Dementia vs Delirium Acad of Med, 21st April

8/2/2019 Dementia vs Delirium Acad of Med, 21st April

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Dr Yau Weng KeongGeriatric Unit, Department of Medicine

Hospital Kuala Lumpur

Dementia VsDelirium
http://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://reginanuzzo.com/wp-content/digitalbrain_01.jpg&imgrefurl=http://reginanuzzo.com/%3Ftag%3Dalzheimers&usg=__CAMuf1VKbk6QHBY2UWM9waKoFqs=&h=1063&w=876&sz=225&hl=en&start=8&tbnid=BDPXuiJy6DUYzM:&tbnh=150&tbnw=124&prev=/images%3Fq%3Dalois%2Balzheimer%26gbv%3D2%26hl%3Denhttp://images.google.com.my/imgres?imgurl=http://www.affordable-home-care.com/images/AloisAlzheimer.jpg&imgrefurl=http://www.affordable-home-care.com/alzheimers.html&usg=__qF8x2NxMk90torrb_y2n_CbjCYI=&h=241&w=200&sz=14&hl=en&start=7&tbnid=lSE0QpcMrjOZXM:&tbnh=110&tbnw=91&prev=/images%3Fq%3Dalois%2Balzheimer%26gbv%3D2%26hl%3Den


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Will Cover the followings

Introduction to dementia

The spectrum of cognitive dysfunction

Evaluation of memory problems Management

Non-pharmacological management

Pharmacological management

Whats in the future for dementia

What about Delirium

Conclusion


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What about Delirium

Conclusion


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World is Ageing!

DEMOGRAPHIC

TIME BOMB


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How common is dementia?

Age group(years)

Meta-analyses

Jorm et al, 1987 Hofman et al, 1991 Ritchie et al, 1992 Ritchie & Kildea,1995

6064 0.7 1.0 0.9

6569 1.4 1.4 1.6 1.5

7074 2.8 4.1 2.8 3.5

7579 5.6 5.7 4.9 6.8

8084 10.5 13.0 8.7 13.6

8589 20.8 21.6 15.5 22.3

9094 38.6 32.2 24.5 31.5

9599 34.7 36.7 44.5

Prevalence rates (%) of dementia in people aged 60 years ofage and older as assessed in four meta-analyses

Jorm et al 1987; Hofman et al 1991; Ritchie et al 1992; Ritchie & Kildea 1995


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Prevalence of dementia andcognitive impairment in Malaysia

There have been few prevalence studies of dementia in Malaysia.

Community

Authors Cognitive Impairment Dementia

Krishnaswamy et al, 1997 6%

Fadhilah et al, 1996 6%

Sherina et al, 2004 24%

Aizan et al, 2003 14.4%

Long Tern Care

Hasanah et al, 1996 45%Al-Jawad et al, 2008 36.5%

National Health and Morbidity Survey (NMHS-III, 2006) - 19.5%

(aged 70-74 years) mental health problems


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Alzheimers disease -Estimated impact on US businesses

Itemizing the Impact

Caregivers

Caregiver absenteeismProductivity lossReplacement of caregivers who leaveContinuing insurance for workers on leave,

fees to temp agencies, and Employee Assistance Programs

Caregiving Total

Medical Care and Medical Research

Business share of healthcare costs

Business share of research on Alzheimers

Medical Total

Total

In Billions (U.S.$)

7.8913.223.59

1.33

26.03

7.090.05

7.14

$33.17

Adapted from Koppel R, Dept. Sociology, Univ. Pennsylvania (1998)


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Prevalence and Treatment Rates

0

200

400

600

800

1000

12001400

1600

1800

2000

Mild Moderate Severe

NumberofPatients

(thousands)

Prevalence1

Diagnosed2

Treated with AChEI3

Sources: 1. Hebert LE, Scherr PA, Bienias J, et al. Arch Neurol. 2003;60:1119-1122.2. Datamonitor AD Treatment Algorithms. 2002.3. Market Measures. 2003.


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AD is Under-diagnosed Early Alzheimers disease is subtle, the diagnosis continues to

be missed

it is easy for family members to avoid the problem and compensate forthe patient

physicians tend to miss the initial signs and symptoms

Less than half of AD patients are diagnosed

Estimates are that 25% to 50% of cases remain undiagnosed Diagnoses are missed at all levels of severity: mild, moderate, severe

Undiagnosed AD patients often face avoidable social, financial,and medical problems

Early diagnosis and appropriate intervention may lessendisease burden

No definitive laboratory test for diagnosing AD exist

Evans DA. Milbank Quarterly. 1990; 68:267-289


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What about Delirium

Conclusion


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No Disease,No Symptoms Early BrainChanges,No Symptoms

Mild MemoryLoss Mild, Moderateand SevereImpairment

MildCognitive

Impairment

Pre-symptomatic

ADNormal AD

Disease ProgressionDisease Progression

Multiple cognitive deficits

Amnesia (Memory loss)

Aphasia (language disturbance)

Apraxia (impaired ability to carry outmotor activities despite intact motorfunction)

Agnosia (failure to recognize or identifyobjects despite intact sensory function)

Executive function disturbance (e.g.,planning, organizing, sequencing,abstracting)

These lead to functional decline

Definition of the dementia synd

American Psychiatric Association: Diagnostic and Statistical Manual ofMental Disorders, 4th edn. Washington DC: APA, 1994


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Inability to choose properclothing to wear

Inability to putOn clothings


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Requiring assistance in

cleanliness in toileting


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8 years average. Range 2-20 years


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Peak Frequency of Behavioral Symptoms asAlzheimers Disease Progresses

Agitation

Diurnalrhythm

IrritabilityWandering

Aggression

Hallucinations

Moodchange

Socially unacc.

