1

Updatess in the Diagnosis, Treatment and Prevention of

Dementia*

Katherine Julian, M.D.

Professor of Clinical Medicine

University of California, San Francisco

October 22, 2014

Conflicts of Interest

No Conflicts of Interest

Case

EM is a 67 year-old man with a h/o high blood pressure. Brought in by wife who is reporting that patient’s personality has changed over the last year. He is becoming more suspicious, and at times talks and “doesn’t make sense”.

Questions...

Does EM have dementia or Alzheimer’s Disease (AD)?

How do I make the diagnosis?

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Outline

Clinical Presentation

Diagnosis

Updates in Treatment

Updates in Prevention

Resources

AD Prevalence

AD estimated prevalence 24.3 million world-wide in 2001

Predicted rise to 42.3 million in 2020

81.1 million by 2040

Lifetime risk of dementia after age 65 is 17-20%

Costs $150 billion/yr

Ferri CP, et al. Lancet 2005; Simmons BB et al. AAFP 2011

Dementia Types

Alzheimer’s: most common, 70%

Vascular: approx 17%

Other types: 13% Parkinson-related

Alcohol

Dementia with Lewy Bodies

Pathophysiology of AD

Neuritic plaques Amyloid precursor protein

cleaved Makes beta amyloid protein Accumulation initiates cell death

Neurofibrillary tangles filaments of abnormally

phosphorylated tau protein Loss of neurons

Cholinergic, noradrenergic, serotonergic neurotransmitters

Is it amyloid deposition that kills neurons OR are neurons being damaged by something else?

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Risk Factors for AD/Dementia

Age

Down’s syndrome

Head trauma

Fewer years of formal education

Female sex

Family history

Vascular risk factors (DM, htn, smoking)

Clinical Presentation of Dementia

Cognitive changes

Personality changes

Changes in day-to-day functioning IADLs that require calculation/planning first to be

impaired

Psychiatric symptoms

Problem Behaviors

Dementia under-diagnosed High index of suspicion

Ask caregivers/surrounding family and friends

Rapid Screening for Cognitive Impairment

2014 USPSTF insufficient evidence to recommend for or against universal screening

Variety of office screening tests MMSE most studied: sens 88.3%; spec 86.2%

(MOCA sens 90% in limited studies for MCI)

Clock drawing sens range 67-97%; spec 69-94.2%

Lin JS, et al. Ann Intern Med, 2013;159:601-612

Definitions of Dementia* by DSM5

Dementia No longer using the term “dementia”

Neurocognitive disorderDue to…

Alzheimer’s Disease

Vascular Disease

Lewy Body, etc

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DSM5 Neurocognitive Disorders (NCD)

Minor neurocognitive disorder Modest cognitive decline from a previous baseline

Can be in any domain (ex: memory, language, executive function, etc)

Based on pt’s concerns AND knowledgeable informant (or clinician) AND

Decline in neurocognitive performance (1-2 SD below normal) on formal testing or equivalent clinical evaluation

Cognitive decline doesn’t interfere with independence but requires some compensation

Can’t occur due to delirium Deficits can’t be from another mental disorder (ex: depression)

Example: Mild cognitive impairment: impairment doesn’t affect function

DSM5 Neurocognitive Disorders (NCD)

Major neurocognitive disorder Evidence of substantial cognitive decline in one or more

domains Based on pt’s concerns AND knowledgeable informant (or

clinician) AND Decline in neurocognitive performance (>2 SD below normal)

on formal testing or equivalent clinical evaluation

Cognitive decline is sufficient to interfere with independence (ex: requires assistance with IADLs or ADLs)

Can’t occur due to delirium Deficits can’t be from another mental disorder

Work-Up of Cognitive Impairment

American Academy of Neurology recommendations: Vitamin B12, thyroid, depression screen

Other tests as indicated: blood count, urine tests, liver tests, syphilis test, lumbar puncture

Neuro imaging (CT or MRI)

Do we need to do this?

“Reversible” Dementias…do they exist?

