Alzheimer s disease and related dementias
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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)

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Alzheimer s disease and related dementias

Alzheimer’s Disease and Related Dementias

Modified from a talk by :

Andrea A. Chiba, UCSD

And

KE Edwards, Amgen


Definition of dementia

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

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

  • 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

Scope of AD Now and in the Future


A healthcare crisis today

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;48:300-304; 3. Miniño et al. Natl Vital Stat Rep. 2006;54:1-50.


Alzheimer e2 80 99s disease and related dementias

AD

  • Can be divided into Early Onset (< 60) and Late 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.


Prevalence is projected to increase dramatically

Prevalence Is Projected to Increase Dramatically

13.2 Million

7.7 Million

Number of Patients (millions)

4.5 Million

Year

*Estimates.

Hebert et al. Arch Neurol. 2003;60:1119-1122.


Economic impact of diseases and drug related problems

Economic Impact of Diseases and Drug-Related Problems

Billions ($) Annually

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

AD and the BrainPlaques and Tangles: The Hallmarks of AD

  • -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

The brains of people with AD have an abundance of 2 abnormal structures:

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

1.

2.

3.

AD and the Brain-Amyloid Plaques

Amyloid precursor protein (APP) is the precursor to amyloid plaque

  • APP sticks through the neuron membrane

  • Enzymes cut the APP into fragments of protein, including -amyloid

  • -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


Plaques

Plaques

  • Extracellular

  • Contain A-beta (sequence cleaved from APP or Amyloid Precursor Protein)

  • Metals (aluminum, zinc)

  • Immunoglobulin G

  • Amyloid P

  • apoE

  • ETC….over 30 other proteins


Ad and the brain

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

AD and the Brain

  • Neurofibrillary Tangles

National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/. Accessed October 5, 2006.


Tangles

Tangles

  • Intracellular

  • Bundles of long unbranched elements that form a 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

ApoE: One Hypothesis for Tangle FormationDetails – only for those who care – not requisite knowledge


What causes ad

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

Progression to Dementia

Normal Cognition

Prodromal Dementia

Dementia

Normal

brainaging

Stable or reversible impairment

Vascular dementia

Mixed

Alzheimer’s disease

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

Possible

Head injury with loss of consciousness

Cerebrovascular disease

Vascular brain lesions

Cardiovascular disease

Environmental toxins

Depression*

History of psychiatric illness*

Risk Factors for AD

*May be premonitory manifestations of the disease process rather than risk factors.

Desai et al. Clin Geriatrics. 1999;7:43-52.


Normal aging

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

The increased significance of aging

  • Increased life expectancy

    • Success of public health

      • Improved sanitation

      • Antibiotics

      • Vaccines

  • “Baby boom” generation

    • 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


Alzheimer e2 80 99s disease and related dementias

HCF: The Hippocampal Formation

  • 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

    Aging vs. Alzheimer’s

    • 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

    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

    MTLS: Medial temporal lobe system

    Mayford et al., Current Biology 1997


    Basis of age related memory deficits

    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

    Mild Cognitive Impairment

    • Memory complaint, preferably corroborated by an 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

    Mild AD: Clinical Correlates

    Cognition

    • Deficits in short-term memory, orientation, problem solving1

    • MMSE score in 20s2,3

      Function

    • Performance of complex tasks begins to deteriorate(eg, shopping, managing money)2

    • Basic functions intact

      Behavior

    • 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

    Moderate AD: Clinical Correlates

    Cognition

    • Recent memory severely restricted1

    • Usually disoriented, social judgment impaired1

    • MMSE scores 10-202,3

      Function

    • 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

    • 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

    Severe AD: Clinical Correlates

    Cognition

    • Severe cognitive deficits observed1

    • For example, MMSE 11

      Function

    • Deficits in complex functions observed (eg, using the telephone, shopping)2

    • Deficits in basic functions observed (eg, toileting, dressing)2

      Behavior

    • 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

    Differential DiagnosesFeatures that favor the diagnosis of …

    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)


    Alzheimer e2 80 99s disease and related dementias

    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

    Pharmacologic Approaches


    Fda approved medications for ad

    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: Ortho-McNeil Neurologics, Inc.; 2005 (A); Namenda (memantine) [package insert]. St Louis, Mo: Forest Pharmaceuticals, Inc.; 2005(A).


    Dosing comparison of cholinesterase inhibitors

    Dosing Comparison of Cholinesterase Inhibitors

    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

    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

    New Formulations of Cholinesterase Inhibitors

    • 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

    Rationale for Memantine

    • 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

    Memantine: Pharmacokinetics

    • 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

    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

    Memantine Adverse Events

    Percentage of Adverse Events Reported in Controlled Clinical Trials in ≥4% of Patients Receiving Memantine and at a HigherFrequency Than Placebo-Treated Patients1

    • 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.


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