Dementia : Causes And Treatment

Associate Professor (Clinical) Dr Rosdinom Razali

Dept of Psychiatry

UKMMC

24 Feb 2014

H-Care Seminar on:

Caring For Persons With Dementia: The Way Forward

1

Dementia: Causes And Treatment

Topics: 1. Demography and epidemiology

2. Normal ageing, MCI & dementia

3. Types of dementia

4. Clinical features of AD

5. The Cholinergic Hypothesis of AD

6. Diagnosing dementia

7. Pharmacological treatment of dementia

2

Malaysia • “Population is ageing due to a steady decline in its

birth rate”- 3rd stage of demographic transition.

• The number of older persons in Malaysia has doubled in the past two decades to almost 1.4 million in 2000.

• By 2020, this number is expected to grow to more than 3.4 million.

3

Prevalence of psychiatric illness

• Study by Fadillah on elderly above the age of 60 in the community in Cheras, showed that out of the 226 elderly, 31% had been physically ill in the last one month and 16% had psychiatric illnesses.

• Out of this 16%, – 7% had depressive illness,

– 6% had dementia and while anxiety disorders, alcoholism and schizophrenia were much rarer,

– 50% of those with dementia had physical illnesses including hypertension, diabetes mellitus and one patient had carcinoma with secondary.

(MMA, 2002)

Relationship between normal ageing, mild cognitive impairment & dementia

5

Clinical Characterization of Mild Cognitive Impairment (MCI)

Petersen Criteria:

• 1. Subjective memory complaint

• 2. Normal activities of daily living (ADLs)

• 3. Normal general cognitive function

• 4. Abnormal memory for age

• 5. Not demented Petersen RC et al; Arch Neurol 1999;56:303-308

Memory declines with age

Age

Memory

and

Cognition

Education Cognitive

demand

I.Q.

Normal

Dementia

MCI

8

Memory : Normal Aging vs. Dementia

Slow

Accurate recall

Remedied by cues e.g.

appointment calendars and lists

Stable

Does not interfere with function

Slow

Inaccurate recall

Reminders fail eventually,

recall poor despite cueing

Progressive decline

Interferes with function

9

Normal Aging Dementia

Misplaces items infrequently

Independent retrieval possible

Can follow directions; oral or

verbal

Capable of self-care

Misplaces items frequently

Needs help from others to find

items

Can hardly follow directions even

with guide

Gradually unable to care for self

Memory: Normal Aging vs. Dementia

10

Normal Aging Dementia

Normal Aging Vs. Dementia

AGE AGE

• Minimal forgetfulness

• no change in other cognitive domains

• intact ADL’s

• normal n/p test result

•Poor memory

•Decline in other cognitive domains

• impaired ADL’s

• abnormal n/p test result

Cognitiv

e S

tatu

s

Cognitiv

e S

tatu

s

11

Dementia is a syndrome that refers to a global impairment of the higher cortical function that causes behavioural, cognitive and emotional impairments.

Sustained acquired decline in intellectual functions which interferes with an individual’s daily activities.

12

…………

TYPES OF DEMENTIA

1) Alzheimer’s Disease (AD) – the most common type

2) Vascular cognitive impairment (VaD)

3) Dementia with Lewy Body (DLB)

4) Fronto-temporal lobar degeneration (FTLD)

5) Jakob-Creutzfeldt Dementia (CJD)

6) Parkinson’s Disease Dementia

7) Huntington’s Disease Dementia

13

Major Dementia Subtypes

Fratiglioni L et al. Neurology. 2000;54 S10-5

Alzheimer's disease

60-70%

Vascular dementia

15-20%

Other dementias, eg,Lewy body disease

Parkinson’s disease

10-25%

14

Alzheimer’s disease

• Most common cause of dementia in the elderly • Average duration is of illness 8- 11 years • Prevalence doubles every 5 years from 6-8% at 65 years • Risk factors: age*, genetic influence*, ApoE status*, Down syndrome (chromosome 21- develop AD if they live past the age of 50 years old.), female gender, lack of education, head trauma, infection, inorganic compounds (aluminum and silicon) , myocardial infarction

