Transcript Alzheimer's Disease Overview

Alzheimer’s Disease and Related Dementias
Modified from a talk by :
Andrea A. Chiba, UCSD
And
KE Edwards, Amgen
Definition of Dementia
 Memory loss and 1 or more cognitive
difficulties, such as
– Disorientation (to time, place)
– Disturbed executive functioning (planning, organizing,
abstraction, judgment)
– Aphasia (impaired word use and comprehension)
– Apraxia (impaired ability to carry out motor tasks)
– Agnosia (cannot recognize objects or faces)
– Impaired attention and concentration
 Significant impairment of social/occupational

function
Change from baseline (prior) function
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders.
4th ed. 1994.
Diagnostic and Statistical Manual (DSM-IV) Criteria
for Dementia of the Alzheimer Type

Development of multiple cognitive deficits manifested by both
– Memory impairment (inability to learn new, or recall old,
information)
– At least 1 of the following: aphasia, apraxia, agnosia, or disturbance
in executive functioning
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Cognitive deficits significantly impair social/occupational
functioning; represent a significant decline from a previous level
of functioning
Characterized by gradual onset and continuing cognitive decline
Not because of other causes of progressive cognitive decline
Deficits do not occur exclusively during the course of a delirium
Disturbance not better accounted for by another medical
disorder
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders.
4th ed. 1994 (C).
Scope of AD Now and in the Future
A Healthcare Crisis Today
 Approximately 1 of every 10 screened patients
over the age of 65 years may have AD1
 As many as 60% of individuals with AD may go
undiagnosed in the primary care setting2
 AD is ranked as the nation’s seventh leading
cause of death among all persons3
1. Evans et al. JAMA. 1989;262:2551-2556; 2. Knopman et al. J Am Geriatr Soc. 2000;48:300304; 3. Miniño et al. Natl Vital Stat Rep. 2006;54:1-50.
AD
 Can be divided into Early Onset (< 60) and Late
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
Onset (>60).
Perhaps two different etiologies
After age 65, the number of cases doubles every 5
years.
3% of people 65-74 have the disease
Approx. 50% of people over 85 have the disease.
Number of Patients (millions)
Prevalence Is Projected to Increase
Dramatically
14
65-74 years
12
75-84 years
10
85+ years
7.7 Million
8
6
13.2 Million
4.5 Million
4
2
0
2000
*Estimates.
Hebert et al. Arch Neurol. 2003;60:1119-1122.
2030*
Year
2050*
Economic Impact of Diseases
and Drug-Related Problems
180
$171
Billions ($) Annually
160
140
120
$104
$104
100
$100
$92
80
$65
60
40
20
0
Cardiovascular
Cancer
Drug-Related
Problems
Alzheimer’s
Disease
Diabetes
Osteoarthritis
Alzheimer’s Disease Education and Referral Center, National Cancer Institute, American Diabetes Association,
Arthritis Association, National Center for Health Statistics.
AD and the Brain
Plaques and Tangles: The Hallmarks of AD
The brains of people with AD have an abundance of 2
abnormal structures:
 -amyloid plaques, which are dense deposits of protein and cellular
material that accumulate outside and around nerve cells
 Neurofibrillary tangles, which are twisted fibers that build up inside the
nerve cell
An Actual AD Plaque
An Actual AD Tangle
National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/.
Accessed October 5, 2006.
AD and the Brain
-Amyloid Plaques
Amyloid precursor protein (APP) is the
precursor to amyloid plaque
1.
1. APP sticks through the neuron
membrane
2. Enzymes cut the APP into fragments
of protein, including -amyloid
2.
3. -amyloid fragments come together
in clumps to form plaques
In AD, many of these clumps form,
disrupting the work of neurons. This
affects the hippocampus and areas of the
cerebral cortex
3.
Plaques
 Extracellular
 Contain A-beta (sequence cleaved from APP or
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Amyloid Precursor Protein)
Metals (aluminum, zinc)
Immunoglobulin G
Amyloid P
apoE
ETC….over 30 other proteins
AD and the Brain
Neurofibrillary
Tangles
Neurons have an internal support structure partly made up of microtubules. A protein called
tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and
tau proteins clump together to form neurofibrillary tangles
National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/.
Accessed October 5, 2006.
Tangles
 Intracellular
 Bundles of long unbranched elements that form a
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
fibrous twisted pair of filaments
Consist of tau protein (a protein that ordinarily
stabilizes cellular microtubules)
Are somewhat correlated with degree of dementia
– post-mortem.
ApoE: One Hypothesis for Tangle Formation
Details – only for those who care – not requisite knowledge
What Causes AD?
 The “amyloid hypothesis” is the most widely