Delusions

Sexually inappr.AccusatorySuicidal

ideation

Paranoia

Depression

100

80

60

40

20

040 30 20 10 0 10 20 30

Months Before/After Diagnosis

Prevalence(%o

fpatients)

Anxiety

Socialwithdrawal

Jost BC, Grossberg GT. J Am Geriatr Soc. 1996;44:1078-1081.


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AD: a progressive CNS disorderimpairingpatients ability to function

INCREASED SEVERITY INCREASED BURDEN

Stage 7 very severe

Stage 6 severe

Stage 6 severe

Stage 5 mod severe

Stage 4 moderate

Stage 3 mild

Stage 2 very mild

Stage 1 appears normal

Years after onset

0 5 10 15 20

Loss of speech, locomotion,consciousness; death

Full-time care needed;institutionalised

Can no longer care for self;incontinent, depressed

Can no longer manage personal affairs;agitated, care needed

Family and friends notice problems

Normal

No noticeable cognitive decline

Mild function deficitforgetful

Definitions from the Global Deterioration Scale Reisberg B et al., 1982

P i f t i t i l d ti


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Lovestone & Gauthier 2000

BURDEN

Progression of symptoms in typical dementia


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What about Delirium

Conclusion
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Steps in diagnosing dementia

History

Physical examination

Cognitive tests

Perform brief cognitive tests

Neuropsychological testsNon-cognitive tests

Assessment of BPSD

Assessment of ADL

Screening co-morbid condition

Establishing diagnoses

Assessing severity and progression

Neuroimaging

EEG

Biomarkers


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Course of Aging, MCI and AD

AAMI / ARCD

MCI

Clinical AD

Time (Years)

CognitiveDec

line

BrainADBrain

AgingMild

Moderate

ModeratelySevere

Severe

(Ferris, 4/03)

Brain Aging


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Differential Diagnosis of Dementia

5% 10% 65% 5% 7% 8%

Dementia with Lewy bodiesParkinsons disease

Diffuse Lewy body diseaseLewy body variant of AD

Vasculardementias and AD

Other dementiasFrontal lobe dementiaCreutzfeldt-Jakob diseaseCorticobasal degenerationProgressive supranuclear palsyMany others

AD and dementia

with Lewy bodies

Vascular dementiasMulti-infarct dementiaBinswangers disease

AD

Small GW, et al . JAMA. 1997;278:1363-1371; American Psychiatric Association. Am J Psychiatry.1997;154(suppl):1-39; Morris JC. Clin Geriatr Med. 1994;10:257-276.


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Differential Diagnosis

Alzheimers disease

Lewy body

dementia

cEPS,

Visual

hallucination

Frontotemporal

dementia

Behaviour,

Language

Vascular

dementia

Stroke,

Focal signs


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Regional distribution of atrophy in thecommon dementias

Alzheimers disease predominantly parietal and temporal

Frontotemporal dementia predominantly frontal and temporal

Dementia with Lewy bodies as for AD, but with additional subcortical pathology

Vascular dementia vascular distribution

Executivefunctions

Praxia

PerceptuospatialfunctionMemory

Language

Functional regionsFTDAD

Differential Diagnosis:


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Differential Diagnosis:Top Ten

(commonly used mnemonic device: AVDEMENTIA)

1. Alzheimer Disease (pure ~40%, +mixed~70%, ? dLbd)

2. Vascular Disease, MID (5-20%)

3. Drugs, Depression, Delirium

4. Ethanol (5-15%)

5. Medical /Metabolic Systems6. Endocrine (thyroid, diabetes), Ears,

Eyes, Environ.

