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Clinical Aspects of Dementia: Emphasis on Alzheimer Disease Summer School of Neuroscience and Aging Venice, Italy 10-14 June, 2013 Richard W. Besdine,

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Presentation on theme: "Clinical Aspects of Dementia: Emphasis on Alzheimer Disease Summer School of Neuroscience and Aging Venice, Italy 10-14 June, 2013 Richard W. Besdine,"— Presentation transcript:

1 Clinical Aspects of Dementia: Emphasis on Alzheimer Disease Summer School of Neuroscience and Aging Venice, Italy 10-14 June, 2013 Richard W. Besdine, MD,FACP Professor of Medicine Professor of Health Services Policy and Practice Greer Professor of Geriatric Medicine Director, Division of Geriatrics and Palliative Medicine Director, Center for Gerontology and Healthcare Research A L P E R TM E D I C A LS C H O O LA L P E R TM E D I C A LS C H O O L

2 Population Aging  Average life expectancy (ALE) at birth in ancient Rome for a citizen was ~25 years; 35 years in Padova when Morgagni was dissecting  In 1900 America, 48: 50 for , 47 for  ; in 2013, 81 and 76, respectively – 1900 years for 1 st 25- year gain in ALE, <100 years for the next  For Italians reaching adulthood in 2013, ALE is nearly 90 for women and >80 for men  Maximum life span increase, though slower than increase in ALE, has not slowed since 1950s

3 Nine Themes of Aging 1 These themes are the conceptual basis for understanding the interactions of aging changes with diseases and risk factors Themes explain relationships of symptoms, signs and diagnostic tests to disease and changes in organ function in older persons - special knowledge base of geriatric medicine The themes facilitate analysis and understanding of the most complex and challenging clinical problems of older patients

4 Nine Themes of Aging 2 1.Pure Aging – Changes in organ function due only to aging – presbyopia 2.Reduced capacity to maintain homeostasis if stressed – delirium, falls in hospitalized elders 3.Geriatrics Syndromes – Disease-age interactions produce specific common function losses – falls, delirium, syncope, dizziness, UI, weight loss 4.Interaction of disease with pure aging produces changes in disease behavior beyond syndromes – SDH more frequent

5 Nine Themes of Aging 3 5.Pure aging misinterpreted as disease – slow information retrieval called dementia 6.Disease misinterpreted as pure aging effect – obvious dementia symptoms called “old age” 7.Medication Hazards – pure aging & disease ↑↑ risks of adverse drug effects – CNS, CV toxicity 8.Multimorbidity – Interactions of multiple diseases accelerate potential for harm 9.Diseases Special in Aging – Common only in elders; geriatricians must know – DCHF, AD

6 What is Human Aging? ● Not nearly as important as we thought? ● A set of predictable, gradual and inevitable changes in biological and psychological function, usually decremental, that occur in healthy persons with the passage of time

7 Age-related Structural Brain Changes Enlarged Subdural space predisposes to SDH Narrower gyri Wider sulci Enlarged ventricles

8 Neurologic Exam Changes of Aging   arm swing,  tone -  Dopamine neurons   DTRs in feet   Gag reflex   Ability to prevent postural sway   Ability to prevent orthostatic hypotension   Baroreflex sensitivity  Reemergence of primitive reflexes   Hand- and foot-tapping speed  Restricted upward gaze

9 Pure Aging Changes in Memory 1 ● Most memory functions change little with pure aging – mild  in attention; elders more easily distracted, so avoid competing tasks ● Processing speed (reaction, retrieval, timed tasks, perceptual), free recall, multi-tasking all decline with age ● Retrieval of names, persons especially, and objects often transiently lost

10 Pure Aging Changes in Memory 2 ● Sensory memory - earliest stage (visual, auditory, tactile) - unstable, rapid decay; no age-related change ● Primary, or working (short-term) memory - rehearsal transfers sensory to short term memory - no loss with age ● Long term (secondary) - hours, days, years + Declarative (explicit) memory: either semantic (facts, meanings; no Δ), or episodic (events, time, place; autobiography), aging decline + Procedural (implicit) – biking, music, knots - no Δ

11 Quality of Scientific Evidence Concerning Risk Factors for AD

12 Declines in Special Senses ● Vision -  accommodation (presbyopia), low-contrast acuity, glare tolerance, adaptation, color discrimination, attentional visual field all decline, due to changes in the eye peripherally and in central processing ● Hearing - Neural, conductive and sensory losses (presbycusis); primarily high tones (consonants) – 50% clinically significant