15

Cortical Atrophy1

Normal

1. Halliday GM, et al. Neurobiol Aging. 2003;24:797-806.

2. Ng'walali PM, et al. Leg Med. 2002;4:223-231.

Alzheimer’s Disease (AD) Is a Progressive, Irreversible Brain Disorder

Alzheimer’s Disease

Amyloid Plaques Extracellular deposits

of -amyloid protein

Neurofibrillary Tangles Abnormal intraneuronal

fibrillar material —

tau protein

Neuropathologic Hallmarks2

16

17

Anatomical hallmarks of Alzheimer’s disease

Extraneuronal

plaques Intraneuronal

neurofibrillary tangles

17

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AD pathology: brain atrophy and distribution of plaques and neurofibrillary tangles

Alzheimer Pathology

18

Shadow of

‘healthy’ brain

Neurofibrillary tangles (pink)

Plaques (yellow)

18

Other dementias: Cerebrovascular pathology (VaD)

19

Vascular Pathology

Multi-infarct dementia

(dark blue)

Leukoaraiosis

(yellow)

19

Other dementias: Frontotemporal lobar degeneration (FTLD)

20

Frontotemporal Degeneration

Semantic dementia

(orange)

Slowly progressive,

non-fluent aphasia

(green)

Frontotemporal

dementia

(yellow)

20

Other dementias: Dementia with Lewy bodies (DLB)

21

Dementia with Lewy Bodies

Substantia nigra

21

22

What these symptoms mean to a person with Alzheimer’s disease

– Forgetting more and more things … and people

– Loss of initiative and decreased judgement

– Disorientation to time and place

– Difficulty in finding the right words or understanding what people are saying

– Difficulty in performing previously routine everyday tasks

– Personality and mood changes – Isolation, depression – Loss of independence

22

23

Alzheimer’s disease doesn’t only affect the patient

• Alzheimer’s disease affects the entire family

• The greatest impact is on the primary caregiver as caregiver burden

• Practical care for the patient 24 hours a day

• Personal and emotional stress

• Time off from paid employment and loss of income

• Spouses likely to be older themselves: difficulty coping with the situation

• If children or young relatives: interference with professional, family and social roles

23

The Cholinergic Hypothesis

24

Deficient Cholinergic Transmission Is a Core Deficit in AD

ACh = acetylcholine; AChE = acetylcholinesterase; CoA = coenzyme A.

Wilkinson DG, et al. Drugs Aging. 2004;21:453-478.

Postsynaptic

Pre synaptic

ACh

ACh

ACh

AChE

ACh

Acetyl CoA

Choline

ACh

acetyltransferase Choline

AChE inhibitor

Choline

+ acetate

ACh release

+

+ –

ACh

25

26

Cholinergic changes in Alzheimer’s disease

• In the cerebral cortex and hippocampus of patients with AD

• Decline in choline acetyltransferase (ChAT) activity1

• Decreased levels of acetylcholinesterase (AChE) 1

• Increased levels of butyrylcholinesterase (BuChE) 1

• Depletion of ACh-positive neurons in the basal forebrain: especially in moderate to severe disease stages2

1. Perry EK, et al. Neuropathol Appl Neurobiol 1978;4:273–7

2. Whitehouse PJ, et al. Science 1982;215:1237–9 26

27

Evolution of the cholinergic hypothesis

• 1970s Cholinergic hypothesis of Alzheimer's disease first proposed1

• 1980s ACh deficit cause of cognitive impairment • Destruction of cholinergic neurons in basal forebrain • Cholinergic system damage correlated with severity • Cholinergic system involved in arousal and attention2

• 1990s Introduction of ChEIs3

• 2000s Recognition of the role of butyrylcholinesterase (BuChE) as well as AChE4

• A potential role in disease progression • An additional therapeutic target • Clinical relevance of dual inhibition remains a hot topic of debate