7. Neurologic (other primary degenerations,fronto-temporal

- Consider diffuse Lewy body dementia,

Parkinson component)

8. Tumor, Toxin, Trauma

9. Infection, Idiopathic, Immunologic

10. Amnesia, Autoimmune, Apnea, AAMI

Adapted from Yesavage, 1979


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Co Morbidity issues

Multiple medical problems

Cumulative effect

Poly pharmacy

Acute illnesses

Under assessment and treatment

..added to dementia in the equation


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DEMENTIACOMORBIDITIES

Cognitive

impairments

Poor reporting of co-morbidities

Under- or late diagnosis of comorbid conditions

Worsening of overall health status

Atypical presentation

Excess morbidity

worsening


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Chronic Disease Model of AD

Diffuse plaques

Neuritic plaques, NFTs,

neuron and synapse loss

Cognitive impairment

Functional loss

Preclinical phase Clinical phase

Death

Diagnosis

Onset of symptomsGenetic & environmentalfactors

Antecedent biomarkers


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Dementia in local services

UMMCMemory

clinic(Geriatric)

HospSeremban

Memoryclinic(Geriatric)

Hosp JohorBahru

Memoryclinic(GeriatricPsych)

Hosp Kajang(Geriatric

psych)

AD 64% 63% 60% 62%

VaD 17% 29 % 24% 25%

Mixed (AD-

VaD)

17% 8 % 15% 15%

Otherdementias

2%

Database: Yau WK et al, Chin A-V,Yusoff S, Vengadasalam


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Diagnostic Thresholds for Dementia

Course of Dementia

CognitiveAbili

ties

Threshold 1

Threshold 2

Threshold 3

Very Mild or

MCI

Mild

Moderate

-Severe

Dementia results from progressive neuronal deterioration, fromminimal to extensive. Conventional diagnosis draws a line in

its course, labeling one side as demented and the other not.

Max Markah


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Max Markahpesakit

5 Orientasi Masa Tahun, bulan, hari, tarikh, waktu (+/- 1 jam)

5 Orientasi Tempat: Negara, Negeri, Bandar,Tempat (hospital/rumah), bilik(wad/klinik)

3 Pendaftaran:Saya akan menguji ingatan awak. Sila dengar dengan teliti,tiga objek yang saya akan baca, iaitu, oren, kunci dan sikat. Sila sebutsemula tiga objek tadi. Ingat betul-betul, kerana saya akan bertanyakemudian.

5 Perhatian dan Pengiraan (sila guna salah satu kaedah)

M-MMSE-7: Sila tolak 7 dari 100 dan teruskan.M-MMSE -3: Atau, tolak 3 dari 20 dan teruskan.

M-MMSE-S: Atau, ejakan perkataan DUNIA dari belakang ke depan.

3 Ingat Kembali

Sila sebut kembali 3 objek yang telah disebut tadi.

2 Penamaan

Namakan benda ini. (Pensel dan Jam Tangan)

1 Ulangan Sebutkan Tidak mungkin dan cukup mustahil3 Arahan tiga peringkat: Ambil kertas dengan tangan kanan, lipat setengah

dan letakkan atas lantai/meja.

1 Pembacaan: Baca dan lakukan ..TUTUP MATA ANDA

1 Penulisan: Tulis satu ayat yang lengkap.

1 Penyalinan

Jumlah


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Clock Drawing Test (CDT)

12

6

39

1

2

4

57

8

10

11

.

10 minutes past 11

Closed circle = 1

All 12 numbers present = 1

12 numbers in correct = 1position

Handsin correct = 1position ___

4

Low score indicates impairment.Cut-off score is subjective & arbitrary.Clinical judgment must be applied.

Nolan KA 1994


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Malay Mini Mental StateExamination

M-MMSE-7(n=300)

M-MMSE-3(n=160)

M-MMSE-S(n=145)

Optimal cut-off 21/ 22 18/19 17/ 18

Sensitivity 88.5 97.1 97.7

Specificity 75.3 90.0 93.3

PPV 53.7 57.6 62.5

NPV 95.5 99.2 100.0AUC 0.9 1.0 1.0

Cut off values and accuracy of the different versions of the Malay MMSE

Ibrahim et al, 2009


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Diagnosing Alzheimers disease

8090% accuracy


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Evaluation of memory problems

Management




What about Delirium

Conclusion


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Mechanism of cognitive impairment

2 mechanism:

Acetycholine

deficits

NMDA receptorantagonist


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Reduces severity of cognitive symptoms

Improved Quality of Life

Decreased caregiver burden

Above - For Mild to Severe disease

Stabilisepts symptoms for a period of 1-3 years

but without modifying progression of thedisease

Ezio Giacobini and Robert E becker, One Hundred Years after the Discovery of Alzheimers

Disease. A Turning Point for Therapy? Journal of Alzheimers Disease 12 (2007) 37-52 IOS Press


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T t t O t i


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Treatment Outcomes in

Alzheimers Disease

Time

Functionalab

ility

Slowing of diseaseprogressionTreatment

Symptomaticbenefit

Maintenanceof function

Cure

Natural Progression

(Ferris, 8/03)

Cli i l Di P i


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Clinical Disease Progression

Years From Diagnosis

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8 9

MMSES

core

Mild SevereModerateCognitiveSymptoms

Diagnosis

Loss of FunctionalIndependence

Behavioral Problems

Nursing Home Placement

Death

Reprinted from Clinical Diagnosis and Management of Alzheimers Disease, H Feldman and S Gracon;Alzheimers Disease: symptomatic drugs under development, pages 239-259, copyright 1996, with permissionfrom Elsevier.