accepted theory of AD etiology, but certainly not
an answer at this time.
Several other potential causative or contributing
factors under research
–
–
–
–
Tau
inflammation
cardiovascular risk factors
disruptions of neuronal signaling pathways.
Progression to Dementia
Normal
Cognition
Prodromal
Dementia
Dementia
Stable or
reversible
impairment
Vascular
dementia
Mixed
Alzheimer’s
disease
Normal
brain
aging
Mixed
Mild cognitive
impairment
(MCI)
Other
dementias
10% to 15% of individuals with amnestic MCI
will be diagnosed with AD
Morris. Geriatrics. 2005;(suppl):9-14 (C).
Risk Factors for AD
Definitive
 Increasing age
 Family history
 Genetics
 APOE 4 allele
 Down’s syndrome
Probable
 Female sex
 Low level of education
*May
Possible
 Head injury with loss of
consciousness
 Cerebrovascular disease
 Vascular brain lesions
 Cardiovascular disease
 Environmental toxins
 Depression*
 History of psychiatric
illness*
be premonitory manifestations of the disease process rather than risk factors.
Desai et al. Clin Geriatrics. 1999;7:43-52.
Normal Aging
 Can have mild deficits
– Slowed mental processing speed
– Difficulty recalling names and other nouns
 Changes should not materially affect ability to

function
Subjective memory loss
Kawas. N Engl J Med. 2003;349:1056-1063 (C).
The increased significance of aging

