Transcript 10:30 AM Dementia - Vanderbilt University Medical Center

Treatment of Alzheimer’s
disease:
2007 Update
Howard S. Kirshner, M.D.
Vanderbilt University
Alzheimer’s disease
Definition: NINCDS/ADRDA ’84, DSM IV
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Acquired syndrome of memory and 2 other
cognitive functions (aphasia, apraxia, agnosia,
executive function)
Progressive
Sufficient to affect daily life
No alteration of consciousness
Age of onset 40-90
No other proved cause
Correlation with pathology 80-100%
Dementia comes to us all
AD Epidemiology
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AD is the most common dementia (50-60% of
dementia cases, another 15% mixed with vascular
disease)
AD affects >4 million patients in U.S.
Estimated ~1 million on Rx
Projected: >14 million patients by 2050
Costs: $90 to $100 billion/year
Average cost of care: $50,000 per patient/year
AD—History Timeline
7th century BC
Age-related
mental
deterioration
recognized
1907
AD first
described by
Dr. Alois
Alzheimer
Early 1960s
Awareness of
AD as a
single disease
1980
Alzheimer’s
Association
established
1991
APOE
implicated
1993
First
cholinesterase
inhibitor
approved
Research
into
treatments
continues
700 BC
2000 AD
~200 AD
Galen
associates
“morosis”
(dementia) with
old age
1978?
1983
Single entity
Cholinergic
established—
deficit
senile dementia
identified
of the Alzheimer’s
type (SDAT)
1992
AHCPR
develops
screening
guidelines
for AD
1994
Brain
inflammatory
response
identified as
pathogenetic
10 Warning Signs of AD
(AAN Practice Parameter ’01)
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Memory loss that affects job skills
Difficulty performing familiar tasks
Problems with language
Disorientation to time and place
Decreased judgment
Problems with abstract thinking
Misplacing objects
Changes in mood or behavior
Changes in personality
Loss of initiative
Differential Diagnosis of AD
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Delirium: (drugs,
toxins, systemic dz)
Depression
Metabolic (thyroid)
Normal pressure
hydrocephalus
Subdural hematoma
Tumor
Infections
• Creutzfeldt Jakob Dz
• Vascular dementia
• Dementia due to
Parkinson's disease
• Dementia with Lewy
bodies
• Frontotemporal
dementia
Dementia: Differential Dx
Vascular dementias
Multi-infarct dementia
Binswanger’s disease
Other dementias
Frontal lobe dementia
Creutzfeldt-Jakob disease
Corticobasal degeneration
Progressive supranuclear
palsy, many others
Lewy body dementias
Parkinson’s disease
Vascular dementias
Diffuse Lewy body disease
and Alzheimer’s disease
Lewy body variant of AD
(AD)
AD
10% 10%
AD and Lewy
body dementias
60%
Adapted with permission from Zurad E. Drug Benefit Trends. 2001;13:27-40.
5%
7%
8%
Mild Cognitive Impairment
• Preclinical period termed MCI
• Memory performance below normal
• No significant loss of function
• Clinical course shows gradual decline
• Some patients have MCI for 10-15 yrs
• Conversion to AD 12-16%/yr (Petersen)
• Do all cases eventually develop AD?
Mild Cognitive Impairment -2Donepizil trial (Petersen, 2005): modest
benefit at 1 year, none at 3 years
 APOE subgroup: benefit at 3 years
 Vitamin E: no effect
 Galantamine trial stopped (13 deaths, 2
placebo)
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Clinical Progression of AD and MCI
Time (y)
Time?
Cognitive function
MCI
MMSE 24–30
•Mild
subjective/
objective
memory
loss
•Normal
function
0y
10 y
Mild AD
MMSE 20–23
•Forgetfulness
•Repetitive
questions
•Daily function
impaired
Moderate
AD
MMSE 10–19
•Progression of
cognitive deficits
•Short-term memory
loss
•Word-finding
difficulties
Severe AD
MMSE 0–9
•Agitation
•Altered sleep patterns
•Total dependence:
dressing, feeding,
bathing
Functional Decline in AD
Keep appointments
25%
75%
Activities of daily living (ADLs)
Telephone
Obtain meal/snack
Loss of optimal
(independent) performance
Travel alone
Use home appliance
Find belongings
Select clothes
Dress
Groom
Maintain hobby
Dispose of litter
Clear table
Walk
Eat
25
20
15
10
MMSE score
Progressive loss of function
Adapted with permission from Galasko et al. Eur J Neurol. 1998;5(suppl 4):S9-S17.