AntidepressantCHEi

CHEiMemantine

CHEi+/-Memantine

Atypical Antipsychotics

CHEi+/-MemantineAtypical Antipsychotics


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Dementia CPG 2nd

Ed

Mdm LKM mom of senior radiographer


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Mdm LKM, mom of senior radiographerin Hosp Seremban

1stnotice memory problem in 1995, forgotten her

medications, content of conversation s over phone andthings around her. Still driving and MMSE 26/27

2001Hiding things (family found rotten buns), forgottento lock door.

2002. Worst. Agnosia, lost way home, cantcommunicate with others well. Manages ADL but

stopped IADL. Treated with Rivastigmine.

Till 2009 - on and off UTI, incontinence. Daughter comefor medications. Cant do MMSE. Hardly talk. Admitted in2009, stormy progress. DNR discussed. Needed RTfeeding. Bedridden mostly. Bedsore dressed by

daughter. Had stopped talking all together. August 2009 started memantine. RT off. Become more

chatty. Ask maid to move aside as she want to watchTV, started walking back again with 2 and bed soresettled.


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H Cayton, N Graham, J Warner, Alzheimers at your fingertips, 1997


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Barbara Sherman, Dementia with dignity. A Handbook for Carers, Revised Ed1994


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Amyloid Generation

Neuritic Plaque

NFT Excitotoxicity Oxidation

Cell

Death

Cholinergic Deficit

Inflammation

Cummings 2004


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Disease-Modifying Strategies

APP A

Neurondeath

-secretase

-secretase

inflammationoxidative stress

excitotoxicitydirect toxicity

secretasemodulators

immunotherapy

amyloid binders

anti-inflammatoriesantioxidantsneuroprotectants

Primary Prevention Trials in AD


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Study Agent Enrollmentcriteria

Noenrolled

Duration Currentlyactive

Outcomemeasures

Result

ADAPTNaprosynCelecoxib

Cognitivelyscreened, >70, 1stdegree relativewith AD

2496enrolled

7-10yrs Tx stopped ConversionStudyto dementia andcognitive decline

No result yet

Neg - 2008

GEM Gingko Bilobaextract

Asymptomatic,>75

5000 5-7 yrs Active Inc of dementiaor cognitivedecline

No result yet

Neg - 2009

HERS Estrogen andmedroxyprogesterone

Asymptomaticwomen, mean age67

1063 4.2 yrs Completed Cognitive test 1 test improved

HeartProtectionStudy

Vit E, C, and betacarotene

Asymptomaticwith CVS rsikfactors, age 40-80years

20536 5 yrs Completed TICS andincidentdementia

No differencebtwn tx and untxarm

HeartProtectionStudy

Simvastatin Asymptomaticwith CVS rsik

factors, age 40-80years

20536 5 yrs Completed TICS andincident

dementia

No differencebtwn tx and untx

arm

PREADVISE Selinium, Vit E Asymp men, >60yrs

10,400 12 yrs Completed Incidentdementia andcognitive tests

No result yetMaybe in 2012 /2013

Sano M, Current Concept in the Prevention of AD, Cns spectrum 2003:8: 846-853

y

Primary Prevention Trials in AD Cont ..


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Study Agent Enrollmentcriteria

Noenrolled

Duration Currentlyactive

Outcomemeasures

Result

WHI-PERT Estrogen nmedroxyprogest.

Women

withoutdementia,ages 65-80

4532 4 yrs completed Incident

dementia, MCIand 3MS score

Treated

subjects hadelevated riskof dementiaand worse3MS score

WHI-ERT Estrogen. Womenwithoutdementia,

ages 65-80

2497 5 yrs completed Incidentdementia, MCIand 3MS score

Treatedsubjects hadelevated risk

of compositeMCI/dementiaand worse3MS score

GUIDAGE Gingko Bilobaextract

Subjectivememorycomplaints,>70

2600 4 yrs Ongoing Incidentdementia

Not yetavailable

PHS-II Vit E, Folate, betacarotene

Asymptomatic, >65 yrs

10, 000 9yrs Ongoing TelephonecognitiveTesting

Not yetavailable

Sano M, Current Concept in the Prevention of AD, Cns spectrum 2003:8: 846-853

CONNECTION trial, MC RCT,


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, ,phase 3, of almost 600 patientswith AD, result negative, after 6months of treatment.- mac 2010

CONCERT trial, a 12-month studytesting latrepirdine in patients withmild-to-moderate AD who are

taking donepezil;

CONTACT and CONSTELLATIONtrials, 6-month trials of latrepirdine

in patients with moderate-to-severe AD also taking donepeziland memantine, respectively.


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The etiology of Alzheimer's disease remains elusive, althoughconsiderable progress has been made in understanding its biochemicaland genetic mechanisms.