13 Strength and Balance ● Major confounders are disuse and disease ● Muscle mass, strength  ; modifiable by training – at best ~15%  by 80; fast twitch type 2  ● Sarcopenia (>50%  ) common, NOT pure aging ● Strength, cerebellar integrity, hearing and vision all play a role in balance ● Vestibular portion of 8 th CN – degeneration of otoconia (otolith granules) – multiple diseases, 8 th N sensitivity to drugs are confounders ● Single stance, eyes closed a powerful discriminator

14 “Soon she developed a rapid loss of memory...” “…only a tangle of fibrils indicates the place where a neuron was previously located.” Alois Alzheimer - 1906 Auguste D

15 Immunocytochemical staining (anti-amyloid antibody) of neuritic plaques in the hippocampus of an AD patient  -amyloid Plaques

16 Neurofibrillary Tangles Immunocyto-chemical staining (anti-tau antibody) of neurofibrillary tangles in hippocampus of an AD patient

17 Epidemiology of AD 1 10% > age 65, ~40% > age 85 No clear ethnic or racial patterns – China data: 2.6% 65-67, 60% 95-99 (Chan KY et al. Lancet 2013; 381: 2016–23) Is it getting more common? – probably not AD is a women’s problem + Majority of AD patients women; lifetime risk 32%, 18% men; prevalence > in 11 studies, up to 2:1 + Women live longer once they have the disease + Women are caregivers for AD victims

18 Epidemiology of AD 2 60-80% of dementia >65 is AD (US studies) >5 million now, 3-fold increase as baby boomers turn 70 and 80 beyond 2025 Costs of care in US $157-215 billion/yr (Hurd MD et al. NEJM. 2013;368:1326-34). 5th leading cause of death Survival after diagnosis <4 years (length bias), like aggressive cancer or severe CHF; should be on everyone’s hospice list Wolfson C, et al. NEJM 2001;344:1111-6

19 Prevalence of Dementia by Age 0 5 10 15 20 25 30 35 40 45 60–6465–6970–7475–7980–8485–89> 90 All types of dementia Alzheimer's disease Vascular dementia Age (years) Prevalence (%)

20 Worldwide dementia: the numbers will double every twenty years!! Ferri et al., 2005, Lancet 366:2112-17 Million

21 If We Live Long Enough, Will We All be Demented? Dementia prevalence doubles ~ every 5 years between age 65-85 Prevalence levels off in later years, as censoring by death from other causes outstrips rising incidence; does risk diminish?  ~ 47% at 85 years (Evans,1989)  ~ 58% at >95 years (Ebly,1994) l Universal cognitive aging - WAIS-R IQ “normal” at age 85 is 50% of correct answers at age 21

22 Median survival of women in the longest-lived countries has increased 3 months/year since 1840 We And Many Of Our Patients Will Live Long Enough To Develop AD Oeppen J et al. Science. 2002;296:1029-1031 Life Expectancy in Years Year

23 What is Dementia? An acquired disorder producing decline in memory and other cognitive functions sufficient to affect daily life in an alert patient Progressive and disabling NOT a part of pure aging Very different from normal cognitive lapses AD by far the most common cause

24 When to be Concerned  Sometimes it is the psychomotor slowing of aging + Recall of words or names temporarily lost + Misplacing the car keys + Worrying about memory + Why are you in front of the refrigerator?  Never retrieving names or words  Losing the car, major financial mistakes  Forgetting entire conversations or events  Not recognizing that there is a memory problem  Repetition not just for emphasis

25 AD Is Often Underdiagnosed  Early AD is subtle - the initial signs and symptoms are easily missed  Fewer than half of AD patients (autopsy) are accurately diagnosed  Undiagnosed AD patients face unnecessary added social, financial and medical problems  Early diagnosis and appropriate intervention may lessen disease burden Sano M et al. N Engl J Med. 1997:336:1216-1222

26 AD Often Misdiagnosed Patient initially diagnosed with AD Patient’s first diagnosis other than AD Yes 28% No 72% 21% 7% 9% 14% 35% Normal aging Depression No diagnosis Dementia (not AD)Stroke Other

27 Clinical Picture l Insidious, progressive, global decline in cognitive abilities – peak onset ~75, but as young as 30s l Prominent specific cortical deficits, personality changes, executive troubles, catastrophic reactions l Behavioral disturbances very common l Depression occurs in > 50% l More than 1/3 of incident cases do not fit classic picture; thus less likely diagnosed

28 The Impact of Dementia 75% of AD victims go to NH, stay >3 years Economic  ~$200 billion annually for care and lost productivity – most expensive of all  In the US, Medicare, Medicaid, private insurance provide only partial coverage  Families bear greatest burden of expense Emotional  Direct toll on patients  Nearly half of caregivers suffer depression

