Transcript Keys to Care - Pennsylvania Neurological Associates

Artistic Regression
• Distortion – comic-grotesque representation Condensation – filling
to overflowing
• Transformation (neomorphism) – anatomic changes and strange
facial features (physiognomy)
• Stereotype – ornamental stereotype and repetition of particular
motives
• Woodenness – geometrical and diagrammatic design and pictures
enclosed with a frame, lack of depth (lack of shading) and lack of
movement (wooden rigidity)
• Disintegration – neglect of spacial relationships between objects and
loosening of physiognomy of human beings and animals.
• Regression – relapse into primitive or child-like drawings and lack of
perspective
– Maurer K, Frolich L, ALZHEIMER INSIGHTS Paintings of and Artist
With Alzheimer Disease
Clock Drawing
Life expectancy with Dementia
• 3.3 years, comparable to some malignancies
• In patients diagnosed with dementia
• Wolfson et al NEJM 2001;344:1111-1116
Alzheimer Brain Atrophy
From Whole Brain Atlas
Volume 344:1516-1526
May 17,
2001
Neurodegenerative Diseases and Prions
Stanley B. Prusiner, M.D.
Twenty-five years ago, little was known about the causes of neurodegenerative diseases.
Number
20
Stanley Prusiner Nobel 1997
Thesis:
• Degenerative Disease is caused by the
accumulation of toxic substances
• Deranged metabolism over long pds of
time.
• Primarily diseases of elderly
• As in cholesterol and homocysteine in
atherosclerosis
Neurologic Diseases attributed to
Protein deposition
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Alzheimer disease: Aβ42
Amyloid Angiopathy: Aβ42
Huntington Disease: Huntingtin
Prion Disease: PrP sc
“Tauopathies: Pick’s, FT dementia, PSP
Parkinson Disease, Lewy body Dementia (alpha synuclein)
Spino-cerebellar Degenerations: Ataxins
ALS: Neurofilament
Macular Degeneration: A2E
Macular Degeneration=“Age
Related Maculopathy”
• 5% of 60 year olds, 20% of 80 year olds
• Disorder of Phagocytosing cells in Retinal
Pigment epithelium
• Accumulation of drusen or lipofuscin in
Retinal Pigment Epithelium
• Genetic forms: may be “A2E” accumulation
• Retinal Alzheimer’s Disease
Macular Degeneration
Pathogenesis of Macular
Degeneration from
Scientific American
10/2001
First Hints to Causation
• Genetics
• Familial Alzheimer Disease
• Trisomy 21
Alzheimer Genes: Chromosome #s
• 21: Abn APP Gene
<5%*
• 14: Presenilin 1
18-50%*
• 1 : Presenilin 2
<1%*
• 19:APOE-epsilon 4: Incr risk in Caucasions
• 19:APOE-epsilon2 on Chr 19: decr risk
*of early-onset Disease
Apolipoprotein E4
• Variant alleles E2,E3
• Variants differ by only 1 amino acid
• E4 is present in 64% of late-onset Alz
patients as 34% of unaffected controls
• 2 copies (homozygote) of E4 increases risk
of Alz from 45% to 91%
All have in Common:
• Increased Accumulation of b Amyloid
– Abnormal Accumulation
– Defective Degradation
Alzheimer Disease
• Cerebral Amyloidosis
The Amyloid Hypothesis
Pathogenesis
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Beta-Amyloid Accumulation
Decrease in Acetylcholine, AchE
Injury
Free-Radical Formation
Genetics
– Polygenic
– ApoE4
– FAD
Characteristic Changes
• Pathology
– Tangles, plaques, Granulo-vacuolar degeneration,
Atrophy,neuronal loss
• Biochemistry
– Decreased Ach, AchE
• Imaging
– Atrophy
– Decreased metab activity in post’r cerebral association
Cortices
Senile Plaque
• A hallmark pathologic lesion specific for
AD is senile plaque. Plaques are composed
of amyloid-beta (A-beta), which is found in
soluble form in the body fluids of patients
with AD. Initially, A-beta aggregates into
diffuse plaques that lack definite borders.
Later, it matures into compact plaques
formed of A-beta fibrils that may be toxic to
surrounding neurons.
Amyloid Plaques
• Between Cells (extra-cellular)
• Appear before Tangles do
• Associated with Microglia (inflammation)
– (microglia are phagocytes of the brain)
Amyloid Precursor Protein
• 695-770 Amino Acids
• Transmembrane protein
• Beta-Amyloid is snipped out precursor
protein
• Beta-Amyloid- transmembrane component
Cast of Characters
• Amyloid Precursor Protein (APP)
• Secretases – alpha, beta, Gamma
– Enzymes that cut up Amyloid Precursor Protein
• Beta-Amyloid (or Aβ42)
• Beta-Amyloid is the villain
• Setting: The neuron cell membrane
Secretase Steps
• Alpha then Gamma – OK
• Beta then Gamma – yields Beta Amyloid
• 40 Amino Acid fragment is OK but minority
cut into toxic 42 Amino acid fragment
which constitutes plaque (Aβ42)
Presenilins
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Early Onset Alzheimer's
Trans-membrane Protein Cleavers
PreI: Chr 14, PreII:Chr 1
Knockout for these proteins: No Beta
Amyloid
• Forms of Gamma-Secretase??
