Institute of Health and Clinical Excellence in their draft clinical practice guidelines for people with dementia (2006). The second is for diagnostic purposes. A substantial number of studies have evaluated the utility of structural imaging in the diagnosis of individuals with AD and Mild Cognitive Impairment (MCI). While studies have shown structural imaging to have limited ability to distinguish between individuals with MCI and normal controls subjects (Feldman & Jacova, 2005) the technique results in good differentiation between AD and normal ageing. A systematic review of 121 studies that included neuroimaging results from 3511 patients with AD and 1632 normal healthy controls reported a number of structural imaging measures that were clearly able to discriminate between the two groups. Reliable measures included volume loss within the superior temporal lobes, right/left and whole amygdala, thalamus, temporal horns, left temporoparietal cortices and right/left hippocampi (Zakzanis, Graham, & Campbell, 2003). When duration of illness was taken into account, volume loss within the hippocampus was the most reliable measure for discriminating between patients with AD in the early stages and normal control subjects. In comparison, volume loss within the medial temporal lobes was the most sensitive measure for identifying AD patients with an illness duration of more than four years. Although the results of volumetric measurements are more reliable than those based on visual evaluation, volumetric measurements are not often employed in clinical practice due to the labour intensive nature of the measurement and the easy applicability of visual rating scales (Wahlund, Julin, Lindqvist, & Scheltens, 1999).

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A pooled analysis of studies that used MRI visual and linear measurements of medial temporal lobe atrophy for the detection of mild to moderate AD compared to controls reported a sensitivity of 85% and a specificity of 88% (Scheltens, Fox, Barkhof, & De Carli, 2002), showing these measures to be quite sensitive for AD. It has also been reported that moderate medial-temporal-lobe atrophy, measured qualitatively or quantitatively, is a strong predictor (positive predictive value 80% and overall classification accuracy more than 90%) of the development to AD in people with MCI (van der Flier & Scheltens, 2005). The utility of serial structural imaging to predict those most likely to progress from MCI to dementia has also been assessed. The results of studies that have combined serial MRI measures of the medial and lateral temporal lobes to predict conversion have generally reported rates of accuracy of between 75% and 96% (Feldman & Jacova, 2005). The utility of serial imaging to monitor the progression of dementia is currently being evaluated by the NIH Neuroimaging Initiative (see below). A key question to be addressed is whether the technology may be useful in assessing response to treatment in clinical trials. Although structural imaging is well able to detect cerebral lesions and brain atrophy, it is less helpful in distinguishing AD from other types of dementia as hippocampal atrophy also occurs in other dementias including VaD, DLB and FTD (van der Flier & Scheltens, 2005). Variations in the patterns of atrophy, however, can be suggestive of the type of dementia. For instance, atrophy of the medial-temporal lobe has been shown to be less extensive in DLB than in AD, while patients with DLB and AD appear to have a similar distribution of white matter changes on MRI, intermediate in severity between those with VaD and normal controls (Barber et al., 1999). While frontal and temporal lobe atrophy are listed as supportive features of FTD in the consensus criteria for the condition (Neary et al., 1998) and can be observed on CT and MRI, the absence of these features do not exclude the diagnosis. Asymmetrical, predominantly left-sided perisylvian atrophy characterises progressive non-fluent aphasia while asymmetrical anterior-temporal lobe atrophy is characteristic of semantic aphasia (Scheltens et al., 2002). The diagnostic criteria for VaD, according to the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l”Enseignement en Neurosciences (NINFS-AIREN), (Roman et al., 1993) specifies clinical and neuroimaging evidence of vascular lesions that are aetiologically relevant to VaD. While studies to date have failed to yield any pathognomic changes specific to VaD, the condition is associated with a number of cerebral vascular changes, including cortical infarcts, lacunes and extensive white matter lesions (Roman et al., 1993). While the absence of any cerebrovascular disease on structural imaging strongly suggests VaD not to be the diagnosis, vascular disease is also observed on MRI in patients with AD as well as those with VaD (van der Flier & Scheltens, 2005). 6.5.2 Functional Imaging Single-photon emission computed tomography (SPECT) and positron emission tomography (PET). SPECT assesses changes in regional blood flow and oxygen metabolism by intravenously injecting a SPECT ligand; the most commonly used ligand is ^sup 99m^Technetium-hexamethyl-propylenamine oxime (99mTc-HMPAO; Dougall, Bruggink, & Ebmeier, 2004). These tracers are distributed by cerebral blood flow and quickly react to a compound that is bound in-situ in each cell. Regional cerebral blood flow patterns are mapped and retained.

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In comparison, PET assesses glucose metabolism using the tracer -[18F]fluoro-2-deoxy-D-glucose (FDG). Both methods have reasonable to good discriminatory power in discriminating between patients with AD and controls with both sensitivity and specificity in the range 85-90% (Jagust, 2004). A systematic review of the diagnostic accuracy of 99mTc-HMPAO SPECT reported a pooled sensitivity of 77.1% and specificity of 89% in distinguishing between AD and normal comparison groups with AD patients having reduced glucose metabolism and perfusion in the temporal and parietal lobes (Dougall et al., 2004). A sensitivity of 71% and specificity of 76% was reported for separating AD from VaD, and a sensitivity of 71% and specificity of 78% was reported for distinguishing between AD and FTD (Dougall et al., 2004). Patients with AD showed decreased blood flow in the parietal lobes while patients with FTD demonstrated decreased blood flow in the frontal lobes with relative sparing of the posterior cortex. In a comparison with clinical criteria (as judged by pathological verification), clinical criteria were found to be more sensitive in detecting AD than SPECT (81% versus 74%) but SPECT provided higher specificity against other types of dementia than did clinical criteria (91% versus 70%; Dougall et al., 2004). The authors concluded that SPECT can be helpful in the differentiation of AD, in particular from FTD and VaD. Other studies have suggested that perfusion SPECT is particularly helpful when there is diagnostic uncertainty, for example in cases of possible as opposed to probable AD (Jagust et al, 2001). A direct comparison of the ability of HMPAO-SPECT and FDG-PET to differentiate AD from VaD, however, has shown higher diagnostic accuracy of PET, regardless of the severity of the dementia (Mielke & Heiss, 1998). SPECT and PET scanning studies that have compared patients with AD and those with DLB have reported different patterns of glucose metabolism and cerebral blood flow that may assist in the differential diagnosis of the conditions. A greater degree of hypoperfusion or hypometabolism of the occipital lobe has been demonstrated in DLB compared to AD and occipital hypometabolism on PET has been shown to distinguish between pathologically confirmed DLB and AD with a specificity of 80% and sensitivity of 90% (Hoffman et al., 2000). PET glucose metabolism studies in patients with DLB indicate decreased regional metabolism in the lateral and medial occipital areas as well as the frontal, posterior temporal and parietal areas in comparison to patients with AD (Imamura et al., 1999). SPECT studies have also shown that patients with DLB experience a greater loss of dopamine transporter function than in AD and while patients with DLB demonstrate severe degeneration of the nigrostriatal pathway, patients with AD show a mild-to-moderate degree of nigrostriatal degeneration (Donnemiller et al., 1997). Although SPECT and PET studies may assist in the differential diagnosis of DLB by identifying differing patterns of cerebral hypometabolism and degeneration, further studies are required to confirm the utility of SPECT in discriminating between AD and DLB. The utility of functional imaging to diagnose MCI as well as to predict those likely to progress to dementia has also been assessed in several studies. PET measurements of reduced glucose metabolism in the hippocampi of patients with MCI relative to healthy elderly individuals has been found to improve diagnostic accuracy over MRI hippocampal measurements (De Santi et al., 2001). Other PET studies have reported that reductions in metabolism in the temporoparietal cortical area (Arnaiz et al., 2001) and impairment in the posterior cingulate gyrus are associated with a greater risk of progression to AD in individuals with MCI (Drzezga et al., 2003).

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Serial measurements using PET imaging have shown that further deterioration in this area plus additional impairment in the ventro-lateral prefrontal cortex to be characteristic of the clinical progression from MCI to AD (Drzezga et al., 2003). The extent to which these findings, based on carefully selected samples, are generalisable to the MCI population that presents to dementia clinics and general practice is currently unknown and further studies are needed to determine the diagnostic usefulness of MRI and PET in "real-world" patients. Currently neither SPECT nor PET imaging is recommended for routine use in the diagnostic evaluation of dementia by the American Academy of Neurology as they are not demonstrably superiority to clinical criteria. In comparison, in the UK, SPECT is recommended for use in the differential diagnosis of AD, VaD, FTD and DLB when the diagnosis is in doubt and PET imaging may be used for this purpose when SPECT is unavailable (National Institute for Health and Clinical Excellence, 2006). 6.5.3 Other Neuroimaging Techniques Functional MRI, MR spectroscopy, diffusion weighted MR and magnetisation transfer MR imaging techniques have also been investigated in the assessment and diagnosis of dementia. MR spectroscopy showed that a decrease in the ratio of the neuronal metabolite N-acetyl aspartate (NAA) to the metabolite myoinositol (MI) distinguished between patients with clinically confirmed AD from healthy individuals with a sensitivity of 83% and a specificity of 98% (Shonk et al., 1995). A decrease in NAA levels on MR spectroscopy of the frontal lobe also distinguished clinically diagnosed patients with FTD from patients with AD with an accuracy of 84% (Ernst, Chang, Melchor, & Mehringer, 1997). Another functional imaging technique, dynamic susceptibility MR imaging, has demonstrated comparable sensitivity and specificity to SPECT in measuring temporoparietal hypoperfusion in AD (Harris et al., 1998). The diagnostic accuracy of other quantitative MR imaging techniques (eg. diffusion-weighted MR imaging [DWI] and magnetisation transfer MR imaging) in distinguishing between patients with clinically confirmed AD from healthy elderly individuals, however, has been lower than that of clinical evaluation (Kantarci et al., 2001). The usefulness of these techniques remains to be confirmed against that of autopsy confirmed cases and the current limited evidence means they cannot be recommended for clinical use at the current time (National Institute for Health and Clinical Excellence, 2006). The use of a novel amyloid-imaging PET tracer, the Pittsburgh Compound-B (PIB) has recently been reported (Klunk et al., 2004). Compared with control subjects, patients diagnosed with mild AD showed significantly higher retention of PIB in areas known to contain large amounts of amyloid. There was no difference between the two groups in PIB in areas known to be relatively unaffected by amyloid deposition including subcortical areas. These results suggest that PET imaging with the novel tracer PIB may be a useful method for quantifying the amount of amyloid deposition in living patients. 6.5.4 The National Institute of Health Neuroimaging Initiative The NIH Neuroimaging Initiative (ADNI) is a major research study, sponsored by the American (?) National Institutes of Health, to determine whether brain imaging can assist in the prediction of those who will develop AD and monitor progression of the disease.

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The study was launched in early 2006 and will assess 800 participants with MCI, early AD and normal controls for up to three years in 58 sites across the United States and Canada. The study will test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early AD. The information obtained by studying changes in the brain images of MCI and AD patients and healthy individuals, as well as other assessment tools, will be used to determine the best methods for measuring treatment effects in patients with MCI and AD. Further information is available from the website: http://www.nia.nih.gov/Alzheimers/ResearchInformation/ClinicalTrials/ADNI.htm 6.6 Biomarkers Criteria for an ideal biomarker for the detection of AD have been proposed by the Consensus Group on Molecular and Biochemical Markers of Alzheimer's disease ("Consensus report of the Working Group on: "Molecular and Biochemical Markers of Alzheimer's Disease". The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group," 1998) and the diagnostic accuracy of three CSF biomarkers, total tau (T-tau), phosphorylated tau (P-tau), and β-amyloid42, has been assessed in a large number of studies. The three biomarkers have high sensitivity to differentiate Alzheimer’s disease from normal ageing, depression and some forms of dementia (e.g., alcohol related) but have much lower specificity against other dementias, including FTD, DLB and VaD (Andreasen & Blennow, 2005). For example, studies have demonstrated sensitivities (78 to 92%) and specificities (81 to 83%) for CSF β-amyloid42 in distinguishing patients with AD from normal elderly controls (Galasko et al., 1998; Hulstaert et al., 1999). Similarly, CSF tau has been reported to separate AD from normal controls with 80 to 97% sensitivity and 86 to 95% specificity (Andreasen et al., 1999; Galasko et al., 1997). However, elevated CSF tau has also been detected in patients with other neurodegenerative disorders (Arai, Higuchi, & Sasaki, 1997) making it less useful for discriminating between dementia subtypes. The simultaneous measurement of both β-amyloid42 and CSF tau may result in improved reliability and sensitivities of 85% and specificities of 87% have been reported (Galasko et al., 1998; Hulstaert et al., 1999) although additional studies are required to evaluate the combined use of these biomarkers over a good clinical diagnosis. The CSF 14-3-3 protein assay is useful in the diagnosis of Creutzfeldt-Jakob disease (CJD) and is recommended by the American Academy of Neurology guidelines for confirming or rejecting the diagnosis of CJD in clinically appropriate circumstances (Knopman et al., 2001). It has been demonstrated to have high sensitivity and specificity (both >90%) for detecting CJD (Hsich, Kenney, Gibbs, Lee, & Harrington, 1996) and has been shown to be superior to EEG and MRI in the identification of cases (Poser et al., 1999). In comparison, no biomarker has emerged that is appropriate for routine use in the clinical evaluation of patients with suspected AD (Knopman et al., 2001) or other dementias including DLB (Galasko, 2004). Neither has any biological marker for AD yet been shown to surpass the sensitivity and specificity that is already available through a thorough clinical examination. In the immediate future, biomarkers for AD are more likely to be used in clinical trials than in clinical practice (Thal et al., 2006).

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6.7 Electroencephalogram (EEG) Many studies have evaluated the usefulness of the EEG in distinguishing between AD and normal ageing (Jonkman, 1997) and, less commonly, other causes of dementia (M. P. Walker et al., 2000). In general, the EEG is not a sensitive test for detecting dementia and findings on an EEG are usually normal until there is little clinical doubt about the likelihood of dementia (Smith, 2005). While generalised slowing of the background rhythm on electroencephalography (EEG) is a frequent finding in AD, the EEG changes are not specific for AD and can also be found in other diffuse neuroencephalopathies and hence the EEG has limited ability to distinguish among different organic conditions. It is uncertain yet whether quantitative EEG methodologies, which identify abnormalities in frequency or spatial distribution of cerebral rhythms not clearly visible to the eye, or longitudinal EEG studies in an individual patient will be more diagnostically helpful especially in early detection of dementias (Smith, 2005). While the EEG is not currently recommended by the American Academy of Neurology (Knopman et al., 2001) as a routine test for the diagnosis of dementia, it may be helpful in distinguishing dementia from other conditions including depression, delirium, atypical seizures and in cases of sporadic Creutzfeldt-Jakob disease (sCJD; Jenssen, 2005). Periodic complexes (PC) are a sufficiently characteristic EEG finding in sporadic CJD (sCJD) for this pattern to be included by the World Health Organization (World Health Organisation, 1993) as one of the criteria for diagnosis. 6.8 Brain Biopsy In highly selected cases a brain biopsy, usually of non-dominant frontal cortex, may sometimes be considered necessary when a treatable disorder, such as an infective, metabolic or inflammatory condition, is suspected but which cannot be diagnosed by other means. A retrospective study showed that this resulted in a diagnosis in 57% cases, with 11% of people having complications such as bleeding or seizures (Warren et al., 2005). However, it should be noted that even in this highly selected group referred for biopsy, yields of reversible causes of dementia were low (around 10%). 6.9 Genetic Tests A genetic test for the most common of the three genes known to cause rare, inherited forms of AD, presenilin-1, is commercially available from Elan Pharmaceuticals. It may be recommended for individuals with a clear family pattern of Alzheimer's with an unusually early onset. A commercial test is also available for apolipoprotein E isoform ε4 (APOE- ε4), a biological risk modifier for late-onset AD, but due to the relatively limited gain in diagnostic accuracy, routine use of APOE genotyping is not generally recommended (Alzforum, 1994). The American Academy of Neurology guidelines does not recommend genetic testing for suspected AD, DLB, FTD or CJD (Knopman et al., 2001).

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6.10 Summary There is no single diagnostic test for Alzheimer’s Dementia (AD) or most of the other forms of dementia and a diagnosis is made on the basis of standardised criteria. Widely accepted criteria exist for the diagnosis of Alzheimer’s disease, Vascular dementia, dementia with Lewy bodies and Frontotemporal dementia. These generally have high specificity but sensitivity can be low as there is substantial overlap in the pattern of clinical and cognitive features among the conditions. A range of diagnostic tools including neuropsychological assessment and neuroimaging techniques are currently available and are useful in determining the diagnosis as well as excluding other conditions including cerebral lesions, metabolic disorders and head injury. The utility of serial imaging in identifying those likely to develop dementia is currently being assessed by the NIH Neuroimaging Initiative. Other techniques including EEG and brain biopsy are useful in only a minority of cases. With the exception of the 14-3-3 brain protein for the detection of Creutzfeldt-Jakob disease, no other biomarker has emerged that is appropriate for routine use in the clinical evaluation of patients with suspected dementia. Nevertheless, work in this area is progressing with the aim being to identify a biomarker or combination of biomarkers that are able to improve diagnostic accuracy over and above that currently available from a comprehensive clinical diagnosis.

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7.0 Treatment of Dementia 7.1 Literature Search This section summarises the results of a comprehensive literature search of the treatment of the most frequently occurring dementia variants. Included are all therapies that have demonstrated evidence of their effectiveness. Pharmacological therapies (e.g. cholinesterase inhibitors) that are designed to improve cognitive function as well as treatments that target non-cognitive (psychological and behavioural) symptoms of the disease including antidepressant medication, psychological therapies, behaviour therapy, music therapy and interventions utilising cognitively stimulating activities and physical exercise are reviewed. The effectiveness of other therapies including vitamin E and complementary therapies (e.g ginkgo biloba, homeopathy) as are details of clinical trials currently in progress, including trials evaluating the efficacy of newly developed vaccines. The treatment and management of concurrent physical conditions in patients with Vascular dementia including hypertension, diabetes, heart disease and hypercholesterolaemia is also briefly reviewed. The following computerised databases were searched for studies relevant to the treatment of dementia:

• AMED (Allied and Complementary Medicine) • Clinical Trials.gov • Cochrane Library, • Cumulative Index to Nursing and Allied Health Literature (CINAHL), • MEDLINE, • MIMS Online • PsycINFO • PubMed

Additional websites that were searched included:

• Alzheimer’s Australia • Australian Clinical Trials Registry • Commonwealth Department of Health and Ageing, Australia • Mental Health Institute of Victoria • UK NHS National Institute for Health and Clinical Excellence • NHMRC Clinical Trials Centre

In addition, abstracts from the 10th International Conference on Alzheimer’s disease and Related Disorders (Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 2006, 2:S1) were searched. Keywords used in the searches included dementia, Alzheimer’s disease, Vascular dementia, Mixed dementia, Lewy body dementia, Parkinson’s disease, Frontotemporal dementia, early onset dementia and mild cognitive impairment in conjunction with treatment, pharmacotherapy, drug treatment, intervention, cholinesterase inhibitor, antidepressant, antipsychotic, behaviour therapy, cognitive rehabilitation, prevention, psychological, therapy, acupuncture, ginkgo biloba, vitamin E, exercise and physical activity.