29 Mortality of Dementia Noale M et al. Dement Geriatr Cogn Disord 2003

30 Evaluation of Dementia 1 Screening  At annual physical >70 or earlier if red flags  Ask patient about any new problems with memory, mood, behavior and driving  Baseline MMSE and clock drawing or 3-word recall and clock (mini-cog) Evaluation for positive screen  Add reliable informant to interview  Structured criteria – DSM or NINCDS-AD  Search for causes  Identify and manage co-morbidities  Genetic testing not recommended in 2012

31 Chemistries (BUN/Creatinine, electrolytes, BS, calcium), CBC, Liver function tests Thyroid, pituitary-adrenal axis Vitamin levels – B 12, folic acid (?) Serology for Lyme, HIV, Syphillis Brain image (CT without contrast) if <65, symptoms recent (<2yrs), focal neurologic signs, suspicion of NPH, or recent trauma Neuropsychological testing if diagnosis unclear Evaluation of Dementia 2 Small GW, et al. JAMA. 1997;278:1363-1371

32 Criteria for Diagnosis of Dementia Global cognitive impairment with clear sensorium  Development of multiple cognitive deficits, with memory impairment, and one or more of: + Aphasia + Apraxia + Agnosia + Disturbance in executive functioning  Cognitive deficits are a significant decline from baseline and cause significant functional impairment  Deficits are not caused by delirium (R/O by work up)

33 In academic referral centers, accuracy of probable AD diagnosis is 81-100% (Galasko et al, 1994; Morris et al, 1988; Tierney, 1988) In one post-mortem series, 77% of cases of “possible” AD had AD (Galasko et al, 1994) In a community-based post-mortem series, accuracy of probable AD diagnosis was 75% (Lim et al, 1999) Accuracy of NINCDS Criteria for AD

34 Risk Factors for AD DefinitePossible/Probable AgeFamily History Head InjuryDiabetes Atherosclerosis (stroke) History of depression Hypertension (stroke)HSV Apolipoprotein E4 Education (-) Down’s SyndromeMediterranean diet (-) Female GenderExercise (-) Multiple mutationsIntellectual work (-) SmokingApolipoprotein E2 (-)

35 Quality of Scientific Evidence Concerning Risk Factors for AD

36 Proteolytic Cleavages of Amyloid Precursor Protein (APP) That Produce A  42 Peptide Selkoe DJ et al. JAMA. 2000;283:1615-1617.  -amyloid precursor protein  -secretase A  peptide  -secretase Extracellular space TMCytoplasm COOH NH 2 alpha-secretase

37 Courtesy of Dr. Mark Mintun ~10 years

38 Jack et al. Lancet Neurology, 2010 Cascade Model of Neurodegeneration in AD

39 Petersen RC et al. Current concepts in Mild Cognitive Impairment. Arch Neurol 2001;58:1985-1992. Over time, persons with amnestic MCI are at risk of developing AD dementia 6-Year Change of Mild Cognitive Impairment

40 “The Prevention Paradigm” Years Cognitive function MCI Preclinical Dementia An intervention here might “prevent” people from developing MCI or dementia

41 The Genetics of AD Mutations on chromosomes 1, 14, 21 (APP regions) are associated with:  Rare early-onset (<60) familial forms of AD  Down syndrome Apolipoprotein E alleles on chromosome 19  APOE 4 allele a powerful risk for AD (1 allele 3X, 2 alleles 10X), and earlier by ~10 years  APOE 2 allele probably has protective effect  APOE in  -amyloid plaques and neurofibrillary tangles; affect protein–protein interactions?

42 Presenilins and Their Role in AD Presenilin 1 (PS1) and presenilin 2 (PS2) on chromosome 14 – mutations in the proteins coded by these genes are most common genetic cause of familial Alzheimer’s Disease PS1 and PS2 cause increased secretion of the more amyloidogenic form of  - amyloid (A  42 )

43 >100 subjects each of clinically characterized (research criteria) elders as AD, MCI or normal Low amyloid 1-42 (Aβ 42 ) level, high total tau protein (T-tau), and elevated phosphorylated tau protein 181 (P-tau 181) in >90% of AD patients, 73% MCI, 39% controls ( ↑↑ AD pattern, Apo E  4) Sensitivity 90% for AD, specificity 64% in 3 distinct data sets, by post-mortem AD CSF pattern (low Aβ 42, high P-tau 181) identified all MCI cases progressing to AD in 5 yrs Diagnosis of AD - CSF Aβ 42,Tau Meyer GD et al. Arch Neurol. 2010;67(8):949-956

