Dementia What’s New In Medicine 2014 September 13, 2014 Jeffrey Wallace MD, MPH Professor,...

Dementia

What’s New In Medicine 2014

September 13, 2014

Jeffrey Wallace MD, MPHProfessor, Internal Medicine & Geriatrics

University of Colorado Health Sciences Center

Learning Objectives

What’s new in prevention & early detection of Alzheimer’s disease

Review current treatment and important considerations for helping patients (and their caregivers) with dementia

Dementia

Dementia: Epidemiology

Prevalence 1% at age 60, doubles q5 years

Community 65-74 yo 5%

80+ yo 20-40%

90+ yo 50+%

Hospital 33-50% > age 70 impaired

DetectionFamily informants 20% failed to recognize dx

Primary Care group 75% screened (+) w/o chart dx

Med Clin NA 2002;86:455

Screening for cognitive impairment

Prevalence rates age 71+ Dementia 14%

Cognitive impairment, not dementia 22%

USPSTF – no clear recs pro or con d/t ? benefit dx

Most pts desire (or at least accept) cog screen

Affordable Care Act clinicians must assess for pts 65+ for cognitive

impairment as part of annual wellness visit

Ann Intern Med 2013;159:601 JAGS 2012;60:1027 & 1037

Case Hx: Possible early impairment 76yo M semi-retired accountant c/o forgetfulness

Pt/spouse note ability to remember names and misplacing items over past yr. Pt more irritable. He is aware of memory Δ’s but feels getting along fine. He has continued to do accounting work during tax season & enjoys usual activities of playing cards & attending theatre.

P.E. - unremarkable, non-focal neurologic, MMSE is 26/30 (error w/date, 1 of 3 STM recall, error in copy figure)

What is patient’s most likely dx?

1) Age associated memory impairment

2) Mild Cognitive impairment

3) Alzheimer’s disease

4) Normal aging

Case Hx: Possible early impairment

76yo M semi-retired accountant c/o forgetfulness

Normal Aging

Some decline in processing speed and depth of recall of new information: slower, harder

Can learn new info but slower acquisition speed

Non-verbal info more affected than verbal

spontaneous recall

Reminders work—visual tips, notes

Absence of significant effects on ADLs or IADLs

Mild Cognitive Impairment (MCI)

Dx Criteria: 2011 NIA-Alzheimers Assoc workgroup

change in cognition recognized by pt or observers

objective impairment in 1 or more cognitive domains

independence in functional activities preserved

with minimal aid or assistance

application of this criterion is the challenge

Alzheimers Dement 2011;7(3):270-79

Mild Cognitive Impairment (MCI)DSM 5: “mild neurocognitive d/o”

Grey zone between normal aging and dementia

Most often memory problem without deficits in other domains (amnestic MCI)

No functional impairment, social or occupational

Predicts risk: 10-15%/yr progress to dementia dx

Neurology 2001;56:1133 Ann Intern Med 2008;148:427

Mild Cognitive Impairment

Which med tx has shown some benefit for pts w/MCI?

1. Cholinesterase inhibitors

2. High dose vitamin E

3. Statins

4. Ginkgo biloba

5. Fish oil

Vitamin E and Donepezil for Tx of MCI NEJM 2005;352:2379-88

Vitamin E and Donepezil for Tx of MCI NEJM 2005;352:2379-88

p-values adjusted for multiple comparisons donepezil NS for all subjects at 24 mo (p=0.052) and APO 4 carriers at 36 mo (p=0.078)

Mild Cognitive Impairment

Non-pharmacologic interventions that may help slow transition from MCI to dementia?

Physical activity - 50 minutes walking 3 days/wk

Mental activity - games, crosswords, leisure activitiescognitive training (eg Lumosity)

JAMA 2008;300:1027-37

NEJM 2003;348:2508 Ann Intern Med 2010;153:182

JAMA 2008;300:1027-37

Walking is good for the body --- and brain!

170 pts w/memory concerns in Australia, age 70

Tx: > 150 minutes moderate-intensity physical activity/wk (three 50-minute sessions/wk), mostly walk

6 months activity, monitor cognition for 18 months

6 mo: activity 0.26 vs 1.0 no tx (ADAS-cog)

18 mo: activity 0.73 vs 1.27 on ADAS-Cog

Conclude: in adults w/subjective memory concerns, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month f/u period.

