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Dementia: from prevention to cure. Christopher Patterson McMaster University, Hamilton, Ontario Canada. Objectives. Define dementia Describe epidemiology of dementia in India Distinguish the common types of dementia Describe “standard” investigation of suspected dementia

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dementia from prevention to cure

Dementia: from prevention to cure

Christopher Patterson

McMaster University,

Hamilton, Ontario

Canada

objectives
Objectives
  • Define dementia
  • Describe epidemiology of dementia in India
  • Distinguish the common types of dementia
  • Describe “standard” investigation of suspected dementia
  • Introduce principles of management
  • Touch on future trends
dementia a syndrome
Dementia: A syndrome
  • An acquired disorder
  • Diffuse cognitive deficits: memory (usually) aphasia, apraxia, agnosia, executive dysfunction
  • Deficits sufficient to interfere with daily function
  • Not occurring solely in delirium or depression

CMAJ 1999;160 (12 suppl)

prevalence of dementia in india
Prevalence of dementia in India
  • Low estimate 1.9% over age 65(Ferri C et al Lancet 2005; 366: 2112)
  • Higher estimate 2.7% over age 65 (Kalaria R et al Lancet Neurology 2008; 7:812)
highest estimate of prevalence kerala india
Highest estimate of prevalence: Kerala India
  • Door to door survey
  • Screen with MMSE
  • Full assessment if < 23

Shaji S et al Br J Psychiatr 2005; 186: 136

risk factors for alzheimer s disease
Risk Factors for Alzheimer’s disease
  • Age
  • Family history
  • Lifestyle

Physical exercise

Mental exercise

Diet

Tobacco

Head injury

  • Hypertension
  • Elevated serum cholesterol
  • Elevated serum homocysteine
can we predict who will develop dementia
Can we predict who will develop dementia?

Knowing the following risk factors in middle age a calculation of future likelihood of dementia:

  • Age
  • Level of permits education
  • Systolic BP
  • BMI
  • Total serum cholesterol
  • Degree of physical activity

Patterson C et al CMAJ 2008; 178:548

types of dementia
Types of Dementia
  • Alzheimer’s
  • Mixed
  • Lewy-body
  • Frontotemporal
  • Vascular
  • Other neurodegenerations (e.g.Huntingdon’s)
  • Infections (e.g. HIV,Jakob-Creutzfeld)
types of dementia14
Types of Dementia
  • Alzheimer’s
  • Mixed ► 80% of all dementias
  • Lewy-body
  • Frontotemporal
  • Vascular
  • Other neurodegenerations (e.g.Huntingdon’s)
  • Infections (e.g. HIV,Jakob-Creutzfeld)
interactions between vascular dementia and alzheimer s disease
Interactions Between Vascular Dementia and Alzheimer’s Disease

AD

Mixed

VaD

80% of all Dementias

the nun study
The Nun Study
  • Longitudinal study of the Teaching Sisters of Notre Dame (USA)
  • 678 enrolled since 1991 aged 75-102
  • Written autobiographies within 2 years of entry
  • Annual cognitive testing
  • Brain autopsies
  • 400 deceased by 2003

Snowdon DA Ann Intern Med 2003;139: 450

the nun study18
The Nun Study
  • Early linguistic ability predicts later dementia
  • Severity of Alzheimer changes (amyloid plaques, neurofibrillary tangles) did not always correlate with cognitive changes
  • Presence of stroke (especially small WM) increased clinical dementia (RR=20)
the nun study pathology of those with dementia
The Nun Study: pathology of those with dementia

Alzheimers alone 43%

Mixed (AD + strokes) 34%

Other types of pathology 20%

Vascular alone 2.5%

pure vascular dementia is relatively rare
Pure vascular dementia is relatively rare
  • Several clinicopathological studies
  • Vascular dementias suspected commonly in life
  • At autopsy, vascular pathology alone rarely explained clinical features
  • Mixed pathology common
  • BUT may be more common in Asian counties
symptomatic domains of ad over time

Functional

Autonomy

Cognitive

Function

Motricity

(Motor

Function)

Behaviour

Problems

Mood

Symptomatic Domains of AD Over Time

Deterioration

Time

Adapted from Gauthier et al. Clinical Diagnosis and Management of Alzheimer’s Disease, 1999.

natural history of ad
Natural History of AD

Severe

Early diagnosis

Mild-to-moderate

30

Symptoms

25

Diagnosis

20

Loss of functional independence

15

Mini-Mental State Examination (MMSE)

Behavioural problems

10

Nursing home placemen

t

5

Death

0

1 2 3 4 5 6 7 8 9

Time (years)

Reproduced with permission from Feldman and Gracon, 1996.

alzheimer s disease progresses through distinct stages
Alzheimer’s Disease Progresses Through Distinct Stages

