Dementia
What’s New In Medicine 2014
September 13, 2014
Jeffrey Wallace MD, MPH
Professor, Internal Medicine & Geriatrics
University of Colorado Health Sciences Center
Dementia
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: Epidemiology
Prevalence
Community
1% at age 60, doubles q5 years
65-74 yo 5%
80+ yo
20-40%
90+ yo
Hospital
50+%
33-50% > age 70 impaired
Detection
Family 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)
Case Hx: Possible early impairment
76yo M semi-retired accountant c/o forgetfulness
What is patient’s most likely dx?
1) Age associated memory impairment
2) Mild Cognitive impairment
3) Alzheimer’s disease
4) Normal aging
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
JAMA 2008;300:1027-37
Mental activity - games, crosswords, leisure activities
cognitive training (eg Lumosity)
NEJM 2003;348:2508
Ann Intern Med 2010;153:182
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 6month program of physical activity provided a modest
improvement in cognition over an 18-month f/u period.
JAMA 2008;300:1027-37
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
Cognitive Impairment Screening Rationale
● 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
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
Cognitive Screen: Mini-Cog



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
JAGS 2003;51:1451
Cognitive Screen Instruments
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)
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
Etiology
Alzheimer’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
Sxms at Presentation
AD
Cognitive fluctuations*
% (range)
58 (8-85)
% (range)__
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
Etiology
Alzheimer’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

Sufficiently severe to interfere with usual function

Gradual onset and continuing decline

Other causes excluded
- Aphasia
- Apraxia
- Agnosia
- Executive dysfunction
}
prob
AD
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
Dementia: Treatment and Management

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
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 Inhibitors
Very 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
AD2000: Lancet 2004; 363:2105-15
BMJ 2005;331:321
AGS/ABIM Choosing Wisely
List of 5 Things Physicians & Patients
Should Question: Part 2
Don’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 nonpharm 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
SIB-Cog

2
0
-2
memantine
placebo
-4
-6
-8
-10
-12
0
4
12
28
Weeks NEJM 2003;348:1333
Dementia: Memantine Monotherapy
US Trial mod-severe AD (MMSE 3-14), n=252
ADL

1
0
-1
-2
-3
-4
-5
-6
-7
memantine
placebo
0
4
12
28
Weeks NEJM 2003;348:1333
Dementia: Memantine Monotherapy
US Trial mod-severe AD (MMSE 3-14), n=252
CIBIC Global Score

5
4.8
memantine
placebo
4.6
4.4
4.2
4
0
12
28
Weeks NEJM 2003;348:1333
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
3
Sev impair battery

2
donep+mem
1
0
donep+placeb
o
-1
-2
-3
0
4
8
12
Weeks
18
24
JAMA 2004;291:317
Dementia: Donepezil + Memantine

US Trial mod-severe AD (MMSE 5-14), n=404
1
donep+mem
ADL
0
donep+placebo
-1
-2
-3
-4
0
4
8
12
18
24
Weeks JAMA 2004;291:317
Donepezil and/or Memantine for
Mod-Severe Alzheimer’s Dz
RCT mod-severe AD (MMSE 5-13), n=295
MMSE

placebo
donepezil
memantine
donep + mem
10
9
8
7
6
5
4
3
2
1
0
0
6
18
30
Weeks
52
NEJM 2012;366:893
Donepezil and/or Memantine for
Mod-Severe Alzheimer’s Dz
RCT mod-severe AD (MMSE 5-13), n=295
ADLs

placebo
donepezil
memantine
donep + mem
42
40
38
36
34
32
30
28
26
0
6
18
30
Weeks
52
NEJM 2012;366:893
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?
Health Study 400 IU qod, no benefits, 
hemorrhagic CVA
JAMA 2008;300:2123
 Physicians
 SELECT
Prostate CA: 400 IU qd  prostate CA
JAMA 2011;306:1549
 Vitamin
E meta-analysis: 400+ IU/d  mortality
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
IU/d
(95%CI)
20
50
100
200
500
1000
2000
Adjusted for other vits/min
Risk difference*
Risk ratio
-16 (-45 to 14)
- 8 (-42 to 25)
2 (-35 to 38)
15 (-26 to 56)
38 (-11 to 87)
57 (-1 to 115)
76 (8 to 145)
0.98 (0.95-1.02)
0.99 (0.96-1.03)
1.00 (0.97-1.04)
1.01 (0.98-1.05)
1.04 (0.99-1.08)
1.06 (1.00-1.11)
1.08 (1.01-1.14)
* Deaths per 10,000 persons
Ann Intern Med 2005;142:37
Vitamin E and/or Memantine
for Mild-Moderate AD

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
JAMA 2014;311:33-44
Vitamin E and/or Memantine for
Mild-Moderate AD: 1o outcome Funx
Vit E vs placebo
-  decline 19%/yr
- ~6 mo , p=.03
- No harms seen
Memantine vs plac
- no benefit
Combo vs plac
- no benefit
JAMA 2014;311:33-44
Vitamin E and/or Memantine for
Mild-Moderate AD: 2o outcomes
MMSE - NS
NPI - NS
All NS but all analyses favor Vit E
ADAS-cog - NS
CAS - NS
JAMA 2014;311:33
Vitamin E and/or Memantine
for Mild-Moderate AD
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???
JAMA 2014;311:33-44
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 Upcoming
Pharmacologic Treatment Options

Supplements



Fish oil
Ginkgo
Medical Foods
 Axona, 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;69:143040, NEJM 2013;369:341-50)
Clin Ther 2013;35:1480
Any advice while waiting on advances?
Dementia: Risk/Protective Factors
Protective
APOE2 allele
Definite
Intellectual activity Possible
Physical activity
Mediterranean diet
Omega-3 fatty acids
____
Risk Factors
Age
Family Hx
APOE4 allele
Other genes†
Tobacco use
Head Trauma
Low Education
Metabolic Syn_
† Rare, early onset familial AD assoc w/mutations on
chromosomes 1, 12, 14, 21
Ann Intern Med 2010;153:182
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
Arch Intern Med 2010:170;2036
Lifestyle and Dementia

Bronx 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;144:73
JAMA 2004;292:1447

“ read while on exercise bike” (preferably
w/heavy book that you intermittently lift)