1. Davies P, Maloney AJ. Lancet 1976;2:1403

2. Rossor M. Brain 1982;105:313–30

3. Davis KL, et al. N Engl J Med 1992;327:1253–9

4. Mesulam M, et al. Neurobiol Dis 2002;9:88–93

27

28

The cholinergic hypothesis updated: AChE and BuChE co-regulate ACh

AChE without

BuChE with

AChE with

BuChE without

ACh

28

Diagnosing Dementia

29

Dementia is a clinical diagnosis

• Assessment of presenting problems

• Taking an informant-based history

• Physical and neurological examination

• Evaluation of cognitive, behavioral & functional status

30

SIGNS NORMAL NOT NORMAL

1. Memory Loss

affects home or job

skills

a. Occasionally forgets

names, appointments, phone

numbers, deadlines

(remembers later)

a. Frequently forgets

things ( unable to

remember later)

b. Unexplained confusion

2. Difficulty

performing familiar

tasks

a. Washing clothes, forgets

to hang ( remembers later)

b. Brings home important

assignment for presentation;

wakes up middle of night and

prepares.

a. Forgets she washed

clothes at all.

b. Wakes up in the

morning and cannot

explain why he

brought home

something.

3. Problems with

language

a. Difficulty finding the right

word, substitutes related

word.

a. Forgets simple word,

substitutes inappropriate

word.

- Adapted from AAN, 2002

History: 10 Common Presenting

Symptoms of Dementia

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SIGNS NORMAL NOT NORMAL

4. Disorientation in

time and place

a. Momentarily forgets the

day or time.

b. Sometimes forgets

purpose why he gets to a

place (store).

a. Frequently forgets time

and place.

b. Getting lost in a

familiar place; or why he

is in a certain place at all.

5. Poor or decreased

Judgement

a. Choosing not to bring

umbrella or sweater ( which

maybe important).

a. Appearing in public

inappropriately dressed,

and not minding it.

6. Problems with

complex tasks and

abstract thinking.

a. Difficulty sending text

messages.

b. Depositing/withdrawing

money from banks maybe

confusing.

c. Sometimes forgets

birthdays.

a. Do not know what cell

phone is.

b. Cannot recognize

checkbook.

c. Do not know what

birthday means.

History: 10 Common Presenting

Symptoms of Dementia

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SIGNS NORMAL NOT NORMAL

7. Misplacing things a. At times people misplace

watches, keys, wallets, etc.

(remembers later).

a. Misplace things in

inappropriate places;

clothes in refrigerator,

food in closet.

8. Changes in mood

and behavior

a. Common to have bad day;

moody, sad.

a. Having rapid mood

swings – for no apparent

reason.

9. Changes in

Personality

a. People change with age

(mellowing).

a. Drastic change

( suspicious, confused,

withdrawn).

10. Loss of initiative a. Losing interest at times

(daily routines) regain later.

a. Remaining uninvolved,

passive and respond

only with repeated

prodding.

History: 10 Common Presenting

Symptoms of Dementia

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Physical Examination

• Hypertension and signs of vascular disease

• Signs of cardiac disease, particularly features that increase risk

for cerebral embolism.

• Signs suggestive of endocrine disturbance.

• Neurologic abnormalities, such as focal weakness, gait and

balance disturbance, tremors or other movement disorders.

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ADL

Cognition

Behavior

Dementia

The ABC’s of Dementia

35

DIAGNOSTIC CRITERIA

The widely used diagnostic criteria for dementia of the Alzheimer’s

type are those of the :

1. Diagnostic and Statistical Manual of Mental Disorders (DSM 5 ),

published by the American Psychiatric Association.

2. The National Institute of Neurological and Communicative

Disorders and Stroke and the Alzheimer’s Disease and Related

Disorders Association (NINCDS/ADRDA).

Using these criteria, the ability to make an accurate diagnosis of

AD has improved to about 90% of patients.