5
0
AD Symptoms Correlate With
Affected Areas of the Brain
Motor
cortex
Central
sulcus
Primary somatic sensory cortex
Parietal
lobe
Prefrontal
association
cortex
Frontal
lobe
Parietaltemporaloccipital
association
cortex
Occipital
lobe
Temp-parietal
junction
Temporal lobe
Primary
visual
cortex
Cummings JL. Am J Psychiatry. 2000;157:4-15. Van Hoesen GW et al. Cereb Cortex. 2000;10:243-251.
Cortical atrophy
Normal
AD
Amyloid Plaques and
Microglial Activation
This photo shows an Alzheimer
amyloid plaque (white) surrounded
by reactive astrocytes (brown) and
a cluster of microglial cells (black)
sitting on top
Amyloid is made up of A-beta
peptides of amyloid, 40-42 amino
acids
Source: www.interchg.ubc.ca/mcgeerpl/curres.html.
Neurofibrillary Tangles
(tau filaments)
AD: Research on etiology
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Genetics: Chromosome 21, APP gene,
associated with early AD (also Down’s)
Chromosomes 1, 14 also associated with
early onset AD; presenilins 1, 2 shown to be
part of gamma secretase
APO E4 associated with sporadic, late onset
AD; APO E4 is involved with assembly of Abeta peptides
Amyloid hypothesis: A-beta peptide is toxic
to neurons
Inflammation in plaques: NSAIDS
Vascular risk factors: HTN, lipids
Proteolytic Cleavages of Amyloid
Precursor Protein (APP) Produces A
Peptide
-amyloid precursor
protein
A
peptide
NH
2
-secretase
Selkoe DJ et al. JAMA. 2000;283:1615-1617.
Extracellular
space
TM
Cytoplasm
COO
H
-secretase
Molecular biology of AD
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Current emphasis on amyloid A-beta peptide
Aggregates of A-beta may modify kinases,
causing overphosphorylation of tau, leading to
formation of “twisted tubules”
Tau may be involved in microtubule transfer,
disrupted in twisted tubules
Tau is a byproduct of A-beta in AD, may be
genetically altered in other conditions such as
frontotemporal dementia, PSP
Treatment of Dementia
Therapy for AD: Overview
•Cholinesterase inhibitors
•Other drug therapy - memantine
•Antioxidants (Vitamins C, E)
•Rx of behavioral disorders
•NSAIDS: ineffective, risky
• Estrogens: Harmful
• Statins: ?
•Nonpharmacologic approaches
Other AD Treatment Options
Rx largely disproved
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Chelation therapy
Lecithin, choline
Ergot mesylate (Hydergine)
Other compounds under
investigation
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Vaccines: active on hold;
passive, pending
Gamma secretase inhibitors
Inhibitors of plaque formation
(Alzhemed, binds to A-beta)
Treatment of behavioral
symptoms in AD
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Antidepressants (SSRI’s)
Atypical antipsychotics (risperidone,
olanzepine, quetiapine) * FDA warning
Avoid phenothiazines, haloperidol
Avoid benzodiazepines
Trazodone for sleep, valproate for agitation
Acetylcholinesterase inhibitors
Memantine (Cummings et al, Neurology ’06)
Antioxidants
• Oxidative stress hypothesis: excess
accumulation of amyloid beta-peptide generates
free radicals, which induce neuronal death
• Vitamin E: 2000 IU (Sano ’97)
- ? Slowed disease progression
- 2005 MCI study: no effect
• Vit E & C: ? Reduced incidence (Cache Cy,
Utah, Arch Neurology 1/04)
• Ginkgo biloba: One + trial, one – trial,
others pending
Sano M, Ernesto C, Thomas RG, et al. N Engl J Med. 1997.