Are “Pre-Senilins” forms
of Secretase??
Amyloid Plaque
Pathogenesis of Senile Plaque
• Toxic Beta Amyloid fragments build up
outside the cell
• E4 may be selectively removed from the
extracellular space in place of beta-amyloid
• Beta-Amyloid is toxic and leads to other
pathology
Cutting β-Amyloid Precursor Protein
• Alpha and Gamma Secretase give rise to
harmless p3 protein
• Beta then Gamma secretase yield either:
– Harmless 40 amino acid residue of BetaAmyloid OR
– Toxic 42 Amino Acid residue of Beta Amyloid
Gamma Secretase: a trans-membrane
protease
Beta Amyloid Mediated Damage
• Ca++ Deregulation
• Creation of Free Radicals
• Immune Aggregation
Beta Amyloid
• 4.2 kD fragment, 42-43
• Abnormal cleavage of Beta Amyloid
precursor protein (APP)
– APP part of family of 70kD transmembrane
proteins
• Beta-Secretase, APP cleaving Protein
• Injury, ischemia incr APP
• Amyloid is neurotoxic
Mechanism of Amyloid destruction
• Liberating Calcium in Cells
• Damaging Mitochondria
• Enhancing inflammatory (Microglial)
Response
New Strategies
• Beta-Amyloid
Vaccine
• Beta and Gamma
Secretase Blockers
• Zinc and Copper
Chelators
Strategies to Prevent and treat
Alzheimer’s
• 1. Inhibition of the proteases (enzymes) that
produce Aβ42 ;
2. Inhibition of Aβ42 aggregation that
precedes A deposition;
3. Inhibition of Aβ42 -induced neurotoxicity
• Vaccine or antibody to Aβ42
Dennis Selkoe & Howard Weiner
Mouse Trials of Vaccine
• Nasal Administration
• Genetically affected mice make excessive
Beta Amyloid
• Mice show evidence of Dementia
• 50% reduction in plaque formation
• Improvement on tests
• Human phase II trials begin this year
Elan Pharmaceutical trial
• In PDAPP mouse (a genetically engineered
mouse model with Alzheimer’s-like
pathology)
• AN-1792, both reduces pre-existing
deposits of amyloid and inhibits
accumulation
Gene linkage
• Long arm of Chromosome 10 in late onset
Alzheimer
• ?Connected with degradation of Beta
Amyloid?
• Insulin processing protein
• Rudy Tanzi Dec22,2000 Science
Treatment Cornerstones
• Cholinesterase Inhibitors
• Ancillary Symptoms
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Anxiety
Agitation
Disorientation and Wandering
Sleep Disturbance
• Placement
• Caring for Caretaker
Other Pathology
CSF in Alzheimer’s Disease
• They found levels of CSF beta-amyloid protein
were significantly lower, on
average, in people with Alzheimer's disease than
the comparison group (183
pg/mL vs. 491 pg/mL). In addition, levels of CSF
tau protein were
significantly higher in Alzheimer's disease patients
than in the others (587
pg/mL vs. 244 pg/mL).
Diagnosis Criteria
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Alzheimer's disease is characterized by progressive decline and ultimately
loss of multiple cognitive functions, including both:
* Memory impairment--impaired ability to learn new information or to
recall previously learned information.
* And at least one of the following:
Loss of word comprehension ability, for example, inability to respond to
"Your daughter is on the phone." (aphasia);
Loss of ability to perform complex tasks involving muscle coordination,
for example, bathing or dressing (apraxia);
Loss of ability to recognize and use familiar objects, for example,
clothing (agnosia);
Loss of ability to plan, organize, and execute normal activities, for
example, going shopping.
B. The problems in "A" represent a substantial decline from previous abilities
and cause significant problems in everyday functioning.
C. The problems in "A" begin slowly and gradually become more severe.
D. The problems in "A" are not due to:
* Other conditions that cause progressive cognitive decline, among them:
stroke, Parkinson's disease, Huntington's chorea, brain tumor, etc.
* Other conditions that cause dementia, among them: hypothyroidism, HIV
infection, syphilis, and deficiencies in niacin, vitamin B12, and folic acid.
E. The problems in "A" are not caused by episodes of delirium.
F. The problems in "A" are not caused by another mental illness: depression,
schizophrenia, etc.