Meta-analysis in 2003 5620 subjects; potentially reversible causes in 9%;

0.6% actually resolved Causes of “dementia” in meta-analysis

56% AD 20% vascular 1% metabolic 0.9% depression 0.1% medications 15% Other (NPH, subdural hematoma, B12, tumor,

Parkinson’s disease, HIV, frontal lobe)

Clarfield AM. Archives of Internal Medicine, 2003;163.

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“Reversible” Dementias…do they exist?

Most reversible dementias were in patients who: Were relatively young

Had mild or atypical symptoms

Neuroimaging detected conditions in 2.2% 0.9% tumor, 1% NPH, 0.3% SDH

Most did not change course of illness

Reversible dementias less common

Must weigh costs/benefits of neuro-imaging AGS recommends imaging: age <60, rapid decline

(weeks/months), CA, HIV, anti-coagulation

Clarfield AM. Archives of Internal Medicine, 2003;163.

Neuro-Imaging – Updates

Semi-quantitative MRI Medial temporal lobe atrophy in AD New studies looking at hippocampal and cortical

thickness Aß PET with florbetapir F-18 (Amyvid) highlights

brain beta-amyloid Approved by FDA April 2012 Median sensitivity 92% (range 69-92%) and median

specificity 95% (range 90-100%) Positive scan does not establish the dx—use as adjunct

May overlap with other brain pathologies

Pearson SD, et al. JAMA, 2014;174(1).

Example of 18F-FDG-PET

Alzheimer’s Disease Neuroimaging Initiative, Jan 2010

Diagnosis of AD – Updates

Abnormal CSF biomarkers Low beta-amyloid

Increased tau/phosphotauconcentrations

No consensus on cutoff points for real practice

Perfusion SPECT Resolution less but less

expensive

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Diagnostic Instruments Mini Mental Status Exam

Maximum score 30

Score <24 suggests delirium or dementia Decline of 4 points over 1-4 years significant

Scores correlated with education level; inversely correlated with age

Not sensitive in people with higher levels of education

Diagnostic Instruments

MMSE Survey of 18,056 adults

Scores relate to age Median score 29 in those 18-24 years

Median score 25 in those >80 years

Scores relate to educational level Median score 29 in those with >9 years schooling

Median score 22 in those with 0-4 years schooling

Crum RM et al. JAMA, 1993;269(18)

Diagnostic Instruments…Take Home Points

Caution in interpreting MMSE score Consider appropriate age/education median scores

MMSE scores for age/education available on the web

Median LR for positive result 6.3 (CI 3.4-47)

If positive initial screen, can consider further testing if appropriate

Holsinger T, et al. JAMA, 2007;297.

Diagnostic Instruments…Take Home Points

Highly educated individuals Neuropsychological testing

May be better in detecting early impairment

Holsinger T, et al. JAMA, 2007;297.

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Diagnostic Instruments…Take Home Points

Tests not quite ready for “prime time” but coming…

PET scanning (although approved)

MRI

CSF ß-amyloid

CSF tau

APOEε4 genotyping

Case

78 year-old woman recently diagnosed with Alzheimer’s Disease. MMSE score is 19. What should you do next?

1) Start an acetylcholinesterase inhibitor (ex: donepezil or aricept)

2) Start memantine3) Do not start any medications at this

time4) Discuss with the family/patient their

wishes regarding treatment

Treatment of AD Clarify goals

Preserve function and independence

Maintain quality of life

Minimize excess disability and ensure safety

Make long-term decisions early

Treatment Options Symptomatic treatment of memory disturbance

Symptomatic treatment of behavioral disturbance

Disease-modifying treatment

Symptomatic Treatment of Memory Disturbance

Cholinesterase Inhibitors delay degradation of acetylcholine at the synaptic cleft. For mild-mod Alzheimer’s Disease

Slow titration

Donepezil (Aricept)--5-10mg/day

Rivastigmine (Exelon)--6-12mg/day—weight loss

Galantamine (Razadyne)--24-32mg/day or patch 4.6-9.5mg----weight loss

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Cholinesterase Inhibitors

Donepezil and Galantamine Metabolized by cytochrome P450 system

ChEIs Common side effects: nausea, vomiting, diarrhea

Take with food

Interruption of meds = start back at lowest dose

If changing meds due to SE, washout period 7-14 days

Vivid dreams: take in am

Bradycardia, AV block

Cholinesterase Inhibitors…What’s the Data?