Increased life expectancy

“Baby boom” generation

– Success of public health
 Improved sanitation
 Antibiotics
 Vaccines
– 1946-64: 75 million babies
 By the year 2030
20%
of the US > age 65
Live long and prosper?
– Disease-free aging vs.
age-related disorders
 AD (5-10%), PD, ALS, HD
 Age-related memory deficits
HCF: The Hippocampal Formation
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Damage/dysfunction:
– Anterograde amnesia for
new facts and events
– Patient H.M.
– Alzheimer’s Disease
– Aging
Components:
– Entorhinal Cortex
– Hippocampus
 Dentate Gyrus
 Ammon’s horn (CA1-CA3)
– Subiculum
Unidirectional circuit
– EC
DG
HC
Sub
Aging vs. Alzheimer’s
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Normal “cognitive” aging
– No neuronal loss
– A few NFTs (neurofibrillary tangles)
in EC layer II, rarely in CA1
Very Mild AD
– Significant ~30% neuronal loss in
entorhinal cortex layer II, CA1
– Increasing density of NFTs
Severe AD
– ~90% loss in entorhinal cortex layer
II
– ~50% loss in other EC layers, CA1,
ITC
– Extensive neurofibrillary tangles
(NFTs)
– Cortical atrophy
Morrison and Hof, Science
Remember HM and his memory issues.
Aspects of this circuit
MTLS: Medial temporal lobe system
Mayford et al., Current Biology 1997
MTLS: Medial temporal lobe system
Mayford et al., Current Biology 1997
Basis of age-related memory deficits
 Theories of brain aging:
– Neuronal loss
 Glucocorticoid stress
 Oxidative stress
 Inflammation- gliosis
 Neurogenesis
– Neuronal dysfunction
 Calcium homeostasis
 Synaptic dysfunction
 Neurotrophic factor loss
 Signal transduction deficits
– Environmental factors
Apoptosis
Mild Cognitive Impairment
 Memory complaint, preferably corroborated by an
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informant
Impaired memory function for age and education
Normal general cognitive function
Normal activities of daily living
Not demented
Petersen et al. Arch Neurol. 2001;58:1985-1992 (C).
Mild AD: Clinical Correlates
Cognition
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Deficits in short-term memory, orientation, problem solving1
MMSE score in 20s2,3
Function
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Performance of complex tasks begins to deteriorate
(eg, shopping, managing money)2
Basic functions intact
Behavior
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Agitation, apathy, disinhibition, and irritability most
frequent3
1. Hughes et al. Br J Psychiatry. 1982;140:566-572 (B); 2. Galasko. Eur J Neurol.
1998;5(suppl 4):S9-S17 (B); 3. Mega et al. Neurology. 1996;46:130-135 (B).
Moderate AD: Clinical Correlates
Cognition
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Recent memory severely restricted1
Usually disoriented, social judgment impaired1
MMSE scores 10-202,3
Function
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Progressive loss of abilities to perform complex tasks
(eg, travel alone, use home appliances)2
Basic functions may require prompting (eg, dressing, grooming)2
Behavior
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Agitation, apathy, disinhibition, and irritability increase3
Anxiety, dysphoria, wandering/restlessness, delusions,
hallucinations may also emerge3
1. Hughes et al. Br J Psychiatry. 1982;140:566-572 (B); 2. Galasko. Eur J Neurol.
1998;5(suppl 4):S9-S17 (B); 3. Mega et al. Neurology. 1996;46:130-135 (B).
Severe AD: Clinical Correlates
Cognition
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Severe cognitive deficits observed1
For example, MMSE 11
Function
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Deficits in complex functions observed (eg, using the
telephone, shopping)2
Deficits in basic functions observed (eg, toileting,
dressing)2
Behavior
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Apathy, aberrant motor patterns, depression, anxiety, and
agitation were most prominent behavioral symptoms3
1. Feldman et al. Neurology. 2001;57:613-620 (A); 2. Feldman et al. J Am Geriatr Soc.
2003;51:737-744 (A); 3. Gauthier et al. Int Psychogeriatr. 2002;14:389-404 (A).
Differential Diagnoses
Features that favor the diagnosis of …
Vascular Dementia1
Lewy Body Dementia2
Frontotemporal
Dementia3
Abrupt onset
Focal neurological signs
Visual hallucinations
Extrapyramidal symptoms
Behavioral disinhibition
Apathy/social withdrawal
“Personality change”
Socially inappropriate
and symptoms
Stepwise deterioration
Atherosclerosis/TIAs
(transient ischemic attacks)
History of strokes
History of hypertension
–Shuffling gait
–Masked facies
–Rigidity
–Gait instability
Waxing/waning alertness
Neuroleptic supersensitivity
behavior
Euphoria/irritability
Nonfluent aphasia
1. Román et al. Neurology. 1993;43:250-260 (C); 2. McKeith et al. Lancet Neurol. 2004;3:19-28 (C); 3. Neary et al.
Neurology. 1998;51:1546-1554 (C); Liu et al. Neurology. 2004;62:742-748 (B)
GRADING SYSTEM
Grade 1 (top row of 4 images) corresponds to mild cerebral atrophy and ventricular
dilatation. Note this degree of change may be assessed as compatible with normal
aging. Thus, grade 1 accomodates scoring of brains from nondemented control
subjects with minimal or no gross neuropathology.
Grade 2 (middle row of 4 images) corresponds to moderately severe cerebral atrophy
and ventricular dilatation. Note widening of sulci, rounding of frontal horns, and
expansion of the area of the body and 3rd ventricle.
Grade 3 (bottom row of 4 images) corresponds to severe cerebral atrophy and
ventricular dilatation. Dramatic shrinkage of gyri, gaping of some sulci, and extreme
ventricular dilatation is obvious. Note also the white matter area is markedly
diminished from the amount noted in grade 1 brains.
Pharmacologic Approaches
FDA-Approved Medications for AD
 Cholinesterase inhibitors
–
–
–
–
Tacrine (Cognex)* - rarely prescribed
Galantamine (Razadyne)*
Rivastigmine (Exelon)*
Donepezil (Aricept)†
 N-methyl-D-aspartate receptor antagonist
– Memantine (Namenda)†
*Approved for use in mild-to-moderate AD; †mild through severe AD.
Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005; Exelon
(rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp;
2004 (A); Razadyne ER (galantamine hydrobromide) [package insert]. Titusville, NJ: OrthoMcNeil Neurologics, Inc.; 2005 (A); Namenda (memantine) [package insert]. St Louis, Mo:
Forest Pharmaceuticals, Inc.; 2005 (A).
Dosing Comparison of
Cholinesterase Inhibitors
Characteristic
Donepezil
Rivastigmine
Galantamine
Galantamine
ER
Doses per day
1
2
2
1
Initial dose
(mg/d)
5
3
8
8
4-6 weeks
2 weeks
4 weeks
4 weeks
5-10
6-12
16-24
16-24
With/without
Yes
Dose escalation
Clinically
effective
dose range
(mg/d)
Given with food
Recommended Recommended
Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005; Exelon
(rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004
(A); Razadyne ER (galantamine hydrobromide) [package insert]. Titusville, NJ: Ortho-McNeil
Neurologics, Inc.; 2005 (A).
Side-Effect Profile for Cholinesterase Inhibitors
 Gastrointestinal side effects include nausea,
vomiting, diarrhea, and abdominal pain
– Resulting in anorexia and weight loss
 Cardiovascular side effects include bradycardia,
tremor, and dizziness
– Resulting in asthenia and fatigue
 Neuromuscular side effects include muscle

