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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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-4
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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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0 4 12 28Weeks
AD
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memantineplacebo
Dementia: Memantine Monotherapy US Trial mod-severe AD (MMSE 3-14), n=252
NEJM 2003;348:1333
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CIB
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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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-2
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0
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2
3
0 4 8 12 18 24Weeks
Se
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pa
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donep+mem
donep+placebo
Dementia: Donepezil + Memantine US Trial mod-severe AD (MMSE 5-14), n=404
JAMA 2004;291:317
-4
-3
-2
-1
0
1
0 4 8 12 18 24Weeks
AD
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donep+mem
donep+placebo
Donepezil and/or Memantine for Mod-Severe Alzheimer’s Dz
RCT mod-severe AD (MMSE 5-13), n=295
NEJM 2012;366:893
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0 6 18 30 52Weeks
MM
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placebodonepezilmemantinedonep + mem
Donepezil and/or Memantine for Mod-Severe Alzheimer’s Dz
RCT mod-severe AD (MMSE 5-13), n=295
NEJM 2012;366:893
262830323436384042
0 6 18 30 52Weeks
AD
Ls
placebodonepezilmemantinedonep + mem
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)