Granulo-vacuolar Degeneration
Granulo-vacuolar degeneration
• 5 m clear intracytoplasmic vacuole
• Argyrophillic core
• Pyramidal cell region of hippocampus
Neurofibrillary Tangles
Neurofibrillary Tangles
Neurofibrillary Tangle
Neurofibrillary Tangles
• Paired Helical Filaments associated with
Tau which binds to microtubules
• Phosphorylation of Tau inhibits its ability to
stabilize microtubules
• Leads to microtubule agglomeration as PHF
• Test for Tau in CSF
Neurofibrillary Tangle
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Tau protein –Ass’d with microtubules
Correlates more with degree of dementia
Appear after than Senile plaque
Not Specific for Alzheimer Disease
Neurofibrillary Tangle
• Abnormal intracellular structure caused by
phosphorylation of the tau protein in the
cytoskeleton of the neuron.
• Microglial cell proliferation, especially in
association with senile plaques, suggests
inflammatory processes play a role in the
disease process.
Fuel and Longevity
• Daf-2 gene in C. elegans
– When not functioning lifespan increases from 10
to 30 days
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An insulin receptor gene in humans
Rat experiments with caloric reduction
Monkey and human receptors
Gary Ruvkun, Harvard Med’l School
Causes of Dementia
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Alzheimer –55%
Vascular - 20%
Lewy Body –15%
Pick’s and lobar atrophy –5%
Other 5%
– Small,GW et al JAMA 1997,278:1363-71,
APA, Am J Psychiatry 1997,154 (suppl)1-39;
– Morris JC Clin GeriatrMed. 1994,10:257-76
Multi-infarct dementia
Whole brain Atlas
Hachinski Score for Dx of
Vascular Dementia
• Abrupt onset
• Stepwise deterioration
• Fluctuating course: improvement between
strokes
• Relative preservation of personality
Nocturnal confusion
• Depression
Hachinski Score (cont’d)
• Somatic complaints
• Emotional incontinence
• History of hypertension
• Evidence of atherosclerosis
– Pvd, MI
• Focal Neurological symptoms (TIA)
Focal neurological signs
Vascular Dementia
• CT or MRI critical
• Either large volume of brain affected, preferably
in both hemispheres or multi-infarcts in strategic
locations
• Small Vessel
– Lacunar State, deep strokes
– Subcortical deficits
• Multiple Cortical Infarcts:aphasia, agnosia,
apraxia
Behavior cont’d
Wandering:
can be dangerous, medications not effective
provide a "sheltered freedom". Example:
Cover door knob with shoe boxes.
Screaming:
very disturbing, may be related to pain,
delusion or Neuroleptic induced akathisia. ?
background music may be helpful. Sleep
disruption & Sundowning: very common
Agitation and Dementia
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Structure and routine.
Follow regular, predictable routines.
Keep things simple.
Distract.
Behavior
• Why is depression relatively uncommon??
• Anosognosia for dementia
Simple and Active
• Break down complex tasks into many
small, simple steps that the person can
handle Folding towels while one is doing
the laundry. Allow time for frequent
rests. Redirect. Get the person to do
something else as a substitute. A person
who is restless and fidgety can be asked
to sweep, dust, rake, fold clothes, or take
a walk or a car ride with the caregiver.
• Repetitive simple movement
Distract
• Offer a snack Put on a favorite videotape
or some familiar music Be flexible. Know
when to back away from a task- a bath or
dressing and reapproach later
Soothe. When agitated, do simple,
repetitive activities such as massage, hair
brushing, or giving a manicure. Reassure.
Let the person know that you are there
and will keep him or her safe.
Sleep and Anxiety
• Nonpharmacologic: Daytime
stimulation, adequate supervision,
avoidance of napping.
• Neuroleptics: may be helpful for
delusion and agitation. 20% may get
worse.