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Management




What about Delirium

Conclusion

100 years of AD major milestone
http://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DG


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100 years of AD- major milestone

Slides fr Professor Roy Jones Director Research Institute for Care of Elderly,Bath presented at the 11th InternationalGeneva/Springfield Symposium on Advances in Alzheimer Therapy March 24 27, 2010Geneva

Presenile dementiaRareYoung onset

Separation of SenileDementia fr VaD andDepression

1950s 1960s

Presenile Dementia= Senile Dementia=ADStructures of tangles and plagues determinedNeuritis plagues contains amyloid protein

Cholinergichypothesis of AD

AD recognised asmajor health issue

1970s

Tacrine trials amyloid sequenced

Role of NFTs and tau

Age of geneticsAPP, presenilin 1 and 2 mutationAPOE4 E4 susceptibility

Amyloid cascade hypothesis of AD

CHEIs approved

Role of glutamate approved

Memantine approved

1980s 1990s /2000s

THE FUTURE


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THE FUTURE1. Better detection

- GPs, public

2. Better diagnosis- biomarkers- imaging amyloid and

tangles

3. Disease prevention / delay

4. Disease cure?

- eg vaccination

5. Better support


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http://clinicaltrials.gov/ct2/results?term=DEMENTIA

http://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htm

http://www.alzforum.org/dis/tre/drc/default.asp

Ongoing NIA-Funded AD/MCI Prevention and TreatmentClinical Trials as of November 2009
http://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htmhttp://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htmhttp://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htmhttp://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htm


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Trial Name Principal

Investigator

Intervention Population

CardiovascularACCORD-MIND (Action to ControlCardiovascular Risk inDiabetes/Memory in Diabetes)*

Lenore Launer Intensive glucose, bloodpressure, and lipidmanagement

People ages 40-79 with type2 diabetes mellitus

Effects of Simvastatin on CSF AD

Biomarkers

Cynthia Carlsson Simvastatin People ages 45-65 at high

risk of AD (family history,APOE 4)

ESPRIT (Evaluating Simvastatins

Potential Role in Therapy)Cynthia Carlsson Simvastatin People ages 35-69 at high

risk of AD (family history)

SPRINT-MIND (Systolic BloodPressure Intervention Trial-MIND)*

Lawrence Fine Blood pressure loweringto


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Trial Name PrincipalInvestigator

Intervention Population

Hormones

lzheimers Disease:Potential Benefit ofIsoflavones

Carey Gleason Novasoy (soyisoflavonesphytoestrogens)

People with AD

ELITE (Early versus LateIntervention with Estradiol)

Howard Hodis 17-estradiol Healthy early (less than 6years) or late (10 years +)menopausal women

KEEPS-CA (Kronos Early

Estrogen Prevention Study -Cognitive and AffectiveStudy)*

Sanjay Asthana Oral conjugated

equine estrogen (CEEor Premarin)and

transdermal 17-estradiol (tE2)

Healthy perimenopausal

women ages 42-58

Raloxifene for Women withAlzheimer's Disease

VictorHenderson

Raloxifene (selectiveestrogen receptor

modulator or SERM)

Older women with AD

SMART (Somatotrophics,Memory, and AgingResearch Trial)

Michael Vitiello Growth hormonereleasing hormone(GHRH)

People with MCI andhealthy older adults ages55-80

TestosteroneSupplementation in Men withMCI

MoniqueCherrier

Testosterone Older men with MCI andlow testosterone

Page last updated Jan 12, 2010


Ongoing NIA-FundedAD/MCI Prevention and Treatment ClinicalTrials as of November 2009 Cont
http://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htmhttp://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htm


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Other Interventions

AAV-NGF Gene Delivery inAlzheimers Disease

Paul Aisen Nerve growth factor(NGF) gene delivery

People with AD

fMRI Activation in MildCognitive Impairment

MichelaGallagher

Levetiracetam People with MCI

GAP (GammaglobulinAlzheimers Partnership) NormanRelkin Immune globulinintravenous (IVIg),

passiveimmunization

People with AD

Study on Thalidomide asBACE1 Inhibitor in

Alzheimers Disease

Yong Shen Thalidomide People with AD


Trials, as of November 2009 Cont

AD treatment 2010 and Beyond
http://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htmhttp://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htm


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AD treatment 2010 and Beyond2010

ACHEIs, Memantine, Combination

Other cognitive enhancers (Dimebon?, 5HT6, H3)

Improved and Early Diagnosis

Patient segmentation(genetics)

Disease modifying therapies

Community-wide preventive initiatives (diet, exercise)

2020

Slides fr Professor Roy Jones Director Research Institute for Care of Elderly,Bath presented at the 11th InternationalGeneva/Springfield Symposium on Advances in Alzheimer Therapy March 24 27, 2010Geneva

Overlap between Alzheimers


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Probable Possible Possible ProbableMixed

disease and vascular dementia

VaD

Stroke/TIAHypertension

DiabetesHypercholesterolemia

Heart disease

AD

Amyloid plaquesGenetic factors

Neurofibrillary tangles

MixedAD/CVD

Amyloid plaquesGenetic factors

Neurofibrillary tangles

Stroke/TIAHypertensionDiabetes

HypercholesterolemiaHeart disease

Kalaria RN, Ballard C. Alzheimer Dis Assoc Disord. 1999;13(Suppl 3):S115-123.