Studies range 12 weeks to 3 years Pts on ChEIs compared to placebo

ADAS-cog evaluates memory, attention, language, orientation (score 0-70) Average difference 1-3 points

Statistically significant differences, but most do not show clinically significant changes

USPTF, Ann Intern Med, 2014

What’s Clinically Significant?

Long-term donepezil treatment evaluated 565 patients with mild-mod AD randomly assigned

to donepezil 5mg or placebo for 12-week run-in Followed up to 3 years End points: Institutionalization or progression of

disability (loss of ADLs)

AD2000 Collaborative Group, Lancet 2004;363.

Symptomatic Memory Treatment?

Long-term donepezil treatment No difference in rates of institutionalization or

disability progression

No difference in care costs, unpaid caregiver time, behavioral/psychological symptoms

Costs of drug not offset by any positive outcomes

AD2000 Collaborative Group, Lancet 2004;363.

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Cholinesterase Inhibitors…Take Home Points

Likely no disease modifying effects – modest cognitive improvement Delay progression 6mo-1yr

Guidelines: “Base the decision to initiate therapy on individualized assessment”

Insufficient evidence regarding head-to-head comparisons; choose medication based on SE and dosing

Case

78 year-old woman recently diagnosed with Alzheimer’s Disease. MMSE score is 19. What should you do next?

1) Start an acetylcholinesterase inhibitor (ex: donepezil or aricept)

2) Do not start any medications at this time3) Discuss with the family/patient their wishes

regarding treatment

Other Options in Memory Treatment?

80 year-old woman with progression of her Alzheimer’s Disease. She is currently being treated with Aricept at 10mg/day. Her recent MMSE=11. Are there other treatment options?

Other Options in Mod-Severe AD?

Memantine (Namenda) NMDA-receptor antagonist

Glutamate stimulates NMDA receptor; overstimulation results in neuronal damage

Pooled estimate from 3 trials (vs. placebo)Statistically significant improvements on

ADAS-cog scale but modest clinical improvement

Memantine combined with other ACHEI

Qaseem A, et al. Ann Intern Med, 2008;148Tariot PN et al. JAMA, 2004;291(3).

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Other Options in Mod-Severe AD?

Donepezil 23mg daily approved 2010 for moderate-severe AD

Guidelines in Memory Treatment?

Take Home Points…

First line therapy in mild-mod AD (if treatment decided) is cholinesterase inhibitors

If treatment failure/not tolerated, can either:Change to another ChEI

Add memantine

Change to memantine (or increase donepezil)

Consider memantine for moderate-to-severe dementia

Guidelines in Memory Treatment?

When to stop treatment? If quality of life benefits no longer possible (as

determined by family, provider)

Pt dependent in all basic activities of daily living

Disease-Modifying Treatment of AD

Anti-oxidants? Vitamin E

Anti-inflammatories?

Statins?

Ginkgo biloba?

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Treatment of AD: Vitamin E Free radicals and oxidative damage

contributes to neuronal death Vitamin E traps free radicals

Mixed results in studies 1997 study showing some benefit of vitamin E

2008 Cochrane review: no benefit of vitamin E

2014 JAMA: 2000 IU resulted in slower decline (approx. 6 mo) in mod-sev AD. Study underpowered

Sano et al. NEJM, 1997;336Issac MD et al. Cochrane Database Syst Review, 2008

Dysken MW, JAMA, 2014;311(1)

Side Effects of Vitamin E?

Can increase risk of bleeding—particularly in pts on coumadin

Meta-analysis of 19 RCT 135,967 patients on vitamin E (16.5-2000 IU/d)

Dose >400 IU associated with increased mortality (Risk difference 39 per 10,000 people CI 3-74)

Lower-dose vitamin E associated with decreased mortality

IOM now recommending dose <1000 IU/day

Miller ER, et al. Ann Intern Med, 2005;142:37-46.

Treatment of AD

Negative trials Anti-inflammatories (ibuprofen, naproxen,

celecoxib, indomethacin)

Statins (simvastatin, atorvastatin)

Dietary supplements (multi-vitamins, fatty acids) Mixed data on Gingko – Cochrane review inconsistent

benefit High doses: GI SE, may increase bleeding in patients on

ASA/coumadin

Birks J, et al. Cochrane Database of Systematic Reviews, 2007;2.