Preventing Alzheimer Disease
Alzheimer’s Burden
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4 Million Americans
14 Million Projected by 2050
1/10 over 65
85+ one of three has AD
Life expect: 8 years
in U.S .$110 B. in yr 2000
Half of all NH patients
$12500-70000/person year, avg lifetime
cost=$174000
Alzheimer’s Burden (cont’d)
• Prevalence doubles every 5 years after 65
• 360,000 new cases/yr
• Higher in non-Caucasians whose numbers
are growing in population
• 65+ now 13% but will reach 18% by 2025
• Sltly more than 50% receive care at home
Neurological Diseases
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Alzheimer’s
4 Million
Affective Disorders 17 Million
Drug & etoh
15Million
Intractable Pain
Parkinson’s
500,000
Schizophrenia
2 Million
Stroke
700,000/yr
MS
350,000
– Source:JAMA 285:594(2001)
$110 Bn
$44Bn
$240Bn
$65 Bn
$5.6Bn
$30Bn
$30Bn
Neurological Disease
(Prevalence)
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Alzheimer Disease:
Stroke:
Traumatic Brain Inj:
Epilepsy:
Parkinson’s:
4 million
3-4 Million
2.5-3.7 Million
1.75 Million
1.5 Million
Future Burden
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2011: first baby boomers turn 65
18% of population by 2025
85+ now 4 million, 8.5 million by 2030
50% of Alz pts are at home, 50% in care
Risks
• Advanced Age
– Half of those >85; 1/10 of those >65
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Female Sex
“Mild Cognitive Impairment”
Head Injury
APOE4
Family History
Low Education
Down’s
?Race
Estrogen
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2/3 of Alzheimer Patients are women
Onset After Menopause
May increase cholinergic transmission
Neurotrophic effects
Anti-amyloidogenic properties
Association with Neurotrophins
Regulates synapse formation in
hippocampus
Estrogen
• 3 studies in Neurology 2000;54 show no effect in
women already Diagnosed
• Baltimore Long. Study “After adjusting for
education, the relative risk for AD in ERT users as
compared with nonusers was 0.46”
• Tang MX et al. Effect of estrogen during
menopause on risk and age at onset of
Alzheimer's disease. Lancet 1996;348:429-432
• Jury Still Out
• Prospective treatment trials
Estrogen Reviews
• NEJM 344:1242-1244 April 19, 2001
Number 16 Richard Mayeux
• Neurology 2000;54:2035-2037 Marder
and Sano
Women’s Health Initiative Memory
Study (WHIMS)
• In May 2003, scientists taking part in the Women's
Health Initiative Memory Study (WHIMS), part of
the Women's Health Initiative, reported new health
risks for women over age 65 using a type of
combined estrogen plus progestin known as
Prempro™.
• The WHIMS scientists found that the number of
women over age 65 who began having symptoms
of dementia while using this form of estrogen plus
progestin was twice as high as those not taking
any hormones.
Homocysteine
• Eight years
• RR= 1.4 for each increase of 1 SD in the logtransformed homocysteine value either at base line or
eight years earlier
• RR of Alzheimer's disease was 1.8 per increase of 1 SD
at base line
• RR=1.6 per increase of 1 SD eight years before base
line.
• Plasma homocysteine level greater than 14 µmol per
liter doubled the risk of Alzheimer's disease.
– Seshadri et al. N Engl J Med 346:476-483 February 14, 2002
NSAIDs
• Prospective, population-based cohort study of
6989 subjects 55 years of age or older who were
free of dementia at base line.
• Relative risk of Alzheimer's disease was 0.95 in
subjects with short-term use of NSAIDs
• RR= 0.83 with intermediate-term use
• RR= 0.20 wit long-term use.
• Risk did not vary according to age
• Use of NSAIDs was not associated with a
reduction in the risk of vascular dementia.
– Bas A. in 't Veld, N Engl J Med 2001; 345:1515-1521, Nov 22, 2001
Baltimore Longitudinal Study of
Aging
Relative risk of Alzheimer's disease of 0.50
among regular users of NSAIDs, as
compared with nonusers
Stewart et al Neurology 1997;48:626-632
Alzheimer Genes
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21: Abn APP Gene
14: Presenilin 1
1 : Presenilin 2
19:APOE-epsilon 4: Incr risk in Caucasions
19:APOE-epsilon2 on Chr 19: decr risk
Late Stage
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Mixes up past and present
Expressive and receptive aphasia
Misidentifies familiar persons and places
Parkinsonism and falls risk
More mood and behavioral disturbances
Needs help with all ADL’s, Incontinent
Ongoing Studies
From May 16, 2002 ELEENA DE LISSER, The Wall Street Journal
STUDY
WHO'S ELIGIBLE
CONTACT
People 70+ who have not been
diagnosed with Alzheimer's but
have a relative who had the
disease.
1-866-2-STOP-AD or
www.2stopad.org
PREPARE (Preventing
Postmeno-pausal Memory Loss
and Alzheimer's with
Replacement Estrogens)
Women 65+
1-877-DELAY-AD or
www.delay-ad.org
PREADVISE (Prevention of
Alzheimer&apos;s Disease by
Vitamin E and Selenium)
Men 60 to 90 years old
1-800-333-8874 or
www.mc.uky.edu/coa
People 75+, Closed to new
participants without dementia.
www.alz.org/research/clintrials/#
prevention
Study sponsors: National Institute
on Aging (ADAPT, PREPARE,
PREADVISE) and National
Center for Complementary &
Alternative Medicine (GEM) at
the National Institutes of Health.
ADAPT
PATHWAYS TO (Alzheimer&apos;s
PREVENTION?