Dementia Criteria: DSM-V Definition

“Dementia” out, “major neurocognitive disorder” in

Requires

Significant cognitive decline in 1 or more domains eg, memory, speech, judgment, visuospatial, behavior

As noted by pt, family or clinician

Objective evidence of “substantial” impaired cognition

Sufficiently severe to interfere with usual function in everyday activities

Am Psych Assoc. 2013 Diagnostic and Statistical Manual 5th Ed

● USTSPF insuff evidence for routine screen (2013)

● Yet: 50+% cases mild impairment missed

● Screening tests reasonably accurate, eg MMSE: 88% sensitivity, 86% specificity

Mini-cog: 76-100% sens/ 54-85% specific

Dx prompts w/u, MD/pt/family understanding

Tx available (non-pharm & meds)

Screen: stigma dx vs awareness, w/u, f/u, tx

Cognitive Impairment Screening Rationale

Ann Intern Med 2013;159:601 JAMA 2007;297:2391

Cognitive Impairment Screen Instruments

Mini Mental State Exam (MMSE) Most common, most studied 7 minutes, copyrighted

MMSE details/nuances Screen: 24-30 nl; 18-23 mild, 0-17 severe Education (< 27 abnl college ed, not for < 8th grade ed) Language barrier Anxiety Scoring: inexact answers, 3 item recall, world/7s

Likelihood ratios (LR): (+) test 6.3, LR (-) test 0.19

JAMA 2007;297:2391 Ann Intern Med 2013;159:601

Three item recall (apple, table, penny) score: 0-3 (# items recalled)

Clock Test: draw clock face, hands at 11:10 scored nl (2 points) or abnormal (0 pts)

Total Score 0-5 3-5 probably not impaired 0-2 probably impaired

Cognitive Screen: Mini-Cog

JAGS 2003;51:1451

Simpler yet --- inquire about memory probs

Patient c/o memory difficulties LR: (+) 1.8, (-) 0.36 Specificity issue: also associated w/depression

Informant relates memory difficulties LR: (+) 6.5, (-) 0.1 More accurate if informant lives with pt

Either way, pt/informant c/o should trigger eval (for both cognitive and mood related d/o)

Cognitive Screen Instruments

Neurology 2000;55:1724 JAMA 2007;297:2391

Adjunct Cognitive Tests

MMSE has ceiling effect (esp higher ed pts)

Montreal Cognitive Assessment (MoCA)30 pts, 10 min www.mocatest.org

sensitivity, but is this desirable???

Executive funx, visuospatial, verbal fluency clock test

animal naming (4-legged animals/1 minute)

words starting with letter (eg, F, then A, then S)

Dementia Dx Criteria

Remember screen test = screen, dementia dx Cognitive or behavioral ’s involve 2 or more of:

impaired ability to acquire/recall new info impaired reasoning, judgment, decision making ↓ visuospatial abilities impaired language (speak, read, write) in personality, behavior, comportment

Sufficiently severe to interfere with usual function

Dementia: Epidemiology

EtiologyAlzheimer’s 50-70%

Multi-Infarct 10-30%

Lewy Body/Parkinsons 10-20%

ETOH 5-10%

Other < 5%

Dementia: Epidemiology

Which clinical feature is most suggestive of dementia with Lewy Bodies?

1) Rapid disease progression

2) Cognitive fluctuations

3) Falls

4) Good response to haldol

Dementia: Lewy Body vs AD

Lewy Body Dz AD

Sxms at Presentation % (range) % (range)__

Cognitive fluctuations* 58 (8-85) 6 (3-11)

Visual hallucinations* 33 (11-64) 13 (3-19)

Auditory hallucinations 19 (13-30) 1 (0-3)

Parkinsonism* 43 (10-78) 12 (5-30)

Neuroleptic sensitivity 61 (0-100) 15 (0-29)