36

DSM-IV-TR: Diagnostic Criteria for Dementia of the Alzheimer’s Type

1. Memory impairment

2. At least one of the following:

3. Disturbance in 1 and 2 interferes with daily function

4. Course is gradual in onset with continuing cognitive decline

5. Does not occur exclusively during delirium

6. Other etiologies ruled out prior to diagnosis

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Text Revision. Washington, DC: American Psychiatric Press; 2000:157.

Aphasia Disturbances in language—misuse of words or inability to

remember and use words correctly

Apraxia Disturbances in skilled movements—impaired ability to carry

out motor activities despite intact motor function

Agnosia Disturbances in recognition—unable to recognize objects even

though sensory function remains intact

Disturbances in

executive functioning

Ability to think abstractly and to plan, initiate, sequence,

monitor, and stop complex behavior

37

Differences between DSM 5 and DSM 4R

38

• Introduction • DSM 5 has replaced the term “dementia” with “major

neurocognitive disorder” and “mild neurocognitive disorder”.

• Reason for change: To reduce stigma as “dementia” means “mad” or “insane”

• However, APA still uses “dementia” as it has been widely used and understood by many people.

39

Dementia vs. Neurocognitive Disorder

1. Focusing on Abilities—Not Disabilities

• DSM 5 focuses on a decline rather than a deficit in function.

2. Memory and Early Detection

• DSM 5 is less focussed on memory impairment

• a) Major neurocognitive disorder (Major NCD) exhibits cognitive deficits which interfere with independence

• b) Mild neurocognitive disorder (Mild NCD) may retain ability to be independent.

40

Types of Neurocognitive Disorder (NCD):

• Delirium

• Major ND

• Mild ND

41

Major Neurocognitive Disorder

A. Evidence of significant cognitive decline in one or more cognitive domains from:

• Patient, informants or clinicians

• Substantial impairment in cognitive perforamance (using neuropsychological tests or other clinical assessments)

B. Cognitive deficits interfere with independent ADL

C. Not due to delirium

D. Not due to other psychiatric conditions (eg. depression or schizophrenia)

42

Specify whether due to: • Alzheimer disease

• Frontotemporal lobar degeneration

• Lewy body disease

• Vascular dementia

• Traumatic brain injury

• Substance/medication use

• HIV infection

• Prion disease

• Parkinson disease

• Huntington disease

• Another medical condition

• Multiple aetiologies

• Unspecified

43

• Specify presence of:

• Without behavioural disturbance

• With behavioural disturbance (identify disturbance)

• Specify severity

• Mild

• Moderate

• Severe

44

Mild Neurocognitive Disorder A. Evidence of modest cognitive decline in one or more cognitive

domains from:

• Patient, informants or clinicians

• Modest impairment in cognitive perforamnce (using neuropsychological tests or other clinical assessments)

B. Cognitive deficits do not interfere with independent ADL

C. Not due to delirium

D. Not due to other psychiatric conditions (eg. depression or schizophrenia)

45

Specify whether due to: • Alzheimer disease

• Frontotemporal lobar degeneration

• Lewy body disease

• Vascular dementia

• Traumatic brain injury

• Substance/medication use

• HIV infection

• Prion disease

• Parkinson disease

• Huntington disease

• Another medical condition

• Multiple aetiologies

• Unspecified

46

Mild/ Major NCD Due To Alzheimer Disease 1. Insidious onset and gradual progression of impairment in 1 or

more cognitive domains

2. Probable AD if either is present:

• i. Family history or positive genetic testing OR

• ii. All 3 are present:

• Decline in memory & learning or at least another cognitive functions (history or neuropsychological tests)

• Gradual but steady decline in cognitive functioning

• No other aetiologies

47

NINDS-AIREN criteria for VaD

A. Impairment of memory and of two or more cognitive domains.

Must interfere with patient functioning (ADL) independently of physical defects

A. Evidence for cerebrovascular disease (CVD) from Neuroimaging (multi-infarcts & white matter lesions) & Physical examination (focal signs on neurological examination)

C. Possible or probable relationship between dementia and CVD:

a) onset of dementia within 3 months following a recognized stroke;

b) abrupt deterioration in cognitive functions; or fluctuating, stepwise progression of cognitive deficits.