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Systematic reviews and meta-analyses were retrieved in the first instance. For areas that had not been systematically reviewed, review articles were obtained. Additional articles were identified by reviewing the reference lists of retrieved papers and primary research was obtained in instances where systematic and review articles for a particular topic were limited. A flowchart of the literature search process is shown in Figure 7.1. Summary tables of the Cochrane reviews included in this section and those excluded appear in Appendix A, at the end of the section. Figure 7.1 Flowchart of identification of systematic reviews and meta-analytic studies for inclusion in the treatment of dementia

Included: 60 Systematic reviews/Meta-Analysis including 52 Cochrane reviews [In addition, 2 Review articles, 10 primary research articles, 2 Government/Commissioned reports, 1 Clinical guideline & 5 other documents (statements/ letters/press release) were included]

Titles Identified n = 1133

Abstracts inspected n = 326

Full copies retrieved n = 126

Excluded n = 46

Excluded at title stage n = 807

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7.2 Pharmacological Treatments 7.2.1 Cholinesterase Inhibitors (ChEIs) Alzheimer’s disease (AD) is associated with reduced levels of the neurotransmitter acetylcholine. ChEIs inhibit acetylcholinesterase, an enzyme responsible for the destruction of acetylcholine leading to increased concentrations of acetylcholine in central synapses, and the increased concentrations are believed to be responsible for the improvement seen during treatment. Three ChEIs, Donepezil, Rivastigmine, and Galantamine, are licensed to treat mild to moderately severe AD in Australia, and although they improve the symptoms they do not slow progression of the disease. A fourth drug (Memantine), licensed to treat moderately severe to severe AD, is a non-competitive n-methyl-D-aspartate (NMDA) receptor inhibitor that blocks the excessive release of glutamate and thereby preventing the influx of calcium ions which is thought to be associated with neuronal degeneration. The UK NHS National Institute for Health and Clinical Excellence (National Institute for Health and Clinical Excellence, 2004) recently conducted a systematic literature review and meta-analyses of studies that had examined the clinical and cost-effectiveness of the three cholinesterase inhibitors, Donepezil, Rivastigmine, Galantamine, and Memantine for the treatment of Alzheimer’s disease. 7.2.1.1 Donepezil (Aricept) – Clinical Efficacy Donepezil is a reversible, highly specific, inhibitor of acetylcholinesterase. Thirteen published and one unpublished randomised controlled trials (RCT) as well as two systematic reviews of the efficacy of Donepezil for the treatment of mild to moderate AD were included in the UK NHS NICE review. Due to a difference in inclusion criteria, the Cochrane review of Donepezil for the treatment of AD (Birks & Harvey, 2006) was not included. Six RCTs that were reviewed showed a statistically significant improvement on the cognition subscale of the Alzheimer’s disease Assessment Scale (ADAS) following treatment with Donepezil in comparison to a placebo group with higher doses associated with greater benefit. Eight RCTs demonstrated trends towards improved Mini-Mental Status Examination (MMSE) scores following treatment with Donepezil in comparison to placebo. Seven RCTs assessed global measures of outcomes and significantly better results were reported for patients treated with Donepezil compared to placebo - results that were confirmed by meta-analysis. Results also generally showed that Donepezil resulted in short-term improvement on functional measures although the effect was not always statistically significant. Similarly, a small but statistically significant effect was found for behavioural measures while the results for quality of life measures were unclear. A greater number of adverse events were reported by patients taking Donepezil in comparison to placebo and more patients receiving high-dose Donepezil withdrew from the studies due to adverse events than did patients receiving either placebo or low-dose Donepezil. The authors concluded that, overall the results indicated that Donepezil is beneficial for treating mild to moderate AD when global and cognitive outcome measures are used and there appears to be a dose-response relationship with higher doses more likely to produce benefit. The effects of Donepezil on functional and behavioural measures were less clear although Donepezil may produce a benefit in these domains over shorter durations of follow-up (up to six months). Donepezil was recommended as a treatment option for patients with moderate AD only (MMSE scores 10 – 20).

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A Cochrane review of Donepezil for dementia due to Alzheimer’s disease was conducted in June 2005 (Birks & Harvey, 2006). The results of 23 trials involving patients with mild, moderate and severe AD were included in the analyses. The results indicated a statistically significant improvement for cognition for both 5mg and 10mg/day of Donepezil when compared with placebo. Further, it was concluded that Donepezil demonstrates some improvement in global clinical state and benefits of treatment were also evident on measures of activities of daily living (ADLs) and behaviour, but not on quality of life measures. A variety of adverse events were also noted. It was concluded that Donepezil is beneficial for patients with mild, moderate and severe AD although the effects of treatment are small. As benefits of 10mg/day dose were only marginally better than the 5mg/day dose, the authors cautioned that, taking into consideration the better tolerability of the smaller dose compared to the larger dose and the associated lower cost, the lower dose may be the better option. There is also evidence that treatment that is initiated early in the course of AD confers a greater benefit than treatment initiated at a later stage. The results of a double-blind cross-over study of Donepezil showed that patients with AD who had been treated with the drug early in the course of the disease had significantly better Mini Mental State Examination (MMSE) scores at the end of the three year study than did comparable patients for whom treatment had been delayed by one year (Winblad, Engedal, & Soininen, 2003). 7.2.1.2 Donepezil for Mild Cognitive Impairment A Cochrane review of Donepezil in people with mild cognitive impairment was undertaken in January (2006) (Birks & Flicker, 2006). Data from two studies involving 782 patients were included in the review although it not possible to pool the data due to differences in the design of the studies. One study demonstrated a modest treatment effect of Donepezil on a measure of cognition although significantly more side effects were apparent in the treatment group. It was concluded that there is no evidence to support the use of Donepezil for patients with mild cognitive impairment (MCI). 7.2.1.3 Donepezil for Vascular Cognitive Impairment A Cochrane review of the safety and efficacy of Donepezil for vascular cognitive impairment was undertaken in June 2005 (Malouf & Birks, 2004). Two large-scale RCTs with a total of 1,219 participants were identified for inclusion. Results of the pooled analyses indicated that patients receiving either 5mg or 10mg/day of Donepezil demonstrated a statistically significantly better performance on a measure of cognition and on the MMSE in comparison to placebo. Patients receiving the 10mg/day dose also showed a statistically significantly better outcome on a measure of global functioning in comparison to both placebo and the 5mg/day dose while patients receiving the 10mg/day dose were improved on a measure of activities of daily living compared to placebo. Donepezil was well tolerated and the reviewers concluded that Donepezil is beneficial for patients with mild or moderate vascular cognitive impairment.

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7.2.1.4 Donepezil – Current Clinical Trials Nine trials, listed on the US Clinical Trials database, are currently recruiting patients to participate in studies to evaluate the efficacy of Donepezil in dementia:

• A twelve-week, multicentre, open-label study to evaluate the effectiveness and safety of Donepezil Hydrochloride (Aricept) in Hispanic patients with mild to moderate Alzheimer’s disease (NCT00230568)

• A double-blind, randomised, placebo-controlled, parallel group study to

investigate the effects of SB-742457, Donepezil and placebo on cognition in subjects with mild to moderate Alzheimer’s disease (NCT00348192). SB-742457 is a new treatment which is thought to increase the levels of certain chemicals in the brain that are often decreased in patients with Alzheimer’s disease.

• A study to assess the correlation between regional brain volume and

response to Donepezil treatment in AD Patients (NCT00165750).

• A one year, multicentre, randomised, double-blind, placebo-controlled evaluation of the efficacy and safety of Donepezil Hydrochloride in subjects with Mild Cognitive Impairment (MCI) (NCT00100022).

• Vaspect Study – an open-label trial of Donepezil in Vascular and Mixed

Dementia (NCT00174382). The aim of the study is to evaluate whether Donepezil will improve cognition in patients with Vascular dementia and mixed dementia (Alzheimer’s disease/Vascular dementia).

• A three-month, randomised, double-blind, placebo-controlled, multicentre,

safety, tolerability, and efficacy study of three doses of Lecozotan (SRA-333) SR in outpatients with mild to moderate Alzheimer’s disease with Donepezil as active control (NCT00151398).

• An open label study on the efficacy and safety of Donepezil Hydrochloride

(Aricept) in Vascular dementia (NCT00165763).

• Prevention of Cognitive Decline in Alzheimer’s disease by Ingested Interferon Alpha as an adjunct to Donepezil (NCT00031018).

• Brain Imaging and Mental Disorders of Aging Intervention. The aim of this

study is to determine if a cholinesterase inhibitor is more effective than placebo in delaying cognitive and brain functional decline in people at risk for Alzheimer’s disease. Measurements include neuropsychological assessment and PET and MRI scans (NCT00267163).

7.2.1.5 Galantamine (Reminyl) – Clinical Efficacy Six published RCTs, one unpublished RCT and one systematic review of the efficacy of Galantamine in treating patients with mild to moderate AD were included in the UK NHS NICE review. Again, due to differences in the inclusion criteria, the Cochrane review of Galantamine for the treatment of AD and mild cognitive impairment (Loy & Schneider, 2006) was not included. In the six published and one unpublished RCTs, patients treated with Galantamine achieved statistically significantly better scores on the cognition subscale of the ADAS when compared to placebo.

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While individual studies demonstrated improvement on global outcome measures for patients treated with Galantamine in comparison to placebo, a pooled analysis of the data failed to reach significance. The results for behavioural outcomes were inconsistent, while across RCTs more patients treated with Galantamine withdrew from studies due to adverse events in comparison to those treated with placebo. The number increased with higher doses of Galantamine. The reviewers concluded that Galantamine is beneficial for patients with mild to moderate AD with improvements in cognition and function more likely at higher doses. A Cochrane review of the efficacy of Galantamine in patients with probable or possible AD and in patients with mild cognitive impairment (MCI) was undertaken in April 2005 (Loy & Schneider, 2006). Ten RCTs with a total of 6805 subjects were included in the analysis and data were pooled where appropriate. Results of the analysis revealed that treatment with Galantamine at all doses except for 8mg/day, resulted in significantly better outcomes on a global measure of dementia in comparison to placebo. Treatment with Galantamine also resulted in significantly better scores on the cognition subscale of the ADAS at both three and six months when compared with placebo. The adverse effects profile of Galantamine appeared similar to that of other ChEIs and appeared to be dose-related. Data from two trials of the efficacy of Galantamine in patients with MCI suggested marginal clinical benefit but a statistically significantly greater death rate in comparison to placebo that was unexplained. Overall, it was concluded that Galantamine improves global and cognitive symptoms at doses of 16mg/day or greater for six months or longer, in people with mild to moderate AD. The use of Galantamine in MCI is not recommended due to its association with an excess death rate. 7.2.1.6 Galantamine for Vascular Cognitive Impairment A Cochrane review of the efficacy of Galantamine in the treatment of people with Vascular dementia or mixed dementia was undertaken in April 2005 (Craig & Birks, 2005). Two RCTs met the inclusion criteria and were included in the review. The results of one trial indicated some benefit of Galantamine in the areas of cognition and executive functioning compared to placebo although the results were not replicated in the second trial. In both studies there was a higher incidence of gastrointestinal side-effects in comparison to placebo. It was concluded that, on the basis of the limited evidence available, there was no consistent evidence of the efficacy of Galantamine in treating vascular cognitive impairment. Further studies are required before a firm conclusion can be made. 7.2.1.7 Galantamine – Current Clinical Trials Three clinical trials of the efficacy of Galantamine in improving cognitive functioning in patients with neurodegenerative disorders are currently recruiting patients.

• A prospective, open-labeled, multi-center study of Galantamine on the attention and frontal function of the patients with dementia of Alzheimer type (NCT00216515).

• Treatment of severe Alzheimer’s disease in a residential home, nursing

home, or geriatric residential setting: evaluation of efficacy and safety of Galantamine Hydrobromide in a randomised, double-blind, placebo-controlled study (NCT00216593).

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• Galantamine CR potential enhancement of attentional and executive function in non-demented patients with Parkinson’s Disease (NCT00211588).

The following study is not yet recruiting patients: An observational study of clinical outcomes and safety profile of Galantamine in the treatment of patients with Alzheimer’s disease over an eighteen-month Period (NCT00299676). 7.2.1.8 Rivastigmine (Exelon) – Clinical Efficacy Four published and two unpublished RCTs as well as three systematic reviews of the efficacy of Rivastigmine for patients with mild to moderate AD were included in the UK NHS NICE review. In this instance, the Cochrane review (Birks, Grimley Evans, Lakovidou, & Tsolaki, 2000) was included although the results of that review are presented separately for comparative purposes. Four RCTs showed significantly better outcomes on the cognition subscale of the ADAS for patients treated with high-dose Rivsatigmine (6-12 mg/day) in comparison to placebo while one RCT showed no benefit and no study showed any benefit for low-dose Rivastigmine (1-4 mg/day). Four RCTS showed significantly better MMSE scores treated with Rivastigmine in the high dose regimen (6-12mg/day) compared to placebo while none of the studies found statistically significant differences for low dose Rivastigmanie (1-4mg/day). Three of the four RCTs that assessed global impression of dementia severity showed a statistically significant improvement in the high dose group only and in general, patients treated with 6-12 mg/day Rivastigmine demonstrated statistically significant functional improvement than those who received placebo. Considerably more patients receiving high-dose Rivastigmine withdrew from the studies due to adverse events than did patients treated with placebo. The reviewers concluded that evidence from studies using cognitive and global outcomes suggest that Rivastigmine is beneficial for patients with AD at higher doses (6-12 mg/day), while the evidence for functional outcomes was less consistent and no statistically significant benefit of Rivastigmine on measures of mood and behaviour were reported. Rivastigmine for Alzheimer’s disease – Cochrane review A Cochrane review of the efficacy of Rivastigmine for treating AD was undertaken in July 2005 (Birks et al., 2000). Seven RCTs, involving 3450 participants, were included in the analysis. The results indicated that patients treated with daily doses of 6 to 12 mg of Rivastigmine demonstrated improvements in cognitive functioning, activities of daily living and severity of dementia compared with placebo. The higher dose of the drug was associated with a higher incidence of adverse effects. The reviewers concluded that Rivastigmine is beneficial for patients with AD although further trials are required to determine the optimal dose of the drug with minimal side effects. 7.2.1.9 Rivastigmine Transdermal Patch The results of the first trial of a rivastigmine transdermal patch were recently reported at the 10th International Congress of Alzheimer’s and related Disorder in Madrid last month (Winblad & Cummings, 2006).

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The IDEAL (Investigation of Transdermal Exelon in Alzheimer’s disease) study was a double-blind, randomised, placebo-and active-controlled trial of the safety and efficacy of a once-daily rivastigmine patch compared to rivastigmine capsules in patients with moderate AD. The results of the 24 week trial involving 1,195 patients showed that the patch was similarly effective to the highest dose of the capsule in improving cognitive functioning and both were superior to placebo. The patch resulted in far fewer gastrointestinal side effects than the capsule and an added advantage of the patch was that care-givers reported preferring the patch as the administration was easier. 7.2.1.10 Rivastigmine for Vascular Cognitive Impairment A Cochrane review of the efficacy of Rivastigmine for Vascular Cognitive Impairment was conducted in December 2004 (Craig & Birks, 2005). The reviewers were unable to perform a meta-analysis as no suitable RCTs were identified in the literature search. The authors concluded that although there was some evidence of benefit of Rivastigmine in several cognitive and non-cognitive domains in patients with vascular cognitive impairment, the trials indicated that further large scale RCTs are needed Rivastigmine – Current Clinical Trials There is currently one RCT of Rivastigmine in AD recruiting patients: A prospective, 26-Week, open-label, multi-center, single-arm pilot study to evaluate the safety and tolerability of Rivastigmine capsule with add on Memantine HCl in patients with probable Alzheimer’s disease (MMSE 10-20) (NCT00305903). 7.2.1.11 Cholinesterase Inhibitors for Parkinson’s Disease Dementia A Cochrane review of the efficacy of ChEIs in Parkinson’s disease dementia was undertaken in April 2005 (Maidment, Fox, & Boustani, 2006). Only one RCT of Rivastigmine involving 541 patients was identified in a detailed literature search. The results of that trial showed that patients treated with Rivastigmine showed statistically significant improvement in outcome measures of cognitive functioning and activities of daily living relative to placebo. Clinically meaningful improvement was evident in 15% of patients treated with Rivastigmine although significantly more patients withdrew from the trial due to adverse events associated with Rivastigmine than with placebo. Side effects included nausea, tremors and gastrointestinal upset. However, significantly fewer patients died on Rivastigmine than placebo. The reviewers concluded that Rivastigmine appears to improve cognition and, to a lesser extent, activities of daily living in patients with Parkinson’s disease dementia, although further studies are required to confirm this finding.

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7.2.1.12 Cholinesterase Inhibitors for Dementia with Lewy bodies and Frontotemporal Dementia A Cochrane review of the efficacy of ChEIs in patients with Lewy body dementia was conducted in February 2002 (Wild, Pettit, & Burns, 2003). Only one RCT of Rivastigmine with a total sample of 120 patients was identified for inclusion in the review. A statistically significant effect of Rivastigmine was observed on the Neuropsychiatric Inventory when observed cases were considered – the effect was not significant using Intention-to-treat analyses. No other significant effect of Rivsatigmine on any outcome measure was reported. The placebo group experienced significantly fewer adverse effects than the treatment group although when using Intention-to-treat analysis of 20-week data, there was no significant difference between the two groups when serious adverse events were considered. It was concluded that there was no convincing evidence that Rivastigmine is beneficial for treating patients with Lewy body dementia and further trials are needed. A recently conducted open label trial of Rivastigmine in twenty patients with Frontotemporal dementia (FTD) reported a significant improvement in behavioural symptoms at twelve months in comparison to a control group (Moretti et al., 2004). Caregiver burden was also reduced in the Rivastigmine group although there was no benefit on global cognitive functioning. It was concluded that Rivastigmine was beneficial in ameliorating the behavioural and psychological symptoms in patients with FTD and that further studies of Rivastigmine in this patient group are warranted. 7.2.1.13 Donepezil, Galantamine, Rivastigmine – Comparative Studies The UK NHS NICE review also included three RCTs that compared the efficacy of the three ChEIs. Two studies compared Donepezil with Rivastigmine and one study compared Donepezil with Galantamine although the quality of the included studies was judged to be poor. The trial of Donepezil with Rivastigmine resulted in a small, not statistically significant difference in cognition and function between the two treatment groups although the number of adverse events tended to be higher in the Rivastigmine group and more participants withdrew due to adverse events in the Rivastigmine group. The small study that compared Galantamine with Donepezil was funded by the manufacturers of Donepezil. Results of the study revealed that while participants treated with either drug demonstrated improvements on the ADAS-Cog scale, treatment with Donepezil conferred a statistically significant benefit to participants on the scale when compared to treatment with Galantamine. Patients receiving Donepezil also demonstrated significant improvement on a measure of ADL compared to patients treated with Galantamine. Rates of mild to moderate adverse events were shown to be higher in the Galantamine group compared to the Donepezil group, however, rates of serious adverse events appeared to be higher in the Donepezil group. Higher proportions of participants withdrew due to adverse events in the Galantamine group than the Donepezil group. A Cochrane review of comparative studies of the three ChEIs included one double-blind RCT that compared Donepezil with Rivastigmine for the treatment of AD that had not been included in the UK NHS NICE review (Birks, 2006). The results of that study also indicated no significant difference between the two treatments on measures of cognitive function, activities of daily living, behavioural disturbance or global assessment. There appeared to be fewer adverse events associated with Donepezil compared to Rivastigmine.

