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Treatment of Alzheimer’s disease: 2007 Update. Howard S. Kirshner, M.D. Vanderbilt University. Alzheimer’s disease Definition: NINCDS/ADRDA ’84, DSM IV. Acquired syndrome of memory and 2 other cognitive functions (aphasia, apraxia, agnosia, executive function) Progressive

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treatment of alzheimer s disease 2007 update

Treatment of Alzheimer’s disease: 2007 Update

Howard S. Kirshner, M.D.

Vanderbilt University

alzheimer s disease definition nincds adrda 84 dsm iv
Alzheimer’s diseaseDefinition: NINCDS/ADRDA ’84, DSM IV
  • 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%
ad epidemiology
AD Epidemiology
  • 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
slide6

AD—History Timeline

7th century BCAge-related mental deterioration recognized

1907AD first described by Dr. Alois Alzheimer

Early 1960sAwareness of AD as a single disease

1980Alzheimer’sAssociationestablished

1991APOE implicated

1993First

cholinesterase

inhibitor

approved

Research into treatments continues

700 BC

2000 AD

~200 ADGalen associates “morosis” (dementia) with old age

1978?Single entity established—senile dementia of the Alzheimer’s type (SDAT)

1983Cholinergic

deficit identified

1992AHCPR

develops screening

guidelines for AD

1994Brain inflammatory response identified as pathogenetic

10 warning signs of ad aan practice parameter 01
10 Warning Signs of AD(AAN Practice Parameter ’01)
  • 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
Differential Diagnosis of AD
  • 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
Dementia: Differential Dx

Other dementias

Frontal lobe dementia

Creutzfeldt-Jakob disease

Corticobasal degeneration

Progressive supranuclear palsy, many others

Vascular dementias

Multi-infarct dementia

Binswanger’s disease

Lewy body dementias

Parkinson’s disease Diffuse Lewy body disease Lewy body variant of AD

Vascular dementias

and Alzheimer’s disease (AD)

AD and Lewybody dementias

AD

10%

10%

60%

5%

7%

8%

Adapted with permission from Zurad E. Drug Benefit Trends. 2001;13:27-40.

mild cognitive impairment
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 2
Mild Cognitive Impairment -2-
  • Donepizil 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)
slide13

Clinical Progression of AD and MCI

Time (y)

0 y

10 y

Time?

MCIMMSE 24–30

Mild ADMMSE 20–23

  • Mild subjective/objective memory loss
  • Normal function
  • Forgetfulness
  • Repetitive questions
  • Daily function impaired

Moderate ADMMSE 10–19

  • Progression of cognitive deficits
  • Short-term memory loss
  • Word-finding difficulties

Cognitive function

Severe ADMMSE 0–9

  • Agitation
  • Altered sleep patterns
  • Total dependence: dressing, feeding, bathing
functional decline in ad

Keep appointments

25%

75%

Telephone

Obtain meal/snack

Loss of optimal

(independent) performance

Travel alone

Use home appliance

Find belongings

Select clothes

Dress

Activities of daily living (ADLs)

Groom

Maintain hobby

Dispose of litter

Clear table

Walk

Eat

25

20

15

10

5

0

MMSE score

Progressive loss of function

Adapted with permission from Galasko et al. Eur J Neurol. 1998;5(suppl 4):S9-S17.

Functional Decline in AD
ad symptoms correlate with affected areas of the brain

Motor cortex

Primary somatic sensory cortex

Central sulcus

Parietal-temporal-occipital association cortex

Parietal lobe

Frontal lobe

Prefrontalassociationcortex

Occipital lobe

Primary visual cortex

Temp-parietal junction

Temporal lobe

AD Symptoms Correlate With Affected Areas of the Brain

Cummings JL. Am J Psychiatry. 2000;157:4-15. Van Hoesen GW et al. Cereb Cortex. 2000;10:243-251.

amyloid plaques and microglial activation
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.

ad research on etiology
AD: Research on etiology
  • 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 A-beta 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

Extracellular space

TM

Cytoplasm

A peptide

COOH

NH2

-secretase

-secretase

Proteolytic Cleavages of Amyloid Precursor Protein (APP) Produces A Peptide

Selkoe DJ et al. JAMA. 2000;283:1615-1617.

molecular biology of ad
Molecular biology of AD
  • 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
therapy for ad overview
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
slide26

Other AD Treatment Options

Rx largely disproved

  • Chelation therapy
  • Lecithin, choline
  • Ergot mesylate (Hydergine)

Other compounds under investigation

  • Vaccines: active on hold; passive, pending
  • Gamma secretase inhibitors
  • Inhibitors of plaque formation (Alzhemed, binds to A-beta)
treatment of behavioral symptoms in ad
Treatment of behavioral symptoms in AD
  • 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
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
Memantine(Reisberg et al, NEJM 348:1333, ’03;Tariot et al, JAMA 291:317, ’04)
  • Memantine: glutamate receptor blocker
  • Reisberg: 181 pts, mod-severe AD (MMSE 3-14, 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
results cognition sib1

Memantine in Moderate to Severe AD—OLEX

Results: Cognition—SIB*

Patients Who Switched From Placebo to Memantine Improved Relative to the Projected Rate of Decline

Double-Blind Phase

Open-Label Extension

5

Improvement

0

P<.001†

P=.002†

Mean Change From Baseline

in SIB Score (± SEM)

-5

-10

Deterioration

Memantine to

Memantine

-15

P=.049‡

Placebo to

Memantine

Placebo to

Placebo (projected)

-20

0

4

12

28

40

52

Week

n =

95

95

74

66

94

n =

80

80

79

75

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.

cholinergic hypothesis
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

OC

H

Cholinergic Pathways From theBasal Forebrain

Cummings JL. Am J Psychiatry. 2000;157:4-15.

anticholinesterase mechanism of action

Acetic acid

Choline

Drug inhibits AChE*

Anticholinesterase:Mechanism of Action

Presynaptic nerve terminal

Muscarinic receptor

Postsynaptic nerve terminal

ACh

Acetylcholinesterase(AChE)

Nicotinic receptor

* 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
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
Anticholinesterase drugsIs one better than another?
  • 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
slide40

Clinical

improvement

Clinical

decline

Endpoint

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)

P=.0004

3

P<.0001

P=.0019

2

1

MMSE change from baseline

0

-1

Aricept (n=144)

Placebo (n=146)

-2

0

12

24

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
Rivastigmine and Cholinergic Function

Acetyl

CoA

Glia

Presynaptic

neuron

+

Choline

Choline

BuChE

ChAT

ACh

BuChE

Synaptic cleft

ACh

Choline

+

AChE

Acetate

Postsynapticneuron

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
Rivastigmine: Dose Response

-2

-1

Improvement

0

Mean Change in ADAS-CogScore From Baseline

1

2

Decline

3

95% CI

Predicted response(n=1923)

4

0

2

4

6

8

10

12

Last Prescribed Dosage (mg/day)

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.

long term effects of exelon on cognition mean change in adas cog from baseline through week 52
LONG TERM EFFECTS OF EXELON ON COGNITION: MEAN CHANGE IN ADAS-COG FROM BASELINE THROUGH WEEK 52

*

*

*

*

*

*

*

*

*

All Patients

Taking Exelon

Adapted from Proceedings, Satellite Symposium, IPA 9th Cong. Aug, 99, P11 * p < 0.05 v/s projected placebo

investigational uses of acetylcholinesterase inhibitors
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
dementia conclusions
Dementia: Conclusions
  • 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