Epidemiology of dementia. TA Treves, MD

Transcription

1 Epidemiology of dementia TA Treves, MD

2 Dementia Definition Multiple Cognitive Deficits: Memory dysfunction especially new learning, a prominent early symptom At least one additional cognitive deficit aphasia, apraxia, agnosia, or executive dysfunction Cognitive Disturbances: Sufficiently severe to cause impairment of occupational or social functioning and Must represent a decline from a previous level of functioning

3 Dementia Alzheimer s disease (AD) 10% AD vascular dementia 8% Vascular dementia 53% 5% 8% 6% Frontotemporal dementia Other 10% DLB AD + dementia with Lewy bodies (DLB)

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

5 Epidemiology Prevalence: 1% at age 60 Doubles every five years 30-50% by age 85 Prevalence curve flattens out at about age 90 4 th leading cause of death in the elderly Life expectancy after diagnosis 3-15 years, recent data suggests shorter life expectancy Wolfson, NEJM April, 2001

6 Age is a Primary Risk Factor Prevalence of AD(%) Ages Prevalence = 3% = 18.7% 85+ = 47%

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8 EOFAD represents ~2% of all AD 3 genes associated with Early Onset FAD EOFAD with known mutation to date: Presenilin 1 (PS1) % Presenilin 2 (PS2) -- <5% of Amyloid Protein Precurser(APP) % There must be other EOFAD causative genes that remain to be identified... If genetic test result is negative what can we say about recurrence risks for concerned relatives? GENES FOR LATE ONSET FAD HAVE YET TO BE IDENTIFIED

9 APO-E genotype and AD onset e2 -- 7% of the population e % of the population (54% - 91%)» (Pygmies - Sardinians) e % of the population (5% - 41%)» (Mayans - Pygmies) (Fullerton et al., 2000) ε3/3 - average age of onset = 74 y/o ε3/4 and e4/4 average age = 69 y/o

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11 Age at Onset (Hx, MMSE, SPECT) age of onset for ε3/3 vs ε4/4, p<0.02; for ε3/3 vs ε3/4, p<0.05 (Ashford, Kindy, Shih, Aleem, Cobb, Tsanatos, Cool) APOE genotype Number Mean age of onset (years) Standard deviation (years ε3/ ε3/ ε4/ MALE VETERANS - Memory Disorders Clinic; n=50

12 APOE is the only confirmed genetic risk factor for AD Others may include interleukin 1 polymorphisms, cystatic C promotor region, Glutathione S-Transferase P1 *C Allelic Variant

13 protective

14 74 72 Age of onset by schooling Age of onset LS MS HS Schooling All patients, ANOVA, p<.001 Reported age of onset of dementia (Treves & Korczyn, 2016)

15 Statins: slightly less amyloid load no correlation with clinical severity (Arvanitakis et al, 2008)

16 HT+hypercholesterolemia: OR=3.5 [ ] (Kivipelto et al, 2001)

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

18 Score % developed dementia (low risk) score % (moderate risk) Score >7 56% (high risk) NPV=89%, PPV=57% Barnes et al, 2009

19 Diabetes RF for dementia (Ott et al, 1999) not RF for AD (MacKnight et al, 2002; Hassing et al, 2002) RF for VD (MacKnight et al, 2002; Hassing et al, 2002) RF for AD (Leibson et al, 1997; Xu et al, 2006)

20 Non-modifiable RF (AD) Age Family Hx 3x risk with 1 st degree relative APO-E4 chr19, LOAD, onset age in dose-related fashion TOMM40 (Roses, 2010) APOE4 more frequent among offspring with parental history of AD (Van (Exel et al, 2009)

21 Risk factors: identify, critical period of exposure, interactions Age APOE RF for LOAD, but not too late (Frisoni et al, 1998; Lutz et al, 2010) Education/occupation > family Hx, LA (Bowler et al, 1998) Familiality decreases at later ages (Silverman et al, 1994, 2003) Role of environmental factors increase with onset age (Silverman et al 2005) Smoking (EURODEM, 1999) Vascular: EOAD > LOAD ( Artemis Project, 2012) Middle age DM: earlier age onset dementia (Zilken et al, 2013) Liability to AD even late in life twins study (Pedersen et al, 2004) DM increase, stroke decrease (Langa et al, 2008)