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It was concluded that there was no evidence of any difference between the efficacy of Donepezil and Rivastigmine for the treatment of AD. It was suggested that a gradual titration of the dose of Rivastigmine over several months may assist to improve its tolerability. 7.3 Memantine Memantine (Ebixa, Australia, Europe; Namenda, USA) is a partial glutamate receptor antagonist that blocks the excessive release of glutamate which is thought to be associated with cholinergic damage. It is approved in Europe and Australia for the treatment of patients with moderately severe to severe AD, and in the USA for the treatment of patients with moderate to severe AD. It has not been approved for Vascular dementia or earlier stages of Alzheimer disease in any of these countries. The UK NHS National Institute for Health and Clinical Excellence also conducted a systematic review of the efficacy and cost-effectiveness of Memantine for Alzheimer’s disease (National Institute for Health and Clinical Excellence, 2006). Two RCTs, both of which had assessed the efficacy of Memantine for patients with moderate to severe AD, met the inclusion criteria for the review. A further trial of Memantine was identified during the course of the review and additional data were supplied to the Institute by the drug manufacturer. While the results of the two originally identified RCTs were inconsistent, analysis of the pooled data indicated a statistically significant effect of Memantine on a number of measures of cognition and activities of daily living in comparison with placebo. The magnitude of the effect, however, was modest. A Cochrane review of the safety and efficacy of Memantine in the treatment of dementia was conducted in February 2006 (McShane, Areosa Sastre, & Minakaran, 2006). Twelve RCTs that had examined the efficacy and tolerability of various dosages of Memantine (10 to 30mg/day) in different types of dementia and at different stages of the disease were identified that met the inclusion criteria. The pooled results of three trials in patients with moderate to severe AD suggested that taking 20 mg Memantine daily had a positive effect on cognition, mood, behaviour and the ability to perform activities of daily living although there was considerable heterogeneity between studies in the effect on cognitive function. The results were supported by a positive effect in the clinical impression of change suggesting that the effect is clinically detectable. A consistent effect throughout the studies of moderate-to-severe dementia was a small reduction in the incidence of agitation. The results in patients with mild to moderate VaD suggested a beneficial effect of 20 mg/day of Memantine on cognitive function measured at 28 weeks. However, the results were not supported by an effect on the clinical impression of change, suggesting that in patients with mild to moderate Vascular dementia, the effect on cognitive function is not translated into clinically detectable changes. The results of trials in patients with mild to moderate AD indicated a beneficial effect of 20 mg/day of Memantine on cognitive function measured at 24 weeks supported by a small positive effect in the clinical impression of change. The drug was well tolerated with generally low drop-out rates and no difference in the adverse events profile between the treatment and placebo groups. It was concluded that the published data suggest that Memantine appears to be effective for use in patients with moderate and severe AD and should therefore only be prescribed for patients with that condition, typically defined as those with an MMSE less than 15.

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7.3.1 Memantine – Current Clinical Trials Eight clinical studies are currently listed on the US Clinical Trials Database to evaluate the efficacy of Memantine in patients with neurodegenerative disorders. Studies currently recruiting patients include:

• A Double-Blind placebo-controlled trial of Memantine for treatment of Cognitive Impairment in patients with Parkinson’s Disease and dementia (NCT00294554).

• A Double-Blind, parallel group, Placebo-Controlled Trial of the efficacy and

tolerability of Memantine (20 Mg) in Frontotemporal dementia (FTD) Patients (NCT00200538).

• The Effect of Memantine on Brain Structure and chemistry in Alzheimer’s

disease Patients: A randomised, placebo-controlled, 52-Week clinical trial (NCT00255086). Outcome measures include cognitive performance as measured by the ADAS-Cog, caregiver and clinician ratings as well as MRI scans.

• An Open-Label Exploratory Study With Memantine: Assessment of Selected

Measures of Volumetric MRI and Cognition in Patients With Moderate Dementia of the Alzheimer’s Type (NCT00334906).

• Memantine and Comprehensive, Individualised, Patient Centered

Management of Alzheimer’s disease: A Randomised Controlled Trial (NCT00120874).

• A Prospective, 26-Week, Open-Label, Multi-Center, Single-Arm Pilot Study to

Evaluate the Safety and Tolerability of Rivastigmine Capsule With Add on Memantine HCl in Patients With Probable Alzheimer’s disease (MMSE 10-20) (NCT00305903).

• Efficacy of a psycho-educational programme designed to support and train

carers of Alzheimer’s disease (AD) patients in conjunction with anticholinesterase drug treatment alone/or associated to Memantine treatment. (NCT00190372).

• A Randomised, double-blind, placebo-controlled evaluation of the safety and

efficacy of Memantine in patients with moderate-to-severe dementia of the Alzheimer’s Type (NCT00322153).

The following clinical trial is not yet recruiting patients: Vitamin E and Namenda (Memantine) for the Treatment of Patients With Mild to Moderate Alzheimer’s disease on Aricept (Donepezil) (NCT00235716). 7.4 Cost Effectiveness of Donepezil, Galantamine, Rivastigmine and Memantine The UK NHS National Institute for health and Clinical Excellence also assessed economic evaluations of the three Cholinesterase Inhibitors (ChEIs) and Memantine. Included in the review were eleven cost evaluations of Donezepil, five of Rivastigmine and five of Galantamine from the published literature, submissions from industry as well as additional analyses conducted by the UK NHS NICE Secretariat.

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After consideration of all the evidence, the Committee concluded that the prescription of the three ChEIs for people with Alzheimer’s disease of moderate severity (MMSE scores between 10 and 20) is cost effective. It was recommended that the ChEIs should be made available in the NHS as one part of the management of some people with mild and moderate Alzheimer’s disease. Five economic evaluations of Memantine in addition to the manufacturer’s submission were also included in the review. Although the studies suggested that treatment with Memantine was cost-effective in comparison to no treatment, additional analyses by the UK NHS NICE Secretariat indicated otherwise. It was concluded that the currently available evidence of the efficacy of Memantine is insufficient and the drug cannot be considered a cost-effective treatment for patients with moderate to severe AD. It was recommended that Memantine should not be publicly funded for the treatment of moderately severe to severe AD, except as part of well-designed clinical studies. 7.5 Medications specifically for the treatment of Psychological and Behavioural Symptoms of Dementia (BPSD) Behavioural and psychological symptoms of dementia (BPSD) include disinhibited behavior, delusions, and hallucinations. Symptoms of anxiety, mood and sleep disturbances are also common. Although atypical antipsychotic medication has not been approved for use in patients with dementia, they are frequently prescribed to manage BPSD in this population. 7.5.1 Atypical Antipsychotics The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in patients with Alzheimer’s disease was recently reviewed by the Cochrane Collaboration (Ballard & Waite, 2006). Although sixteen RCTs were identified, only nine had sufficient data to contribute to a meta-analysis. The results indicated that there was a significant improvement in aggression in patients treated with Risperidone and Olanzapine in comparison to placebo. A significant improvement in psychosis in patients treated with Risperidone was also reported. There were insufficient data to examine the impact of these drugs on cognition. There was, however, a significantly higher incidence of serious adverse events including cerebrovascular events (inc. stroke) and extra-pyramidal side effects in patients treated with Risperidone and Olanzapine, and there were significantly more drop-outs in patients treated with these medications than with placebo. The reviewers concluded that while atypical antipsychotics are useful in reducing aggression and psychosis in patients with dementia, the risks of adverse events may outweigh the benefits, particularly with long term treatment. Neither medication should be routinely used to treat aggression or psychosis in patients with dementia. Another systematic review of the safety and efficacy of atypical antipsychotics (Carson, McDonagh, & Peterson, 2006) included two studies that had compared the efficacy of Risperidone with Olanzapine for patients with dementia. Neither study found a difference between treatment groups on any outcome measure after two weeks or two months although both trials were rated to be of poor quality. In their review, Carson and her colleagues also included two RCTs that had compared Risperidone, an atypical antipsychotic against an older, typical antipsychotic, Haloperidol for the treatment of BPSD in patients with AD and VaD (Carson et al., 2006).

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In the two RCTs, about two-thirds of patients were diagnosed with AD and one-third with vascular dementia. The two studies were judged by the reviewers to be of fair quality with the duration of both trials being twelve weeks and the dosage range for the drugs was the same in each trial (0.5–2.0 mg/d). The results of the comparison revealed no significant difference between the two drugs on measures of behavioural disturbance or agitation. There were no significant differences between the Risperidone and Haloperidol groups in overall withdrawal rates or withdrawals due to adverse events, although patients receiving Risperidone showed improvement on some measures of extrapyramidal symptoms compared with patients receiving Haloperidol. Although atypical antipsychotics generally result in fewer side-effects than typical antipsychotics, serious concerns regarding the safety of atypical antipsychotic medications in elderly people with dementia have recently been raised. A possible elevated risk of adverse cerebrovascular events and mortality associated with the use of atypical antipsychotics in older patients with dementia in comparison with placebo was recently reported (Brodaty et al., 2003; US Food and Drug Advisory, 2005; Schneider, Dagerman, & Insel, 2005). This resulted in a safety warning regarding the use of the atypical antipsychotic medications, Risperidone and Olanzapine, being issued in 2004 by the Medicines and Healthcare Products Regulatory Agency’s Committee on Safety of Medicines (CSM) (UK). Specifically, the CSM advised that there is clear evidence of an increased risk of stroke in older patients who are treated with Risperidone or Olanzapine, with the magnitude of the risk sufficient to outweigh the likely benefits. CSM had advised that Risperidone or Olanzapine should not be used for the treatment of behavioural symptoms of dementia and that use of Risperidone for the management of acute psychotic conditions in older patients who have dementia should be limited to the short-term. The debate, however, is far from over with proponents on one side citing research evidence of the harmfulness of these medications in elderly patients (Ballard & Cream, 2005) and equally convincing arguments, on the other side, that such evidence is flawed (Shah and Suh, 2005) and that Risperidone is not associated with an risk of cerebrovascular events in comparison to other available treatment alternatives (Finkel et al., 2005). Until more definitive results from large-scale trials are forthcoming, it appears that the decision of whether or not to prescribe atypical antipsychotic medication to older patients with dementia should to be determined on a case-by-case basis, considering the likely benefits of the medication in relation to the potential risks for each individual patient. 7.5.2 Antipsychotics in patients with Dementia with Lewy bodies Antipsychotic medications should be avoided in patients with Lewy body dementia as they may be particularly sensitive to severe adverse reactions (McKeith et al., 1996). 7.5.3 Atypical Antipsychotics – Current Clinical Trials Currently, there are six clinical trials recruiting patients to evaluate the efficacy of atypical antipsychotics in treating psychosis and behavioural symptoms including agitation in neurodegenerative disorders. These are:

• A randomised comparison of monotherapy (Risperidone, Quetiapine, or Olanzapine) versus combination therapy (Risperidone, Quetiapine, or Olanzapine + Divalproex) in the Management of dementia with agitation: A pilot comparison of two standard therapies (NCT00208819).

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• A study to assess the efficacy of a central nervous system stimulant (dextroamphetamine) and an atypical antipsychotic (quetiapine) in treating the behavioral symptoms of Frontotemporal dementia. (NCT00088751).

• A comparison of the metabolic effects of newer antipsychotics in older

patients who require treatment with antipsychotic medication (Aripiprazole; Olanzapine; Quetiapine; Risperidone) (NCT00245206).

• A randomised, double-blind trial to compare the safety and effectiveness of

citalopram and Risperidone to treat people with dementia-related behavior problems (NCT00073658).

• A study is to assess the safety and efficacy of quetiapine (Seroquel) for the

treatment of psychosis and/or agitation in patients with primary dementia complicated by coexistent parkinsonism, or patients with Parkinson’s disease with dementia [PDD] who have episodes of agitation or psychosis (NCT00043849).

• A randomised, double-blind, placebo control to assess the safety and efficacy

of Depakote ER versus quetiapine (Seroquel) for agitated behaviors in nursing home care patients with Dementia (NCT00315900)

7.5.4 Antidepressants A Cochrane review of the clinical efficacy of antidepressants for treating depression in dementia was undertaken in April 2005 (Bains, Birks, & Dening, 2002). Seven RCTs met the inclusion criteria and were included in the review, of which there were two studies of the more common selective serotonin reuptake inhibitors (SSRIs). The RCTs were of relatively short duration (six to twelve weeks) and overall the results revealed only weak evidence that antidepressant medication is effective for treating patients with depression and dementia. The reviewers concluded that research regarding the efficacy of antidepressants in this population is very limited and there were no studies of the efficacy of newer classes of antidepressants (e.g. selective noradrenergic reuptake inhibitors). A review of the atypical antidepressant Trazodone (not available in Australia) was undertaken by the Cochrane Collaboration (Martinon-Torres, Fioravanti, & Grimley, 2004) that included two RCTs. The reviewers reported that there was no evidence of benefit for Trazodone in patients with dementia and that larger scale studies are needed to explore the safety and efficacy of Trazodone in this population. 7.5.5 Antidepressants – Current Clinical Trials Currently, there are three RCTS of antidepressant medication in patients with dementia in progress that are recruiting patients:

• An exploratory study to assess the efficacy of Escitalopram versus placebo in the treatment of depressive syndrome in Alzheimer’s disease, vascular dementia and mixed vascular and Alzheimer’s dementia (NCT00229333).

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• An open label study to determine the safety and efficacy of Escitalopram (Lexapro) in patients with Alzheimer’s disease who are also experiencing agitation. (NCT00260624).

• A study is to learn whether treating individuals with Alzheimer’s disease and

depression with the anti-depressant medication Sertraline (Zoloft) is helpful to people with Alzheimer’s disease and to their families and caregivers (NCT00086138).

7.5.6 Mood Stabilisers A systematic review of the efficacy of mood stabilising medication for the treatment of neuropsychiatric symptoms in dementia was recently undertaken (Sink, Holden, & Yaffe, 2005). Three RCTs of the efficacy of Sodium Valproate and two that had assessed the efficacy of Carbamazepine were included in the review. The results indicated that Valproate was not efficacious in the management of neuropsychiatric symptoms in patients with dementia and its use was associated with more adverse events in comparison to placebo. The use of Sodium Valproate was therefore not recommended for the management of BPSD in patients with dementia. The two small trials of Carbamazepine resulted in inconsistent findings and it was concluded that there is currently insufficient evidence of the efficacy of Carbamazepine to recommend its use for patients with dementia, particularly in light of the potential adverse effects associated with use of the drug. 7.5.7 Mood Stabilisers – Current Clinical Trials Three clinical trials are currently recruiting patients to participate in studies to evaluate the efficacy of mood stabilisers in dementia:

• A randomised, double-blind, placebo-controlled trial of Valproate to attenuate the progression of Alzheimer’s disease (AD). The aim of the study is to determine whether valproate therapy delays the emergence of agitation and/or psychosis in outpatients with probable Alzheimer’s disease (AD) who have not experienced agitation and psychosis in their illness (NCT00071721).

• An open-label prospective study of Depakote for behavioral and psychological

symptoms in dementia (BPSD): Use alone and in co-prescription with atypical antipsychotic medications (NCT00197834).

• A prospective, randomised, double-blind, placebo-controlled trial to assess

the efficacy of Oxcarbazepine in the treatment of agitation and aggression in dementia (OBAD) (NCT00145691).

7.6 Treatment of Risk Factors and Concurrent Physical Conditions in Patients with Vascular Dementia The UK NHS National Institute for Health and Clinical Excellence, in collaboration with the Social Care Institute for Excellence, has recently released a Draft Practice Guideline for the treatment of people with dementia and their carers (National Institute for Health and Clinical Excellence, 2006).

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The Guideline was developed following a series of systematic reviews of the best available research evidence and includes recommendations for the treatment of risk factors in patients with VaD. The Guideline suggests that patients with vascular dementia should be treated with the appropriate medications to control associated risk factors. These include drugs that control glucose levels for patients with diabetes, statins and other lipid lowering drugs to manage and reduce high cholesterol levels, and antihypertensive medications including β-blockers and ACE inhibitors for the treatment of hypertension. The Guideline Development Group systematically reviewed the literature with regard to the safety and efficacy of these medications for the treatment of patients with VaD and concluded that there is currently no evidence that these treatments have any beneficial effect on cognitive symptoms. Literature reviews of some of these medications are listed below: 7.6.1 Aspirin for Vascular Dementia A Cochrane review of the efficacy of aspirin for VaD was undertaken in July 2005, although no eligible trials were identified for inclusion (Rands, Orrel, & Spector, 2000). Thus, the authors concluded that there was no evidence of the effectiveness of aspirin in treating patients with a diagnosis of vascular dementia and that further trials are needed to assess the effect of aspirin on cognition and on other outcomes including behaviour and quality of life in patients with VaD. 7.6.2 Ibuprofen for Alzheimer’s Disease A Cochrane review of the efficacy of Ibuprofen (a non-steroidal anti-inflammatory drug) for the treatment of AD was also undertaken in December 2002 (Tabet & Feldmand, 2003). A systematic search of all available databases and other sources failed to identify any completed RCTs of Ibuprofen for the treatment of AD and thus, there is no evidence that ibuprofen is an efficacious treatment for the treatment of AD. A search of the Medline and PubMed databases on 25 July 2006 failed to reveal any studies of Ibuprofen or NSAIDS that have been subsequently been conducted. 7.6.3 NSAIDS – Current Clinical Trials Two trials are currently recruiting patients to participate in studies to evaluate the efficacy of NSAIDS in dementia: A clinical trial of Ibuprofen to test the hypothesis that the possible role of Ibuprofen in preventing AD in healthy older subjects (≥ 70 years) can be detected in changes in biomarkers of AD (NCT00239746). There is also a RCT currently recruiting subjects to assess the safety and efficacy of Curcumin in the treatment of patients with AD (NCT00099710). Curcumin is a yellow substance found in the spice turmeric, has antioxidant, non-steroidal anti-inflammatory (NSAID), and cholesterol-lowering properties. 7.6.4 Pentoxifylline for Vascular Dementia A systematic review of studies that had trialed pentoxifylline (a pharmacologic agent that has been demonstrated to increase cerebral blood flow) in the treatment of VaD was conducted in 2002 (Sha & Callahan, 2003).

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Four RCTs met the inclusion criteria and were included in the review. The four studies were relatively small with three studies enrolling fewer than 100 subjects. While no study reported a statistically significant effect of pentoxifylline on any measure of cognition, the studies reported a trend towards improved cognitive functioning in patients with VaD who were treated with pentoxifylline. Three of the studies performed a sub-group analysis using a stricter definition of VaD and in each subgroup analysis, the results of the primary cognitive measures in the treatment group gained statistical significance. The subgroup cohorts, however, were considerably smaller than the overall study populations and the authors tentatively concluded that pentoxifylline may be efficacious in patients with vascular dementia. 7.6.5 Calcium Channel Blockers Calcium channel blockers are frequently prescribed in a number of European countries for the treatment of dementia. Nimodipine is an isopropyl calcium channel blocker, the primary action of which is to restrict the number of calcium ions into neurons, and, by vasodilatation, to improve blood flow to the brain. A Cochrane review of the efficacy of Nimodipine for primary degenerative, mixed and vascular dementia was undertaken in August 2005 (Lopez-Arrieta & Birks, 2002). Fourteen RCTs of Nimodipine were included in the review and analyses of the pooled data (all diagnoses) indicated a benefit associated with Nimodipine (90mg/day at twelve weeks) on measures of cognitive function, on clinical global impression but not on measures of activities of daily living. When data for the AD and VaD trials were pooled separately, similar significant results were found for the drug. Nimodipine was well tolerated in the studies with a similar rate of withdrawals in the treatment and placebo groups. It was concluded that there was evidence of some short-term benefit of Nimodipine for patients with AD, VaD and mixed dementia although it was suggested that new research should focus on longer term outcomes. 7.6.6 Calcium Channel Blockers – Current Clinical Trials One clinical trial is currently recruiting patients to participate in studies to evaluate the efficacy of Calcium Channel Blockers in dementia:

• Safety and efficacy of MEM 1003 versus placebo in improving cognitive function in patients with mild to moderate Alzheimer’s disease (NCT00257673).