Average duration 7-10 years

Mild Moderate Severe

Stage

Symptoms

  • Memory loss
  • Language problems
  • Mood swings
  • Personality changes
  • Diminished judgment
  • Behavioural, personality changes
  • Unable to learn/recall new information
  • Long-term memory affected
  • Wandering, agitation, aggression, confusion
  • Require assistance w/ADL
  • Gait, incontinence, motor disturbances
  • Bedridden
  • Unable to perform ADL
  • Placement in LTC needed
alzheimer s disease anatomical correlates 3 phases of illness
Alzheimer’s disease anatomical correlates: 3 phases of illness
  • Limbic system: memory
  • Parietal: spatial organization, function
  • Frontal: behaviour
frontotemporal dementia28
Frontotemporal dementia

3 clusters of features:

(a) Behavioural (disinhibition, apathy, poor insight and judgement)

(b) Language (progressive expressive type aphasia, contraction of language)

(c) Self neglect

First described by Arnold Pick

frontotemporal dementia29
Frontotemporal dementia
  • Familial in 50%
  • Serotoninergic (vs. cholinergic) deficit
  • Memory not a prominent feature until late
  • Often difficult to manage
slide30
Lewy (or Lewey) body dementia

Also known as:

  • Dementia with Lewy bodies
  • Lewy body dementia
lewy body dementia
Lewy body dementia

Core features (2 probable, 1 possible):

  • Fluctuating cognition
  • Recurrent well formed detailed visual hallucinations
  • Spontaneous Parkinsonism

Suggestive features (1 possible, 1 plus above, probable:

  • REM sleep disorder
  • Severe neuroleptic sensitivity

McKeith I, et al Neurology 2005; 65: 1863

lewy body dementia32
Lewy body dementia

Supportive features:

  • Repeated falls
  • Systematized delusions
  • Dementia occurs before or concurrently with Parkinsonism
  • Early visuospatial dysfunction
  • May progress more rapidly than AD
lewy body dementia33
Lewy body dementia
  • Severe cholinergic deficit
  • Anti Parkinsonian medications may worsen psychosis
  • Antipsychotic agents may worsen Parkinsonism
  • Cholinesterase inhibitors often work well
vascular dementia
Vascular dementia
  • Dementia follows in wake of stroke
  • Presentation will depend upon location and size of stroke
  • Clear history of stroke not always present
  • Large overlap with Alzheimer’s disease (i.e. mixed dementia)
brain imaging of vascular dementia
Brain Imaging of Vascular dementia

3 Types of VaD

Multiple large

vessel infarcts

Bilateral strategic

thalamic infarcts

Binswanger’s

disease

Source: Stephen Salloway, MD

assessment of dementia domains
Assessment of Dementia: domains
  • Cognitive
  • Functional
  • Behavioural
  • Affective
80 year old lady
80 year old lady
  • Brought to you by only daughter
  • Forgot daughter’s birthday this year
  • Missed payment of several bills
  • Housework and personal hygiene slipping slightly
80 year old lady history39
80 year old lady: history
  • Onset and duration
  • Focal neurological symptoms
  • Precipitating events
  • Past history and risk factors
  • Social history and risks (fire, wandering, summoning help, low TI medications)
  • Medications (all of them)
  • Order lab tests?
80 year old lady examination41
80 year old lady: examination
  • Overall appearance (e.g. cleanliness, grooming, trauma, clothing)
  • General physical ( e.g. HF, hypoxia, thyroid, tumours)
  • Focal neurological signs
  • Gait, balance
80 year old lady mental status43
80 year old lady: mental status
  • MMSE or equivalent
  • Clock drawing
  • Montreal Cognitive Assessment (MoCA)
  • Measures of insight & judgement
80 year old lady laboratory45
80 year old lady: laboratory
  • CBC
  • Blood sugar
  • Electrolytes
  • TSH
  • B12
  • Calcium
80 year old lady neuroimaging47
80 year old lady: neuroimaging
  • Age under 65
  • Focal neurological symptoms
  • Focal neurological signs
  • Short history
  • Head trauma
  • Anticoagulants or bleeding
  • Malignancy that might metastasize
  • Atypical features i.e. not suggesting AD
80 year old lady management49
80 year old lady: management
  • Disclosure
  • POA, advance directives
  • Risk assessment (consider OT)
  • Transport
  • Education and support
  • Alzheimer’s Society or other support organization
  • Case manager
  • Education sessions
  • Medications
a family intervention for people with ad
A Family Intervention for people with AD

97 dyads (care giver plus patient ) NYC

Intervention:

  • 2 individual and 4 family counselling sessions (education & resource information)
  • After 4 months caregivers meet weekly in support groups
  • Continuously available counsellors
a family intervention for people with ad52
A Family Intervention for people with AD

Control group received “usual care”

Follow up to 8 years

Results:

Median time to nursing home placement increased by 329 days p=0.02

RR of NH admission 0.65 (0.45,0.94)

