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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

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artistic regression
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
life expectancy with dementia
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
Alzheimer Brain Atrophy

From Whole Brain Atlas

slide9

Neurodegenerative Diseases and Prions

Stanley B. Prusiner, M.D.

Twenty-five years ago, little was known about the causes ofneurodegenerative diseases.

thesis
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
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

Neurologic Diseases attributed to Protein deposition
macular degeneration a ge r elated m aculopathy
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
slide15

Pathogenesis of Macular

Degeneration from

Scientific American

10/2001

first hints to causation
First Hints to Causation
  • Genetics
  • Familial Alzheimer Disease
  • Trisomy 21
alzheimer genes chromosome s
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
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
All have in Common:
  • Increased Accumulation of b Amyloid
    • Abnormal Accumulation
    • Defective Degradation
pathogenesis
Pathogenesis
  • Beta-Amyloid Accumulation
  • Decrease in Acetylcholine, AchE
  • Injury
  • Free-Radical Formation
  • Genetics
    • Polygenic
    • ApoE4
    • FAD
characteristic changes
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
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
Amyloid Plaques
  • Between Cells (extra-cellular)
  • Appear before Tangles do
  • Associated with Microglia (inflammation)
    • (microglia are phagocytes of the brain)
amyloid precursor protein
Amyloid Precursor Protein
  • 695-770 Amino Acids
  • Transmembrane protein
  • Beta-Amyloid is snipped out precursor protein
  • Beta-Amyloid- transmembrane component
cast of characters
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
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
Presenilins
  • 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??
pathogenesis of senile 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 amyloid precursor protein
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 Beta-Amyloid OR
    • Toxic 42 Amino Acid residue of Beta Amyloid
beta amyloid mediated damage
Beta Amyloid Mediated Damage
  • Ca++ Deregulation
  • Creation of Free Radicals
  • Immune Aggregation
beta amyloid
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
Mechanism of Amyloid destruction
  • Liberating Calcium in Cells
  • Damaging Mitochondria
  • Enhancing inflammatory (Microglial) Response
new strategies
New Strategies
  • Beta-Amyloid Vaccine
  • Beta and Gamma Secretase Blockers
  • Zinc and Copper Chelators
strategies to prevent and treat alzheimer s
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
mouse trials of vaccine
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
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

Gene linkage
treatment cornerstones
Treatment Cornerstones
  • Cholinesterase Inhibitors
  • Ancillary Symptoms
    • Anxiety
    • Agitation
    • Disorientation and Wandering
    • Sleep Disturbance
  • Placement
  • Caring for Caretaker
csf in alzheimer s disease
CSF in Alzheimer’s Disease
  • They found levels of CSF beta-amyloid protein were significantly lower, onaverage, in people with Alzheimer\'s disease than the comparison group (183pg/mL vs. 491 pg/mL). In addition, levels of CSF tau protein weresignificantly higher in Alzheimer\'s disease patients than in the others (587pg/mL vs. 244 pg/mL).
diagnosis criteria
Diagnosis Criteria
  • Alzheimer\'s disease is characterized by progressive decline and ultimatelyloss of multiple cognitive functions, including both:* Memory impairment--impaired ability to learn new information or torecall 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, forexample, going shopping.B. The problems in "A" represent a substantial decline from previous abilitiesand 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, HIVinfection, 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 degeneration1
Granulo-vacuolar degeneration
  • 5 m clear intracytoplasmic vacuole
  • Argyrophillic core
  • Pyramidal cell region of hippocampus
neurofibrillary tangles2
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 tangle1
Neurofibrillary Tangle
  • Tau protein –Ass’d with microtubules
  • Correlates more with degree of dementia
  • Appear after than Senile plaque
  • Not Specific for Alzheimer Disease
neurofibrillary tangle2
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

An insulin receptor gene in humans

Rat experiments with caloric reduction

Monkey and human receptors

Gary Ruvkun, Harvard Med’l School

Fuel and Longevity
causes of dementia
Causes of Dementia
  • 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
Multi-infarct dementia