7.6.7 Antihypertensive medications- Current Clinical Trials One clinical trial is currently recruiting patients to participate in a study to evaluate the efficacy of an antihypertensive medication in dementia: A randomised, double-blind, placebo controlled trial to assess the efficacy of Prazosin in the treatment of agitation and aggression in persons with Alzheimer’s disease and other types of dementia in late life (NCT00161473)

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7.6.8 Medications for Cholesterol Lowering Drugs – Current Clinical Trials One clinical trial is currently recruiting patients to participate in a study to evaluate the efficacy of a cholesterol lowering medication in dementia: A randomised, double-blind, placebo controlled trial to assess the safety and efficacy of Ketasyn, a medium chain triglyceride, in subjects with mild to moderate, probable Alzheimer’s disease (NCT00142805) 7.6.9 Medications for Glucose Control – Current Clinical Trials Three clinical trials are currently recruiting patients to participate in studies to evaluate the efficacy of medications for glucose control in dementia:

• A double-blind, randomised, placebo-controlled trial to investigate the effects of Rosiglitazone (Extended Release Tablets) on cerebral glucose utilisation and cognition in subjects with mild to moderate Alzheimer’s disease (AD) (NCT00334568).

• A randomised, double-blind, placebo controlled study to evaluate the effects

of Rosiglitazone on functional brain activity (as measured by PET scanning) and cognition in patients with mild to moderate Alzheimer’s disease (AD) (NCT00265148).

• A randomised, double-blind, placebo controlled trail to assess the efficacy of

Rosiglitazone on cognition in patients with MCI (NCT00242593). 7.7 Other Pharmacological Treatments 7.7.1 Hormone Therapy A Cochrane review of the efficacy of Hormone Replacement Therapy (HRT) for maintaining cognitive function in women with dementia was undertaken in May 2002 (Hogervorst, Yaffe, Richards, & Huppert, 2002). A total of five trials with 210 women with AD were included in a meta-analysis. Most of the trials had tested oestrogen only therapy (ERT). The results indicated that there was a short-term benefit of ERT on memory although the effect was not maintained over the longer term. The reviewers concluded that there was no evidence that oestrogen replacement therapy can maintain cognitive function for up to twelve months in women with AD and neither ERT nor HRT is indicated as a treatment for women with AD. Since then, the results of the one large-scale RCT of hormone replacement therapy in postmenopausal women reported a two-fold increased risk of dementia in female subjects with the use of combined estrogen and progestin therapy (Shumaker et al., 2003) and HRT use is not indicated as a treatment for dementia (Madison, 2004). 7.7.2 Hormone Therapy – Current Clinical Trials Nevertheless, there is currently one RCT of hormone replacement therapy in patients with AD recruiting patients (NCT00066157). The aim of the trial is to determine whether estrogen or combined estrogen and progesterone can improve memory function and the ability to live independently in postmenopausal women with mild to moderate AD in comparison with placebo.

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A second RCT is currently recruiting patients to assess whether a human growth hormone releasing hormone (GHRH; TH9507) can improve memory and problem solving ability, or cognitive function in healthy older adults and in those with mild cognitive impairment (NCT00257712). A third RCT is currently recruiting patients to participate in a trial to assess the efficacy of the hormone drug leuprolide acetate in stabilising cognitive function in patients with mild-to-moderate AD. The aims of the study are to assess the safety and efficacy of VP4896, a gonadotropin releasing hormone (GnRH) agonist, in treating patients with AD and to determine whether it will improve cognitive function and activities of daily living in these patients (NCT00231946). 7.7.3 A Vaccine for AD Although the amyloid β (Aβ) peptide vaccination was shown to be effective in reducing the Aβ burden in Alzheimer model mice (Schenk et al. 1999), the first RCT of the safety and efficacy of a vaccine (a 42-amino acid form of Aβ to treat mild to moderate AD was halted in early 2002 due to serious adverse events (Check, 2002). Nevertheless, research into the development of a vaccine is ongoing and researchers in Japan have recently reported on the development of a nonviral Aβ DNA vaccine that has been demonstrated to be effective in reducing pathology in Alzheimer model mice. The investigators are hopeful that this may eventually lead to the development of an effective vaccine for use in humans (Okura et al., 2006). 7.7.4 Vaccines – Current Clinical Trials Two RCTs of a vaccine for use in patients with AD are currently recruiting patients. The trials are to evaluate the safety and tolerability of the humanised monoclonal antibody, AAB-001, which binds to and clears beta amyloid peptide, in patients with mild to moderate AD (NCT00112073; NCT00174525). It is hoped that AAB-001 will attach to the amyloid protein in the brain and assist to remove it. In addition, another RCT is currently recruiting patients to evaluate the safety, efficacy and biological mechanisms of action of Intravenous Immunoglobulin (IVIg) in the treatment of mild to moderate stage AD (NCT00299988). IVIg contains antibodies against the amyloid beta protein and it is hypothesised that IVIg treatment will reduce the levels of beta amyloid in the brain and improve cognitive abilities relative to placebo. 7.7.5 Other Cochrane reviews have assessed the efficacy of a range of other treatments including the pharmacological agents Piracetam, Propentofylline, Nimodipine and Hydergine for dementia. These are summarised in Table 2, Appendix A. In the majority of cases, the reviewers concluded that while there was a suggestion that these treatments may have some benefit, the evidence was very limited and precluded drawing a firm conclusion. Further research into these interventions is therefore needed before a solid conclusion can be reached.

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7.8 Complementary Therapies 7.8.1 Ginkgo Biloba Several systematic reviews and meta-analyses of the efficacy of Ginkgo Biloba in the treatment of the symptoms of dementia have been conducted and reported in the literature (e.g. Birks, Grimley, & Van Dongen, 2002; Ernst & Pittler, 1999) including a Cochrane review conducted in June 2002 (Birks et al., 2002). Thirty-three RCTs were included in the review although a number of the earlier studies were judged to be methodologically unsound and heterogeneous in nature with a range of patients with different conditions and disease severity included. The results of five studies were included in the meta-analysis that indicated a number of benefits were associated with treatment with Gingko. For doses of less than 200mg/day, small but significant improvements were evident on measures of cognition, activities of daily living and mood in patients with cognitive impairment and dementia in comparison to placebo. The authors concluded that Ginkgo Biloba appeared to be safe with no excess side effects in comparison to placebo. Overall, there was some evidence of improvement in cognition and functioning with ginkgo although publication bias could not be entirely excluded. They considered there to be need for a large RCT that would permit robust estimates of the effect size and mechanism of any treatment effects. A comparison of the effectiveness of Ginkgo Biloba in comparison to acetylcholinesterase inhibitors (ChEIs) in the treatment of dementia was also recently reported by Kurz and Van Baelen (Kurz & Van Baelen, 2004). They utilised data from the Cochrane Collaboration and reported that while a positive effect of gingko upon cognition was only apparent when the study results were pooled, a significant effect on cognitive functioning was evident for each of the three ChEIs (Donepezil, Galantamine, Rivastigmine) included in the review. It was concluded that overall, the acetylcholinesterase inhibitors demonstrated a greater and more robust effect for cognitive function in patients with dementia than did Gingko Biloba. Ginkgo Biloba – Current Clinical Trials A pilot RCT of Curcumin and Ginkgo for treating Alzheimer’s disease is currently being conducted by the Chinese University of Hong Kong (NCT00164749). The aim of the trial is to evaluate the safety and efficacy of Curcumin and Gingko in delaying the progression the disease in patients with AD. 7.8.2 Acupuncture for the Treatment of Vascular Dementia Three RCTs of the efficacy of acupuncture in treating vascular dementia were identified in a search of Medline and AMED databases. One study assessed the efficacy of acupuncture in 46 patients with multi-infarct dementia in comparison to a control group. The results showed a beneficial effect of the use of acupuncture treatment on the hemodynamics of patients with multi-infarct dementia (Liu, 2004). Two additional studies have reported significant treatment effects of acupuncture for patients with VaD including one study that demonstrated significant improvements in patient’s MMSE scores and on a measure of activities of daily living (Gao et al., 2001; Yu, Zhang, Liu, Meng, & Han, 2006). The sample sizes in all three trials were small, however, the results are promising indicating the need for larger scale RCTs to further assess the efficacy of acupuncture for VaD and its potential for treating other dementia subtypes.

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7.8.3 Homeopathy A Cochrane review of the efficacy of homeopathy for dementia was conducted in April 2005 (McCarney, Warner, Fisher, & Van Haselen, 2003). Although one randomised controlled trial was identified, it was deemed ineligible for inclusion in the review. The authors concluded that there was no evidence that homeopathy is effective in treating dementia due to absence of evidence. They added that as the extent of homeopathic prescribing is not clear, it was difficult to comment on the importance of conducting trials in this area. 7.8.4 Aromatherapy Aromatherapy uses pure essential oils from fragrant plants such as Peppermint, Sweet Marjoram and Rose, to help relieve health problems and improve quality of life. A Cochrane review of the efficacy of aromatherapy for dementia was conducted in April 2006 (Thorgrimsen, Spector, Wiles, & Orrell, 2003). Although two RCTs were identified, the results were not in a format that was suitable for meta-analysis. Hence, the authors obtained individual patient data from one of the trials. Additional analyses of that data revealed a statistically significant treatment effect of aromatherapy on measures of agitation and neuropsychiatric symptoms in patients with dementia. They concluded that one small trial is insufficient evidence for the efficacy of aromatherapy for dementia and that well designed large-scale RCTs are needed before conclusions can be made regarding the efficacy of aromatherapy for dementia. 7.8.5 Vitamin E for Alzheimer’s Disease A Cochrane review of the efficacy of vitamin E treatment for patients with AD was conducted in June 2002 (Tabet, Birks, & Grimley Evans, 2000). Only one RCT was identified that met the inclusion criteria for the review. While the study demonstrated some benefit of vitamin E in comparison to placebo, with fewer participants reaching one of four endpoints: death, institutionalisation, loss of two out of three basic activities of daily living, or severe dementia, the reviewers cautioned that there is insufficient evidence of the efficacy of vitamin E in the treatment of patients with AD and that further research is warranted. More recently, however, there have been reports of serious adverse events associated with long-term use of high doses of vitamin E. For example, the results of a large international, randomised, double-blind, placebo controlled trial of vitamin E indicated that doses of vitamin E of 400 IU or more over a period of 6.9 years in patients with pre-existing vascular disease or diabetes mellitus increase the risk of heart failure with no other outcome benefits reported (Lonn et al., 2005). The authors concluded that, due to the lack of benefit and increased risk of harm, vitamin E should not be used in patients with vascular disease or diabetes mellitus. Vitamin E – Current Clinical Trials Nevertheless, there is one RCT of vitamin E for use in patients with AD, currently recruiting subjects in the United States:

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A randomised, double-blind, placebo controlled trial to assess the safety and efficacy of anti-oxidant treatment in patients with Alzheimer’s disease (NCT00117403). The aim of the study is to evaluate the safety and efficacy of vitamins E and C, Alpha-lipoic acid and coenzyme Q in patients with mild to moderate AD. 7.8.6 Melantonin Melatonin is a naturally-occurring hormone secreted by the pineal gland in the centre of the brain and it has been suggested that a relationship exists between decline of melatonin function and the deficits of dementia. A Cochrane review of the efficacy of melantonin for dementia was conducted in October 2005 (Jansen, Forbes, Duncan, & Morgan, 2006). Three RCTs were identified for inclusion in the review and results of the pooled data revealed no benefit of melantonin on measures of cognition although there was some evidence of improvement of behavioural problems in one small-scale study. The authors concluded that there was insufficient evidence to support the effectiveness of melatonin for managing cognitive function. 7.8.7 Complementary Therapies – Current Clinical Trials Three clinical trials are currently recruiting patients to participate in studies to evaluate the efficacy of complementary therapies in dementia:

• A study to determine whether vitamin B12 and folate supplementation can preserve cognitive function in subjects with early dementia (NCT00164970).

• A randomised, double-blind, placebo controlled pilot study to evaluate the

potential effects of soy isoflavone supplements on cognitive function for men and women with Alzheimer’s disease (NCT00205179).

• A randomised, double-blind, placebo-controlled trial to evaluate the safety

and efficacy of the Chinese herb Huperzine A to improve cognitive function in patients with Alzheimer’s disease (AD) (NCT00083590).

7.9 Psychosocial Interventions to Promote Health, Cognitive Functioning and Well-being A wide range of psychosocial interventions to improve the cognitive and non-cognitive symptoms of dementia have been evaluated, although these have been less extensively investigated than the pharmacological approaches. These include physical exercise, psychological approaches including validation, reminiscence and reality orientation, behaviour management, sensory stimulation and the use of music therapy. 7.9.1 Physical Exercise Studies of the effects of physical activity among people with cognitive impairment and dementia were systematically reviewed (Heyn, Abreu, & Ottenbacher, 2004). Thirty RCTs that had enrolled a total of 2,020 subjects were identified for inclusion in the review and meta-analysis. Most of the studies were small in size and a majority was based on walking as the intervention. Most of the studies were judged to be of medium quality.

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The results indicated a significant positive effect of medium size for physical exercise on measures of physical fitness and on measures of functional behaviour and cognition in patients with cognitive impairment and dementia relative to control subjects. The authors concluded that exercise training increases fitness, physical function, cognitive function, and positive behavior in people with dementia and related cognitive impairments. Larger scale RCTs are recommended to further evaluate the efficacy of physical exercise as an intervention in this population. Aerobic Exercise – Current Clinical Trials There is currently one RCT in progress to evaluate the efficacy of aerobic activity in adults with mild cognitive impairment: A randomised study of the efficacy of six months of aerobic activity for the enhancement of cognitive activity in adults with MCI (NCT00220467 Non-aerobic Exercise – Current Clinical Trials Another RCT, being conducted in Tasmania, is currently recruiting older adults with a range of health conditions including AD, to participate in a trial of the efficacy of resistance training or flexibility training. Outcome measures include cognitive functioning, fitness, mood and quality of life (ACTRN012605000534684). 7.9.2 Cognitive Rehabilitation/Cognitive Training A Cochrane review of the efficacy of cognitive rehabilitation and cognitive training interventions aimed at improving memory functioning in people in the early stages of AD or Vascular dementia (VaD) was conducted in April 2003 (Clare, Woods, Moniz Cook, Orrell, & Spector, 2003). Six studies were identified for inclusion in the review and results of the analysis revealed no statistically significant effect of the intervention on any outcome measure. No RCT that included a fully individualised cognitive rehabilitation approach was identified and therefore it was not possible to evaluate the effectiveness of this intervention for people with mild to moderate AD or VaD. The authors concluded that further research is required to properly evaluate the efficacy of cognitive rehabilitation or training as a treatment for people with mild to moderate AD or VaD. 7.9.3 Cognitive Stimulation Livingston and his colleagues (Livingston, Johnston, Katona, Paton, & Lyketsos, 2005) also conducted a systematic review of studies that had assessed the efficacy of Cognitive Stimulation as a treatment for dementia and included two additional RCTs. A significant improvement in depression in the treatment group relative to the control group was reported in one study, although the number of participants was very small (<20 per group), while the second indicated some improvement in quality of life. The reviewers concluded that there was some evidence to suggest that cognitive stimulation was useful in the treatment of dementia, although the results were not always consistent. Cognitive training – Current Clinical Trials Two trials are currently recruiting participants to take part in studies evaluating the efficacy of cognitive training in people with mild cognitive impairment and dementia:

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• A study to assess the efficacy of a computerised training program on cognitive function in older persons with normal cognition, mild cognitive impairment, and early dementia (NCT00146263).

• Another RCT is being conducted in Australia, to evaluate the efficacy of a

five-week memory group intervention for people with mild cognitive impairment. The intervention will focus on the management of everyday memory failures and also involve the family in developing increased awareness of memory issues and specific strategies to prevent everyday memory failures (ACTRN012605000711617).

7.9.4 Reminiscence Therapy Reminiscence therapy involves the discussion of past activities, events and experiences with another person or group of people, usually with the aid of tangible prompts such as photographs or other familiar items. A Cochrane review of the efficacy of reminiscence therapy for people with dementia was conducted in May 2004 (Woods, Spector, Jones, Orrell, & Davies, 2005). Five RCTs were included in the review although only four trials with a total of 144 participants had extractable data. The results indicated a statistically significant improvement in cognition for the treatment group in comparison to both a no treatment and a social contact control group. Improvement was also evident on a measure of general behaviour in patients with dementia as well as a significant decrease in caregiver strain for those participating in groups with their relative. The studies, however, were small and of relatively low quality and it was concluded that although there is some evidence that reminiscence therapy may be effective for patients with dementia, the results are inconclusive and more research is warranted. 7.9.5 Behaviour Management The aim of behaviour management is to modify problem behaviours by analysing the circumstances in which the behaviour occurs in order to identify important antecedents and consequences of the behaviour. Behavioural modification is then undertaken by changing these circumstances and/or teaching participants new behaviours. Livingston and his colleagues (2005) included 25 studies that had assessed behaviour management for the treatment of neuropsychiatric symptoms of dementia in their systematic review, although only four were RCTs. Of the RCTs, two studies resulted in a significant improvement in behavioural symptoms, although the sample sizes in the studies were small. The remainder of the studies were single-case studies that had implemented and evaluated individually tailored behavioural interventions. Most of those studies reported improvement in behavioural symptoms including aggression and depression, demonstrating that an individually tailored approach is an important element of the intervention. Although the reviewers concluded that behaviour management appeared to be an effective treatment for dementia, it was suggested that further RCTs are needed to confirm the efficacy of the intervention. The importance of an individually tailored approach to behavioural intervention was clearly demonstrated in a larger, non-randomised controlled trial of (predominantly) psychosocial interventions in comparison to a (predominantly) pharmacological approach (Bird, Llewellyn-Jones, Smithers, & Korten, 2002). Forty-four patients with challenging behaviours secondary to dementia were randomly allocated to either a psychosocial group or a control group that involved usual clinical practice.

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The psychosocial intervention involved a range of strategies, including changes in staff and carer behaviour as well as environmental modifications, and was developed following a detailed analysis of the behaviour at the outset. Results for the psychosocial group showed a 43% decrease in the behaviour for which the patient had been referred and significant improvements in staff or carer distress and attitudes. In addition, the psychosocial intervention was less time-consuming in the longer term. 7.9.6 Validation Therapy Validation therapy is based on the general principle of validation, the acceptance of the reality and personal truth of another’s experiences and includes a variety of techniques (Feil, 1993). A Cochrane review of the efficacy of reminiscence therapy for people with dementia was conducted in August 2005 (Neal & Briggs, 2003). Three RCTs were identified that met the inclusion criteria, although it was not possible to pool the data due to methodological differences among the studies. The results indicated no statistically significant effect for measures of cognition or ADLs although one study reported a statistically significant improvement on one measure of depression in the validation therapy group following twelve months of treatment. It was suggested that the evidence is insufficient to warrant a conclusion regarding the efficacy of validation therapy for patients with dementia or cognitive impairment. 7.9.7 Reality Orientation Reality orientation is based on the idea that impairment in orientating information (day, date, time and use of names) prevents patients with dementia from functioning well and that reminders can improve functioning. Livingston et al (2005) conducted a systematic review of studies that had evaluated reality orientation as a treatment for neuropsychiatric symptoms of dementia. Although eleven studies were identified from the literature, only two were RCTs and all involved small sample sizes. Overall, the results indicated some improvement in improved mood and behaviour in the treatment group in comparison to control groups. It was concluded, however, that the evidence was very limited that reality orientation was not effective as a treatment for dementia. 7.9.8 Bright Light Therapy (BLT) for managing sleep, behaviour, and mood disturbances in Dementia A Cochrane review of the efficacy of BLT for improving sleep, behaviour and mood disturbance in patients with dementia was conducted in December 2005 (Forbes et al., 2004). Although five studies were identified for inclusion in the review, only three were included in the analyses due to an inability to utilise the data. The reviewers concluded that there was no evidence that BLT is effective in managing sleep, behavioural or mood disturbances associated with dementia. The reviewers also considered that the three studies included in the analysis were of poor quality and that further research is required.