Cholinergic deficit

Hypertension


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Hypertension

A systematic review & meta-analysis of 4studies:

non-sig: RR =0.8, 95%CI 0.6 - 1.0

Hypertension in the Very Elderly TrialCognitive Function Assessment (HYVET-COG) Non-sig: HR 09, 95%CI 07 - 11

These data -combined in meta-analysis withother placebo-controlled trials of a/HPT rx , favoured treatment(HR 09, 95%CI 08 to10, p=0045).[46]Level I, fair
http://images.google.com.my/imgres?imgurl=http://www.gothypertension.com/images/hypertension-mercury.jpg&imgrefurl=http://www.gothypertension.com/hypertension/&usg=__tCOVERRaSJ-UVPLy0riwzAUQyS8=&h=328&w=246&sz=22&hl=en&start=17&tbnid=iPnwJKG9lyJPQM:&tbnh=118&tbnw=89&prev=/images%3Fq%3Dhypertension%26gbv%3D2%26hl%3Den


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Recommendation

Hypertension, occurring at mid-life (40-60 years)is a risk factor for dementia and should beappropriately treated. (Grade A)

Hypertension in the VeryElderly Trial Cognitive

Function Assessment(HYVET-COG)

Diabetes


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Swedish HTA report - evidence linkingdiabetesmod strong.[47] Level 1, good

A recent meta-analysis of 15 prospectivecohort studiesdiabetes was associated with a 47%

increased risk for all dementia,39% for Alzheimers dementia,

>2-fold risk for vascular dementia,(community dwelling )

Diabetes mellitus is a modifiable risk factor for thedevelopment of dementia and shouldbeappropriately treated. (Grade C)

Lifestyle Risk Factors
http://images.google.com.my/imgres?imgurl=http://www.just-diagnosed-diabetes-mellitus.com/images/Spoonfull_of_Sugar_and_Diabetes_500x320.jpg&imgrefurl=http://www.just-diagnosed-diabetes-mellitus.com/what-is-diabetes.html&usg=__tIZ2U9WOo55Xqw4chLmty-GhgbI=&h=332&w=500&sz=31&hl=en&start=57&tbnid=y91FyR_Uk3sDuM:&tbnh=86&tbnw=130&prev=/images%3Fq%3Ddiabetes%2Bmellitus%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D40http://images.google.com.my/imgres?imgurl=http://novarider.com/wp-content/uploads/2009/04/diabetes.jpg&imgrefurl=http://novarider.com/2009/04/diabetes-cause-eye-diseases/&usg=__byTDBIUaN3lFMQu8M30Bpq6-dt0=&h=320&w=480&sz=25&hl=en&start=14&tbnid=TDMYA_0mn0c3UM:&tbnh=86&tbnw=129&prev=/images%3Fq%3Ddiabetes%2Bmellitus%26gbv%3D2%26hl%3Denhttp://images.google.com.my/imgres?imgurl=http://www.geneplanet.com/_files/51/sladkorna_bolezen_tipa_2.jpg&imgrefurl=http://www.geneplanet.com/have_your_dna_analyzed/what_you_can_learn_from_dna_analysis/potential_diseases/type_ii_diabetes_mellitus&usg=__E2fQebCXEvTHbISLdG2JKsLUidE=&h=300&w=400&sz=161&hl=en&start=55&tbnid=mo6XUQRxmaCRDM:&tbnh=93&tbnw=124&prev=/images%3Fq%3Ddiabetes%2Bmellitus%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D40http://images.google.com.my/imgres?imgurl=http://www.just-diagnosed-diabetes-mellitus.com/images/Spoonfull_of_Sugar_and_Diabetes_500x320.jpg&imgrefurl=http://www.just-diagnosed-diabetes-mellitus.com/what-is-diabetes.html&usg=__tIZ2U9WOo55Xqw4chLmty-GhgbI=&h=332&w=500&sz=31&hl=en&start=57&tbnid=y91FyR_Uk3sDuM:&tbnh=86&tbnw=130&prev=/images%3Fq%3Ddiabetes%2Bmellitus%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D40http://images.google.com.my/imgres?imgurl=http://novarider.com/wp-content/uploads/2009/04/diabetes.jpg&imgrefurl=http://novarider.com/2009/04/diabetes-cause-eye-diseases/&usg=__byTDBIUaN3lFMQu8M30Bpq6-dt0=&h=320&w=480&sz=25&hl=en&start=14&tbnid=TDMYA_0mn0c3UM:&tbnh=86&tbnw=129&prev=/images%3Fq%3Ddiabetes%2Bmellitus%26gbv%3D2%26hl%3Den


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Lifestyle Risk Factors

Smoking

Alcohol

Obesity

Head Injury

Exercise

Education / Mental stimulation

Social network

LEARNING AND LON

GEVITY OF THE BRAINNUNS d


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The Nun Study is a longitudinal study of aging and Alzheimer'sdisease funded by the National Institute on Aging.