Whole brain Atlas

hachinski score for dx of vascular dementia
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
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
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
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
Agitation and Dementia
  • Structure and routine.
  • Follow regular, predictable routines. 
  • Keep things simple. 
  • Distract. 
behavior
Behavior
  • Why is depression relatively uncommon??
  • Anosognosia for dementia
simple and active
Simple and Active
  • Break down complex tasks into many small, simple steps that the person can handleFolding 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
Distract
  • Offer a snackPut on a favorite videotape or some familiar music Be flexible. Know when to back away from a task- a bath or dressing and reapproach laterSoothe. 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
Sleep and Anxiety
  • Nonpharmacologic: Daytime stimulation, adequate supervision, avoidance of napping.
  • Neuroleptics: may be helpful for delusion and agitation. 20% may get worse.
alzheimer s burden
Alzheimer’s Burden
  • 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
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
Neurological Diseases
  • Alzheimer’s 4 Million $110 Bn
  • Affective Disorders 17 Million $44Bn
  • Drug & etoh 15Million $240Bn
  • Intractable Pain $65 Bn
  • Parkinson’s 500,000 $5.6Bn
  • Schizophrenia 2 Million $30Bn
  • Stroke 700,000/yr $30Bn
  • MS 350,000
    • Source:JAMA 285:594(2001)
neurological disease prevalence
Neurological Disease(Prevalence)
  • Alzheimer Disease: 4 million
  • Stroke: 3-4 Million
  • Traumatic Brain Inj: 2.5-3.7 Million
  • Epilepsy: 1.75 Million
  • Parkinson’s: 1.5 Million
future burden
Future Burden
  • 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
Risks
  • Advanced Age
    • Half of those >85; 1/10 of those >65
  • Female Sex
  • “Mild Cognitive Impairment”
  • Head Injury
  • APOE4
  • Family History
  • Low Education
  • Down’s
  • ?Race
  • ?Homocysteine?
estrogen
Estrogen
  • 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
estrogen1
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
Estrogen Reviews
  • NEJM 344:1242-1244April 19, 2001Number 16 Richard Mayeux
  • Neurology 2000;54:2035-2037 Marder and Sano
women s health initiative memory study whims
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
Homocysteine
  • Eight years
  • RR= 1.4 for each increase of 1 SD in the log-transformed 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 346:476-483February 14, 2002
nsaids
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
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
Alzheimer Genes
  • 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
Late Stage
  • 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
Ongoing Studies From May 16, 2002 ELEENA DE LISSER, The Wall Street Journal

PATHWAYS TO PREVENTION?

Ongoing clinical trials related to Alzheimer&apos;sdisease and possible modes of prevention:

adapt
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
Prevent AD with Estrogen
  • National Institute on Aging
  • Mary Sano, PhD
  • 5 year study
strategies
Strategies
  • Vitamin E and Selegeline or donepezil
  • Estrogens
  • NSAIDs
  • B12,B6,Folate (homocysteine)
  • Statins
  • Valproate ?”Neuroprotective”
  • IPA (Indole-3-Propionic Acid) anti-oxidant
homocysteine1
Homocysteine
  • Does this mean that lowering H. levels will prevent A’s Disease?
  • No one knows
homocysteine2
Homocysteine
  • 50 Mg pyridoxine
  • Up to 4 mg. of Folate
  • 500 mcg of B12
nsaids1
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
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
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 disease1
Alzheimer Disease
  • Dissolution of the Personality
  • Inexorable Progression
keys of therapy
Keys of Therapy
  • Early Recognition of Disease
  • Cholinesterase Blockers
  • Treatment of Ancillary Symptoms
  • Maintaining Patient in own Environment
  • Family Support
diagnosis
Diagnosis
  • Index of Suspicion
  • Age!
  • Sensitivity to Patients and Family
vigilance
Vigilance
  • Now Important because there are now early treatments that help.
10 warning signs
10 Warning Signs:
  • Dysfunction on Job
  • Problem with Language function
  • Difficulty performing Familiar Tasks
  • Disorientation
  • Poor Judgment
  • Altered Abstract thinking
more signs
More Signs
  • Misplacing Objects
  • Personality Change
  • Altered Mood and Behavior
  • Loss of initiative
diagnostic criteria for dementia
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
Diagnostic Criteria (cont)
  • Cognitive Deficits are not due to other processes incl
    • Substances
    • Systemic processes
    • Delirium and acute conditions
    • Not better accounted for by another Axis I disorder
diagnosis keys
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
Alzheimer Dementia
  • Often “anosognosia” unawareness of problem on part of sufferer
  • Also denial
pseudo dementia
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 dementia1
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 dementia2
Pseudo-Dementia
  • Associated with severe depression
  • Lack of reactivity “psychomotor retardation”
  • More abrupt onset
  • Some old folks have combined organic dementia and severe depression
slide110
MCI
  • 6-25% progress to Alzheimer’s disease per year.
stages mild
Stages: Mild
  • 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
Stages: Moderate
  • 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
Evaluation
  • 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
Evaluation: compare betw visits
  • Folstein Mini-Mental Status
  • Clock-drawing
  • Scale of level of Function as reported by family member
  • Language function
rule out
Rule Out
  • Alcohol
  • Depression
  • Drug s
  • Metabolic Derangement
  • Nutritional Deficiencies
  • Infection
causes of dementia1
Causes of Dementia
  • 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 dementia1
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 d1
Hachinski Score (cont’d)
  • Somatic complaints
  • Emotional incontinence
  • History of hypertension
  • Evidence of atherosclerosis
        • Pvd, MI
  • Focal Neurological symptoms (TIA)   Focal neurological signs
vascular dementia1
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
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
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
“Others”
  • Creutzfeldt-Jakob
  • Cortico-Basal Degen
  • Progressive Supranuclear Palsy
  • Frontal Lobe Dementia
parkinson related 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
Parkinson’s and Dementia
  • Diffuse Lewy Body Disease
  • Alzheimer changes in the aged
  • Parkinson-dementia complex
  • Parkinson related diseases
  • Anti-esterases seem effective here too
treatment cornerstones1
Treatment Cornerstones
  • Cholinesterase Inhibitors
  • Ancillary Symptoms
    • Anxiety
    • Agitation
    • Disorientation and Wandering
    • Sleep Disturbance
  • Placement
  • Caring for Caretaker
cholinergic hypothesis
Cholinergic hypothesis
  • Diffusely projecting area: Nucleus Basalis of Meynert
  • Layers I and II major cholinergic cortical innervation
  • Amygdala and hippocampus lgest innervation
ache inhibitors
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
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. 
slide130