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7.9.9 Snoezelen A Cochrane review of the efficacy of Snoezelen (or multi-sensory stimulation) for patients with dementia was conducted in April 2004 (Chung, Lai, Chung, & French, 2002). Two trials that had examined the short term effects of Snoezelen therapy (four and eight treatment sessions respectively) on mood, behaviour and cognition in patients with dementia were included in the review and a quantitative synthesis of the data was performed. The results indicated that there was no significant difference between a group treated with Snoezelen therapy and a control group on any measure of behaviour, mood or cognition. It was concluded that there is currently no evidence that Snoezelen therapy is effective for the treatment of dementia, although the evidence base is very limited. There is a need for well conducted research into the clinical efficacy of Snoezelen therapy for patients with dementia. 7.9.10 Music Therapy A Cochrane review of the efficacy of music therapy for people with dementia was conducted in December 2005 (Vink, Birks, Bruinsma, & Scholten, 2004). Five studies were included in the review although the methodological quality of studies was deemed to be poor and the study results could not be validated or pooled for further analyses. It was concluded that there was no substantial evidence to either support nor discourage the use of music therapy in the care of people with dementia. Livingston and colleagues (2005) also evaluated music as a treatment for dementia although the majority of the included studies were uncontrolled. Many of the studies, however, showed a reduction in agitation and disruptive behaviour during and immediately following the music therapy session indicating that music therapy appears to be useful in the very short term. There was, however, no evidence of a longer term benefit in ameliorating the neuropsychiatric symptoms of dementia. A similar result for music was reported by the authors of an earlier systematic review that had assessed psychosocial approaches as interventions for managing challenging behaviours in patients with dementia (Opie, Rosewarne, & O'Connor, 1999). Included in the review were five studies that had evaluated the efficacy of music as an intervention and although the studies had methodological limitations, most reported positive effects of music and a reduction in agitation. Thus, it appears that music may have a useful role in alleviating agitation in patients with dementia, at least in the short-term. 7.9.11 Transcutaneous Electrical Nerve Stimulation (TENS) A Cochrane review of the efficacy of TENS for dementia was conducted in December 2002 (Cameron, Lonergan, & Lee, 2003). Eight RCTs were included in the review although data from only three trials could be included in the meta-analysis. The results suggested that TENS may result in some short term benefit in cognition and behaviour but that the data were too limited to draw any firm conclusions and more research is warranted. 7.10 Miscellaneous Clinical Trials The following trials are currently recruiting patients to assess the safety and efficacy of various treatments for dementia:

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Dopaminergic Drugs • A trial of Levodopa to enhance learning and memory in healthy adults and

patients with dementia or Mild Cognitive Impairment (NCT00306124). Levodopa, the metabolic precursor of dopamine, is currently prescribed for the treatment of movement disorders including Parkinson’s disease.

• A study to assess the role of the dopaminergic brain reward system in apathy

associated with Alzheimer’s disease – Trial of Dextroamphetamine and Methylphenidate (NCT00254033).

• A trial to assess the efficacy of the dopaminergic agent, Amantadine for the

treatment of behavioral disturbance in Frontotemporal dementia (NCT00127114).

Other Medications There is one RCT of a hypnotic drug that acts on the sleep-wake cycle, for use in patients with AD, currently recruiting subjects in the United States: A double-blind, randomised, placebo-controlled study of the efficacy, safety and tolerability of Rozerem 8 Mg (QHS) in sleep disturbed, community dwelling, mild to moderately severe Alzheimer’s disease subjects (NCT00325728). 7.11 Summary The most effective, currently available pharmacological treatments for the cognitive symptoms of AD of moderate severity are the three ChEIs, Donepezil, Galantamine and Rivastigmine, although the effects of treatment are fairly modest. While the three drugs appear to be equally effective in improving cognitive functioning in these patients, Donepezil appears to result in fewer side effects than Galantamine and Rivastigmine. Donepezil and Rivastigmine also appear to be beneficial for VaD, and Rivastigmine appears to improve cognition in patients with dementia secondary to Parkinson’s disease. For moderately severe to severe cases of AD, Memantine appears to result in improved cognitive and global functioning. Of the complementary therapies, Gingko Biloba appears to be the most effective in improving cognitive functioning in patients with cognitive impairment and dementia, and results in few adverse effects. The treatment effects, however, are also modest. Similarly, three small scale RCTs of acupuncture resulted in improvement in patients with VaD and further large scale RCTs are warranted to determine its potential for treating other dementia variants. The results for aromatherapy and homeopathy were inconclusive. Only limited research into non-pharmacological approaches to treat the cognitive and behavioural symptoms of dementia has been undertaken to date and few RCTs have been conducted. The best evidence, however, is for physical exercise, reminiscence therapy and behaviour management while there is no evidence that reality orientation, bright light therapy or snoezelen are effective treatments for dementia.

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Of the interventions that have demonstrated some benefit, further large-scale, well-designed RCTs are required to further assess the safety and efficacy of the intervention and to determine estimates of the effect size. Studies are also needed to determine whether the treatments are equally effective for the various subtypes of dementia and whether combinations of pharmacological and psychosocial interventions are more effective than either treatment alone. Currently, a range of clinical trials are recruiting patients to assess the safety and efficacy of a variety of interventions including two trials of a vaccine for dementia.

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Appendix A Table 7.1 Summary of included Cochrane reviews of dementia treatments

Intervention Date of Review Number of Identified Studies Results Conclusion

Donepezil for Alzheimer’s disease (AD) June 2005

Twenty-three randomised controlled trials (RCTs) included involving 5272 participants

Significant improvement in cognition in patients treated with 5 or 10mg/day Donepezil compared to placebo; Global clinical state and activities of daily living (ADLs) also improved on Donepezil

Donepezil is beneficial for people with mild, moderate and severe AD

Donepezil for Mild Cognitive Impairment (MCI)

January 2006 Two RCTs with 782 participants; Meta-analysis not possible

One RCT demonstrated a modest treatment effect on cognition and adverse side effects

There is no evidence to support the use of Donepezil in patients with MCI

Donepezil for Vascular Cognitive Impairment June 2005

Two large-scale RCTs were included with 1219 patients with Vascular dementia (VaD)

Significant improvement in cognition and ADLs for patients treated with 5mg or 10mg/day Donepezil; Significant improvement on global functioning for 10mg/day

Donepezil is beneficial for patients with mild or moderate vascular cognitive impairment

Galantamine for Alzheimer’s disease April 2005

Ten RCTs involving 6805 subjects with AD or Mild Cognitive Impairment

Treatment group significantly improved on global functioning and cognition compared to placebo

Galantamine (16mg/day) for six months improves global and cognitive symptoms in patients with AD

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Galantamine for Vascular Cognitive Impairment April 2005 Two RCTs included

One RCT reported a significant benefit of Glanatamine on Cognition; Finding not replicated on second RCT; Galantamine associated with GI upset

No consistent evidence of efficacy for treating vascular cognitive impairment

Rivastigmine for Alzheimer’s disease July 2005 Seven RCTs involving 3450

subjects

Improved cognition and ADLs in patients treated with Rivastigmine compared to placebo

Rivastigmine is beneficial for patients with AD

Rivastigmine for Vascular Cognitive Impairment

December 2004

No RCTs identified Nil No evidence of benefit of Rivastigmine for VaD

Cholinesterase Inhibitors for Parkinson’s Disease Dementia (PDD)

April 2005 One RCT involving 541 patients

Improved cognition and ADLs in patients treated with Rivastigmine compared to placebo; Rivastigmine associated with GI upset

Rivastigmine appears to moderately improve cognition and ADLs in patients with PDD

Cholinesterase Inhibitors (ChEIs) for Alzheimer’s disease

June 2005 Thirteen RCTs included

Significant improvement i+D2n cognition for patients treated with ChEIs for six and twelve months; Some benefit of treatment for ADLs and behaviour

The three ChEIs are efficacious for mild to moderate AD. The treatment effects are modest

Cholinesterase Inhibitors for Dementia with Lewy bodies (DLB)

February 2002 One RCT involving 120 patients

No significant effect using intention-to-treat analyses; Significant treatment effect on Neuropsychiatry Inventory for observed cases

No convincing evidence that Rivastigmine is efficacious for DLB; Further trials are needed

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Memantine for dementia February 2006 Twelve RCTs included

Improved cognition, mood, behaviour and ADLs in patients with moderate-severe AD treated with Memantine compared to placebo

Memantine has a small, beneficial effect for patients with moderate - severe AD. Memantine is well tolerated

Atypical antipsychotics for Alzheimer’s disease

December 2004

Sixteen RCTs identified; nine were included in meta-analysis

Significant improvement in aggression in patients treated with Risperidone and Olanzapine; Significant improvement in psychosis in patients treated with Olanzapine; Significantly more serious adverse events in patients treated with these medications

Neither Risperidone nor Olanzpine should be routinely used to treat aggression or psychosis in patients with dementia

Antidepressants for dementia in Alzheimer’s disease

April 2005

Seven RCTs identified; Data from four RCTs (137 subjects) included in meta-analysis; Only two RCTs of SSRIs

One RCT reported a significant improvement in depression; Adverse effects associated with antidepressant use

Insufficient evidence of the safety and efficacy of antidepressants for depression in dementia

Trazodone for agitation in dementia June 2004 Two RCTs identified with data

for 104 patients with dementia

No significant difference between treatment & control groups

Insufficient evidence to make a recommendation regarding the use of Trazodone in patients with dementia

Nimodipine August 2005 Fourteen RCTs with 3166 patients with dementia included in meta-analysis

Significant improvement on measures of cognition and global impression in treatment group compared to placebo

There is evidence of some short-term benefit of Nimodipine for dementia

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Hormone Replacement Therapy May 2002 Five RCTs identified involving

210 women with AD

A short-term benefit of HRT on one measure of memory was evident in the treatment group

No evidence of efficacy; HRT is not recommended as a treatment for women with AD

Gingko Biloba June 2002 Thirty-three RCTs identified; data from five RCTs included in meta-analysis

Small, but significant improvement in cognition, ADLs & mood in patients treated with Gingko for twelve weeks compared to placebo

Some evidence that Gingko Biloba is an effective treatment for dementia

Aroma Therapy for dementia April 2006

Two RCTs identified but data not useable; Individual patient data from one RCT obtained & analysed

A statistically significant improvement in neuropsychiatric outcomes was revealed for patients treated with Aroma therapy

Insufficient evidence of the efficacy of Aroma therapy for dementia

Vitamin E for Alzheimer’s disease June 2002 One RCT identified involving

341 participants

Some benefit of vitamin E but patients taking vitamin E had more falls

Insufficient evidence of the efficacy of vitamin E for dementia

Melantonin for Cognitive Impairment October 2005 Three RCTs

Poole analysis revealed no significant effect; results of one small study reported improved behaviour in treatment group versus placebo

There is insufficient evidence to indicate that Melantonin is an effective treatment for dementia.

Reminiscence therapy for dementia May 2004

Five RCTs identified; four RCTs had extractable data for 144 participants

Significant improvement for cognition, mood and general behaviour in treatment group. Trials were small or of relatively low quality

The evidence is inconclusive regarding the efficacy of Reminiscence therapy for dementia

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Cognitive rehabilitation and cognitive training for early-stage Alzheimer’s disease and Vascular dementia

April 2003 Six RCTs included+C9 No significant treatment effect

No evidence of the effectiveness of cognitive training; Insufficient evidence to evaluate efficacy of individualised cognitive rehabilitation; Further studies are required

Bright Light Therapy (BLT) for behavioural disturbances in dementia

December 2005

Five RCTs identified, only three included in the analyses; data not pooled

One study demonstrated improvement in cognition following BLT but sample size small; No other evidence of effect

There is no evidence that BLT is effective for dementia

Snoezelen for dementia April 2004 Two RCTs identified & data analysed

Mostly no difference between treatment & control groups

There is no evidence to indicate that Snoezelen is an effective treatment for dementia

Music therapy for dementia

December 2005

Five RCTs identified, no meta-analysis possible

Individual studies report benefits of music therapy on a range of outcomes

The methodological quality of the included studies was too poor to draw any useful conclusion

Transcutaneous Electrical Nerve Stimulation (TENS) for dementia

December 2002

Eight RCTs identified, only three included in meta-analysis

?? Insufficient evidence to allow a conclusion to be drawn.

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Validation therapy for dementia August 2005

Three RCTs identified with data for 116 patients and 74 control subjects

Significant improvement in behaviour at six weeks and depression at twelve months in the treatment group compared to placebo

Insufficient evidence to allow a conclusion to be drawn.

Homeopathy for dementia April 2005 No RCTs identified Nil

There is no evidence regarding the efficacy of homeopathy as a treatment for dementia

Ibuprofen for Alzheimer’s disease

December 2002 No RCTs identified Nil

There is no evidence regarding the efficacy of Ibuprofen for the treatment of AD

Aspirin for Vascular dementia July 2005 No RCTs identified Nil

There is no evidence regarding the efficacy of Aspirin for VaD

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Table 7.2 Summary of Cochrane reviews of dementia treatments not included

Treatment

Conclusion

Author

Year

Acetyl-l-carnitine

No evidence of benefit for dementia

(Hudson & Tabet)

(2003)

Alpha Lipoic acid

No evidence of efficacy

(Sauer, Tabet, & Howard)

(2004)

Cytidinediphosphocholine (CDP-choline)

There was some evidence of benefit on memory & behaviour in the short-term

(Fioravanti & Yanagi)

(2005)

Clioquinol

No convincing evidence of benefit; Further research is needed to determine efficacy

(Jenagaratnam & McShane)

(2006)

D-cycloserine

Treatment with D-cycloserine is not beneficial for dementia; Not recommended

(Laake & Oeksengaard)

(2002)

Haloperidol

Haloperidol reduces aggression in patients with dementia but due to the risk of adverse events, is not recommended for routine use

(E. Lonergan, Luxenberg, & Colford, 2002)

(2002)

Hydergine

The evidence is inconclusive

(Olin, Schneider, Novit, & Luczak)

(2000)

Indomethacin

Indomethacin is not recommended as a treatment for AD

(Tabet & Feldman)

(2002)

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Lecithin

The available evidence does not support the use of lecithin in the treatment of patients with dementia

(Higgins & Flicker)

(2000)

Metrifonate

Due to adverse events, Metrifonate has been withdrawn from further development

(Lopez-Arrieta & Schneider)

(2006)

Nicergoline

Some evidence of benefit & adverse effects

(Fioravanti & Flicker)

(2001)

Nicotine

No data upon which to draw a conclusion

(Lopez-Arrieta, Rodriguez, & Sanz)

(2001)

Piracetam

Some limited evidence of benefit suggests that further research is warranted

(Flicker & Grimley Evans)

(2001)

Physostigmine

Limited evidence of benefit for dementia

(Coelho & Birks)

(2001)

Propentofylline

Limited evidence of benefit for dementia

(Frampton, Harvey, & Kirchner)

(2003)

Selegiline

No evidence of benefit & no further research is justified as a treatment for dementia

(Birks & Flicker)

(2003)

Subjective barriers to prevent wandering

No RCTs have been published. There is no evidence of efficacy

(Price, Hermans, & Grimley Evans)

(2000)

Thiamine

Insufficient data upon which to base a conclusion.

(Rodriguez-Martin, Qizilbash, & Lopez-Arrieta)

(2001)

Thioridazine for dementia

There is no evidence to support the use of

(Kirchner, Kelly, & Harvey)

(2001)

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thioridazine for dementia

Valproate preparations for agitation in dementia

Valproate is not recommended for the management of agitation in dementia

(E. T. Lonergan, Cameron, & Luxenberg)

(2004)

Velnacrine

Velnacrine is not beneficial for AD and is not recommended. There are no grounds for further research

(Birks & Wilcock)

(2004)

Vinpocetine

The current evidence is inconclusive and does not support clinical use

(Szatmari & Whitehouse)

(2003)

Zhiling decoction

No RCTs have been published. Further research is needed

(Jirong, Xiaoyan, Taixiang, Defen, & Birong)

(2004)

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8.0 Care and Support for People with Dementia and their Carers 8.1 Introduction Over the past decade, there has been a growing consensus among policy makers of the importance of providing flexible and person-centred forms of care for older people. In the case of dementia care, the rising importance of a ‘person-’ or ‘client-centred’ approach redirects the focus of service from concern with arresting cognitive decline and controlling behavioural symptoms to preventing excess disability and promoting well-being and quality of life of people with the illness. The person-centred approach recommends the organisation of care and service around the therapeutic potential of interactions and relationships as essential to the maintenance of personhood and well-being. It suggests that care addresses the full spectrum of needs of people with dementia – including psychological, emotional, social and spiritual - rather than focusing exclusively on controlling cognitive and behavioural symptoms. The approach also emphasises the need to take the experience and perspective of the person with dementia into account and not just that of the professionals or carers. Healthcare practitioners are encouraged to recognise individual differences and to work towards promoting therapeutic relationships with the clients, respecting their right to autonomy, dignity and engagement with others. This section summarises research findings and trends in the area of social support and care for persons with dementia and their carers over the past ten years. Specifically, it covers the following topics: palliative care, activities of daily living, behavioural and psychological symptoms, accessing the perspective of people with dementia, support for carers, housing provision and environmental design, cultural differences in carer experience, and ethical issues in dementia care. 8.2 Literature Search A literature search of published research articles between 1995 and 2006 was conducted using the following databases. Table 8.1 Search Strategy

Titles of Database Group

Databases Selected Search Terms Used

Cambridge Scientific Abstract (Social

Sciences Section)

PsycINFO, Social Services

Abstracts, Sociological Abstracts

EBSCO CINAHL, Medline,

Social Health: Nursing/Academic Edition

dementia, Alzheimer’s disease, care, carer,

caregiver, service, support, palliative, feeding, mobility,

hygiene, driving, behavioural and

psychological symptoms, housing, environment,

quality of life, evaluation, race, ethnic, ethics

Relevant papers that were not captured through the database search were identified by examining references in review articles or empirical studies. Grey literature was identified and retrieved by searching:

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• Google • GreyNet (http://www.greynet.org/greynethome.html) • Social Care Online (http://www.scie-socialcareonline.org.uk/default.asp) • The Joanna Briggs Institute (http://www.joannabriggs.edu.au) • The National Institute for Health and Clinical Excellence (http://www.nice.org.uk) As the evidence base was large, findings of recent high quality English-language systematic reviews and meta-analyses were first summarised. Additional reviews on particular issues were also identified and retrieved from the Cochrane Database of Systematic Reviews. This section adopted the following inclusion criteria for systematic reviews and meta-analyses: • The review addresses an appropriate and clearly defined question; • The methodology of literature search is clearly described, reproducible and is

rigorous enough to identify all relevant materials; • The reviewer(s) has assessed and taken into account the quality of the studies

being reviewed; • For meta-analysis, the pooling methods should be clearly described and

appropriate. In cases where there was no systematic review or meta-analysis in a particular area, literature reviews plus a number of interventional or observational studies in that area published within the past ten years were identified and their findings summarised. The inclusion criteria for interventional and observational studies were: • The literature review/study is published in a peer-reviewed journal; • The content of study is related to dementia care or how people feel or experience

situations that related to dementia care or caregiving; • The study has adopted appropriate research design and data collection methods; • The researcher(s) has described clearly the methodology used, results, and

ethical approval; • For quantitative studies, priority is given to randomised controlled trails or trials

with comparison group; • For qualitative studies, priority was given to those that had explained in detail the

steps of analysis, demonstrated how findings were grounded in data, and triangulated different research methods.

