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Dementia: from prevention to cure Christopher Patterson McMaster University, Hamilton, Ontario Canada.

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Presentation on theme: "Dementia: from prevention to cure Christopher Patterson McMaster University, Hamilton, Ontario Canada."— Presentation transcript:

1 Dementia: from prevention to cure Christopher Patterson McMaster University, Hamilton, Ontario Canada

2 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

3 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)

4 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)

5 Highest estimate of prevalence: Kerala India Door to door survey Screen with MMSE Full assessment if < 23 Age % Shaji S et al Br J Psychiatr 2005; 186: 136

6 Global burden of Dementia 10/66 Dementia Research Group

7 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

8 Risk Factors for Alzheimer’s disease

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10 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

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12 Calculating future risk Patterson C et al CMAJ 2008; 178:548

13 Types of Dementia Alzheimer’s Mixed Lewy-body Frontotemporal Vascular Other neurodegenerations (e.g.Huntingdon’s) Infections (e.g. HIV,Jakob-Creutzfeld )

14 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 )

15 VaD AD Mixed Interactions Between Vascular Dementia and Alzheimer’s Disease 80% of all Dementias

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17 The Nun Study Longitudinal study of the Teaching Sisters of Notre Dame (USA) 678 enrolled since 1991 aged Written autobiographies within 2 years of entry Annual cognitive testing Brain autopsies 400 deceased by 2003 Snowdon DA Ann Intern Med 2003;139: 450

18 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)

19 The Nun Study: pathology of those with dementia Alzheimers alone 43% Mixed (AD + strokes) 34% Other types of pathology 20% Vascular alone 2.5%

20 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

21 Symptomatic Domains of AD Over Time Mood Cognitive Function Functional Autonomy Behaviour Problems Adapted from Gauthier et al. Clinical Diagnosis and Management of Alzheimer’s Disease, Time Deterioration Motricity (Motor Function)

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23 Natural History of AD Time (years) Symptoms Diagnosis Loss of functional independence Behavioural problems Nursing home placemen t Death Mini-Mental State Examination (MMSE) Early diagnosis Mild-to-moderate Severe Reproduced with permission from Feldman and Gracon, 1996.

24 Alzheimer’s Disease Progresses Through Distinct Stages Mild Moderate Severe Mild Moderate Severe Memory lossMemory loss Language problemsLanguage problems Mood swingsMood swings Personality changesPersonality changes Diminished judgmentDiminished judgment Behavioural, personality changesBehavioural, personality changes Unable to learn/recall new informationUnable to learn/recall new information Long-term memory affectedLong-term memory affected Wandering, agitation, aggression, confusionWandering, agitation, aggression, confusion Require assistance w/ADLRequire assistance w/ADL Gait, incontinence, motor disturbancesGait, incontinence, motor disturbances BedriddenBedridden Unable to perform ADLUnable to perform ADL Placement in LTC neededPlacement in LTC needed Average duration 7-10 years Stage Symptoms

25 Alzheimer’s disease anatomical correlates: 3 phases of illness Limbic system: memory Parietal: spatial organization, function Frontal: behaviour

26 Cholinergic Pathways From the Basal Forebrain PCPC OC FCFC BFBF H

27 Frontotemporal Dementia

28 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

29 Frontotemporal dementia Familial in 50% Serotoninergic (vs. cholinergic) deficit Memory not a prominent feature until late Often difficult to manage

30 Lewy (or Lewey) body dementia Also known as: Dementia with Lewy bodies Lewy body dementia

31 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

32 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

33 Lewy body dementia Severe cholinergic deficit Anti Parkinsonian medications may worsen psychosis Antipsychotic agents may worsen Parkinsonism Cholinesterase inhibitors often work well

34 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)

35 Multiple large vessel infarcts Bilateral strategic thalamic infarcts Binswanger’s disease Brain Imaging of Vascular dementia 3 Types of VaD Source: Stephen Salloway, MD

36 Assessment of Dementia: domains Cognitive Functional Behavioural Affective

37 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

38 80 year old lady: history

39 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?

40 80 year old lady: examination

41 Overall appearance (e.g. cleanliness, grooming, trauma, clothing) General physical ( e.g. HF, hypoxia, thyroid, tumours) Focal neurological signs Gait, balance

42 80 year old lady: mental status

43 MMSE or equivalent Clock drawing Montreal Cognitive Assessment (MoCA) Measures of insight & judgement

44 80 year old lady: laboratory

45 CBC Blood sugar Electrolytes TSH B12 Calcium

46 80 year old lady: neuroimaging

47 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

48 80 year old lady: management

49 Disclosure POA, advance directives Risk assessment (consider OT) Transport Education and support Alzheimer’s Society or other support organization Case manager Education sessions Medications

50 AD Caregiver Time by Disease Severity Hux et al. CMAJ, 1998.

51 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

52 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

53 “Behavioural” Interventions Establish routine Day programs e.g activities, exercise, socializing In home respite Distraction, coaching Behavioural observation

54 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

55 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

56 Clinical improvement Clinical decline No change 0Week 24 LOCF (72) (73) 4 n=69 n= Donepezil Placebo p= p= p= p= p=0.002 p=  = 0.7 CIBIC-plus Donepezil in Advanced AD (sMMSE 5-12):Global Function Study week LS mean score ± SE Donepezil Placebo Gauthier S et al. Neurology, 2003.

57 Cholinesterase Inhibitors: do they work? Donepezil (Aricept) Rivastigmine (Exelon) Galantamine (Reminyl) All show modest positive effects on: ADAS-Cog: WMD -2.62; -3.41; CIBIC+: RR 1.37; 1.77; 1.28 AHRQ publication No. 04-E018-2 April 2004

58 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…)

59 Preventing Dementia: The SYST-EUR Study Multicentre RCT in Europe 2470 participants over age 60; SBP 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

60 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

61 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

62 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

63 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

64 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

65 Antibiotics for AD Standardized ADAS 6 months difference of 2.75/70 between treated and placebo group 6 but not 12 months) Standardized MMSE score 2.2/30 (but not 3 or 6) months Intriguing results! Larger study in planning stages Loeb M, Molloy DW et al JAGS 2004;52:381

66 Lipid lowering and AD Previous observations suggested lower risk of AD in those taking “statins” Recently presented at 8 th 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

67 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!


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