Transcript OU Neurology Alzheimer`s Disease

Management of
Alzheimer’s Disease and
Other Dementias
Linda A. Hershey, MD, PhD
Professor of Neurology
University of Oklahoma
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Disclosures

I receive an honorarium to write for Medlink
Neurology about Memory Disorders.

Our laboratory is funded by Baxter Healthcare
Corporation to perform a clinical trial of IVIg
on patients with mild-moderate Alzheimer’s
disease.
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Learning Objectives of this Talk
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To classify three common dementing illnesses
(Alzheimer’s disease, dementia with Lewy bodies and
vascular (mixed) dementia).
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To describe the use of cholinesterase inhibitors and
memantine in treating patients with AD, DLB and
vascular (mixed) dementia.
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To report the role of antidepressants, anxiolytics and
antipsychotic agents in treating patients with AD and
other dementing illnesses.
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Question #1

Alzheimer’s disease is an illness associated with
all of the following features, EXCEPT:
a) memory loss
b) diffuse brain atrophy
c) focal signs of weakness
d) motor apraxia
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Question #2

Dementia with Lewy bodies is a an illness
associated with all of the following features,
EXCEPT:
a) memory loss
b) vertical gaze palsy
c) parkinsonism
d) visual hallucinations
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Question #3

In the recent Great Britain study of drugs in moderatesevere AD, which statement is the most accurate
summary of the results?
a) Those assigned to donepezil alone had the best
cognitive outcome at 12 months.
b) Those assigned to the combination of donepezil and
memantine had the best cognitive outcome at 12 mo.
c) Those assigned to placebo had the best behavioral
outcome at 12 months.
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Question #4