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The flowchart below summarises the process and results of the literature search: Figure 8.1 Flowchart of literature search process for dementia care

8.3 Palliative Care The palliative care model is consistent with a person-centred care approach focusing on promoting well-being and quality of life by addressing the physical, psychosocial, and spiritual aspects of living with serious or life-threatening diseases. This model has attracted the attention of policy makers and dementia care workers over the past decade. One systematic review of the efficacy of a palliative care approach for people with advanced dementia was identified (see Table 8.2).

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Table 8.2 Systematic review of palliative care in dementia Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

Sampson et al.

Comparison of end-of-life outcome measures between patients receiving and not receiving palliative service

Two

Up until 1 October 2003

2005

Sampson and colleagues (2005) identified 49 articles in their literature search and narrowed down to four for full appraisal. Only two papers fulfilled the inclusion criterion of controlled clinical trial and were included in the review. The marked contrast between the small numbers of controlled studies and the number of reviews on the palliative model suggests that there is increasing interest and recognition of the need for adequate end-of-life care in persons with dementia. Overall, there is a lack of robust research on the effect of a palliative care approach for people with advanced dementia. Methodological problems such as the lack of standard measures of quality of care and difficulties in gaining ethical approval for research were reasons that explain why so little is known about the topic. Although the evidence base is scant, findings of studies on people with cancer do support the efficacy of palliative care. The palliative care model has long been integrated into the research agenda and clinical practice of oncology with a large evidence base on its effectiveness accumulated. As the needs and solutions identified in persons with cancer are similar to those for people living with serious chronic illness, the findings of studies on cancer patients are likely to apply to the case of dementia. Lorenz and colleagues (2004) of the RAND Corporation conducted a systematic review on patient end-of-life care and its outcome. They found that existing evidence supports the efficacy of palliative care for improving quality of life of patients as well as for reducing caregiver burden. A synthesis report of the World Health Organization (2004), based largely on systematic reviews of studies of older people with cancer, also endorsed the use of a holistic palliative care model. In future, more research on assessing the efficacy of the palliative service in dementia care is recommended. 8.4 Activities of Daily Living Dementia is associated with a decline of reasoning, memory and other cognitive functions. This decline impairs the ability of the person with dementia to carry out activities of daily living (ADLs) such as household chores, walking and driving as well as personal care like eating, dressing and bathing. There is a consensus among care practitioners that helping people with dementia to accomplish ADLs takes considerable time and resources, and problems in these activities contribute significantly to caregiver burden. The management of ADLs is an important area of support as it goes beyond simple hygiene and is central to self-care, independence and dignity of persons with dementia.

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8.4.1 Feeding Food is important in dementia care as it is both a matter central to quality of life and an indicator of positive care. Abilities to choose or prepare food and to eat properly are central to self-care, independence and dignity of people with dementia. While eating is a complex social and cultural behaviour, current research has been dominated by a problem-based approach focusing largely on the difficulties of carrying out this activity, especially from the perspective of health professionals (Manthorpe & Watson, 2003). Relatively little has been known about the experience of people with dementia as well as how feeding activity is carried out at home. One systematic review in relation to feeding was identified (see Table 8.3). Table 8.3 Systematic review of strategies to assist eating in people with dementia Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

Watson and Green

Interventions in assisting persons with dementia to eat

13

1993-2003

2006

Watson and Green (2006) reviewed 13 interventional studies on assisting people with dementia to eat, published between 1993 and 2003. The articles reviewed originated from Sweden, Belgium, UK and USA. Most of the participants were women over 65 years old who were living in residential units or in their own homes. Only one of the studies was a randomised controlled trial and none had reported on the analysis of statistical power. There were also variations on the reporting of statistical methods and outcome measures used. A wide range of intervention variables were examined in these studies. These included changing meal service systems, restructuring staff assignment, introducing nutritional assessment and subsequent food provision, changing food texture, occupational and behavioural interventions, playing music and moving dining rooms. All studies reported beneficial outcomes from these interventions. However, methodological limitations of many of these studies prevented any definitive recommendation on specific treatment to be made. On a fairly general level, environmental factors are found to be important to conducive eating with music being the most commonly used intervention component. Prompting and reinforcing interventions have also demonstrated potential in improving feeding behaviour of people with dementia. Given the diversity of feeding difficulties in older people, it is unlikely that a single intervention can be applicable to all cases. Further rigorous research is needed on assessing the efficacy of different interventions and to identify possible confounding factors. Eating and drinking are processes situated within the broader set of activities of ordinary life. As Manthorpe and Watson (2003) have pointed out, involving people with dementia in meal preparation has therapeutic and rehabilitative effects. In addition to giving the person a sense of engagement and control, it provides them an opportunity to pick up essential self-care skills. Healthcare workers should avoid reinforcing the sense of dependence when supporting people with dementia to eat.

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They also need to be sensitive to cultural and social meanings of food and mealtimes. A precise measure of the level of feeding difficulty experienced by individuals with dementia is essential for designing appropriate service and personal interventions. The Edinburgh Feeding in Dementia Scale is such a tool designed for use in hospital or institutional settings. The scale ranks feeding difficulties in a hierarchy as perceived by nurses involved in caring for the patient (see Watson, 1994; 1996). Another issue related to eating is the use of tube feeding (for an overview of the issue see Sarti et al., 1998). Finucane and colleagues (1999) categorised research findings between 1966 and 1999 on the efficacy of the practice of tube feeding in people with advanced dementia. They found no evidence to support the use of enteral feeding tubes in preventing malnutrition, prolonging survival, and reducing the risk of pressure ulcers or sores. In contrast, the practice was found to be associated with substantial risk of aspiration pneumonia, local and systemic infection as well as serious adverse effects on function and comfort of the client (cf. Gillick, 2000). Based on this evidence, the use of enteral feeding tubes in cases of severe dementia is discouraged. Instead, the use of a comprehensive and conscientious program of hand feeding is recommended. 8.4.2 Ambulation People with dementia often face a decrease in mobility and an increased risk of falling. One systematic review of the general effects of dementia on gait was identified (see Table 8.4). Table 8.4 Systematic review of gait disturbance in dementia Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

van Iersel et al.

Comparison of gait between people with dementia and healthy persons

7

1980-2002

2004

van Iersel and colleagues (2004) reviewed seven controlled studies comparing the gait of people with dementia with that of healthy older persons. They made the following observations taking into consideration shortcomings and inconsistencies between methodologies of different studies: • there is a decrease in walking velocity of people with dementia and the degree of

reduction is in proportion to the severity of the disease; • dementia was associated with a shortened step length, an increased support time

and step to step variability; • people with vascular dementia have more severe gait disorders than people with

Alzheimer’s disease.

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Previous research on the prediction of falls in older people found that individuals who have difficult walking and doing a second task at the same time have a significantly less safe gait, have performed basic mobility more slowly, and are more dependent in ADLs (de Hoon et al., 2003; Olsson-Lundin, Nyberg, & Gustafson, 1997). In short, dual task performance, such as walking and having conversation at the same time, is a powerful predictor of falls in cognitively impaired older persons. Hauer and colleagues (2003) compared the degree of postural control during dual tasks of healthy adults with geriatric patients. They found that even simple additional tasks led to a loss of significant amounts of postural stability and an almost one hundred percent increase in postural sway in geriatric patients with a history of falls plus cognitive impairment. While research findings have proved that specifically designed programs are effective in preventing falls and maintaining physical functioning in older people (Lord et al., 2003), existing evidence on how to administer specific treatment of these programs to people with dementia is thin and equivocal. Five interventional studies on improving mobility or reducing risk of fall of people with dementia are identified. All of these studies were conducted in institutional or long-term aged care facilities. Pomeroy and colleagues (1999) examined the effect of physiotherapy treatment and non-physical activities intervention on improving mobility skills of people with dementia during a hospital respite admission. The study involved 81 subjects from twelve clinical centres. No significant difference between the treatment and control group on mobility score and on distance the subjects walked was detected. Tappen and colleagues (2000) conducted a controlled trial to assess the effect of exercise on preventing deterioration of functional mobility. They administered assisted walk plus conversation sessions, walk-only sessions or conversation-only sessions to 65 subjects randomly assigned into three groups. Performance outcome of these groups was then compared. The researchers found that an exercise program consisting of 30 minutes of walk-and-talk session three times a week was effective in preventing deterioration of functional mobility. They suggested that social interaction during exercise may be critical to the efficacy of any exercise program for people with dementia. A study with a similar design conducted by Cott and colleagues (2002) failed, however, to replicate this result. The researchers found no significant difference in levels of communication, ambulation and function between the subjects that received walk-and-talk sessions, talk-only sessions or no intervention. The level of cognitive impairment of the subjects, measurement issues and differences in nature of the care setting were possible factors that accounted for the lack of effect of intervention in this study. Jensen and colleagues (2003) conducted a controlled trail on 362 subjects from nine residential care facilities. The study examined the efficacy of a multifactorial fall prevention program (comprising staff education, environmental adjustment, exercise, drug review, aids, hip protectors, and post-fall problem-solving conferences) in reducing risks of fall and injury of older people with different levels of cognition. Results indicated that while the program had a significant effect on the group with higher level of cognition (MMSE = 19 or above), it had no impact on the lower MMSE group. The number of femoral fractures in the lower MMSE group was reduced but this may be explained by the use of hip protector in this group. The findings of Jensen and colleagues were corroborated by a randomised controlled trail of 274 cognitively impaired older people from two accident and emergency departments in the UK (Shaw et al, 2003). The researchers found that multifactorial intervention after a fall was less effective on older people with a lower level of cognition and dementia.

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8.4.3 Hygiene and Personal Care One systematic review was identified (see Table 8.5) Table 8.5 Systematic review of oral hygiene in dementia Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

Chalmers and Pearson1

Review of oral hygiene care for people with dementia in residential aged care facilities

306

1980-2002

2005

Chalmers and Pearson (2005a) reviewed publications between 1980 and 2002 on managing the oral health of residents with dementia in long-term aged care facilities. They found that poor oral health was a common problem in this group of people. Specifically, residents with dementia are prone to develop coronal and root caries, gingivitis, plaque accumulation, oral mucosal lesions and denture problems. Currently there is no agreement among practitioners on what is the best oral hygiene care strategy for this group of clients. There is also limited evidence to support the efficacy of existing approaches. The reviewers suggested the use of a combined preventive approach that includes the use of topical and systemic fluorides, saliva stimulants and substitutes, oral products that contain chlorhexidine gluconate and regular removal of dental plaque using manual cleaning. These practices had been proved to be successful in other groups of older persons. The employment of oral assessment screening tools by nurses was also recommended. The Brief Oral Health Status Examination (BOHSE) is the only published, validated and reliable assessment tool that was developed specifically for use in long-term care settings. Two interventional studies and one observational study on dressing and bathing are identified: Cohen-Mansfield and colleagues (2006) conducted detailed observation on the dressing routines of twenty nursing home residents with dementia. They recorded not only the time the residents spent on dressing but also details of the physical environment, timing, dressing articles, as well as participation and communication between staff members and residents in the process. The researchers found that although the task of assisted dressing was complex and involved individually designed interventions, the caring staff had managed to complete it fairly quickly. However, there was insufficient time for contact and communication between residents and staff. It was emphasised that assisted dressing is an opportunity for people with dementia to experience a therapeutic encounter as well as achieving a sense of independence. Rogers and colleagues (1999) examined the efficacy of a behavioural intervention program on improving dressing performance and other ADLs of nursing home residents. Eighty-four subjects were provided with usual care for five days. Then they received a functional rehabilitative program that integrated behavioural and occupational therapy techniques for another five days. 1 The authors published a slightly different version of this review elsewhere (Chalmers and Pearson 2005b). This review is excluded for the reason of duplication.

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Finally, the subjects received a follow-up habit training of 15 days aimed at reinforcing the intervention. Overall, the subjects showed a 26% gain in self-dressing as well as increases in both independence in performing dressing subtasks and participation in assisted dressing. An increase in active participation and a decrease in disruptive behaviour of the subjects during other ADLs was also observed. Sloane and colleagues (2004) designed a randomised controlled trial to examine the effectiveness of person-centred showering and towel-bath in reducing agitation of people with dementia during bathing. The study involved 73 participants from fifteen nursing homes. Results showed that all measures of agitation and behavioural symptoms declined remarkably following introduction of the interventions. Discomfort scores of the two experimental groups also declined significantly compared with that of the control group. This dramatic reduction in symptoms indicated that these behavioural problems were likely a product of interaction between person and social environment. Neither intervention had adversely affected skin condition or led to accumulation of pathogenic bacteria. The findings of this study support the use of these bathing techniques in institutional care facilities. 8.4.4 Driving Driving is a contentious issue in dementia care. In many societies, driving is a symbol of independence and the decision to suspend someone’s licence has profound social, financial and emotional consequences for the individual and his or her family. While previous studies produced conflicting results on the influence of normal ageing on the ability to drive, scientists do reach a consensus on the profound impact of advanced dementia and driving. Deficits in memory and impairments in judgement, attention and visual-spatial skills would significantly reduce the driving ability of individuals with dementia (Hakamies-Blomqvist & Peters, 2000; Lloyd et al., 2001). The exact point at which the ability to drive is lost varies greatly however. The importance of cognitive decline in traffic accident causation has stimulated interest in the study of driver diagnostics, especially the development of objective and reliable testing that can determine whether an older driver with dementia is safe to operate a vehicle or not. Two systematic reviews of driving in people with dementia were identified (see Table 8.6). Table 8.6 Systematic review of driving in dementia Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

Dubinsky et al.

Rates of crashes and driving performance of people with Alzheimer’s disease

14

1966-1998 with articles before 1966 added manually

2000

Adler et al.

Assessment of driving performance of persons with dementia

11

1994-2003

2005

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Dubinsky and colleagues (2000) reviewed fourteen studies published between 1966 and 1998. To compare research findings, they converted measurements of dementia severity used in these studies to the Clinical Dementia Rating (CDR) scale which is a functional assessment tool. Results indicated that drivers with Alzheimer’s disease had an increased crash rate as well as significant impairment in driving ability. In particular, this group of drivers had suffered from significant visual processing problems. For drivers at CDR stage 0.5, they had an increased risk of accidents similar to those in the sixteen to nineteen year age group. For those at CDR stage 1.0, their risk of crashing was greater than any other group of drivers in society. Adler and colleagues (2005) examined eleven studies that focused on assessing driving performance of people with dementia. Different approaches or combination of approaches to assessment including road tests, driving simulators and neuropsychological tests were compared. Existing evidence supports that neuropsychological tests on specific cognitive domains are correlated with driving performance. Testing for items like visual spatial skills, attention and reaction time of the driver was recommended to be included in future driving-related evaluation. Whilst existing literature has not agreed on a standardised and reliable approach to assessing driving safety in people with dementia, several general guidelines for assessment and management exist: • Discontinuation of driving for drivers with a severity of CDR 1 or greater

(Dubinsky et al., 2000); • Close monitor and regular assess those drivers with a severity of CDR stage 0.5

(Dubinsky et al., 2000) or a MMSE scores less than 24 (Adler et al., 2005); • Reassessment of driving ability of people with dementia once every six months

(Adler et al., 2005; Dubinsky et al., 2000); • Involve occupational therapist in the assessment process (Adler et al., 2005); • Encourage family member to monitor and communicate any declines in driving

performance of people with dementia to professionals or service provider (Adler et al., 2005; Dubinsky et al., 2000).

8.5 Behavioural and Psychological Symptoms of Dementia Challenging or disruptive behaviours such as wandering, agitation, aggression and noisiness occur frequently in people with dementia. These behaviours are referred to as the Behavioural and Psychological Symptoms of Dementia (BPSD). The problem of BPSD has attracted much attention over the years and there is a huge stock of literature plus a wide variety of interventions proposed to manage it2. Eight systematic reviews of interventions for BPSD were identified (see Table 8.7).

2 This section focuses on psychosocial approaches to prevention and treatment of BPSD. Refer to Section 7 for pharmacologic interventions for BPSD.

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Table 8.7 Systematic reviews of interventions for BPSD Systematic Review

Focus No. of Studies Reviewed

Period of Search

Date Published

Opie et al.

Efficacy of psychosocial approaches to behaviour disorders in dementia

43

1989-1998

1999

Cohen-Mansfield

Efficacy of psychosocial interventions for inappropriate behaviours in dementia

83

Not specified

2001

Bates et al.

Effects of psychosocial interventions for people with a mild dementia

4

Up to June 2002

2004

Verkaik et al.

Effects of psychosocial methods on depressed, aggressive and apathetic behaviours

19

Up to February 2003

2005

Finnema et al.

Effects of emotion-oriented approaches in the care for people with dementia

45

1985-1997

2000

Forbes et al.

Efficacy of bright light therapy in managing sleep, behaviour, mood, or cognitive disturbances

5 identified and 3 included

Up to December 2005

2004

Wang and Moyle

Efficacy of physical restraints on people with dementia in long-term care setting

42

1992-2003

2005

Price

Efficacy of subjective barriers to prevent wandering

39 identified and 0 included

Up to 2005

2001

Opie et al. (1999), Cohen-Mansfield (2001), Bates et al. (2004), Verkaik et al. (2005) and Finnema et al. (2000) reviewed a wide variety of psychosocial interventions for BPSD. Table 8.8 summarises the details of the intervention variables and findings of these systematic reviews. Overall, most of the studies examined in these reviews reported positive results on the reduction or control of BPSD. As these studies are different in scope and quality and many of them adopted diverse outcome measurements with no control procedures, it is very difficult to compare findings and to make definitive recommendations on particular treatment. Moreover, given all of them were conducted in nursing or residential care facilities, little is known about the effect of the interventions in the home situation. This is an area that requires further investigation.

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Table 8.8 Psychosocial Interventions used with patients with BPSD Systematic Review

Intervention Variables

Summary of Findings

Opie et al.

Environment Alteration Activity Programs Exposure to Music and Voice Behaviour Therapy Massage and Aromatherapy Light Therapy Multidisciplinary Teams Caregiver Education

There was evidence that supports the effectiveness of activity programs, music, behaviour therapy, light therapy, carer education and environment alteration. Findings on multidisciplinary teams, massage and aromatherapy were inconclusive.

Cohen-Mansfield

Sensory Enhancement/Relaxation Social Contact (Real or Stimulated) Behaviour Therapy Structured Activities Environmental Interactions Medical/Nursing Care Interventions Combination Therapies

For every major category of intervention type, 91% reported a beneficial outcome and 53% reported a significant improvement.

Bates et al.

Reality Orientation Procedural Memory Stimulation Counselling

Evidence was found on the effect of reality orientation in improving cognitive ability. No evidence was found for the effectiveness of counselling and procedural memory stimulation.

Verkaik et al.

Validation/Integrated Emotion-Oriented Care Validation/Reality Orientation Multi Sensory Stimulation/Snoezelen Reminiscence

Some limited evidence supported the effectiveness of multi sensory stimulation/snoezelen, behavioural therapy and psychomotor therapy groups.

Finnema et al.

Validation Sensory Stimulation/Integration Simulated Presence Therapy Reminiscence

There were an increase in social interaction and decrease of behavioural problems of the people with dementia.

Generally, the necessary ingredients for any programs in preventing and minimising BPSD appear to be a relaxed and comfortable environment, properly trained staff, and well-planned and executed activities. This finding lends support to the claim that BPSD is a product of interaction between person and environment.