NINDS-AIREN - National Institute of Neurological Diseases and Stroke & Association

Internationale pour la recherche et L’Enseignement en Neuroscience

48

49

What is MMSE (Mini-Mental State

Examination)?

It is the most widely recognized clinical instrument used to

evaluate cognition in patients with Alzheimer’s Disease. Most

clinicians consider the MMSE to be a routine part of the

diagnosis of the disease.

The MMSE is a brief ( 5-10 minutes) mental status exam that

is used to evaluate cognitive aspects of mental function in

terms of orientation, memory, attention, language and praxis.

50

Mini Mental State Examination

Items tested are :

•Orientation to time (5)

• Orientation to place (5)

• Registration (3)

• Attention (5)

• Recall (3)

• Language (9): naming (2), repetition (1), comprehension

(3), reading (1), writing (1), copying (1)

51

• The subtests most useful in detecting relatively early Alzheimer’s disease are the recall of 3 items, followed by orientation and drawing.

• Language tests are the least sensitive.

• MMSE is susceptible to ‘floor effects’ in patients with severe dementia as they tend to score very low, beyond which, progression cannot be further assessed.

52

Mini-Mental State Examination

(MMSE)

The highest total possible score is 30.

• 27 to 30 - no AD

• 26 to 20 - mild AD

•10 to 19 - moderate AD

• < 10 - severe AD

53

CLOCK DRAWING TASK (CDT)

The Clock Drawing Task is particularly useful as a screening tool

to differentiate normal elderly individuals from individuals with

cognitive impairment.

Takes about 3 to 5 minutes and can be administered by

paramedical staff.

The patient is asked to draw the face of the clock, placing the

numbers in the correct positions. After this task is completed, the

patient is asked to draw in the hands indicating 10 minutes after

11 or 20 minutes after 8.

54

CLOCK DRAWING TASK

One point is earned by the patient for each of the following tasks

involved in the CDT:

•DRAWING A CLOSE CIRCLE (1 mark)

•PLACING NUMBERS IN CORRECT POSITION (1 mark)

•INCLUDING ALL 12 CORRECT NUMBERS (1 mark)

•PLACING HANDS IN CORRECT POSITION (1 mark)

55

ADAS-cog (Alzheimer’s Disease

Assessment Scale - cognition)

• It measures the severity of cognitive and non-cognitive

impairments; cognitive portion (ADAS-cog) has 11 items that

test memory, orientation, language, and praxis functions that

have been extensively validated in patients with AD.

• Scored from 0 to 70, with higher score indicating greater

magnitude of cognitive impairment.

• Score increases by 6 to 10 points per year in patients with

mild to moderately severe AD.

56

CDR- CLINICAL DEMENTIA RATING

It employs a semi-structured clinical interview, with both the patient

and an informant, to rate performance in six domains: Memory ,

Orientation, Judgement, and Problem Solving, Community Affairs,

Home and Hobbies, and Personal Care.

The scale is scored from 0 ( no impairment) to 3 ( severe

impairment). A questionable category is scored as 0.5 or Mild

Cognitive Impairment (MCI).

57

NPI – Neuropsychiatric Inventory

The Neuropsychiatric Inventory (NPI) was developed to assess 10

behavioral disturbances occurring in dementia patients: delusions,

hallucinations, dysphoria, anxiety, agitation/aggression, euphoria,

disinhibition, irritability, apathy, aberrant motor activity (appetite and

sleep).

The NPI uses a screening strategy to minimize administration time,

examining and scoring only those behavioral domains with positive

responses to screening questions. Both the frequency and severity of

each behavior are determined.

Information for the NPI is obtained from a caregiver familiar with

patient’s behavior.