22 RELATIVE RISK FACTORS FOR ALZHEIMER S DISEASE Family history of dementia 3.5 ( ) Family history - Downs 2.7 ( ) Family history - Parkinson s 2.4 ( ) Maternal age > 40 years 1.7 ( ) Head trauma (with LOC) 1.8 ( ) History of depression 1.8 ( ) History of hypothyroidism 2.3 ( ) History of severe headache 0.7 ( ) Roca, 1994

23 Can prevention help to reduce the burden of dementia? Exposure Meta-analysed RR - association with AD Diabetes 1.39 ( ) 2.4% Midlife hypertension 1.61 ( ) 5.1% Midlife obesity 1.60 ( ) 2.0% Physical inactivity 1.82 ( ) 12.7% Smoking 1.59 ( ) 13.9% Depression 1.90 ( ) 10.6% Low education 1.59 ( ) 19.1% COMBINED TOTAL 50.7% More realistically.. (WHO Report, 2012) Population attributable risk fraction (PARF%) (Barnes and Yaffe 2011) 10% reduction in risk exposure 250,000 fewer new cases (3.3% reduction) 25% reduction in risk exposure 680,000 fewer new cases (8.8% reduction

24 Protective factors Leisure activity, cognitively stimulating activities (Kondo et al, 1994; Scarmeas et al, 2001; Wilson et al, 2002) NSAID (> 2 years, Meta-analysis, Etminam et al, 2003)

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26 WHEN? Neurofibrillary Tangles Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles.

27 Sensitivity and Specificity Gold Standard No Disease Disease Positive TP FP Test Result Negative FN TN Sensitivity Specificity TP/TP+FN TN/FP+TN

28 Diagnostic Tests for AD Serum Tau increased in CSF Sensitivity 85% Specificity 87% Aβ42 decreased in CSF Sensitivity 78-92% Specificity 81-83%

29 MCI Issues Can MCI be defined clearly in a clinical setting? Yes, but it requires careful examination and neuropsychological testing and/or a reliable informant Are there valid criteria for the diagnosis of MCI? Yes, at least amnestic MCI, in a specialty clinic, has predictive validity. Still some uncertainty about the underlying pathology Hippocampal atrophy is the best structural predictor

30 Synucleinopathies AD Β-amyloid Tau PCA LBD Ubiquitine Synuclein Parkin PD Parkin Synuclein β MSA Synuclein Ubiquitine VaD CBD β MCI Tau PSP Tau FTD Amyloidopathies Tau Ubiquitin FTD-MN Taupathies Proteinopathies

31 Frontotemporal lobar dementia (FTD) Early onset dementia Early loss of insight Behavioral disorders (perseverations, dietary ) Extrapyramidal signs (dopa non-responsive) Primary progressive aphasia Non fluent, agrammatism, phonemic paraphasia, anomia, alexia, agraphia Late behavior changes Semantic aphasia Fluent, empty, semantic paraphasia Preserved ability to read aloud & write to dictation Behavior changes (parsimony, loss of empathy) Extrapyramidal signs Preserved day-to-day memorizing Not rare (Ratnavalli et al, 2002); 5% of dementia, 10% EOD

32 ICD-10 Diagnostic Criteria for Pick s Disease 1. Dementia. 2. Slow steady deterioration. 3. Two or more of the following: a. Emotional blunting b. Apathy or restlessness c. Coarsening of social behavior d. Aphasia 4. Relative preservation of memory & parietal-lobe functions.

33 FTD Criteria Consortium Revised criteria for bvftd 2010 Possible bvftd Progressive deterioration of behavior or cognition with early appearance (first 3 years of sx) of at least 3 of the following characteristics: behavioral disinhibition apathy or inertia loss of sympathy or empathy Perseverative, stereotyped, or compulsive/ritualistic behavior Hyperorality or dietary changes Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions Probable bvftd: Clinical syndrome with supportive imaging bvftd with definite FTLD pathology Exclusion criteria Pattern of deficits is better accounted for by other nondegenerative nervous system or medical disorders or psychiatric disorder Presence of biomarkers consistent with AD