Disease Anti-inflammatory
Prevention Trial)
Ongoing clinical trials related to Alzheimer&apos;s disease and possible modes of prevention:
GEM (Ginkgo Evaluation of
Memory)
ADAPT
• Alzheimer Disease Anti inflammatory
Prevention Trial
• Use celecoxib or naproxen for years
• Evaluation at Center
– 3 X first year
– 2 X per year after that
• Phone follow up
Prevent AD with Estrogen
• National Institute on Aging
• Mary Sano, PhD
• 5 year study
Strategies
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Vitamin E and Selegeline or donepezil
Estrogens
NSAIDs
B12,B6,Folate (homocysteine)
Statins
Valproate ?”Neuroprotective”
IPA (Indole-3-Propionic Acid) anti-oxidant
Homocysteine
• Does this mean that lowering H. levels will
prevent A’s Disease?
• No one knows
Homocysteine
• 50 Mg pyridoxine
• Up to 4 mg. of Folate
• 500 mcg of B12
NSAIDs
• Inflammation is part of Aβ Accumulation
• Longitudinal Studies show dose related
effect of NSAID’s
• Nature Nov. 8, 2001 NSAID’s directly
decrease deposition of Aβ42
– ASA,Celebrex, Naprosyn – no effect
– Others at very high doses decreased production
in cells up to 80%
Selegiline and Vitamin E
• 2000 Units of Vitamin E and 10 mg. Selegiline
• S. -4 month delay in disease progression e.g. to
NH placement
• E. 6 month delay in Disease progression
• No difference on cognitive scores
• Combined treatment did slightly worse than either
treatment alone
– Sano et al. N Engl J Med 1997;336:1216-1222
Gingko Biloba
• 1 year
• 120 mg.
• 2.4% decrease in Alzheimer’s disease
Assessment scale Cognitive subscale
• Very little other evidence
Le Bars PL et al.JAMA 1997;278:1327-1332
Alzheimer Disease
• Dissolution of the Personality
• Inexorable Progression
Keys of Therapy
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Early Recognition of Disease
Cholinesterase Blockers
Treatment of Ancillary Symptoms
Maintaining Patient in own Environment
Family Support
Diagnosis
• Index of Suspicion
• Age!
• Sensitivity to Patients and Family
Vigilance
• Now Important because there are now early
treatments that help.
10 Warning Signs:
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Dysfunction on Job
Problem with Language function
Difficulty performing Familiar Tasks
Disorientation
Poor Judgment
Altered Abstract thinking
More Signs
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Misplacing Objects
Personality Change
Altered Mood and Behavior
Loss of initiative
Diagnostic Criteria for Dementia
• Multiple Cognitive Deficits with Both
– Memory Impairment plus one or more of foll’g:
– Aphasia, Apraxia, Agnosia, Executive function
– Impaired abstraction, judgement
• Impaired Social or Occupational Function
– DSM IV (1994), 133-35
Diagnostic Criteria (cont)
• Cognitive Deficits are not due to other
processes incl
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Substances
Systemic processes
Delirium and acute conditions
Not better accounted for by another Axis I
disorder
Diagnosis: Keys
• Not patient, but Persons Other than patient
complain of decreased cognitive function.
• Backing away from or ceasing to
participate in previous hobbies and
activities
• Take spouse, signif other, employer reports
seriously!!
Alzheimer Dementia
• Often “anosognosia” unawareness of
problem on part of sufferer
• Also denial
Pseudo-Dementia
• Often patient will themselves complain of
memory loss
• Younger patient
• Memory problem complained of
• Spouse and co-worker find no problem
• Pre-occupation
• Anxiety is the enemy of recall
Pseudo-Dementia
• Some sharp or compulsive persons notice a
normal slipping with age
– Ready recall
– Word-finding
• Again, no complaints from others
• Difficult distinction
• May require psychometrics to distinguish
Pseudo-Dementia
• Associated with severe depression
• Lack of reactivity “psychomotor
retardation”
• More abrupt onset
• Some old folks have combined organic
dementia and severe depression
MCI
• 6-25% progress to Alzheimer’s disease per
year.
Stages: Mild
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Routine loss of recent memory
Mild aphasia or word-finding difficulty
Seeks familiar and avoids unfamiliar places
Some difficulty writing and using objects
Apathy and depression
Needs reminders for some ADL’s
Stages: Moderate
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Chronic loss of recent memory
Moderate Aphasia
Gets lost at times even inside home
Repetitive actions, apraxia
Possible mood and behavioral disturbances
Needs reminders and help with most ADL’s
Evaluation
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Thorough Hx/Pex
Mental Function Evaluation
CBC, Chems, RPR, LFT’s,Thyroid, B12
HIV testing in selected cases
Imaging (CT, MRI) in most cases
Neuropsych testing if dx is uncertain
LP in doubtful cases
– Tau and amyloid beta
• Apolipoprotein genotype??