44 Vascular Dementia 2 nd or 3 rd (DLB) most common dementia Affects ~5-10% of the population >90 Associated with stroke, cerebrovascular disease (white matter hyperintensities) Often coexists with AD neuropathology; undetected stroke makes dementia symptoms much worse (Snowdon DA. JAMA. 1997;277:813-817) Decline in cognition, function, and behavior

45 Dementia With Lewy Bodies 15%–25% of all dementia in the elderly Onset ~75–80 years Survival ~3.5 years (<1–20) Slight male predominance Characterized by  Fluctuating cognitive impairment (~80%)  Visual hallucinations, nightmares (>60%)  Parkinsonism (65%–70%)  Frequent severe neuroleptic side effects

46 DLB Biology Alpha-synuclein (α-syn), normally a soluble CNS protein of unknown function, encoded by SNCA gene, can aggregate abnormally to form insoluble fibrils (primary Lewy body structure) in synucleinopathies (DLB, PD, multiple system atrophy) An α-syn fragment, known as the non-Aβ component (NAC) of AD amyloid, originally found in an amyloid-enriched fraction, is fragment of its precursor, NACP (human α-syn) Occasionally, Lewy bodies contain tau; α-syn and tau are two distinct filament subsets in same inclusion bodies α-syn pathology is also found occasionally in both sporadic and familial cases of AD disease

47 Ranked by Frequency of Occurrence (% of Patients) McKeith IG et al. Neurology. 2000;54:1050-58 Apathy/indifference72.5 Appetite; eating disorder34.2 Anxiety70.0 Elation/euphoria18.3 Depression/dysphoria65.8 Disinhibition16.7 Delusions58.3 Agitation/aggression55.0 Irritability/lability55.0 Aberrant motor 53.3 Symptoms >50% of Patients (%) Symptoms <50% of Patients (%) Behavioral Symptoms in DLB

48 * * * * Ballard C et al. Curr Psychiatry Rep. 1999;1:49-60 0 10 20 30 40 50 60 70 80 DLB AD Visual Hallucinations Auditory Hallucinations Delusions Misidentification Depression Percentage of Patients with Symptoms Symptoms in DLB versus AD *P<.05

49 *P<.01 vs placebo; **P<.001 vs placebo Adapted from McKeith, et al, 2000. Baseline Improvement Neuro-psychiatric Inventory (NPI) 10-Item Score * Mean Change from Baseline –8 –7 –6 –5 –4 –3 –2 –1 0 AChEI Placebo 1220 Weeks AChEI 3–12 mg/d (n=59) Placebo (n=61) NPI 10-Item Score—Percentage of Patients Improving by  30% from Baseline * 70 60 50 40 30 20 10 0 Patients Improving (%) Week 20 Cholinesterase Inhibitor (AChEI) Effects on Behavioral Symptoms in DLB

50 Perry, et al, 1985; Korczyn, 2001 Parkinson’s Disease and Dementia At least one-third of Parkinson’s Disease (PD) patients develop dementia Patients with PD show degeneration of the nucleus basalis of Meynert and low brain choline acetyl transferase levels The dementia of PD is not improved by dopaminergic drugs (e.g., L-DOPA, pergolide, bromocriptine, bupropion, dopamine) Cholinesterase inhibitor therapy in PD appears to be beneficial

51 Fronto-temporal Dementia FTD is most common fronto-temporal neuro- degeneration; rarer than AD, Vascular and DLB Characterized more by pattern of behavioral deficits than by neuropsychological impairment Clinical features: 1) distractibility, impersistence, 2) ↓ in personal hygiene, grooming; 2) inflexibility, mental rigidity; 3) hyper-orality, diet change; 4) utilization behavior; and 5) perseverative, stereotyped behavior Current treatment only for symptoms; no evidence of benefit from any drug class, including AChEIs Serotonin deficit may play a role in behavior Perry RJ. Neurology. 2001;56:46-51. Neurology. 2000;54:2277-84. Morris JC. Neurology. 2001;57:173-174.