34 Nonfluent/Agrammatic Variant PPA (NFAV-PPA) Core criteria 1. Agrammatism in language production 2. Effortful, halting speech with inconsistent distortions, deletions, substitutions, insertions, or transpositions of speech sounds, particularly in polysyllabic words (often considered to reflect "apraxia of speech") Supportive criteria (at least 2) 3. Impaired comprehension of syntactically complex sentences 4. Spared single word comprehension 5. Spared object knowledge Imaging-Supported NFAV-PPA Diagnosis 1. Clinical diagnosis of NFAV-PPA 2. Imaging must show one or more of the following results: 1. Predominant left posterior fronto-insular atrophy on MRI 2. Predominant left posterior fronto-insular hypoperfusion or hypometabolism on SPECT or PET

35 Semantic Variant PPA (SV-PPA) Core criteria Poor confrontation naming (of pictures or objects), particularly for low familiarity or low frequency items Impaired single-word comprehension Supportive criteria (at least 3) Poor object knowledge, particularly for low frequency or low familiarity items Surface dyslexia and/or dysgraphia Spared repetition Spared motor speech (no distortions) and grammar Imaging-Supported SV-PPA Diagnosis 1. Clinical diagnosis of SV-PPA 2. Imaging must show one or more of the following results: 1. Predominant anterior temporal lobe atrophy on MRI 2. Predominant anterior temporal hypoperfusion or hypometabolism on SPECT or PET

36 PPA-demographics:(Duffy & Petersen (1992), Westbury & Bub ( 1997) and Rogers & Alarcon (1999) 2:1 male to female ratio Average age of onset: 60.5 years (Range years) Duration of isolated language signs and symptoms = 5.1 years (Range yrs)

37 Primary Progressive Aphasia (PPA) Inclusion Criteria Most prominent clinical feature is difficulty with language: e.g., word-finding deficits, paraphasias, effortful speech, grammatical and/or comprehension deficits These deficits are the principal cause of impaired daily living activities: e.g., problems with communication activity related to speech and language, such as using the telephone; or performing routine job responsibilities that require verbal communication Aphasia should be the most prominent deficit at symptom onset and for the initial phases of the disease. Exclusion Criteria Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders: e.g., neoplasm, cerebrovascular disease, hypothyroidism Cognitive disturbance is better accounted for by a psychiatric diagnosis: e.g., depression, bipolar disorder, schizophrenia, pre-existing personality disorder Prominent initial episodic memory, visual memory and visuo-perceptual impairments: e.g., inability to copy simple line drawings Prominent initial behavioral disturbance: e.g., marked disinhibition, emotional detachment, hyperorality or repetitive/compulsive behaviors

38 Pathology of FTD Frontal and anterio-temporale cortex atrophy Neuronal loss, gliosis, spongiosis Histopathology FTD Tau positive FTD (Pick bodies NFT) = tauopathy FTD with ubiquitin positive inclusions = FTDU FTD lacking distinctive histopathology = DLDH 36% 50% 26% 48% 18% 22%

39 Frontotemporal Dementia Genetic Considerations 40% are inherited in an autosomal dominant pattern 20% involve a mutation of the Chr 17 Miller BL, Cummings JL, et al: Neurology 41: , 1991

40 FTD Survival: 6 years (3-9, Hodges et al, 2003) 50% Family Hx dementia (better prognosis, tau positivity) Dopa non-responsive (Gydensen et al, 2002)

41 MND-Dementia syndrome Fronto-temporal type dementia in about 5% of all cases MND 20-40% of patients have subtle cognitive changes MND may present as dementia or may progress to dementia About 50% of MND/Dementia is familial

42 Synucleinopathies AD Β-amyloid Tau PCA LBD Ubiquitine Synuclein Parkin PD Parkin Synuclein β MSA Synuclein Ubiquitine VaD CBD β MCI Tau PSP Tau FTD Amyloidopathies Tau Ubiquitin FTD-MN Taupathies Proteinopathies

43 Diffuse Lewy Body Disease (DLBD) Fluctuating alertness Dementia (LB in neocortex, attention deficit) Visual hallucinations: early Parkinsonism: early (mild, nigrostriatal LB) Falls, syncope (LB in autonomic ganglia), neuroleptic sensitivity, psychiatric Sx 15%-30% of dementia Sensitivity: 80% but low specificity

44 Corticobasal (ganglionic) degeneration [CBGD, CBD] -Unilateral limb apraxia (64%) /dystonia (43%) -Rigidity, dysarthria -Myoclonus-stimulus induced -action tremor -gaze paresis -Language lately impaired Survival: 8 years (Wenning et al, 1998)