Evaluation: compare betw visits
• Folstein Mini-Mental Status
• Clock-drawing
• Scale of level of Function as reported by
family member
• Language function
Rule Out
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Alcohol
Depression
Drug s
Metabolic Derangement
Nutritional Deficiencies
Infection
Causes of Dementia
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Alzheimer –55%
Vascular - 20%
Lewy Body –15%
Pick’s and lobar atrophy –5%
Other 5%
– Small,GW et al JAMA 1997,278:1363-71,
APA, Am J Psychiatry 1997,154 (suppl)1-39;
– Morris JC Clin GeriatrMed. 1994,10:257-76
Hachinski Score for Dx of
Vascular Dementia
• Abrupt onset
• Stepwise deterioration
• Fluctuating course: improvement between
strokes
• Relative preservation of personality
Nocturnal confusion
• Depression
Hachinski Score (cont’d)
• Somatic complaints
• Emotional incontinence
• History of hypertension
• Evidence of atherosclerosis
– Pvd, MI
• Focal Neurological symptoms (TIA)
Focal neurological signs
Vascular Dementia
• CT or MRI critical
• Either large volume of brain affected, preferably
in both hemispheres or multi-infarcts in strategic
locations
• Small Vessel
– Lacunar State, deep strokes
– Subcortical deficits
• Multiple Cortical Infarcts:aphasia, agnosia,
apraxia
Pick’s Lobar atrophy
• Behavioral disturbances precede dementia
• Disinhibition
– Exaggeration of previous eccentricities
– Exhibitionism and overt sexuality
– Inappropriate humor, loss of social skills
• Ethnic jokes
– Slovenly behavior, decr hygiene and cleanliness
– Distractibility and impersistence
• Language dysfxn rather than memory
Pick’s
• Fronto-temporal atrophy on imaging or
SPECT or PET scans show decr metabolism
• “Tau –opathy”
– Grouped with PSP etc
• May be familial
“Others”
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Creutzfeldt-Jakob
Cortico-Basal Degen
Progressive Supranuclear Palsy
Frontal Lobe Dementia
Parkinson Related Dementia
• Late consequence of Parkinson Disease
• Hallucination prominent
– Dopaminergic Meds, anticholinergics are
hallucinogenic
– Parkinson and age related perceptual changes
Parkinson’s and Dementia
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Diffuse Lewy Body Disease
Alzheimer changes in the aged
Parkinson-dementia complex
Parkinson related diseases
Anti-esterases seem effective here too
Treatment Cornerstones
• Cholinesterase Inhibitors
• Ancillary Symptoms
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Anxiety
Agitation
Disorientation and Wandering
Sleep Disturbance
• Placement
• Caring for Caretaker
Cholinergic hypothesis
• Diffusely projecting area: Nucleus Basalis
of Meynert
• Layers I and II major cholinergic cortical
innervation
• Amygdala and hippocampus lgest
innervation
AChE inhibitors
• Establish a diagnosis of probable AD.
• Determine the stage of the patient (AChE-I
are approved for mild to moderate AD).
• Discontinue agents with anticholinergic
effects.
• Reduce dosage or discontinue if side
effects are intolerable.
• Monitor efficacy by caregiver report,
quantified mental status examination,
effects on activities of daily living, or
effects on behavior.
AChE’s Cont’d
• Continue for 6-12 months if any of the
efficacy measures indicate benefit or there
is stabilization in functional, cognitive, or
behavioral deterioration.
• Continue AChE-I therapy until there is
evidence of ongoing cognitive decline. If
there is evidence of continuing cognitive
decline, reduce the dosage and monitor to
determine if there is an acceleration of
deterioration. If deterioration is
accelerated, reintroduce AChE-I.
Alzheimer Manifestations
Activity of Daily Living
Behavior
Cognitive Dysfunction
All aided by Anti-esterases
Cholinesterase Blockers
Yr avail
1993
1996
2000
2001
Drug
Tacrine
Aricept Exelon Reminyl
Rev
reversabl Revers
class
Acridine Piperidine
AchE
yes
yes
BuChE
yes
minimal yes
Pseudo reversibl
-irrev
carba Phenantr
mate ene
alkaloid
yes
yes
minimal
Cholinesterase blockers
characterist Tacrine Donepzi Rivastigmine Galantamine
ic
Cognex Aricept Exelon
Reminyl
Dose/D
4
1
3
2
Max dose
160 mg 10 mg
12 mg
24 mg
Food?
no
no
yes
Yes
yes
None known Yes, some
5 mg
3 mg
D:D
yes
interaction
s?