144 = total score (12 domains X 12 – severity and frequency)

Severity ( mild, moderate, marked)/ frequency ( frequently, occasional)

58

GDS – Geriatric Deterioration Scale

The Geriatric Deterioration Scale (GDS) provides caregivers an

overview of the stages of cognitive function for those suffering from a

primary degenerative dementia such as Alzheimer's disease.

It is broken down into 7 different stages:

•Stages 1-3 are the pre-dementia stages.

•Stages 4-7 are the dementia stages. Beginning in stage 5, an

individual can no longer survive without assistance.

Caregivers can get a rough idea of where an individual is at in the

disease process by observing that individual's behavioral

characteristics and comparing them to the GDS.

59

Advantages of early and accurate

diagnosis:

• Provides diagnostic answer and education for patient and family.

• Relieve anxiety of a progressive disease.

• Allows treatment for underlying disease if reversible, prevention

and rehabilitation.

• Early treatment of cognitive and behavioral symptoms, delay

dependency in degenerative dementias.

• No cure but treatment is available

60

No laboratory test can confirm

diagnosis of dementia

• Laboratory tests and neuroimaging only assist in diagnosing the

cause of dementia and excluding other differentials.

• Diagnosis is based exclusively on clinical assessment .

61

Clinical Practice Guideline for Dementia

A basic dementia screen should be performed at the first assessment include:

• Routine hematology e. g. full blood count (FBC) and erythrocyte

sedimentation rate (ESR)

• Biochemistry tests (including renal profile, calcium, glucose, and renal and

liver function)

• Thyroid function tests

• Serum vitamin B12 and folate levels

• ECG and CXR for comorbidities

• Routine screening for syphilis is not indicated for all cases, only for suspected cases or those with features of neurosyphilis.

62

Clinical Practice Guideline for Dementia

Neuroimaging: • Structural neuroimaging: brain CTScan & MRI should be done if available

to look for intracranial abnormalities (cortical thinning, subcortical white matter changes & subcortical vascular changes)

Functional neuroimaging: functional MRI, magnetic resonance spectroscopy (MRS), positron emission tomography (PET) & single emission computed tomography (SPECT). Functional neuroimaging is useful for early detection of dementia, subtyping of dementia & predicting changes of MCI to AD.

Neuroimaging biomarkers eg. radioligands Pittsburgh Compound-B (PIB) for PET binds directly to ß amyloid bodies in AD.

Not recommended routinely in diagnosis of dementia

63

Clinical Practice Guideline for Dementia

Genetic biomarkers and plasma lipoproteins

• Useful as prognostic markers for those at risk or to monitor drug therapy

• Impt CNS biomarkers :β amyloid, ApoE, total tau and hyperphosphorylated tau (p-tau).

• In AD, β amyloid is reduced and CSF tau is raised.

• ApoE epsilon (ε) 4 allele is a genetic risk factor for dementia with stroke, including vascular dementia (VaD) and AD with cardiovascular diseases (CVD).

• Not recommended routinely in diagnosis of dementia

64

Treatment of Dementia

3 basic approach to management

• Psychosocial measures

• Behavioural therapy

• Pharmacotherapy

65

Current Treatment Approaches

Behavioural and psychological symptoms of dementia (BPSD)

• Agitiation

• Inappropriate verbal, vocal or motor activity. Symptoms: physical aggression; verbal aggression, wandering

• Depression • Self-pity, rejection sensitivity, anhedonia and psychomotor disturbance

• Psychosis • Visual or auditory hallucinations, delusions

• Sleep-wake pattern disturbance • Disturbances of sleep and day-night reversals

• Anxiety • Pacing, wringing of hands, fidgeting, Godot syndrome (anxiety regarding upcoming events),

fear of being left alone

• Disinhibition • Inappropriate behaviour, emotionally unstable,poor insight

and judgement

• Apathy • Appetite problems • Incontinence

67

Reversible causes of BPSD

• Visiual and auditory disturbances

• Medical illnesses (e.g. urinary infections)