Effects most marked on those with mild and moderate dementia

Mittelman S et al JAMA 1996

behavioural interventions
“Behavioural” Interventions
  • Establish routine
  • Day programs e.g activities, exercise, socializing
  • In home respite
  • Distraction, coaching
  • Behavioural observation
80 year old lady management54
80 year old lady: management
  • Disclosure
  • POA, advance directives
  • Risk assessment (consider OT)
  • Transport
  • Education and support
  • Alzheimer’s Society or other support organization
  • Case manager
  • Education sessions
  • Medications
cholinesterase inhibitors
Cholinesterase Inhibitors
  • Have become standard of treatment for mild to moderate Alzheimers Disease ( but also show efficacy in vascular and Lewy body dementia)
  • 25-33% of people treated show a noticeable improvement
  • Questionable disease stabilization
  • Probably all equally efficacious
slide56

Clinical

improvement

No change

Clinical

decline

0

4

n=69

n=70

8

61

61

12

68

62

24

62

63

18

64

64

Week 24

LOCF

(72)

(73)

Donepezil in Advanced AD(sMMSE 5-12):Global Function

CIBIC-plus

p=0.0017

p=0.0007

3.4

p=0.0004

3.6

p=0.0006

p=0.0002

3.8

p=0.002

4.0

4.2

LS mean score ± SE

4.4

4.6

4.8

Donepezil

5.0

Placebo

 = 0.7

5.2

Study week

Donepezil

Placebo

Gauthier S et al. Neurology, 2003.

cholinesterase inhibitors do they work
Cholinesterase Inhibitors: do they work?
  • Donepezil (Aricept)
  • Rivastigmine (Exelon)
  • Galantamine (Reminyl)
  • All show modest positive effects on:

ADAS-Cog: WMD -2.62; -3.41; -2.77

CIBIC+: RR 1.37; 1.77; 1.28

AHRQ publication No. 04-E018-2 April 2004

preventing dementia
PREVENTING DEMENTIA

We can reduce the incidence of strokes by:

  • Control of blood pressure
  • Control of other vascular risk factors: Smoking,

Cholesterol

  • Regular physical exercise (dancing…)
preventing dementia the syst eur study
Preventing Dementia: The SYST-EUR Study
  • Multicentre RCT in Europe 2470 participants over age 60; SBP 160-319
  • Target: reduction of SBP by 20 mm or <150mm by nitrendipine 10-40mg
  • Up to 5 years follow up
  • After 2 years 11 new cases of dementia in treated; 21 in placebo p=0.06
  • Rate of dementia 3.8 vs 7.7 cases per 1000 person years p= 0.05

Forette F et al Lancet 1998; 352:1347

what is new in pharmacological treatment
What is new in Pharmacological Treatment?
  • Memantine for AD
  • Vaccination against AD
  • Antibiotics for AD
  • Lipid lowering agents for AD
  • A word of caution about novel neuroleptics
memantine
Memantine
  • NMDA antagonist modulates glutamate excitotoxicity
  • 28 week RCT involving 252 people with moderate to severe AD (MMSE 3-14)
  • Significant improvements on CIBIC plus .5/5; Severe ADL 3/7 & SIB in treated group cf placebo
  • Well tolerated
  • Approved in USA, likely in Canada within next year

Reisberg et al New Engl J Med 2003;348:1333

vaccination
Vaccination
  • Anti Abeta immunotherapy reduces amyloid deposition and improved spatial cognition in mice
  • Clinical trial in 298 patients with AD:18 developed inflammatory meningoencephalitis: study halted
  • Autopsy in one: “less amyloid than expected”

Orgogozo J-M et al Neurology 2003;61:46

Mathews P & Nixon R Neurology 2003;61:7

vaccination63
Vaccination
  • In subgroup of 30 patients, those who generated Abeta antibodies had reduced disease progression
  • Attempts being made to reformulate vaccine
  • Passive immunization considered

Hock C et al.Neuron 2003;38:547

Wolfe MS. Nat RevDrug Discov 2002;1:859

antibiotics for ad
Antibiotics for AD
  • Higher than normal titres of Chlamydia in people with AD
  • Multicentre Canadian double blind placebo controlled RCT
  • 101 patients with mild to moderate AD (MMSE 11-25)
  • Daily doxycycline 200mg plus rifampin 300mg or placebo for 3 months
antibiotics for ad65
Antibiotics for AD
  • Standardized ADAS Cog @ 6 months difference of 2.75/70 between treated and placebo group (significant @ 6 but not 12 months)
  • Standardized MMSE score 2.2/30 higher @12 (but not 3 or 6) months
  • Intriguing results!
  • Larger study in planning stages

Loeb M, Molloy DW et al JAGS 2004;52:381

lipid lowering and ad
Lipid lowering and AD
  • Previous observations suggested lower risk of AD in those taking “statins”
  • Recently presented at 8th International Symposium on Advances in AD therapy
  • Atorvostatin treatment associated with less decline in memory, function, mood & behaviour in people with AD
  • Premature to decide until full details available in peer reviewed publication
summary
SUMMARY
  • Dementia relatively uncommon in India at present, but prevalence will rise sharply with aging of population
  • Best strategies for prevention is control of vascular risk factors, especially hypertension
  • Social supports more valuable than medications
  • No cure yet!