The advantages of mirtazapine for sleep in
dementia patients include all of the following,
EXCEPT:
a) It does not cause ataxia.
b) It is not an anticholinergic agent.
c) It does not cause hypotension.
d) It is not habit-forming.
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56 year old female 711 cashier
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CC: “My head is in a fog most of the time”.
May, 2010….Onset of poor conc & memory
(MRI = mild atrophy; MMSE = 25/30…poor recall).
 April, 2011…She lost her job as a cashier at the 711
(MMSE in Aug = 21/30)…..no hallucinations.
 Jan, 2012…..Continued to have memory problems
(IADL =11/16; MMSE = 18/30…exam = motor apraxia,
but no signs of stroke or parkinsonism).
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What is this woman’s diagnosis?
Treatment?
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Alzheimer’s Disease (AD)
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Insidious onset and gradual decline in activities,
behavior and cognition over time.
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Dementia by DSM IV criteria:
….memory loss
….1 or more other cognitive impairments
….functional impairment in IADLs
….exclusion of delirium
McKhann et al. Neurology 1984; 34: 939-944.
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Lawton’s IADL Scale
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Using the telephone….2 (no help)….0 (unable).
Driving………………2….......1……0………
Grocery shopping……2……..1……0………
Preparing meals……...2……...1……0………
Doing housework……2……..1……0………
Doing laundry……….2……...1……0………
Taking medications….2……...1……0………
Managing money…….2……..1…….0………
Lawton & Brody, The Gerontologist 1969; 9:179-186.
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The Cholinergic Hypothesis for AD
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Cholinergic cells in the nucleus basalis of
Meynert die early in AD:
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Management of Mild Alzheimer’s
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Start donepezil (Aricept) 5mg/d
Advise caregiver to attend an AD support group
Advise her wearing an ID (Medic Alert) bracelet
Advise patient to assign POA to caregiver
Obtain screening labs (B12, TSH, RPR, HbA1c)
Reduce alcohol intake to 1-2 beers/d
Begin discussion of “the driving issue”
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What about ginkgo biloba?
Objective: The Ginkgo Evaluation of Memory
study compared 1545 older adults or MCI pts
on G biloba and 1524 older adults or MCI pts
on placebo…they were followed for 6.1 yrs.
 Results: Annual rates of decline on cognitive
tests did not differ between G biloba group
(120mg bid) and the placebo group (attention,
memory, language, executive function).
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Snitz, BE, et al: JAMA 2009: 302: 2663-2670.
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What about Mediterranean diet?
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Objective: To assess the association between
food combination and AD risk.
Design: Prospective cohort study.
Methods: 2148 elderly subjects without
dementia in NYC were evaluated every 1.5 yrs.
Results: 253 subj developed AD within 3.9 yrs.
Lower risk of AD with oils, nuts, fish,
tomatoes, poultry, fruits, vegetables.
Gu Y, et al. Arch Neurol 2010; 67: 699-706.
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47 year old retired supervisor
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CC: memory loss, parkinsonism, visual hallucinations
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2007: He first noted REM sleep behavior disorder.
2008: Memory loss began to impair his work.
2010: Tremors began & he c/o visual hallucinations.
2011: He began to c/o excessive daytime sleepiness.
2011: MMSE=17/30; IADL=12/16.
Exam: Motor apraxia + BL rigidity, bradykinesia.
Shuffling gait with postural instability (eyes closed).
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What is this man’s diagnosis? Treatment?
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Dementia with Lewy Bodies
DLB is 2nd most common dementia after AD.
 REM sleep disorder improves Dx accuracy
(50% of all DLB pts have RBD).
 Two or three core features are needed for Dx:
a) fluctuations in alertness during the day
b) parkinsonism (bradykinesia, rigidity>tremor)
c) visual hallucinations
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Ferman TJ et al: Neurology 2011; 77:875-882.
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The Cholinergic Hypothesis for DLB
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Cholinergic cells in the nucleus basalis of
Meynert die early in DLB:
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Dementia with Lewy Bodies
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SPECT changes in DLB can look like AD.
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Management of DLB
Start donepezil (Aricept) 5mg/d for dementia.
 Start Sinemet 25/100 tid for parkinsonism.
 Start clonazepam 0.5mg qhs for RBD.
 Advise caregiver to attend AD/DLB support group.
 Neuropsychology testing (Dr. Scott/Dr. Adams).
 P.T. x 2/wk for gait & balance training.
 Advise wearing a MedicAlert ID bracelet.
 Recommend that the pt STOP DRIVING
(pt meets criteria for moderate dementia).
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63 year old bench jeweller
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CC: Adm in Oct, 2010 with an acute HTN
emergency (he was acutely confused and
disoriented). He had forgotten to take pills.
Gait disorder and falls had been present x 2 yrs.
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Vascular Dementia
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Acute or subacute onset of gait disorder and/or memory loss.
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Cerebrovascular disease by history, exam, or brain imaging
(and a temporal relationship between the CVD and dementia).
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Dementia according to DSM-IV criteria:
….memory disorder
….other cognitive deficits (loss of exec func)
….functional impairment (IADLs)
….absence of delirium
Roman et al. Neurology 1993; 43: 250-260.
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Management of VaD
Start donepezil (Aricept) at 5mg/d.
 Start ECASA 325mg/d.
 Start lisinopril 10mg/d (keep BP < 140/90).
 Start simvostatin 40mg/d (keep LDL <70).
Advise caregiver to attend caregiver classes.
 P.T. x 2 days/wk for gait & balance training.
 Recommend that the pt STOP DRIVING
(he has homonymous hemianopsia).
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Does Donepezil Improve Symptoms
in Mod-Severe Alzheimer’s?
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Donepezil vs Memantine for ModSevere Alzheimer’s Disease
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Who? 295 community-dwelling AD patients in
Great Britain, who scored 5-13 on the MMSE
and were taking donepezil (Aricept).
What? Randomized to continue donepezil, d/c
donepezil, d/c donepezil and start memantine,
or continue donepezil and start memantine.
Outcomes? Clinically important outcomes=
1.4 pts on the MMSE; 3.5 pts on the BADLs.
Howard, Robert et al: NEJM 2012;366:893-903.
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Kaplan–Meier Actuarial Plot of the Cumulative Probability of Withdrawal from the Assigned Study
Drug.
Howard R et al. N Engl J Med 2012;366:893-903.
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Donepezil vs Memantine for ModSevere Alzheimer’s Disease
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In pts with moderate-severe AD, continued
treatment with donepezil was associated with
cognitive benefits that exceeded the minimum
clinically important difference over 12 months:
Those assigned to donepezil (vs placebo)
had MMSE scores that were 1.9 pts higher.
Those assigned to memantine (vs placebo) had
MMSE scores that were 1.2 pts higher.
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Other Pearls from the NEJM Study
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D/C of donepezil did not produce a withdrawal
phenomenon.
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Memantine was beneficial in moderate-severe
AD, but it was not as dramatic an effect as
donepezil’s benefit.
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There was no significant benefit from adding
memantine to donepezil in mod-severe AD.
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Does Donepezil Delay NH
Placement in AD?
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Objective: To assess relationship between donepezil
treatment and NH placement in AD.
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Design: F/U of 1115 pts enrolled in 3 trials.
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Results: Use of donepezil at a dose of at least 5mg/d
was associated with significant delays in NH placement
(time gained was 17-21 months).
Geldmacher et al. J Am Geriatr Soc 2003;51: 937-944.
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Memantine for Mild-Mod AD
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Memantine for Moderate-Severe AD
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Do Cholinesterase Inhibitors help
DLB patients?
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Objective: To determine whether galantamine would
improve global function, behavior, or cognition in
patients with DLB.
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Design: A 24-wk open-label, multi-center study of 50
DLB patients at 4 centers (VT, WNY, IN, TX).
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Results: At 24 wks, improvements were seen in visual
hallucinations (p=0.01), night-time behaviors (p=0.004)
and global cognitive impression of change (p=0.01).
Edwards et al. Dementia 2007; 23: 401-405.
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Does memantine help DLB ?
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Objective: To determine whether memantine
would help pts with PDD and DLB.
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Design: Double-blind, placebo-controlled
clinical trial in Norway, Sweden and UK (n=72).
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Results: At 24 wks, the pts on memantine had
better clinical global impression of change
scores, compared to the placebo pts (p=0.03).
Aarsland et al. Lancet Neurology 2009; 8: 613-618.
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Does donepezil delay onset of AD in
patients who have MCI?
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No. At three yrs, donepezil pts = placebo pts.
Petersen RC, et al. NEJM 2005; 352: 2379-2388.
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What is the Exception to the MCI
“Rule”?
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Donepezil delays progression to AD in MCI subjects
who have depressive symptoms.
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Design: n=756 participants in the 3-yr study of
donepezil vs placebo in MCI patients.
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Results: n=208 pts were found to be depressed using
the Beck Depression Inventory. These depressed MCI
pts progressed to AD more slowly if they were treated
with donepezil (p=0.025 at 2 yrs).
Lu PH, et al. Neurology 2009; 72: 2115-2121.
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Donepezil for MCI + depression
Lu PH, et al. Neurology 2009; 72:2115-2121.
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Antidepressants for Dementia
Patients who Cannot Sleep
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Mirtazapine (Remeron)…....7.5mg qhs.
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Advantages of mirtazapine for sleep
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It does not cause gait & falling problems like
benzodiazepines (important for DLB & PSP).
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It does not have anticholinergic activity like
diphenhydramine, amitriptyline, trazodone, or
hydroxyzine.
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It is not habit-forming like zolpidem (Ambien).
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Antipsychotic Agents for Dementia
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ID = 68 year old man with a 3 yr Hx of memory
loss, geographic disorientation and excessive
daytime sedation & agitation (“He starts
sundowning at noon”, according to his wife).
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HPI = For the last 2 yrs, this pt has had visual
hallucinations, paranoid ideas, agitation, tremors,
motor restlessness and acting out his dreams at
night (REM sleep behavior disorder).
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Antipsychotic Agents for Dementia
Pts who have Paranoia & Insomnia
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Quetiapine (Seroquel)……..25mg qhs.
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Clinical Outcome Measures
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Clinical Dementia Rating (CDR)
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Instrumental Activities of Daily Living (IADL)
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Neuropsychiatric Inventory (NPI)
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Mini-Mental State Examination (MMSE)
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Clinical Dementia Rating (CDR)
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0.5 = Questionable dementia …..no impairment of
IADLs or BADLs.
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1.0 = Mild dementia…….some impairment of IADLs,
but no impairment of BADLs.
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2.0 = Moderate dementia…pt is dependent on others
for most IADLs and some BADLs.
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3.0 = Severe dementia…...pt is dependent on others for
all IADLs and BADLs.
Morris JC Neurology 1993; 43: 2412-2414
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Lawton’s IADL Scale
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Using the telephone….2 (no help)….0 (unable).
Driving………………2….......1……0………
Grocery shopping……2……..1……0………
Preparing meals……...2……...1……0………
Doing housework……2……..1……0………
Doing laundry……….2……...1……0………
Taking medications….2……...1……0………
Managing money…….2……..1…….0………
Lawton & Brody, The Gerontologist 1969; 9:179-186.
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Neuropsychiatric Inventory (NPI)
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Delusional ideas
Hallucinations
Agitation
Depression
Anxiety
Elation/euphoria
Apathy/loss of interests
Disinhibition
Irritability/lability
Motor disturbance/pacing
Nighttime behaviors
Appetite/weight change
Cummings J L, et al. Neurology 1994;44:2308-2314.
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Question #1