• Drugs

• Pain

• Fatigue

• Constipation

• Environmental changes (illumination, temperature,

change of location, over- or under-stimulation)

68

Treatment of the BPSD

• Evaluation of type, intensity and frequency of symptoms

• Identification and treatment of reversible causes

• Caregiver education

• Non-pharmacological treatment (1st line treatment)

• Pharmacological treatment if symptoms impact severely on patients’ and caregivers’ lives

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Non-pharmacological treatment of the behavioural symptoms of AD

• Environmental modifications (e.g. music, noise, plants, animals)

• Speak slowly, gentle touch

• Simple commands using gestures

• Behavioural management techniques

• Structured activities and use of schedules

• Massage, aromatherapy

• Physical exercise • Pet therapy

70

Pharmacological treatment of the behavioural symptoms of AD

Classes of drugs • Antipsychotics

• Conventional (es. haloperidol, phenothiazines) • Atypical (risperidone, olanzapine, quetiapine, clozapine,

aripiprazole) • Caution: Black box warning!

• Antidepressants • Benzodiazepines • Anticonvulsants • ChEIs • Memantine

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Pharmacotherapy for AD

• Cholinesterase Inhibitors (ChEI)

– Mild to Moderate AD: Rivastigminine, Galantamine

– Mild, Moderate and Severe AD: Aricept® (Donepezil)

• N-Methyl-D-aspartate (NMDA) Receptor Antagonist

– Moderate to Severe AD: Memantine

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Cholinesterase Inhibitors

Generic Brand name

Exelon Rivastigmine

Donepezil Aricept

Galantamine Reminyl

73

EFNS recommendations for the treatment of dementia

Alzheimer’s disease

• Start ChEIs early at diagnosis

• Memantine alone, or in combination with a ChEI, in patients with moderate to severe Alzheimer’s disease

• Insufficient evidence for the use of ginkgo biloba, anti-inflammatory drugs, nootropics, selegiline, oestrogens, vitamin E or statins

Parkinson’s disease dementia

• ChEIs (rivastigmine is the only ChEI approved for PDD)

• Insufficient evidence for the use of memantine

74

75

Starting ChEI therapy

Rivastigmine Donepezil Galantamine

Patch Capsule Capsule Capsule

Starting dose 4.6 mg/24 h 4 mg b.i.d. 5 mg q.d. 4 mg b.i.d.

Titration

(tolerability

permitting)

One-step dose

increase after

4 weeks

Increase dose by

4 mg b.i.d. every

4 weeks

Increase dose after

4–6 weeks

Increase dose by

4 mg b.i.d. every

4 weeks

Target dose 9.5 mg/24 h 12 mg b.i.d. 10 mg q.d. 12 mg b.i.d.

75

Challenges with ChEI therapy

• Not a cure

• Underdosing and poor treatment compliance are key issues

• The answer is to improve therapeutic

benefit by:

• Optimizing dosing

• Monitoring treatment compliance

• Simplifying administration

• Minimizing side effects with smooth drug delivery

76

Most common side effects of ChEIs

77

1. Prescribing information for oral donepezil (2007), galantamine (2007) and

rivastigmine (2006)

2. Winblad B, et al. Int J Geriatr Psychiatry 2007;22:456–67

Prescribing information (older oral meds)1 Patch study2

Placebo Donepezil

10 mg/day

Galantamine

16–24 mg/day

Rivastigmine

6–12 mg/day

Placebo Rivastigmine

9.5 mg/24 h

Nausea 6–12% 11% 24% 47% 5% 7%

Vomiting 3–6% 5% 13%

31% 3% 6%

Diarrhoea 5–11%

10%

9% 19%

3% 6%

Transdermal therapy appears to be an effective

method of reducing reports of nausea and

vomiting

Starting transdermal ChEI therapy

78

Rivastigmine

4.6 mg/24 h

patch

Rivastigmine

9.5 mg/24 h

patch

Starting dose Target dose

4 weeks

One-step dose increase

79

Algorithm for starting or switching to rivastigmine transdermal patch

Start on

4.6 mg/24 h patch

4 w

ee

ks

Switch directly to target

dose 9.5 mg/24 h patch

What oral dose is the patient receiving?