Falls 28 (10-38) 9 (5-14)__* 2 required for probable, 1 for possible LBD dx

Br J Psych 2002;180:144

Dementia: Epidemiology

EtiologyAlzheimer’s 50-70%

Multi-Infarct 10-30%

Lewy Body/Parkinsons 10-20%

ETOH 5-10%

Other < 5%

Alzheimer’s Dementia: DSM-IV Criteria

Impaired memory

One or more- Aphasia- Apraxia- Agnosia- Executive dysfunction

Sufficiently severe to interfere with usual function

Gradual onset and continuing decline

Other causes excluded }probAD

Dementia: Epidemiology

“Reversible” Dementia

Drugs and Depression (pseudodementia) - 10-15%

Other “reversible” causes < 5%

Hypothyroid, B12, NPH, tumor, subdural

Fully reversible cognitive impairment < 1%

Clues to reversibility: duration<1yr, mild dz(MMSE>20), younger age

Finding reversible dementia is uncommon

Attention to 3 ‘Ds’

Coexistent Disease: 50% had unrecognized med dx

Drugs - d/c all possible

Depression - consider, trial of therapy

25% improved with meds/ illness tx/ depression tx

Dementia: Treatment and Management

Dementia: Treatment and Management

Non-Pharmacologic approaches

Adjust environment: clocks, calendars, lists, etc

Physical activity

Caregiver support Education – new HHS website www.alzheimers.gov Counseling, support groups Depression Daycenter Respite

NEJM 2006;295:2148

Pharmacologic Management of Dementia

Cholinesterase Inhibitors: donepezil, rivastigmine, galantamine FDA-approved for mild to severe AD Rivastigmine also approved for PD dementia All approved for vascular dementia Anticholinergics negate effects

NMDA antagonists FDA-approved for mod-severe AD as

monotherapy or combo therapy with AChE-I

*** Trial for benefit typically takes 6mo*** Data for treatment > 1 year is lacking

Efficacy of Cholinesterase InhibitorsVery modest improvement/stabilization in symptoms

Cognition: ADAS-cog (range 0-70) 4 pt improvement 25-50% with tx vs 15-25% with PBO 7 pt improvement 12-20% with tx vs 2-6% with PBO

Function: ADLs Decrease functional decline by 5mo compared to PBO

Behavior: NPI (range 0-120) Improvements inconsistent – as low as 0 to as high as 5.6 pts Donepezil not effective for agitation NEJM 2007;357:1382

Caregiver Burden: Delay in Nursing Home Placement Some studies do suggest, but few data available powered and

controlled to formally look at this AD2000 3 yr RCT – no benefit Lancet 2004; 363:2105

Effects of Cholinesterase Inhibitors on Clinical Outcomes

Likely proceed but with caution: Average effect size is modest in AD; even less in

vascular dementia

Little data showing benefit persists beyond 12 mo

Reports of funx, health care costs & NHP have flaws (eg, open label, self-selection)

ADEs can be substantial GI – n/v/d, anorexia, wt loss Car - bradycardia/syncope/falls GU – urge, frequency

BMJ 2005;331:321AD2000: Lancet 2004; 363:2105-15

AGS/ABIM Choosing WiselyList of 5 Things Physicians & Patients

Should Question: Part 2Don’t prescribe AChEIs for dementia w/o periodic assessment for perceived cognitive benefits and adverse GI effects RCTs indicate modest benefits in delaying cognitive and functional decline and ↓ neuropsychiatric symptoms.

Less established benefits: institutionalization, QOL, caregiver burden

Discuss cognitive, functional & behavioral goals of tx prior to rx

Advance care planning, education, diet & exercise and non-pharm approaches to behavioral issues are integral to care

If goals of tx not attained after reasonable trial (eg, 12 wks), d/c

Benefits beyond a year have not been investigated and the risks and benefits of long-term therapy have not been well-established

J Am Geriatr Soc. 2014;62(5):950

Dementia: NMDA receptor antagonist

Agents- memantine (approved in US 2003)

Activity- blocks excitatory activity of glutamate on

neurons via NMDA receptor

Proposed mechanism of action- overstim of NMDA receptors implicated in

neurodegenerative disorders- memantine glutamate related neurotoxicity

Dementia: Memantine Monotherapy

US Trial mod-severe AD (MMSE 3-14), n=252

NEJM 2003;348:1333

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NEJM 2003;348:1333

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Dementia: Memantine Monotherapy US Trial mod-severe AD (MMSE 3-14), n=252

NEJM 2003;348:1333

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Dementia Medications

Your 84 yo F pt w/AD was started on donepezil 10mg in 2009 when MMSE was 23. MMSE has to 14 in 2013 but she continues to live at home, attends a daycenter 5d/wk. EBM suggests which of the following adjustments to her medications?