Alzheimer’s disease is an illness associated with
all of the following features, EXCEPT:
a)
b)
c)
d)
memory loss
diffuse brain atrophy
*** focal signs of weakness
motor apraxia
OU Neurology
Question #2

Dementia with Lewy bodies is an illness
associated with all of the following features,
EXCEPT:
a) memory loss
b) *** vertical gaze palsy
c) parkinsonism
d) visual hallucinations
OU Neurology
Question #3

In the recent Great Britain moderate-severe AD
study, which statement was the most accurate?
a) ** Those assigned to donepezil alone
had the best cognitive outcomes at 12 mo.
b) Those assigned to the combination of
donepezil and memantine had the best cognitive
outcomes at the end of 12 months.
c) Those assigned to placebo had better
behavioral outcomes at the end of 12 months.
OU Neurology
Question #4

The advantages of mirtazapine for sleep in
dementia patients include all of the following,
EXCEPT:
a) It does not cause ataxia.
b) It is not an anticholinergic agent.
c) ** It does not cause hypotension.
d) It is not habit-forming.
OU Neurology
Summary

Cholinesterase inhibitors and memantine “buy time”
for AD and DLB pts, but they do not change the
underlying disease processes.

The depression and psychosis associated with
dementing illnesses are treatable conditions.
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CDR, IADL, NPI and MMSE are useful outcome
measures to use in a clinical setting to monitor the
effectiveness of drug therapy.
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