Increase to

9.5 mg/24 h patch

Is the patient already receiving oral rivastigmine?

NO YES

< 6 mg/day 6–12 mg/day

Rationale for a transdermal patch in Alzheimer’s disease

80

Providing continuous drug delivery over 24 h for longer duration of action

Allowing easier and faster access to higher doses

Reducing side effects by providing smooth drug delivery

Simplifying treatment for elderly patients often taking many other medicines

Making administration independent of food intake

Avoiding the first-pass effect

Helping family members to monitor treatment compliance

Providing visual reassurance of treatment

Smooth, continuous delivery by transdermal patches keeps drug levels in optimal “therapeutic window”

81

Increased

side effects

Poor activity

Optimal

therapeutic

window

Dru

g le

ve

l in

th

e b

loo

d

Peak

Oral Dose Trough

Patch Time

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Rivastigmine patch: Easy to apply

• Visually reassures that medication is being taken

• Can be dosed at any time of day, with or without food

• Try to apply the patch at about the same time every day

• Apply to: • Upper and lower back • Upper arm • Chest

• The skin must be dry and hairless before the patch is applied

• Normal daily activities, such as bathing, are permitted

Clinical benefits of rivastigmine patch

83

Introducing the “next generation of ChEIs”

Smooth, continuous drug delivery over 24 h

Easier and faster access to high dose efficacy

Avoids the gastrointestinal tract

Target dose provides similar efficacy to highest dose capsules, with three

times fewer reports of nausea and vomiting

Physicians can be more aggressive with dosing without side effect trade-off

Caregiver preference, ease of use, improved tolerability and easier access

to high dose efficacy all have potential to improve compliance potentially

leading to a better clinical outcome

1st cholinesterase inhibitor launched for Alzheimer’s disease treatment

Easy dosing: ONCE-daily

Treatment benefits: Improves COGNITION, BEHAVIOUR, ADL FUNCTION & GLOBAL FUNCTION.

Reduce caregivers burden

Well tolerated, less incidence of adverse events

Extensive clinical publication including MCI, Mild to Severe AD, VAD, Neuroprotection, etc.

1st & ONLY Cholinesterase inhibitor indicated for

Full Spectrum AD Therapy

(Mild, Moderate and Severe AD) 84

Aricept Evess® 5 mg General tablet (Plain)

(Don’t contain active ingredient)

Shortly after

dropping in 30

cc of water

(after 3

seconds)

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Ebixa (Memantine)® Prescribing practicalities

Ebixa Formulations

• Film-coated tablet (10 mg, 20mg) and oral-drop solution (10 mg/g of solution)

• The two formulations are bioequivalent and are therefore clinically equivalent

• Both formulations should be taken orally, and can be taken either with or without food

Dosing and administration

• The maximum daily dose is 20 mg once daily in adults

• To reduce the risk of side effects, treatment should be initiated with 5 mg once daily, and titrated upwards by 5 mg/week over a period of 3 weeks

• Both formulations should be taken orally either with or without food

• Recommended dose for elderly patients (>65 years of age) is 20 mg once daily

• Cautions in renal and liver failure

H. Lundbeck A/S, Ebixa® SmPC

Undesirable Effects

Undesirable Effects

Summary: • Treatment of BPSD is mainly behavioural therapy.

Pharmacotherapy is indicated when behavioural treatment fails.

• ChEIs are efficacious for mild to moderate AD for at least 6 months, with significant benefits seen in:

oActivities of daily living oBehavioural disturbances oCognitive function

• Higher doses generally associated with greater efficacy. • Memantine is an option for the treatment of moderate to

severe AD • Adverse events associated with oral ChEIs are typically

cholinergic in nature (nausea, diarrhoea, vomiting).

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Terima Kasih

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