678 American members of the School Sisters of Notre Damereligious congregation who are 75 to 106 years of age.

Study

http://www.mc.uky.edu/nunnet/ Snowdon et al. JAMA 1997; 277: 813-7

Subcortical infarctionImportance of educationImportance of moodHead size

ALCOHOL & DEMENTIA
http://www.mc.uky.edu/nunnet/http://www.mc.uky.edu/nunnet/


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ALCOHOL & DEMENTIA

Several studies - light to moderate

alcohol consumption assoc.with a lower risk of DementiaAND AD

Rotterdam study1 - 45% < risk ofany dementia in those whodrink 1-3 drinks / day, comparedto non drinkers

1. Ruitenberg et al. Lancet 2002; 359:281-6


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Obesity


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Obesity Several prospective studies found an association

between raised body mass index in mid life and

an increased risk of dementia and AD. A systematic review of 4 cohort (n=22,861) F/U

20 years = significant risk. [59]Level II-2, fair

A meta-analysis of 7 prospective studiesfoundmoderate association

Obesity and incident AD was 1.8 (95% CI1.0 to 3.3)

Obesity and VaD was 1.7(95% CI 0.5 to 6.3)[60] Level II-2, good

Recommendation

Obesity is a modifiable risk factor andmaintenance of normal body mass index isrecommended. (Grade C)

PHYSICAL ACTIVITY
http://images.google.com.my/imgres?imgurl=http://no-bullfitness.com/wp-content/uploads/2009/08/obesity_lifespan-287x300.jpg&imgrefurl=http://www.no-bullfitness.com/&usg=__96cgoDbRXC2fw-JDtuu_3xjdk58=&h=300&w=287&sz=19&hl=en&start=17&tbnid=vJW7_6p2K9GHzM:&tbnh=116&tbnw=111&prev=/images%3Fq%3Dobesity%2Bpictures%26gbv%3D2%26hl%3Denhttp://images.google.com.my/imgres?imgurl=http://going-well.com/wp/wp-content/uploads/2009/09/childhood-obesity-television-fast-food.jpg&imgrefurl=http://going-well.com/category/weight-loss/&usg=__izSmNHxsf3iI9wU6pmXY85O9coE=&h=276&w=460&sz=35&hl=en&start=38&tbnid=dMO1G7WnHrJrzM:&tbnh=77&tbnw=128&prev=/images%3Fq%3Dobesity%2Bpictures%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D20http://images.google.com.my/imgres?imgurl=http://image3.examiner.com/images/blog/wysiwyg/image/obesity3(1).jpg&imgrefurl=http://www.examiner.com/x-12596-Milwaukee-Health-Examiner~y2009m7d23-Obesity-statistics-reveal-glaring-health-disparities-among-minorities&usg=__lo_NISgTPFOcsVye2zEbfEaLYKk=&h=288&w=400&sz=20&hl=en&start=31&tbnid=0FrtNET96-KTcM:&tbnh=89&tbnw=124&prev=/images%3Fq%3Dobesity%2Bpictures%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D20


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0

5

10

15

20

25

1 2 3 4

ACTIVITY QUARTILE

1. Yaffe et al. Arch Intern Med 2001; 161:1703-8

NEW

COGNITIVE

IMPAIRMENT

(%)

Women Who Walk project15,925 woman over age 65

no cognitive impairment at baselinefollow up 6-8 years


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Will C h f ll i


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Management




What about Delirium

Conclusion

Acute Delirium


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Acute Delirium

Confused

Restless

Pulled outCBD

The older patient with


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The older patient withdelirium :

Associated with

longer hospital stays,increased mortality

hospitalized patients with delirium : 22 - 76percent, [2]

1-year mortality rate : 35 - 40 percent. [3]

2. Am J Psychiatry 1999;156:Suppl:1-203. Moran Aust J Hosp Pharm 2001;31:35-40
http://../xToDo0601/Delirium%202006/060510/MDJN%20NEJM/current%20concept%20delirium%20in%20older%20person%20inouye.htmhttp://../xToDo0601/Delirium%202006/060510/MDJN%20NEJM/current%20concept%20delirium%20in%20older%20person%20inouye.htmhttp://../xToDo0601/Delirium%202006/060510/MDJN%20NEJM/current%20concept%20delirium%20in%20older%20person%20inouye.htmhttp://../xToDo0601/Delirium%202006/060510/MDJN%20NEJM/current%20concept%20delirium%20in%20older%20person%20inouye.htm


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quiet patientnon-demanding

good patient

Last cubicle


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Classification-

Lipowski1. Hyperactive-hyperalert

(agitated)

Hypervigilance,agitationHyperactivityHallucinations

Vs

schizophrenia

3. Mixed delirium

2. Hypoactive-hypoalert(somnolent)

lethargic & quietoverlooked in busy wardrespond appropriately

monosyllable answerswithdrawn,

drift off to sleepVS

DepressionUncooperative


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JAGS MARCH 2006VOL.54,NO.3 DELIRIUM SUBTYPES IN THE CRITICALLY ILL 481

J Am Geriatr Soc 54:479

484, 2006.