1. Increase donepezil to 23mg

2. Add memantine to donepezil

3. Stop donepezil and start memantine

4. Stop donepezil

Dementia Medications Your 84 yo F pt w/AD was started on donepezil

10mg in 2009 when MMSE was 23. MMSE has to 14 in 2013, she continues to live at home, attends a daycenter 5d/wk. EBM suggests which of the following adjustments to her medications?

1. Increase donepezil to 23mg

2. Add memantine to donepezil (JAMA 2004)

vs.

3. Stop donepezil, start memantine (NEJM 2012)

4. Stop donepezil

Dementia: Donepezil + Memantine US Trial mod-severe AD (MMSE 5-14), n=404

JAMA 2004;291:317

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JAMA 2004;291:317

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RCT mod-severe AD (MMSE 5-13), n=295

NEJM 2012;366:893

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NEJM 2012;366:893

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When to Rx Memantine FDA approved ONLY for moderate-severe AD

MMSE < 14 in RCTs showing benefit, YET

In 2006, 19% of pts with mild AD in the US on rx

rx’ed in 46% of pts w/mild AD in academic setting

11% pts w/MCI in national studies on memantine

~ 40% of US neurologists reported prescribing memantine at least sometimes to pts w/MCI

Cost: $300+/month

Arch Neurol 2011;68(8):991

Preventing or Treating SDAT

Drug

- Vitamin E

Activity

- Antioxidant/free radical scavenger

Proposed mechanism of action

- Protects against free-radical damage

Vitamin E: 1000 units BID

1997 NEJM RCT w/(+) findings Mod-severe AD: 350 pts, age 74, x MMSE 13 Delayed endpoint of death/institutionalization/loss

of ADLs/severe dementia by 145-215 days↑ risk of falls/syncope with vit E

2005 NEJM RCT w/(-) findings 769 pts with mild cognitive impairment 212 pt developed AD over 3 yr f/u Vitamin E had no beneficial effects

NEJM 1997;336:1216 NEJM 2005;352:2379

Vit E: Falling out of Favor?

Mod-severe AD study had problems

MCI RCT (-)

New concerns?Physicians Health Study 400 IU qod, no benefits,

hemorrhagic CVA

SELECT Prostate CA: 400 IU qd prostate CA

Vitamin E meta-analysis: 400+ IU/d mortality

JAMA 2011;306:1549

JAMA 2008;300:2123

Ann Intern Med 2005;142:37

Vitamin E Safety Issues: Meta-Analysis

Harm Assoc w/High Dose Vit E?19 RCTs, 135K pts, doses 16-2000IU

All cause mortality

RR any dose: 1.01 (0.98-1.04)

RR dose < 400IU: 0.98 (0.96-1.01)

RR dose > 400IU: 1.04 (1.01-1.07,p=.03)

Most studies w/older pts, chronic dz/CHD

Ann Intern Med 2005;142:37

Vitamin E Safety Issues: Meta-Analysis

Vit E dose Adjusted for other vits/min IU/d Risk difference* Risk ratio

(95%CI) 20 -16 (-45 to 14) 0.98 (0.95-1.02)50 - 8 (-42 to 25) 0.99 (0.96-1.03)

100 2 (-35 to 38) 1.00 (0.97-1.04) 200 15 (-26 to 56) 1.01 (0.98-1.05) 500 38 (-11 to 87) 1.04 (0.99-1.08)1000 57 (-1 to 115) 1.06 (1.00-1.11)2000 76 (8 to 145) 1.08 (1.01-1.14)

* Deaths per 10,000 personsAnn Intern Med 2005;142:37

Vitamin E and/or Memantine for Mild-Moderate AD

JAMA 2014;311:33-44

New RCT: 600+ VA pts w/AD all ON CHOL-I

Mild-mod AD: MMSE 12-26, mean 19

Vit E 1000 BID &/or memantine 10mg BID vs placebo

mean 2.3 yr f/u

Main outcome: in ADL funx (ADCS-ADL score)