45 Autosomal Dominant Dementias Disease Linkage Gene Mutations Early-onset AD Ch 21 Ch 14 Ch 1 APP PS 1 PS 2 Clustered missense/duplication Mainly missense Mainly missense CJD/GSS Ch 20 PRNP Mainly missense/insertions PD Ch 4 Ch12 Ch 6 Ch1 SNCA LRRK2 Parkin DJ-1 Missense and dosage Missense Missense and dup/del Missense and del/dup FTD Ch 17 MAPT Missense and splicing HD Ch 4 HD Expanded polyglutamine stretch

46 Probable Vascular Dementia NINDS-AIREN criteria (1993) Subject fulfills criteria for dementia Presence of CVD, defined by the presence of focal signs on neurologic examination and evidence of non relevant CVD by brain imaging including multiple large vessel infarcts or a single strategically placed infarct (angular gyrus, thalamus, basal forebrain, or PCA or ACA territories) As well as multiple basal ganglia and white matter lacunes, or extensive periventricular white matter lesions, or combinations thereof A relationship between the above two disorders, manifested or inferred by the presence of one or more of the following: (a) onset of dementia within 3 months following a recognized stroke; (b) abrupt deterioration in cognitive functions; or fluctuating, stepwise progression of cognitive deficits.

47 Vascular dementia Includes Binswanger s disease, MID, anoxic damage, post-cabg, inflammatory diseases RISK FACTORS: age, hypertension, diabetes and hyperlipidemia 2nd most common dementia but incidence drops after the age of 75 (unlike Alzheimer s disease) In one study, 87% of vascular dementias at autopsy had AD pathology 1 1 Nolan KA, Lino MM, et al. J Am Geriatr Soc, 1998;46:

48 VASCULAR DEMENTIA EPIDEMIOLOGY VaD % ; AD % In Asia : equivalence If > 85 years VaD = 46.9% AD = 4 3.5% Prevalence in Europe 3-9% (oldest group) Incidence 1% in the elderly

49 Vascular Dementias Diagnostic criteria murky Overlap with AD Risk factors Older age Male > female, Black race> white race HTN Cigarettes, AF, DM, hyperlipidemia Ischemic stroke survivors: 9X increased dementia risk

50 Cerebrovascular lesions in Alzheimer s disease Case-control study (Jellinger and Attems, 2003) Lacunes: 44% vs 34% Infarcts, hemorrhages: 13% vs 8% And Alzheimer changes in vascular dementia (Florida Brain Bank, Barker et al, 2002) AD in VaD: 77%

51 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)

52 Late-Life Depression Def n: First Major Depressive Episode occurs after age 65 High correlation with dementia (50% go on to develop dementia within 3 years!) Many of these depression may be vascular or post-stroke depressions

53 Can prevention help to reduce the burden of dementia? Exposure Meta-analysed RR - association with AD Diabetes 1.39 ( ) 2.4% Midlife hypertension 1.61 ( ) 5.1% Midlife obesity 1.60 ( ) 2.0% Physical inactivity 1.82 ( ) 12.7% Smoking 1.59 ( ) 13.9% Depression 1.90 ( ) 10.6% Low education 1.59 ( ) 19.1% COMBINED TOTAL 50.7% More realistically.. (WHO Report, 2012) Population attributable risk fraction (PARF%) (Barnes and Yaffe 2011) 10% reduction in risk exposure 250,000 fewer new cases (3.3% reduction) 25% reduction in risk exposure 680,000 fewer new cases (8.8% reduction

54 Syndrome of Mild Cognitive Impairment (MCI) Mild cognitive decline that is worse than typical for age but less severe than in dementia (Flicker, et al, 1991) Mild Impairment involves memory and generally other cognitive domains that are more impaired in dementia Common activities of daily living (ADL) are intact, but there may be subtle impairment in very complex ADL Often a very early stage of dementia (most eventually progress to dementia, 10-15% per year, 80% over 10 years) When selected using AD inclusion/exclusion criteria, cases generally have prodromal AD (80% have hippocampal atrophy, 60-75% have AD neuropathology at autopsy)

55 Mild cognitive impairment (MCI) MCI-amnestic vs MCI-multiple domains Prevalence: 3%-36% Cross-over rate to dementia: 23%-47% within 2.6 years (Busse al, 2003) Delayed recall, mental control (Tierney et al, 1996) WMC/PVL of no significance (Smith et al, 2000; Bronge & Wahlud, 2003)