Disease-Modifying Treatments...Take Home Points

No real evidence for Vitamin E (Old) guidelines 1000 IU BID; IOM

1000 IU daily

Low-dose even better!

No evidence for other treatments

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What’s Next?

Amyloid precursor protein (APP) → amyloid-beta fragments

Inhibitor of Ƴ-secretase: Semagacestat

Monoclonal Ab binds soluble amyloid beta fragments Solanezumab

Bapineuzumab

ß-secretase Ƴ-secretase

What’s Next?

Question: Does semagacestat improve cognition in patients with probable Alzheimer’s disease?

Study Design: Double-blind, PCT 1537 patients semagacestat (2 doses) vs. placebo

Outcomes: Terminated early—worsened cognition scores, more weight loss, skin cancers, infections

Doody RS, et al. N Engl J Med, 2013;369(4).

What’s Next?

Question: Do monoclonal antibodies Solanezumab and Bapineuzumab improve cognitive scores in mild-mod AD

Study Design: 2 double-blind, RCT

Outcomes: No improvement in cognitive testing. Safety finding: more brain edema

Doody RS, et al. N Engl J Med, 2014;370Salloway S, et al. N Engl J Med, 2014;370

Prevention of ADCase

60 year-old woman with strong family history of Alzheimer’s Disease. She is concerned about her own risk for dementia. What is the best prevention treatment can you offer?

A) She should start ERTB) She should take a statin…forget about that package warning!C) She should start an NSAIDD) She should exercise

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Updates in PreventionEstrogen Replacement Therapy

Women’s Health Initiative Memory Study 4532 healthy post-menopausal women (65-79)

Randomized to estrogen/progestin or placebo

Estrogen/progestin increased risk for probable dementia (HR 2.05)

2947 randomized to estrogen only or placebo Increased risk of development of probable dementia

(HR 1.49; CI 0.83-2.66))

Shumaker SA, et al. JAMA, 2003;289(20).Shumaker SA, et al. JAMA, 2004;291(24).

More on Estrogen/Progesterone

Olmstead county cohort: all women 1950-1987 who underwent oophorectomy prior to menopause for non-cancer indication

1,433 with unilateral; 1,824 with bilateral

Each cohort member matched to control

Oophorectomy before menopause: Increased risk of dementia compared to control (HR 1.46, CI 1.13-1.9)

Rocca WA, et al. Neurology, 2007;69.

Estrogen/Progesterone

Findings supported by 2 other cohort studies showing earlier age with surgical menopause associated with cognitive decline

Is there a “window of opportunity” when hormones are actually beneficial?

Updates in AD PreventionShould Statins be in the Water?

RCT: Pravastatin vs. placebo No difference in cognitive function after 3.2 years

RCT: Simvastatin vs. placebo No difference in incidence of dementia

No evidence statins prevent vascular dementia

Shepard J, et al. Lancet, 2002;360.Heart Protection Study Collaborative Group. Lancet, 2002;360.

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Case reports that statins may worsen cognition

Review of all statin studies: benefits outweigh risks

Meta-analyses: statins not associated with impaired short-term cognition or increased risk of dementia ? Hydrophilic statins (ie, pravastatin and rosuvastatin) less

likely to contribute to cognitive impairment due to limited penetration across the blood-brain barrier

Rojas-Fernadez CH, et al. Ann Pharmacother, 2012.Richardson K et al. Ann Intern Med, 2013Swiger KJ et al. Mayo Clin Proc, 2013

Prevention of AD withAnti-Inflammatory Drugs

Meta-analysis of observational studies NSAIDS >2yrs reduced risk by 73%

Confounding?

RCT 2528 volunteers >70 yrs with FH AD

Naproxen vs. Celebrex vs. Placebo

Study stopped after 3 years: no evidence anti-inflammatories prevent AD

BMJ, 2003(327), Neurology 2007(68)

Sleep and AD Sleep and AD = bidirectional relationship

Brain regions involved in sleep and circadian control affected early in AD

Patients with AD often have worse quality of sleep

Sleep changes may precede onset of cognitive symptoms Amyloid deposition associated with worse sleep quality

Chicken or the egg?