2o outcomes: cognition, behavior, caregiver burden

Vitamin E and/or Memantine for Mild-Moderate AD: 1o outcome Funx

JAMA 2014;311:33-44

Vit E vs placebo- decline 19%/yr- ~6 mo , p=.03- No harms seen

Memantine vs plac- no benefit

Combo vs plac- no benefit

Vitamin E and/or Memantine for Mild-Moderate AD: 2o outcomes

JAMA 2014;311:33

MMSE - NS ADAS-cog - NS

NPI - NS CAS - NS

All NS but all analyses favor Vit E

Vitamin E and/or Memantine for Mild-Moderate AD

JAMA 2014;311:33-44

Take Homes

Memantine c/w prior studies, (-) effect w/milder dz

Vit E

appeared to have some benefit (but not w/memantine)

MOA uncertain

no risk in this trial

Okay to try as long as safe --- is it???

Dementia Rx” “Do” take homes Non-pharm rx for everyone

Daily walks & RT both beneficial

Keep mind active but don’t overchallenge

Try cholinesterase inhibitor (early-late dz)

Probably try Vit E 2000 IU/d (mild-mod dz)

Viable options when dz progresses (mod-sev dz) stay the course w/Chol-I

switch to memantine

add memantine& d/c Vit E?

Dementia Rx” “Do Not” take homes

Do not use memantine early in course of dz (MMSE 20+)

When dz progresses do not increase donepezil > 10mg/d clinical gain marginal, ADE increase significant

Potential concerns Does memantine mitigate Vit E benefit? Consider d/c Vit E if adding memantine

Tx at some point likely w/o benefit, when to trial d/c is far from clear

TALK ENDS HERE

IF TIME PERMITS, FOLLOWING CONSIDERS POSSIBLE NEW TX OPTIONS ON HORIZON +POSSIBLE PREVENTION

Potential options on the horizon – closest may be intranasal insulin

** 2013-14 RCTs in NEJM (-)

*

Alternative and UpcomingPharmacologic Treatment Options

Supplements Fish oil Ginkgo

Medical FoodsAxona, Souvenaid

Experimental Treatments Intranasal insulin Gene therapy B-secretase inhibition B-amyloid peptide vaccine v2.0 HDAC inhibitor J-147 Saracatinib: Src kinase family inhibitor Tau therapies: TRx0237, vaccine AADvac1

Failed/Not marketed Dimebon Solanezumab and Bapineuzumab: monoclonal antibodies to bind amyloid

(NEJM 2014;370:311-21,322-33) B-amyloid removal with IVIg (Lancet Neurol 2013;12:233-243) Avagacestat, Semagecestat: γ-secretase inhibition (Arch Neurol 2012;69:1430-

40, NEJM 2013;369:341-50)Clin Ther 2013;35:1480

Any advice while waiting on advances?

Dementia: Risk/Protective Factors

Protective Definite Risk FactorsAPOE2 allele Age

Family HxAPOE4 alleleOther genes†

Intellectual activity Possible Tobacco usePhysical activity Head TraumaMediterranean diet Low EducationOmega-3 fatty acids ____ Metabolic Syn_† Rare, early onset familial AD assoc w/mutations on chromosomes 1, 12, 14, 21

Ann Intern Med 2010;153:182

Arch Intern Med 2010:170;2036

Resistance Training: Give your brain a lift

155 women age 65-75, 1 yr study

Wt training 1 or 2x/wk vs balance training 2x/wk

60 minute sessions (10 warm-up & down, 40 min core)

Cognitive function testing

improved 11% with resistance training

no change with balance/tone

Lifestyle and DementiaBronx Aging Study: Higher level of education

and cognitive leisure activities “protective” against development of AD

NEJM 2003;348:2508

15 minutes aerobic exercise 3X/week reduces likelihood of dementia

Ann Intern Med 2006;144:73JAMA 2004;292:1447

“ read while on exercise bike” (preferably w/heavy book that you intermittently lift)