Initial dose 40 mg
8 mg
Types of Cholinergic Receptors
• Muscarinic – excitatory
– M1 most common in cortex
– M2 presynaptic autorecptor governing release
in basal forebrain
– Work via G proteins
• Nicotinic –Inhibitory
– Ligand-gated ion channels
Acetylcholine
• Formation: ChAT and Acetyl-CoA
• Degradation: AchE and Butyrylcholinesterase
Butyrylcholinesterase
• Role is minor in normal brain
• Proportionate activity increases in
Alzheimer brain
AChE inhibitors: Progression?
• Patients on AChE inhibitors had a slower
rate of progression than placebo treated
patients
• Raises the issue of possible biological effect
of these agents to slow progression of
disease
Galantamine (Reminyl)
• Start at 4 mg BID (8 mg/day) for at least 4
weeks, then 8 mg bid Available in 4 mg, 8
mg, and 12 mg tablets Most frequent
adverse events that occurred with
placebo, REMINYL 16 mg/day, and
REMINYL 24 mg/day, respectively, were
nausea (5%, 13%, 17%), vomiting (1%, 6%,
10%), diarrhea (6%, 12%, 6%), anorexia
(3%, 7%, 9%), and weight decrease (1%,
5%, 5%).
Reminyl
• Average approx. 4 pts on ADAS-Cog
Scores
Galantamine
•
•
•
•
•
Common snowdrop (Galanthus nivalis)
Binds AChE
Modulator of Nicotinic Receptors
?Enhanced Sexual Fxn
Mythology
– Iliad, Circe, Atropine, Jimsonweed
Rivastigmine
• Exelon Approved in April 2000 for
treatment of mild to moderate Alzheimer's
disease.
• Benefits: Improved activities of daily
living, including eating, dressing, and
household chores. Reduce behavioral
symptoms, such as delusions and
agitation. Improved cognitive function
Reduced use of psychotropic medications
Faster Progression yields
Increased response
• Patients with moderate-stage AD (Mini-Mental
State Examination [MMSE] scores = 10-17) have
a naturally faster rate of disease progression when
taking placebo and a larger magnitude of response
to cholinesterase inhibitors; patients with mildstage AD (MMSE scores = 18-26) have a lesser
magnitude of response.[28] In addition, a
subanalysis of a large rivastigmine trial found that
a faster rate of progression before therapy
initiation (regardless of disease stage at baseline)
predicted a more robust response to treatment.[29]
Rivastigmine
• Shown to improve: Global function,
behavior, and Cognition
Rivastigmine
• Temporarily inactivates Cholinesterase by
forming a Covalent Bond
• 3 mg bid decreases AChE in CSF by 46%
• 6mg bid decreases AChE by 62%
• Duration of signif inhibition lasts up to 6
hours.
Alzheimer Scales
• CIBIC-Plus: 1-7
– Clinician’s interview-based impression of change with
caregiver input
– 1=marked improvement, 4=nc, 7=marked worsening
• ADAS-Cog:0-70
– Higher scores=greater cognitive impairment
– Mild to moderate=15-25
– 6-12 points/yr average deterioration
Rivastigmine: GI Effects
• 18% Men, 26% Women at Max dose
ADAS-Cog Effects
Rivastigmine
• Dose: titrate dosage to achieve optimal
effect. Usual dose: 6 to 12 mg/day given
BID. Start 1.5 mg bid, increase by 3 mg
every 2 weeks. Available in capsule doses
of 1.5, 3, 4.5, 6 mg.
• Half life: 2 hours Few interactions with
other drugs Side effects: No
hepatotoxicity GI disturbances, occur
mainly during dose adjustment.
Aricept (donepezil)
• Indicated for mild to moderate
Alzheimer's dementia
• More selective for acetylcholinesterase,
the cholinesterase common in the brain,
believed to account for the low incidence
of GI side effects
• 5 mg qd for 4 to 6 wk, if tolerate increase
to 10 mg qd
Aricept
• Pharmacology: Half life: 72-hour Steady states
are achieved in 15 days. 94% protein-bound
metabolized by the hepatic P450 enzyme system,
but few drug interactions have been identified.
Adverse effect: nausea, vomiting,
gastrointestinal cramping, diarrhea and muscle
cramping. Does not have hepatoxicity.
Behavior Problems
Personality change: apathetic or more
impulsive
Anxiety:
apprehension over upcoming events
Aggression:
physical or verbal
Behavior cont’d
Wandering:
can be dangerous, medications not effective
provide a "sheltered freedom". Example:
Cover door knob with shoe boxes.
Screaming:
very disturbing, may be related to pain,
delusion or Neuroleptic induced akathisia. ?
background music may be helpful. Sleep
disruption & Sundowning: very common
Agitation and Dementia
•
•
•
•
Structure and routine.
Follow regular, predictable routines.
Keep things simple.
Distract.
Behavior
• Why is depression relatively uncommon??