Chronic disrupted sleep likely has some cognitive effect

Obesity and Risk of AD

Kaiser Permanente 6,583 members Sagittal abdominal diameter (SAD) measured

1964-1973 with medical records f/u 1994-2006

Marker for metabolic syndrome

Higher SAD associated with increased dementia risk Highest quintile of SAD: HR for dementia 2.72 (CI

2.33-3.33)

Thigh adiposity didn’t increase dementia risk

Whitmer RA, et al. Neurology, 2008

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Exercise and Dementia Prevention

Multiple small trials; results uncertain

Meta-analysis 33,816 non-demented patients followed prospectively

Subjects with high-level physical activity protected against cognitive decline (HR 0.62 CI 0.54-0.7)

Low-moderate exercise also protective (HR 0.65; CI 0.57-0.75)

Exercise can’t hurt…

Sofi F et al. J Intern Med, 2011

Leisure Activities and Risk of AD

Multiple small trials May improve short-term global cognitive function in

pts with dementia/MCI

?Protective effect

Likely can’t hurt…

USPTF, Ann Intern Med, 2014

Prevention of AD – Cognitive Reserve

Evidence suggests that cognitive reserve is protective against AD Education

Occupation

Mental activities

β-Amyloid 42/40, Cognitive Reserve and Cognitive Decline

Yaffe K, et al. JAMA, 2011;305(3)

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Cognitive Reserve

Prospective cohort 1995 older adults without dementia

Baseline education/occupation score and mid/late-life cognitive activity (i.e. 3x/week)

Results

Higher education/occupation associated with higher levels of cognition

Higher cognitive activity associated with higher levels of cognition but less of a factor (esp if higher education)

Vemuri P, et al. JAMA Neurol, 2014

Prevention of AD…Take Home Points

Estrogen replacement therapy is out for now…

Statins good for hyperlipidemia but not to prevent dementia

Get out there and exercise! Be a “pear” rather than an “apple” Chess never hurt anyone Stay in school

Prevention of ADCase

60 year-old woman with strong family history of Alzheimer’s Disease. She is concerned about her own risk for dementia. What is the best prevention treatment can you offer?

A) She should start ERTB) She should take a statinC) She should start an NSAIDD) She should exercise

Prevention of AD – Stay Positive!

Observational studies with increased dementia risk Mid-life htn

Current Smoking

Diabetes

No evidence yet that treatment decreases dementia risk

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Prevention of AD – Stay Positive!• To estimate impact of risk factor reduction on AD prevalence for

7 modifiable factors: Diabetes ▪ Mid-life hypertension Mid-life obesity ▪ Depression Physical inactivity ▪ Low education Smoking

• Population attributable risks (PARs)

• Tools to estimate proportion of disease attributable to given risk factor, accounting for prevalence & strength of association

• Calculations

• Risk factor prevalence worldwide, U.S.

• Relative risk from most recent/comprehensive meta-analysis or systematic review

Barnes, DE and Yaffe K. Lancet Neurol, 2011;10

Prevention of AD – Stay Positive

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Barnes DE and Yaffe K. Lancet Neurol, 2011

Evaluation of Driving Risk in Dementia – Practice Parameter

Patient is at increased risk for unsafe driving if: Clinical Dementia Rating Scale > 0.5 (level A)

Caregiver rates patient’s driving ability as marginal or unsafe (level B)

Pt has a h/o crashes/traffic citations (level C)

Pt has reduced driving mileage or self-reported situational avoidance (level C)

MMSE < 24 (level C)

Pt with aggressive/impulsive personality characteristics (level C)

Iverson DJ, et al. Neurology, 2010;74.

Resources

Alzheimer’s Disease Education and Referral (ADEAR) Center 800-438-4380 http://www.nia.nih.gov/alzheimers

Alzheimer’s Association 800-272-3900

www.alz.org

Safe Return Program

American Academy of Neurology http://www.aan.com/go/practice/guidelines

Kathy Julian, M.D. Updated 9/30/14

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