Bastianetto S, Ramassamy C, Dore S, et al. Eur J Neurosci. 2000.
Memantine
(Reisberg et al, NEJM 348:1333, ’03;
Tariot et al, JAMA 291:317, ’04)
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Memantine: glutamate receptor blocker
Reisberg: 181 pts, mod-severe AD (MMSE 314, x 8), memantine 20 mg vs placebo
Less deterioration with memantine,
significant for ADL, borderline for CIBIC
Minimal side effects
Tariot: memantine + donepizil improved
outcomes vs donepizil in mod-severe AD
No evidence yet in mild AD (AAN ’04
abstract, + monotherapy, FDA P)
Clinical use mostly combined with AChE-i
Memantine in Moderate to Severe AD Study
Results: Cognition—SIB
Results: Cognition—SIB
The Memantine Group Exhibited Significantly Superior
Cognitive Function Compared With the Placebo Group
*P=.002 †P<.001
0
-2
-4
Deterioration
Mean Change From Baseline
in SIB Score
2
P<.001
Improvement
P=.068
-6
-8
Memantine
-10
Placebo
-12
0
4
12
28
End Point
96
83
126
126
Week
n=
n=
126
126
119
117
107
106
*OC analysis. †LOCF analysis
Adapted with permission 2004 from: Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. N Engl J Med.
2003;348:1333-1341. Copyright © 2003 Massachusetts Medical Society. All rights reserved.
Memantine in Moderate to Severe AD—OLEX
Results: Cognition—SIB*
0
P<.001†
Open-Label Extension
P=.002†
-5
Deterioration
-10
-15
-20
Week
Double-Blind Phase
5
0
Memantine to
Memantine
Placebo to
Placebo to
P=.049
Memantine
Placebo (projected)
Improvement
Mean Change From Baseline
in SIB Score (± SEM)
Patients Who Switched From Placebo to Memantine Improved
Relative to the Projected Rate of Decline
‡
4
12
28
40
52
n = 95
n = 80
95
80
94
79
74
75
66
70
*OC analysis; †Memantine vs placebo; ‡Rate of decline between placebo group (weeks 1-28) and placebo-memantine
group (weeks 28-52).
Sources: Ferris S, et al. Presented at the 16th Annual Meeting of the American Association for Geriatric Psychiatry;
March 1-4, 2003; Honolulu, Hawaii. Data on file, Forest Laboratories, Inc.
Memantine + Donepezil in Moderate to Severe AD Study
Results: Cognition—SIB
Results: Cognition—SIB
Memantine + Donepezil Produced Sustained Improvement in
Cognition Above Baseline Compared With Donepezil Alone
P=.057 P=.030 P<.001
P=.006
*P<.001 †P<.001
2
1
0
Deterioration
Mean Change From
Baseline in SIB Score
3
-1
-2
Memantine+Donepezil
-3
Placebo+Donepezil
-4
n=
n=
Improvement
4
0
4
8
12
18
24 End Point
198
197
192
194
190
180
185
169
181
164
171
153
Treatment Week
*OC analysis. †LOCF analysis.
Adapted from Tariot P, et al. JAMA. 2004;291:317-324.
Data on file, Forest Laboratories, Inc.
198
196
Cholinergic Hypothesis
• Reduction in acetylcholine, choline
acetyltransferase in cortex
• Degeneration of nucleus of Meynert and
its cholinergic projections to cortex
• Cholinergic deficiency contributes to
memory loss and ? behavioral changes
• Anticholinesterase medications improve
memory and behavior (symptomatic Rx)
Cummings JL, Back C. Am J Geriatr Psychiatry. 1998.
Cholinergic Pathways From the
Basal Forebrain
PC
FC
BF
H
Cummings JL. Am J Psychiatry. 2000;157:4-15.
O
C
Anticholinesterase:
Mechanism of Action
Presynaptic
nerve
terminal
Muscarinic
receptor
Postsynapti
c nerve
terminal
* Clinical significance of this mechanism is unknown.
Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.
Nordberg A, Svensson A-L. Drug Safety. 1998;19:465-480.