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The systematic review conducted by Forbes and colleagues (2004) focused specifically on the efficacy of bright light therapy in managing sleep, behavioural and cognitive disturbances in people with dementia. Five studies that met the selection criteria were identified but two were excluded from the review for reporting or technical problems. The reviewers concluded that available studies were of such a poor quality that there was insufficient evidence to support the effectiveness of the therapy. Whilst there is no definite answer on the efficacy of intervention, there is an ever-growing consensus among researchers that the use of physical restraint is not an effective means to control BPSD. Wang and Moyle (2005) reviewed studies on this topic published between 1992 and 2003. They found no evidence to support the practice on increasing protection or reducing the risk of falls in people with dementia. In contrast, the use of physical restraint was associated with increase in injury, hospitalisation, agitation, psychological traumas and further decline in cognition of people with dementia (cf. Marini, Vulcano, & Costantini, 1998). Healthcare practitioners were recommended to consider alternative approaches to manage BPSD. The use of environmental enhancements and manipulation is one of such alternatives. In recent years, there is a rise in interest in the effectiveness of ‘subjective barriers’ like sounds, images and smells, for managing BPSD. Price and colleagues (2001) conducted a systematic review specifically on the efficacy of subjective barriers on preventing wandering in cognitively impaired people. They identified 39 studies but for methodological reasons none were deemed appropriate for inclusion in the review. In other words, no evidence was found to support this intervention. The reviewers also expressed concern about the possibility that subjective barriers may cause fear, anxiety or bemusement in the client. 8.6 Accessing the Perspective of People with Dementia Over recent decades, service provision for people with dementia has been constructed from the perspective of healthcare professionals and carers. Little effort has been made to involve users in the process of service design and evaluation. The rise of person-centred dementia care in recent years has reversed this trend and practitioners are more attuned to the experience of people with dementia and the need to involve them. This change is reflected in the literature. Depending on the stage of illness, different methods can be used to solicit opinions and gather information from people with dementia (Cheston, Bender, & Byatt, 2000). Three systematic reviews of this area were identified see (Table 8.9).

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Table 8.9 Systematic reviews of instruments to ascertain the perspective of patients with dementia Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

Beavis et al.

Efficacy and methodological considerations of dementia care mapping

9

1992-2001

2002

Brooker

Efficacy of dementia care mapping

34

1993-2005

2005

Ettema et al.

Quality of life instruments used in dementia

38

1990-2003

2005

Given dementia is associated with cognitive decline, memory and language difficulties, many of the traditional methods of gathering opinion are not feasible when used with people with advanced dementia. Observation remains an important method of gaining views and experiences of this group of clients (Brooker, 1995). Dementia Care Mapping (DCM) is probably the most widely used method for evaluating the quality of care and well-being of residents in formal dementia care settings. Beavis and colleagues (2002) conducted a systematic review of DCM. They concluded that while DCM might suffer from sampling problems, a failure to account for confounding variables, as well as being a very time- and resource-consuming method, it remains a moderately valid instrument with relatively good face validity and reliability. Brooker (2005) consulted 34 articles identified from the DCM bibliographic database at the University of Bradford between the period of 1993 and 2005. Existing evidence supports that DCM has concurrent validity with other quality of life measures. It is also possible to achieve an acceptable level of consistency between different assessors with regular checks from a ‘gold standard mapper’. There is evidence that the use of DCM in an organisational framework improves levels of well-being of the client. Overall, the review affirms the unique position of DCM as both an evaluative instrument and a vehicle for practice development in person-centred dementia care. More controlled longitudinal study plus the construction of a large international database of DCM results were recommended to further improve and develop the method. Ettema and colleagues (2005) reviewed the literature on quality of life in the older population, chronic disease and dementia. They concluded that a proper definition of quality of life should reflect the adaptation of different domains of life in following the advance of dementia (cf. Smith et al., 2005). At present there is no gold standard for measuring quality of life in people with dementia and it is unclear whether quality of life in different stages of dementia can be measured by one single instrument.

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Ettema and colleagues (2005) examined 38 studies on quality of life measurement published between 1990 and 2003 in which they identified six dementia-specific measures and eight generic measures. These measures varied considerably in scale content and method of data collection. Affect, self-esteem, activities, enjoyment and social interaction are domains that are found to be associated with dementia-specific instruments. These instruments are particularly relevant in evaluating the experience of people with dementia. In contrast, generic measures tend to focus on health domains and they are more suitable in situations where comparison of health-related quality of life between different populations is made. 8.7 Support for Carers 8.7.1 Prevalence and Nature of Caregiver Burden Three systematic reviews of caregiver burden were identified (see Table 8.10). Table 8.10 Systematic reviews of caregiver burden Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

Cuijpers

Prevalence of depressive disorders among carers of people with dementia

10

Up to May 2004

2005

Black and Almeida

Association between BPSD and burden of care

30

1990-2001

2004

Gottlieb and Wolfe

Relation between ways of coping and health and well-being of the carers

17

1984-2000

2002

Cuijpers (2005) reviewed ten studies (790 subjects in total) on carers of people with dementia. Of the 790 subjects, 22.3% or 176 were diagnosed with depressive disorder. The prevalence rate of depressive disorder among dementia carers (0.15 – 0.32) was higher than that found in studies of older people. One of the studies recorded an incidence rate of depressive disorders of 0.48, while another two reported a 16.4% and 7.3% increase in cases from the baseline. Data from three studies that reported differential rates of males and females suggested that prevalence of the disorder in men was lower than in women. Compared to the control groups, the range of relative risk of carers having a major disorder was 2.80 to 38.68. As sample size of the studies was small, there were no indications of different prevalence rates for different types of carers.

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Black and Almeida (2004) conducted a systematic review on the association between BPSD and burden of care. The review covered 30 studies with cross-sectional data, twelve studies with longitudinal data, and five studies that examined the relationship between BPSD, caregiver burden and rate of institutionalisation. Meta-analysis of data found a direct correlation between BPSD and caregiver burden (pooled correlated coefficient = 0.57), a moderate correlation between BPSD and General Health Questionnaire score of the caregiver (pooled correlated coefficient = 0.41), and a poor to moderate correlation between BPSD and depression of carers (pooled correlated coefficient = 0.30). Due to the small sample size and methodological problems of the studies, little can be concluded about the relationship between specific BPSD symptoms and caregiver depression, or about particular risk factors for subgroups of carers. For the same reason, the relationship between BPSD and caregiver burden over time remains unclear. Research results did indicate that caregiver variables may be more important than BPSD in contributing to institutionalisation of people with dementia (cf. Dunkin & Anderson-Hanley, 1998). Gottlieb and Wolfe (2002) examined seventeen studies on relations between coping strategies and health and well-being of the carers. These studies were cross-sectional and they adapted a wide variety of coping and outcome measures, making comparison of results very difficult. The reviewers did manage to identify a few common patterns in the findings: wishfulness and fantasy were negatively correlated with indicators of mental health of the carers (seven studies), practical problem-solving skills and utilising social support were associated with better mental health (four studies) and less self-blame (two studies). No single way of coping that was consistently associated with health and well-being of the carers was found. 8.7.2 Interventions to Reduce Caregiver Burden Five systematic reviews and three meta-analyses on the efficacy of social, behavioural and psychosocial interventions were identified (see Table 8.11). Systematic reviews conducted by Cooke and colleagues (2001), Pusey and Richards (2001) and Schulz et al. (2002) covered a wide variety of intervention components. These included general education, discussion, support group, social skills training, social support, activities, cognitive problem solving, cognitive therapy, cognitive skills, practical care-giving skills, record keeping, relaxation, behaviour therapy, psychotherapy, counselling, and respite service. Overall, findings were limited and conflicting. The interventions that showed some potential utility were those that contained behavioural (such as strategies for behaviour management) and cognitive or social (such as problem solving and social support) elements. There is no single method for achieving clinically significant effects across different types of caregivers. It is possible that the effect of interventions is dependent upon the nature of the relationship between the caregiver and service recipient. The efficacy of interventions was greater when increasing knowledge of illness of the caregiver was targeted as a goal of treatment. Based on a systematic review of 41 studies, Schulz and colleagues (2005) suggested that combined interventions that target simultaneously multiple sources of distress and individuals (caregiver or care recipient) tend to have greater effect than a single intervention that focuses only on a particular issue. The effect of an intervention also tended to be larger if it was targeted to increase knowledge and skill of the carer than to reduce caregiver burden and depression (cf. Schulz et al., 2003).

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Findings of meta-analysis lend further support to conclusions of the systematic reviews. Brodaty and colleagues (2003) re-calculated results of 30 controlled studies published between 1985 and 2001. They found that at the most recent follow-up, interventions for carers showed modest but significant reductions in caregiver psychological distress (mean effect size = 0.31), improvement in caregiver knowledge (mean effect size = 0.51) and mood (mean effect size = 0.68) of the people with dementia. The reviewers found no evidence for a reduction of caregiver burden. Table 8.11 Systematic reviews of interventions to reduce caregiver burden Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

Schulz et al.

Psychosocial treatment for carers and environmental and behavioural interventions for people with Alzheimer’s disease, stroke, and mental illness

51 (41 on dementia caregivers)

1999-2005

2005

Schulz et al.

Clinical significance of caregiver intervention research

43

1996-2001

2002

Cooke et al.

The effectiveness of psychosocial interventions for carers of people with dementia

40

1970-2000

2001

Pusey and Richards

The effectiveness of psychosocial interventions for carers of people with dementia

30

1967-1999

2001

Flint

Effects of respite care on patients and carers

4

1975-1994

1995

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Table 8.12 Meta-Analyses of interventions for carers of people with dementia Meta-analysis

Focus

No. of Studies Analysed

Date Published

Brodaty et al.

The effectiveness of psychosocial interventions for carers of people with dementia

30 (34 interventions)

2003

Acton and Kang

Treatments to reduce the burden of caregiving for an adult with dementia

24

2001

Lee and Cameron

Effects of providing respite care for people with dementia and their carers

3

2004

Similarly, the meta-analysis of Acton and Kang (2001) on 24 studies of 27 treatments found that the interventions as a whole (support group, education, psychoeducation, counselling, respite-care, and multicomponent interventions) had no impact on caregiver burden. Multicomponent intervention combining various strategies was the only category of treatment that reduced subjective caregiver burden (weighted pooled effect size = 0.46). The researchers recommended that future studies replace the multidimensional and global concept of caregiver burden with better evaluative variables. Respite care is a blanket term that covers a wide variety of services. Flint (1995) conducted a systematic review on its effect on people with dementia and their carers. Five controlled studies published between 1975 and 1994 were examined. Little evidence was found on the effectiveness of respite care on reducing caregiver burden and on improving cognition, function, physical health, or rate of institutionalisation of the care recipient. The meta-analysis conducted by Lee and Cameron (2004) on data of three randomised trials also found no significant effect of respite care on six caregiver outcome variables. However, studies on specific components of respite care did find positive effects. For instance, a quasi-experimental study conducted by Zarit and colleagues (1998) found that the use of adult day care in both short (three months) and long (twelve months) term resulted in lower levels of caregiving-related stress and better psychological well-being in family caregivers. There is also evidence that regular use of day care service is effective in restructuring caregiving time and in providing respite to family members (Joseph E. Gaugler et al., 2003a; 2003b). Finally, findings of caregiver interviews suggested that it was not total amount of help received but specific types of help (such as assistance with ADL care and overnight problems) that delayed nursing home placement of cognitively impaired older people (J. E. Gaugler et al., 2000).

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8.8 Housing Provision and Environmental Design Two systematic reviews on housing provision and environmental design for people with dementia were identified (see Table 8.13). Table 8.13 Systematic review of housing provision and environmental design for people with dementia Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

O’Malley and Croucher

Knowledge and gaps in housing provision for elderly people with dementia in the UK

175

Early 1980s onwards

2005

Day et al.

Design of the physical environment for people with dementia

53

1980 onwards

2000

8.8.1 Housing Provision O’Malley and Croucher (2005) conducted a scoping review on housing provision for older people with dementia in the UK. Findings and discussion were grouped under ordinary/domestic settings and special/collective settings. Existing data indicate that a majority of people with dementia are living in the community. However, large-scale research into the needs of these people and their carers, as well as the services that support them, is lacking. In general, occupational therapy-based modifications and visits were found to be effective in maintaining people with dementia in domestic settings. Regarding the special/collective settings, behavioural problems, cognitive decline and increasing care burden were significant predictors for the transition of people with dementia to long-term care facilities. The optimum size of a residential unit is not clearly determined, or the effectiveness of specific design features. While people at different stages of dementia do require different types of accommodation, the current evidence base offers no definite answer to the questions of efficacy of housing types, or whether a particular type of housing is indicated for different stages of dementia.

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8.8.2 Environmental Design Day and colleagues (2000) reviewed existing literature on four aspects of environmental design for people with dementia: planning principles, environmental attributes, building organisation, and specific rooms and activity spaces. They came up with the following recommendations: • Incorporate small size units; • Separate non-cognitively impaired residents from people with dementia; • Offer respite care as a complement to home care; • Relocate residents, when necessary, in intact units rather than individually; • Incorporate non-institutional design throughout the facility and in dining rooms in

particular; • Moderate levels of environmental stimulation; • Incorporate higher light levels, in general, and exposure to bright light, in

particular; • Use covers over panic bars and door knobs to reduce unwanted exiting; • Incorporate outdoor areas with therapeutic design features; • Consider making toilets more visible to potentially reduce incontinence; • Eliminate environmental factors that increase stress in bathing. To summarise, current research and discussion on housing provisions and design of the built environment have focused on situations in institutional or residential care facilities. Relatively little is known about housing needs and problems of people with dementia in domestic settings. Given the growing consensus among practitioners that moving care from public institutions to the community enhances the sense of independence and self-reliance of people with dementia, more research is needed to explore housing needs and design problems of these people in a domestic environment. 8.9 Cultural Differences in Carer Experience Four systematic reviews and one meta-analysis were identified (see Table 8.14). Torti and colleagues (2004) examined 93 studies across three geographic regions (North America, Europe, Asia and Australia). They found that caregivers across various cultures have faced substantial and measurable problems, with behavioural disturbance being the primary source of stress or depression. The magnitude of caregiver burden was found to be large in the early phase of dementia but reduced over time when carers adapted to the caregiver role. Research findings supported that there were differences in expectation and resources to cope with caregiver burden between societies, as well as between males and females. Women, particularly those from Asian societies, had borne a heavier burden than men.

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Overall, the evidence points to the importance of understanding cultural differences in designing effective interventions and services to support people with dementia and their carers. Connell and Gibson (1997) reviewed twelve studies on racial, ethnic and cultural differences in dementia caregiving published between 1985 and 1995. Janevic and Connell (2001) followed up and examined another 21 studies on the same areas published between 1996 and 2000. Existing evidence shows that non-white caregivers were more likely to be an adult child, friend, or other family member than a spouse of the care recipient. They were also less depressed, had stronger beliefs about filial support, had derived more meaning from the care experience, and were less likely to institutionalise their relative than white caregivers. The review of Connell and Gibson found that non-white caregivers were more likely to use religion or faith as coping strategies but this finding was not supported by the subsequent review. Janevic and Connell also noticed that evidence on differences in social support between white and non-white caregivers was mixed. This implied that non-white caregivers may not have more informal support available from existing social networks. Table 8.14 Systematic reviews of cultural factors in dementia Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

Torti et al

Influence of ethnic, cultural, and geographic factors on dementia caregiver burden

93

Up to June 2002

2004

Janevic and Connell

Racial, ethnic and cultural differences in dementia caregiving

21

1996-2000

2001

Connell and Gibson

Racial, ethnic and cultural differences in dementia caregiving

12

1985-1995

1997

Daker-White et al.

Service needs, provision, and models of good practice of dementia care of minority ethnic groups

67

1985-1999

2001

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Table 8.15 Meta-analysis of cultural factors in dementia Meta-analysis

Focus

No. of Studies Analysed

Date Published

Mahoney et al.

Cross-cultural similarities and differences on impressions of the onset and diagnosis of dementia

3

2005

Daker-White and colleagues (2002) reviewed 67 papers concerning dementia care in minority ethnic groups published between 1985 and 1999. Two-thirds of these articles originated in the US and of these about 40% reported on the experiences of African-Americans. Ethnic minorities were found to have under-used formal dementia care services. It was language skill rather than ethnic membership per se that was the most important reason behind the failure in accessing services. This problem was especially prominent in first generation migrants. The reviewers found no evidence to support the claim that cognitive assessment tools were culturally biased. Findings regarding the claim that African-American carers showed less depression were also equivocal. There was evidence that minority groups in the US did not prioritise dementia as a health problem. People from an Asian background might reject dementia as an acceptable diagnosis because of the stigma associated with the disease. While in general outreach work, cultural awareness and sensitivity training for staff were considered effective interventions for minority groups, there was little consensus on whether specialist services need to be provided to them. Mahoney and colleagues (2005) conducted a meta-analysis of data collected from three qualitative studies involving a total of 22 caregivers (seven African American, eleven Latino, and four Chinese). The study compared experiences of caregiving for older persons in the early stage of Alzheimer’s disease in these three cultures. Findings revealed that there were striking cross-cultural similarities in the initial reaction to the disease. In particular, a lack of knowledge about dementia was common in these three communities and the caregivers tended to normalise the symptoms of memory loss or decline in cognition as a ‘normal’ effect of ageing. The failure of physicians to recognise the disease was another problem that cut across language and ethnic differences. Given the existence of many similarities in needs among the three ethnic communities, it should be possible for service providers to offer quality improvements in dementia services and education across cultures. As the symptoms of dementia progressed, cultural differences began to shape the experience and response of the caregivers. The African Americans would pay special attention to the insensitivity or lack of response from the clinicians. The Chinese in contrast were concerned about the stigma associated with the illness. The Latinos were worried that acculturation to western values would eventually end the traditional practice of family care.

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8.10 Ethical Issues in Dementia Care 8.10.1 Overview Our commitment to respecting the rights of people with dementia and the rapid expansion of services for them offer a powerful incentive to study related ethical issues. These issues arise in just about every aspect of care for people with dementia, from diagnosis to death (Post, 2000). Over the past two decades there has been a substantial increase of literature in this area. Baldwin and colleagues (2003) conducted a bibliometric analysis of relevant materials between 1980 and 2000. Through an examination of the co-occurrences of terms appearing in keywords, titles and abstracts of published articles, they identified the following trends: 1. The focus on ethical issues in dementia was intensifying, with 77% of the articles

in this area published between 1991 and 2000; 2. ‘Professional care’, ‘end of life issues’, ‘decision making’ and ‘treatment’ were the

four thematic categories that appeared consistently over the period; 3. New areas of interest such as ‘driving’, ‘resource allocation’ and ‘genetics’ had

emerged between 1991 and 2000. In particular, ‘family’ had moved from the periphery to become a major area of discussion over this period. 32.1% of the literature dealing with this issue was based on research;

4. There was little research into the day-to-day exercise of power in the caregiving

relationship and into ethical issues faced by different ethnic groups. The increase and change in focus of study on ethical issues not only reflects the advance in technology, it also signifies structural changes in health care policy over the past decades. In particular, the shift of care from medical to community settings and the move towards person-centred dementia care has helped bring the family context into the centre of ethical debates. Nevertheless, mainstream studies on ethical issues in dementia have been dominated by the perspectives of professionals, with no systematic research undertaken from the viewpoint of carers (J. C. Hughes, Hope, Savulescu, & Ziebland, 2002). In reality, the broad range of ethical issues concerning caregivers is far less predictable and more varied than the professional literature has suggested (cf. J. Hughes & Baldwin, 2006). 8.10.2 Disclosure of a Diagnosis of Dementia One systematic review of attitudes and practices of diagnosis disclosure was identified:

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Table 8.16 Systematic review of the disclosure of a diagnosis of dementia Systematic Review

Focus

No. of Studies Reviewed

Period of Search

Date Published

Bamford et al.