52 Physician Role in Dementia Care l Thorough evaluation to make the diagnosis l Honest information - truth, but not bludgeon l Continuing care - "patient" includes family unit, as well as the victim with plaques and tangles l Reality testing - timing and appropriateness of support services and institutionalization l Ethical and appropriate choices for EOL care - not at first encounter, but not to wait for a crisis either + Restricted Rx, advance directives beyond DNR + Code status, tube feeding, hospitalization, Abx

53 Maximize General Medical Health Decrease excess morbidity; i.e., evaluation and optimal care for co-morbidities - all worsen cognition Periodic examinations Routine lab screening, based on problem list Preventive interventions that make sense + Vaccines, mammograms, FOB/endoscopy, OP? + Only if action consistent with advance directives Comprehensive evaluation for sudden decline; delirium common, AD doesn’t worsen overnight

54 Non-pharmacologic Interventions  Care management and psychosocial interventions  Educate caregivers – understand the disease, caregiver stress, avoid antipsychotics  Performance and behavior + Scheduled toileting + behavior modification, avoid triggers; distract, redirect + Exercise + Music, massage, pet therapy  Environmental modification + Safe space to wander + Remove toxins, weapons

55 Does AD Caregiver Support Effect Nursing Home Admission? RCT of >200 early or middle-stage AD caregivers/spouses, follow up nearly 4 years 6 sessions of individual, family counseling within 4 months of enrollment and join support group What happened to the Alzheimer patients after their caregivers attended the 6 sessions? What about nursing home admission? Mittelman MS et al. JAMA. 1996;276:1725-1731

56 Probability of NH Admission After Caregiver Intervention Proportion of AD Patients Remaining at Home Time in Years 2/3 RR, 329 days more at home Caregivers in intervention 1/3 less likely to place spouses in NH; greatest benefit if mild or moderate dementia

57 Dementia Caregiver Interventions Alzheimer’s Association – a remarkable organization providing education and support network FOR caregivers Education and support for caregivers Contact person identified, phone # for emergencies Advance directives, LTC + financial planning Caregivers’ physical, mental health; consider primary care visits coincident with those for AD patient Use of respite and adult day care Simplify and structure home environment Driving and home safety

58 Treatment of AD Symptoms Consider possibility of excess disability Depression - >50% during disease course Agitation, aggression, delusions Wandering – behavioral, caregiver interventions Incontinence – evaluate, treat Malnutrition – treat, but weight loss common Altered sleep – behavioral, modern hypnotics

59 Treatment of AD Pathology  Proven effective therapies + Reduce stroke risk + Cholinesterase inhibitors (“minimally effective”) + Memantine – approved for severe dementia  Proven ineffective therapies + Antioxidants + Ginko biloba + Estrogen + Anti-inflammatory drugs (NSAIDs) + Drugs to improve cerebral blood flow  Statins? Probably not

60 Cholinesterase Inhibitor Side Effects Common, sometimes transient, but may be long- lasting and disabling - dose-related; titrate slowly, take with food + GI – NVD, anorexia, weight loss + Vivid dreams/nightmares + Headache Less common + Agitation + Hypotension

61 Delay in NH Placement with Donepezil

62 Drugs for Dementia Behavior Disorders  Antipsychotics have demonstrated superior results in most randomized trials, but off label use  Be sure symptoms justify these dangerous drugs: agitation, aggression or delusions that disrupt care and impair life quality for caregiver and patient  Data conflicting whether atypical agents are better, but easier to use – fewer daily side effects of sedation or movement disorders, but FDA black box for all antipsychotic agents (stroke, CV death)  Use should be short-term, low dose

63 Risks of Atypical Antipsychotics  FDA review of 15/17 placebo-controlled trials showed numerical increase in risk of death with atypical anti-psychotic drugs in dementia patients (olanzapine, aripiprazole, risperidone, quetiapine)  5,106 subjects, 1.6-1.7x increase in mortality - heart failure, sudden death, pneumonia  May also be true for other atypicals (clozapine and ziprasidone) and typical neuroleptic drugs, but data insufficiently persuasive for FDA  Conflicting reports of increased stroke risk with risperidone; no FDA warning

64 Resources for Managing Dementia Attorney for will, conservatorship, estate planning; can be helpful with advance directives Community: neighbors & friends, aging & mental health networks, adult day care, respite care, home- health agency Organizations: Alzheimer’s Association (caregiver support groups), Area Agencies on Aging, Councils on Aging Services: Meals-on-Wheels, senior citizen centers

65 Principles of Dementia Care  Complicating diseases often missed  Hospitals are dangerous - avoid if at all possible  Dementia brain exquisitely sensitive to drugs - avoid  Useful Rx should not be withheld for age or dementia  Painful Rx should be very carefully considered  Symptomatic Rx without evaluation is dangerous  Stop Rx whose side effects are worse than symptoms  Assess response to Rx often and stop ineffective Rx

66 Summary Dementia is common, but never normal aging AD is most common, followed by vascular dementia and dementia with Lewy bodies Thorough evaluation is mandatory, both for diagnosis and identification of coexisting conditions whose treatment can influence course of dementia Treatment directed at function and quality of life, using drugs and behavioral interventions Social and instrumental resources supplement care for patient, caregivers and family members


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