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FSLee Geriatrics HKL May06 89

Delirium in the Hospitalised ElderlyJuli A Moran, Michael I Dorevitch Aust J Hosp Pharm 2001; 31: 35-40.

3. Inouye SK. The dilemma of delirium: clinical and research controversies regardingdiagnosis and evaluation of delirium in hospitalized elderly medicalpatients. Am J Med 1994; 97: 278-88.

Number of precipitating


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u be o p ec p tat gfactors

Interaction


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FSLee Geriatrics HKL May06

Mx of delirium in hospital


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Mx of delirium in hospital

Prevention

Early diagnosis

Search and treat precipitating factors

Supportive measures, if necessary -medication

Delirium in the Hospitalised Elderly Juli A Moran, Michael IDorevitch Aust J Hosp Pharm 2001; 31: 35-40


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Detection

Lewis and colleagues11

N= 385 patients,prevalence of 10% - CAM.detection rate of delirium by ED

physicians based on chart review -17%.

11. Lewis LM, Am J Emerg Med 1995; 3:142-5.

CAM (Confusion


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CAM(ConfusionAssessment Method)

1. Acute change & fluctuation in mentalstatus and behavior

AND2. InattentionAND EITHER

3. Disorganized thinking

OR4. Altered consciousness

Inouye SK et al. Ann Intern Med 1990;113:941-948.

UTI


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For rehab

Multicomponent Mx of Delirium Symptoms


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www.health.vic.gov.au/acute-agedcare

Features Delirium Alzheimer's diseaseOnset Acute or subacute onset (hours or

days)

Insidious (usually several years)


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days)

Frequent and rapid fluctuations

(hours)

Slow changes (months)

Rapid functional decline Relatively slow functional declineConscious level Attention markedly reduced Attention reduced only in severely

affected patients

Arousal increased or decreased Arousal usually normal

Psychotic

symptoms

Delusions (if present) fleeting Delusions (if present) often

consistent

Hallucinations common often visual Hallucinations infrequent, visual,

and auditory

Motor features Abnormal movements such as

tremor or myoclonus common

Abnormal movements often

absent

Psychomotor activity increased or

decreased

Psychomotor activity usually

normalUnderlying

physical illness

Symptoms and signs usually present Symptoms absent

Day and night

rhythm

Often disturbed with a marked

increase in symptoms during the

night

No clear day and night rhythm.

Symptoms are more consistent

Prevention


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1. Cognitive impairment

2. Sleep deprivation

3. Immobility

4. Visual impairment

5. Hearing impairment

6. Dehydration

Prevention

Delirium: Summary :


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99

Delirium: Summary :

Delirium is under diagnosed.

Hypoactive deliriumMore difficult to diagnose

Poorer outcome

Management :Early Diagnosis

Multifactorial approach

Prevention



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Management




What about Delirium

Conclusion

C l i 1


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Conclusion 1

Normal changes =more forgetful & slower to learn

MCI Mild Cognitive Impairment no functionaldecline

Some eventually develop dementia

Dementia =Chronic thinking problems in > 2 areas

Vascular dementia - covers the whole spectrum ofcerebrovascular disease and cognition

DLB sits on the interface between AD, delirium and

Parkinsons disease FTD dementia without the dementia, revealing how the

frontal lobes govern personality and theory of mind

Delirium =Rapid changes in thinking & alertness Seek cause and treat urgently


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Two elderly ladies had been friends for many decades. Overthe years they had shared all kinds of activities andadventures. Lately, their activities had been limited tomeeting a few times a week to play cards.One day they were playing cards when one looked at the

other and said, "Now don't get mad at me....I know we'vebeen friends for a long time.....but I just can't think of yourname! I've thought and thought, but I can't remember it.Please tell me what your name is." Her friend glared at her.

For at least three minutes she just stared and glared at her.

Finally she said, "How soon do you need to know?"


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Conclusion 2

AD is an expensive illness in human and economic

terms for patients, their caregivers, and society.

Diagnosis is often not made, especially in earlyand mild AD; clinical nihilism can interfere with

initiating or sustaining treatment.

Cholinesterase inhibitors and NMDA receptor

antagonists attenuate symptomatic decline

Early treatment pays off; delaying treatment has

long-term consequences.


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Therapeutic Strategies

Pathogenesis

Symptoms

Disease

Induction Genetic/hereditary

Latency Traumatisms Vascular risk factors

Detection

PrimaryPrevention ?Vaccine ?Estrogen ?Ginkgo

SecondaryPrevention(Mild cognitive

Impairment) ?Antioxydants ?Anti-inflammatories ?Neurotrophic factors ?Estrogens ?Others

SymptomaticTreatment Cholinergic replacement

therapy

Vascular Prevention

Mind your Mind


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Mind your brain cognitive stimulation

Mind your body exercise Mind your head protect head

Mind your habits smoking

Mind your health check BP, cholesterol

Mind your diet antioxidant, polyphenol

Mind your social activities - engagement

Prof Henry Brodaty; Dementia: Can it be prevented?

Alzheimers Australia: Position Paper 6 August 2005


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