Anticholinesterase drugs
• FDA-approved agents:
–
–
–
–
Tacrine (Cognex): 10, 20, 30, 40 mg qid
Donepezil (Aricept): 5 and 10 mg qd
Rivastigmine (Exelon): 1.5, 3, 4.5, 6 mg bid
Galantamine (Razadyne): 4, 8, 12 mg bid
Razadyne ER: 8, 16, 24 mg qd
• Efficacy in mild/moderate AD
• Evidence for long-term treatment and use in
late-stage disease
• All have mainly GI side effects
Krall WJ, Sramek JJ, Cutler NR. Ann Pharmacother. 1999.
Anticholinesterase drugs
Is one better than another?
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No non-industry sponsored head-to-head trials
One donepizil trial: better tolerated than
rivastigmine
Rivastigmine trial: marginally superior to
donepizil (Bullock et al, Curr Med Res Opinion 2005;21:1317-27)
Galantamine, ? Better % improvement at 1 year
vs donepizil, but one donepizil trial found the
opposite
Cognitive Benefits in More
Advanced AD (MMSE: 5-17)
(also Winblad et al, Lancet 2006;367:1057-65)
(Donepizil is FDA approved in advanced AD)
Clinical
improvement
MMSE change from baseline
3
P=.0004
P<.0001
P=.0019
2
1
0
-1
Aricept (n=144)
Placebo (n=146)
Clinical
decline
-2
0
12
24
Endpoint
Study week
Adapted with permission from Feldman et al. Neurology. 2001;57:613-620.
See Appendix for study description and safety information (Moderate to Severe AD [MSAD]).
Rivastigmine and Cholinergic
Function
Presynaptic
neuron
Acetyl
CoA
+
Choline
Glia
Choline
ChAT
BuChE
ACh
Synaptic cleft
Postsynaptic
neuron
ACh
AChE
Choline
+
Acetate
BuChE
AChE
Cholinergic receptor
ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase;
ChAT = choline acetyltransferase; CoA = coenzyme A.
Adapted from Mycek M et al. In: Harvey RA, Champe PC, eds. Pharmacology: Lippincott’s
Illustrated Reviews. Philadelphia, Pa: JB Lippincott Co; 1992:35-44.
Rivastigmine: Dose Response
Mean Change in ADAS-Cog
Score From Baseline
-2
-1
Improvement
0
1
2
Decline
3
4
0
2
4
6
8
10
Last Prescribed Dosage (mg/day)
12
95% CI
Predicted
response
(n=1923)
Pooled study analysis involving approximately 2800 AD patients treated with either rivastigmine (1-12
mg/day) or placebo for 26 weeks in 4 phase III, randomized, double-blind, placebo-controlled trials.
ADAS-Cog Mean Change
from Baseline
LONG TERM EFFECTS OF EXELON ON COGNITION:
MEAN CHANGE IN ADAS-COG FROM BASELINE
THROUGH WEEK 52
1
*
-1
*
*
6-12 mg
-3
*
*
*
1-4 mg
-5
*
Placebo
Proj. PBO
-7
0
20
All Patients
Taking Exelon
40
Study Week
Adapted from Proceedings, Satellite Symposium, IPA 9th Cong. Aug, 99, P11
* p < 0.05 v/s projected placebo
*
*
60
RAZADYNE™ ER (galantamine HBr): Cognition: ADAS-cog/11
RAZADYNE™ ER (galantamine HBr):
ADCS-ADL
Investigational uses of
acetylcholinesterase inhibitors
Vascular dementia: Phase III clinical
trial with galantamine, donepizil
 Diffuse Lewy Body Disease: also
evidence from all drugs
 Memory loss in Multiple Sclerosis,
Traumatic Brain Injury, AIDS Dementia
Complex, ADD: small series
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Dementia: Conclusions
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A varied group of multifocal or diffuse brain
disorders
Neuroscientific understanding is increasing
Treatments are as yet symptomatic (e.g.
anticholinesterase, psychotropic drugs)
Neuroprotective effects of memantine,
antioxidants
Breakthroughs promised