cramps and weakness
CNS effects include insomnia, nightmares,
agitation, and a panic-like state
Bentué-Ferrer et al. CNS Drugs. 2003;17:947-963.
New Formulations of Cholinesterase Inhibitors
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Donepezil oral disintegrating tablets (ODT)
Rivastigmine oral solution
Rivastigmine transdermal patch evaluated in the
IDEAL trial
– 1195 patients randomized to 1 of 2 doses of a transdermal patch
(equivalent to 9.4 mg/24 h or 17.4 mg/24 h), 6-mg oral capsules of
rivastigmine bid or placebo
– Lower dose patch as effective as oral therapy and associated with
one third of the gastrointestinal side effects
– No difference in side-effect profile between higher dose patch and
oral treatment
– Not available yet

Galantamine extended-release (ER) capsules
IDEAL=Investigation of Transdermal Exelon in Alzheimer’s Disease.
Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005 (A);
Exelon (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004 (A).
Rationale for Memantine
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The normal activity of the neurotransmitter glutamate plays
an integral role in neural pathways associated with learning
and memory1
Voltage-dependent, low-moderate affinity, uncompetitive
NMDA-receptor antagonist with fast on/off kinetics2
Blocks the effects of abnormal glutamate activity
(excitotoxicity) that may lead to neuronal cell death and
cognitive dysfunction2
Preserves physiological activation of NMDA receptor,
which is required for learning and memory2
1. Ghosh. Science. 2002;295:449-451; 2. Parsons et al. Neuropharmacology.
1999;38:735-767; Alzheimer’s Association. Available at: http://www.alz.org/Resources/
FactSheets/FSmemantine.pdf. Accessed December 1, 2006.
Memantine: Pharmacokinetics
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Bioavailability: 100%
Protein binding: 45%
T1/2: 60 to 80 hours
Can be administered with or without food
Limited metabolism—eliminated mostly in urine as parent
drug, metabolites inactive
No or minimal effects on CYP450 isoenzymes
No PK/PD interactions with ChEIs
Possible PD interaction with high-affinity NMDA receptor
antagonists?
PK=pharmacokinetic; PD=pharmacodynamic.
Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2005 (A).
Memantine: Suggested Dosing
 Start with 5 mg qd (5101520 mg)

Titrate memantine to 20 mg/d over 4 week period
Decrease dose (to 5 mg bid) in patients with
severe renal impairment (CrCl: 5-29 mL/min)
Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2005 (A).
Memantine Adverse Events
Percentage of Adverse Events Reported in Controlled Clinical
Trials in ≥4% of Patients Receiving Memantine and at a Higher
Frequency Than Placebo-Treated Patients1
Adverse Event
Hypertension
Placebo (n=922)
%
2
Memantine (n=940)
%
4
Dizziness
5
7
Headache
3
6
Constipation
3
5
Confusion
5
6
Coughing
3
4

Memantine 1-year safety data available (28-week, randomized,
double-blind, placebo-controlled period, plus 24-week, open-label
extension phase2)
1. Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc; 2005;
2. Reisberg et al. Arch Neurol. 2006;63:49-54.