• Anosognosia for dementia
Simple and Active
• Break down complex tasks into many
small, simple steps that the person can
handle Folding towels while one is doing
the laundry. Allow time for frequent
rests. Redirect. Get the person to do
something else as a substitute. A person
who is restless and fidgety can be asked
to sweep, dust, rake, fold clothes, or take
a walk or a car ride with the caregiver.
• Repetitive simple movement
Distract
• Offer a snack Put on a favorite videotape
or some familiar music Be flexible. Know
when to back away from a task- a bath or
dressing and reapproach later
Soothe. When agitated, do simple,
repetitive activities such as massage, hair
brushing, or giving a manicure. Reassure.
Let the person know that you are there
and will keep him or her safe.
Sleep and Anxiety
• Nonpharmacologic: Daytime
stimulation, adequate supervision,
avoidance of napping.
• Neuroleptics: may be helpful for
delusion and agitation. 20% may get
worse.
For Sleep
• Chloral hydrate, 500 to 1000 mg prn up to
2/d or 10/wk
• Zolpidem (Ambien), 5 to 10 mg hs prn
• Lorazepam (Ativan), 0.5 to 1 mg prn (up to
2/d or 10/wk)
• Buspirone (Buspar), 5 to 10 mg tid for
short-term (few weeks)
• Trazodone (Desyrel), 50 mg hs, may
increase gradually to 50 mg bid or tid
• Melatonin, 1 to 2 mg hs prn
(investigational)
Agitation
Olanzapine (Zyprexa): 2.5 mg qhs; Max: 10-20
mg/day given in bid.
*Quetiapine (Seroquel): 12.5 mg bid; Max: 75 mg
bid. More sedating, may cause transient
orthostasis.
Risperidone (Risprdal) 0.25-1 mg qd to bid, EPS
may occur at 2 mg.
Little use for older neuroleptics: Haldol etc
Agitation (cont)
Trazadone 25 mg hs, increase as tolerated,
Prozac 10-20 mg qam
*Sertraline 25-100 mg qam
Desipramine 25-100 mg qhs
Nortriptyline 10-100 mg qhs
*Celexa 20 mg: Citalopram
Agitation (Cont)
Anxiolytics: for short term use, long term
use may worsen cognitive function
Lorazepam 0.5 - 2 mg
Buspar: Takes long to act.
Anticonvulsants: Use is common, but
questionable. May ameliorate mood
fluctuations, impulsiveness
Carbamazepine 100 mg bid, titrate
Depakene 125 mg bid, titrate
Beta blockers: ?behavioral outbursts
Vit E + Selegiline
• Slow the progression of AD (Sano et al,
1997).
• Rate of progression -25% less than the
rate in placebo Dose used in study:
• Vitamin E 2000 I.U. Selegiline 5 mg am, 5
mg noon.
• Long-term effects unknown. Side effects:
Selegiline: insomnia, confusion, and
psychosis. Vitamin E: Can potentially
cause a prolonged prothrombin time for
pateints on coumadin
– Selegiline, Vit E treatment - NEJM 1997
Time course in deterioration
Pathogenesis
•
•
•
•
•
Beta-Amyloid Accumuation
Decrease in Acetylcholine, AchE
Injury
Free-Radical Formation
Genetics
– Polygenic
– ApoE4
– FAD
Characteristic Changes
• Pathology
– Tangles, plaques, Hirano bodies, Atrophy,neuronal loss
• Biochemistry
– Decreased Ach, AchE
• Imaging
– Atrophy
– Decreased metab activity in post’r cerebral associaation
Corices
Senile Plaque
• A hallmark pathologic lesion specific for
AD is senile plaque. Plaques are composed
of amyloid-beta (A-beta), which is found in
soluble form in the body fluids of patients
with AD. Initially, A-beta aggregates into
diffuse plaques that lack definite borders.
Later, it matures into compact plaques
formed of A-beta fibrils that may be toxic to
surrounding neurons.
Amyloid
Amyloid Plaque
Neurofibrillary Tangle
• Abnormal intracellular structure caused by
phosphorylation of the tau protein in the
cytoskeleton of the neuron.
• Microglial cell proliferation, especially in
association with senile plaques, suggests
inflammatory processes play a role in the
disease process.
Neurofibrillary Tangles
Beta Amyloid
• 4.2 kD fragment, 42-43
• Abnormal cleavage of Beta Amyloid
precursor protein (APP)
– APP part of family of 70kD transmembrane
proteins
• Beta-Secretase, APP cleaving Protein
• Injury, ischemia incr APP
• Amyloid is neurotoxic
New Strategies
• Beta-Amyloid Vaccine
• Beta and Gamma Secretase Blockers
• Zinc and Copper Chelators
Evolving Therapies
• Vaccine
• Secretin inhibitors
• Blocking Amyloid Accumulation