Evidence regarding diagnostic disclosure in dementia

59

Up to September 2003

2004

Bamford and colleagues (2004) examined a wide range of beliefs and attitudes, as well as reported practices regarding dementia disclosure. They concluded that the process of disclosing the diagnosis was neither simple nor straightforward to many professionals, carers and people with dementia. Findings on the benefit or adverse effect of diagnostic disclosure were also inconsistent. Despite the absence of a clear and shared definition of disclosure, quantitative studies have offered little help in elucidating differences in perspectives or practices. Although diversity in opinion and practice exists, a number of common patterns can be identified: • People with dementia are less often told the diagnosis than are family members; • There is widespread use of euphemisms such as ‘memory loss’ and ‘confusion’

when practitioners disclose the diagnosis to persons with dementia; • Family members generally prefer not to inform people with dementia; despite

agreeing they would want to know the diagnosis if they were in that situation; • Family members tend to believe either people with dementia will be distressed by

the diagnosis or that they are incapable of understanding the information; • People with dementia who have been told the diagnosis generally feel that this is

preferable, although some may find this information upsetting. The literature review of Carpenter and Dave (2004) covering the period between 1972 and 2002 arrived at a similar conclusion. While there is a growing consensus among professionals and care organisations in favour of disclosing diagnosis to the client, in actual practice there is a wide variability in all aspects of disclosure. This finding indicates the existence of a significant discrepancy between guidance and practice of disclosure in the field.

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8.10.3 Decision-Making Ability of People with Dementia Dementia is an illness associated with memory loss and impairments in cognitive skills and judgement. It affects the ability of the patient to make proper decisions and choices in their daily lives. An understanding and proper assessment of the level of ‘awareness’ and ‘competency’ a client retains are important in untangling the complex issue of decision-making. Studies on this issue suggest that ideas such as ‘awareness’ and ‘competency’ are separate and multifaceted concepts and they have to be understood in the contexts of cognitive functioning, psychological response and social interaction (K. Black & Osman, 2005; Clare & Woods, 2005; Woods & Pratt, 2005). Given this complexity, however, awareness and decision-making capacity of people with dementia are often informally or inconsistently assessed in routine clinical practice. Misconceptions about these concepts among professionals are also common. Volicer and Ganzini (2003) conducted a survey of four groups of professionals involved in treatment of Alzheimer’s disease. The subjects were asked about their views on standards for evaluating decision-making capacity of the patients. A majority (n = 481) endorsed five out of the six ‘elements’ presented to them which were extracted from existing standards used in the field. These elements were ‘able to appreciate the consequences of the decision for him/herself’ (98% subjects agreed), ‘able to indicate yes or no to a question’ (87%), ‘able to provide rational reasons for the decision’ (80%), ‘able to explain the treatment’s alternatives, risks, and benefits’ (80%), ‘makes decision that seems reasonable’ (79%). Given a majority of the respondents agreed on these basic elements, only 34.5% of them endorsed all five of them. This result indicated that there was no uniformity among practitioners in the use of standards for evaluating decision-making capacity and the assessment process might be subjective and inconsistent. The researchers suggested two solutions to solve this problem - the use of formal instruments to standardise evaluation and education of professionals in general principles guiding evaluation. Etchells and colleagues (1999) compared results of specific (Aid to Capacity Evaluation or ACE) and non-specific (Standardised Mini-Mental Status Examination or SMMSE) capacity assessment tools with results of expert assessments of patient capacity to consent to treatment. Two independent assessments of the ACE were also administered to test the reliability of the tool. Findings based on 100 inpatients of a medical ward indicated that both results of the specific and non-specific assessment tools agreed closely with expert assessments. The researchers recommended the use of these two instruments as initial steps in evaluation of a patient’s capacity to make medical decisions. Molloy and colleagues (1996) examined the ability of older people to complete an advance directive. They compared results of five different measures of capacity of 96 subjects living in institutional care facilities. The five measures comprised of two reference standards (the competency clinic assessment and geriatrician assessment) and three screening instruments (a generic instrument designed for any advance directive, a specific instrument for the ‘Let Me Decide’ advance directive, and the SMMSE). All measures except the competency clinic assessment were administered twice to half of the subjects to test their reliability. The researchers found that results of the three screening instruments were highly reproducible. In particular, there was a high agreement between the SMMSE score and the reference standards. Both the generic and specific instruments were able to predict ratings of the reference standards. Overall, the findings support the practicality of using simple and flexible screening instruments in assessing decision-making capacity of people with a broad range of intellectual ability.

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Ganzini and colleagues (2003) asked 395 consultation-liaison psychiatrists, geriatricians, and geriatric psychologists to rate and rank a list of common pitfalls and misunderstandings in assessment of decision-making capacity of patients. They found that misunderstandings and knowledge deficits regarding this issue were very common. The assumption that ‘if the patient lacks capacity for one type of medical decision, he or she lacks capacity for all medical decisions’ (36%), and the lack of understanding of the fact that ‘capacity or incapacity is not “all or noting” but is specific to a decision’ (35%) were two pitfalls cited by the respondents as the most important issues for the education of healthcare workers. Other common misconceptions or false beliefs that the researchers identified were: • decision-making capacity (a clinical assessment) and competency (a legal

determination of a formal judicial proceeding) are the same; • cognitive impairment equals lack of decision-making capacity; • lack of decision-making capacity is a permanent condition; • only mental health experts can assess decision-making capacity; • there is no need to assess decision-making capacity unless the person with

dementia goes against medical advice; • the lack of decision-making capacity can be presumed when people with

dementia go against medical advice; • people with dementia who have not been given relevant and consistent

information about their treatment lack decision-making capacity; • all people with dementia who have certain psychiatric disorders lack decision-

making capacity; • people with dementia who have been involuntary committed lack decision-making

capacity. An understanding about these misconceptions highlights areas for further professional education. 8.11 Summary Dementia is one of the biggest health challenges facing our society. Although there have been notable advances on treatment of the disease in recent years, it will remain a significant contributor to demand for social and health services in years to come. This section summarises research findings in the area of social support and care over the past decade.

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While it has highlighted effective services and treatment, this section also reveals a lot of gaps in the evidence base. Different research design and methodology, incompatible outcome measures, and small sample size are common problems that make it very difficult to compare research findings. The nature of dementia care also presents particular problems for the researcher as many interventions cannot be investigated by the controlled trial method for obvious ethical reasons. There are many practices that practitioners believe work, but which have not been subjected to rigorous evaluation. The absence of evidence does not mean that these practices are ineffective, only that we do not know yet. More research evidence is needed to inform the development of better guidelines, protocols and guidance for dementia care/ services. While the randomised controlled trial is considered the gold standard to determine efficacy of treatments, qualitative methods remain an important tool for understanding experiences and for improving user compliance and involvement (Gibson, Timlin, Curran, & Wattis, 2004). Our challenge in the future is to have better designed and more rigorous research on different aspects of dementia care. At the same time, we need to get research into practice and to make constructive use of the experiences of care professionals.

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9.0 Gaps in the Evidence and Recommendations for Future Research Although the substantial international and national research efforts of the past decade have vastly improved our knowledge and understanding of dementia, as demonstrated in this review, gaps in the evidence base remain regarding almost every aspect of dementia. For example, there are no epidemiological studies in many areas of the world; the cellular-molecular mechanisms that underlie the development of brain pathology are not understood; the treatments that are currently available are limited in their effectiveness; and a definitive diagnostic tool does not currently exist. Gaps in the existing evidence base are outlined in this final section for each of the following key areas: epidemiology; aetiology and pathophysiology of dementia; diagnosis and assessment; risk and prevention of dementia; treatments; care and support for people with dementia and their carers. The list is not intended to be exhaustive nor definitive and the proposed questions are not listed in order of priority – rather its purpose is to highlight important indicative areas for future research in dementia. 9.1 Epidemiology There is a lack of high quality epidemiological research in many parts of the world, particularly in India, Africa, South America and parts of South-East Asia (Ferri et al, 2005). The variability of prevalence estimates of dementia syndromes indicates a need for epidemiological studies in different populations using standardised diagnostic criteria. Greater understanding is also required of geographical and regional variations in risk and protective factors. Indicative questions related to prevalence might include:

• Does the prevalence of the dementias (including dementia with Lewy bodies, frontotemporal dementia and mild cognitive impairment) vary across different regions?

• What is the relative prevalence, in community populations, of the different

types of pathology evident in dementia?

• What is the prevalence and incidence of dementia and its subtypes among the Aboriginal and Torres Strait Islander peoples of Australia?

• Is there a true difference in the prevalence of AD and other dementia

subtypes for males and females?

• What is the prevalence and incidence of delirium in patients with chronic cognitive impairment?

9.2 Aetiology and Pathophysiology of Dementia Research into the possible multiple pathways to the development of dementia is still needed, including investigations into the genetic transmission of dementia syndromes. In particular, it is important to know whether the processes that lead to dementia are distinct from normal effects of ageing. A range of indicative questions as they relate to pathology, proteins, Lewy bodies and cerebrovascular disease can be identified:

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Neuropathology • What are the necessary steps in AD pathogenesis that, if inhibited, would

slow or prevent dementia? Which of these steps are most amenable to therapeutic inhibition?

• What cellular-molecular mechanisms lead to brain pathology?

• What is the base rate of amyloid plaques and neurofibrillary tangles in the

healthy older population?

• What role does inflammation play in the pathogenesis of dementia?

• Is neuroinflammation secondary to the AD process or does neuroinflammation directly contribute to the pathogenesis of AD?

Proteins

• Are amyloid plaques a consequence of blood vessel disease and not a cause of dementia?

• Does aggregated Aβ induce neurotoxicity directly (i.e., independently of glial

activation/inflammation)?

• Is there a stepwise inflammatory cascade that follows the initial accumulation and deposition of Aβ42 and Aβ40? What is the temporal order of complement activation, microgliosis, cytokine release, astrocytosis, acute phase protein release, etc?

• Does microglial activation and astrocytosis precede local neuritic/neuronal

changes in AD?

• What biochemical events occur inside neurons that precede the altered phosphorylation / dephosphorylation of tau? What other neuronal proteins also serve as substrates in these reactions?

• How does APOE-ε4 interact with Aβ to promote its aggregation and/or

deposition of, and/or retard its clearance? Lewy bodies

• How does Lewy body formation lead to a clinical dementia syndrome?

• What are the similarities and differences in the underlying pathology, clinical syndromes and treatment response of dementia with Lewy bodies (DLB) and Parkinson’s disease (PD)?

• Does the ‘Lewy body variant’ of AD represent a distinct syndrome as opposed

to DLB or AD? Cerebrovascular disease

• How does cerebrovascular pathology increase the risk of AD or VaD?

• Does ischaemic cerebrovascular disease contribute directly to the development of AD pathology? OR Is it an independent comorbid process that increases the likelihood of a dementia diagnosis in patients with AD pathology?

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• Why do AD and VaD overlap in their clinical symptoms, pathology, disease outcome, and treatment potential?

• How do the pathologies underlying AD and VaD interact as substrates for

dementia?

• Does a vascular etiology explain the anatomical and cellular specificity of Alzheimer pathology?

• What is the role of oxidative stress in dementia?

Finally, as with many other aspects of dementia research, lack of standardised measurement is an issue. Cerebrospinal fluid (CSF) assays have not been standardised and hence it is difficult to compare results from different laboratories. Studies that report on routine CSF analysis are therefore needed to determine the most effective assays for use in this population so that a standard measure can be adopted. 9.3 Diagnosis and Assessment As a definitive diagnostic tool for dementia and its subtypes does not currently exist, there is a clear need for the development of such a tool. Other important unanswered questions regarding the diagnosis and assessment of dementia include:

• Which diagnostic investigations for dementia and its subtypes are most clinically effective and cost-effective?

• Which biomarkers are most effective in diagnosing and monitoring

progression of the disease? Do these vary according to dementia subtype? How do these biomarkers compare with other methods of assessment (e.g. neuropsychological assessment)?

• Which tool is best able to predict the course of the disease and accurately

discriminate between those with mild cognitive impairment who are likely to progress to dementia and those who won’t?

• Does the manifestation of dementia and its subtypes vary according to the

ethnic and cultural background of the person with dementia? The development of culturally appropriate diagnostic and assessment tools will be important for use with minority ethnic groups.

• While a diagnostic tool for dementia has been developed for use with

indigenous communities in Australia, there is also a need for a reliable shorter screening tool that can be used by unskilled workers in these communities.

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9.4 Risk and Prevention of Dementia A range of physical, social and mentally stimulating activities have been identified as protective factors against dementia. However, there are still many important unanswered questions regarding risk and protective factors, including:

• Which protective lifestyle factors identified are the most important? What level of each activity Type 1s optimal? Are the hypothesised protective effects of the activity types cumulative or interactive, e.g. with other factors including gender, genotype and age? Does the importance of these factors vary with dementia subtype?

• Does engagement in mentally stimulating activities throughout the lifespan

reduce the risk of dementia? What level of protection do mentally stimulating activities confer?

• What is the mechanism underlying the apparent association between these

factors and risk of dementia? Do they work by increasing ‘brain reserve’ or some other mechanism?

• Can a change in lifestyle play a major part in prevention of dementia?

• Is an active lifestyle during the whole lifespan more protective of dementia

than in later life only?

• Do omega-3 fatty acids preserve cognitive function in older age?

• What is the optimal level of alcohol consumption required to confer a protective effect? Does this vary according to other factors such as gender?

• Is this true only for wine or does this protection extend to include spirits and

other types of alcohol?

• What optimal level of blood pressure is required to maintain cognitive function in the very old?

• What public health strategy would have the greatest impact on reducing the

prevalence and incidence of dementia?

• What would be the impact for the community of delaying the onset of dementia?

9.5 Treatments Evidence gaps still exist in relation to the use of cholinesterase inhibitors (ChEIs) for the treatment of moderate to severe dementia. The findings of this review are consistent with previous recommendations of the National Institute of Health and Clinical Excellence (2001) for future research in relation to three cholinesterase inhibitors (Donepezil, Galantamine and Rivastigmine). Specific questions include:

• Are Rivastigmine, Galantamine and Donezepil equally effective in treating AD and other subtypes of dementia including VaD, mixed dementia, dementia with Lewy bodies and Frontotemporal dementia?

• Do they improve quality of life for these patients, and to what degree?

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• Does the effect of these drugs establish itself immediately and then decline?

OR Do these drugs have a cumulative effect over time and influence the course of the disease?

• What role do these interventions play in the treatment of severe dementia?

• What role do these drugs play, if any, in the treatment of non-cognitive

symptoms and behavioural disturbance in dementia?

• What effect do the ChEIs have on the rate of institutionalisation, specifically, do they result in a delay in the rate of institutionalisation and for how long?

• Do patients treated with these medications maintain the benefits of treatment

following its cessation? OR Do they decline to the level they would have without the intervention? OR Is the rate of decline accelerated following cessation of treatment?

Other important questions on ChEIs that also remain to be researched include:

• What are the long-term effects of the ChEIs and memantine?

• Which people with PDD benefit from cholinesterase inhibitor drugs and/or memantine, and is the use of these agents cost-effective?

• Is the combined treatment of cognitive stimulation and cholinesterase

treatment more effective than either treatment alone in improving the cognitive symptoms and functioning and quality of life for patients with dementia? Is it cost effective?

More understanding of the possible benefits of many different forms of treatment is still required, in particular whether selected treatment modalities are cost-effective:

• Is treating mild to moderate depression in PD with an antidepressant cost-effective?

• What interventions are the most clinically and cost-effective for managing

behavioural and psychological symptoms of dementia? Do these differ according to dementia subtype?

• Are supportive therapies such as physiotherapy/occupational therapy/speech

therapy in PD cost-effective?

• How effective is physical activity/exercise as an intervention for treating dementia?

• Does the effectiveness of the intervention interact with other factors – e.g.

gender?

• What is the effectiveness of individualised cognitive rehabilitation for people with mild to moderate AD and other dementia subtypes?

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Finally, it is becoming increasingly apparent that AD and VaD often co-exist, however, clinical trials have focused upon the conditions as separate entities (Zekry et al, 2002). Therefore, it is important to know more about:

• What treatment is the most effective for mixed dementia? 9.6 Care and Support for People with Dementia and their Carers Many questions remain about how to provide the best care and support for people with dementia. Although the goal to support people with dementia in their own home is commonly agreed, as revealed by the National Consumer Summit on Dementia in 2005 (Alzheimer’s Australia), many challenges remain about the best way to achieve this and how it relates to quality of life. Indicative questions are related to housing and accommodation, activities of daily living, caregiving, education and training, models of care and special populations. Housing and accommodation

• What are the housing issues and needs of people with dementia in the community?

• What is the most effective way to support people with dementia, including

those without co-resident carers, to remain in their own homes?

• What type of housing is indicated for different stages of dementia?

• How can assistive technology contribute to improving care outcomes for people with dementia?

• What design features can maximise care outcomes for people with dementia

living in residential care? Activities of daily living

• What is the efficacy of different feeding interventions on improving the feeding behaviour of people with dementia and possible confounding factors?

• What is the best oral hygiene care strategy for people with dementia?

• How can falls and fractures best be prevented in patients with cognitive

impairment and dementia?

• The development of a standardised assessment for driving safety in people with dementia

• What interventions for BPSD are most effective in the home setting?

Caregiving The construct of caregiver burden is widely referred to in research, policy and practice, however, further exploration of the concept in relation to dementia care is needed and better evaluative variables developed. Some indicative questions include:

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• What are the experiences and perspectives of caregivers of people with dementia?

• How is power exercised in the caregiving relationship and what are the

implications for different ethnic groups? • To what extent does the relationship between caregiver and recipient

influence the effect of behavioural, cognitive or social interventions?

• What culturally appropriate interventions are effective in reducing burden and improving outcomes for dementia carers from CALD and ATSI backgrounds?

The views of people with dementia

• What are the views and experiences of people with dementia?

• How can people with dementia and their carers best be involved in decisions regarding their care?

Education and training

• What are the education and training needs of different categories of staff caring for people with dementia?

• What GP training is needed to enhance early diagnosis and maximise

treatment and management of dementia?

• What is the best way to increase knowledge and understanding about dementia, including available services, to the general public?

Models of care and special populations

• What is the cost-effectiveness of current dementia care options in the community or residential care?

• Which dementia care option offers the best client outcomes in terms of quality

of care and clinical outcomes?

• What are the needs of people with dementia living in rural and remote parts of Australia?

• What are the needs and service requirements of younger people with

dementia?

• What is the impact of a palliative care approach on quality of dementia care? 9.7 Summary In summary, there are hundreds of unanswered questions regarding dementia that are useful avenues for future research. These cover a very wide range of areas. In many parts of the world there is little information about the prevalence of the disease and while our understanding of the underlying pathology of dementia has progressed, our understanding of the underlying mechanisms of the disease is limited.

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A definitive diagnostic tool does not currently exist and hence diagnosis at an early stage of the disease is problematic and importantly, the currently available treatments are limited in their effectiveness. Understanding the experience and need of people with dementia and their carers is still at a very early stage and further research that utilises qualitative as well as quantitative methods is warranted. Given the multitude of challenges presented by dementia, it is not yet possible to identify all of the knowledge gaps. As questions emerge and are answered through research, so further questions will inevitably be identified. The goal of understanding the causes and mechanisms of dementia is one that will ultimately, it is hoped, lead to the development of more effective treatments.

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References Alzheimer's Australia. (2005). National Consumer Summit on Dementia. Retrieved

July 18, 2006, from http://www.alzheimers.org.au/content.cfm?infopageid=2238

Ferri, C. P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., et al.

(2005). Global prevalence of dementia: a Delphi consensus study. Lancet, 366(9503), 2112-2117.[Link]

National Institute for Health and Clinical Excellence. (2001). Alzheimer's disease -

donepezil, rivastigmine and galantamine. Retrieved July 18, 2006, from http://www.nice.org.uk/page.aspx?o=TA019

Zekry, D., Hauw, J. J., & Gold, G. (2002). Mixed dementia: epidemiology, diagnosis,

and treatment. J Am Geriatr Soc, 50(8), 1431-1438. [Link]


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