Alzheimer Manifestations

Activity of Daily Living

Behavior

Cognitive Dysfunction

All aided by Anti-esterases

types of cholinergic receptors
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
Acetylcholine
  • Formation: ChAT and Acetyl-CoA
  • Degradation: AchE and Butyryl-cholinesterase
butyrylcholinesterase
Butyrylcholinesterase
  • Role is minor in normal brain
  • Proportionate activity increases in Alzheimer brain
ache inhibitors progression
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
Galantamine (Reminyl)
  • Start at 4 mg BID (8 mg/day) for at least 4 weeks, then 8 mg bidAvailable in 4 mg, 8 mg, and 12 mg tabletsMost 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
Reminyl
  • Average approx. 4 pts on ADAS-Cog Scores
galantamine
Galantamine
  • Common snowdrop (Galanthus nivalis)
  • Binds AChE
  • Modulator of Nicotinic Receptors
  • ?Enhanced Sexual Fxn
  • Mythology
    • Iliad, Circe, Atropine, Jimsonweed
rivastigmine
Rivastigmine
  • ExelonApproved 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 functionReduced use of psychotropic medications
faster progression yields increased response
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 mild-stage 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]
rivastigmine1
Rivastigmine
  • Shown to improve: Global function, behavior, and Cognition
rivastigmine2
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
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
Rivastigmine: GI Effects
  • 18% Men, 26% Women at Max dose
rivastigmine3
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 hoursFew interactions with other drugsSide effects:No hepatotoxicityGI disturbances, occur mainly during dose adjustment. 
aricept donepezil
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
Aricept
  • Pharmacology: Half life: 72-hourSteady states are achieved in 15 days.94% protein-boundmetabolized 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
Behavior Problems

Personality change: apathetic or more impulsive

Anxiety:

apprehension over upcoming events

Aggression:

physical or verbal

behavior cont d1
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 dementia1
Agitation and Dementia
  • Structure and routine.
  • Follow regular, predictable routines. 
  • Keep things simple. 
  • Distract. 
behavior1
Behavior
  • Why is depression relatively uncommon??
  • Anosognosia for dementia
simple and active1
Simple and Active
  • Break down complex tasks into many small, simple steps that the person can handleFolding 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
distract1
Distract
  • Offer a snackPut on a favorite videotape or some familiar music Be flexible. Know when to back away from a task- a bath or dressing and reapproach laterSoothe. 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 anxiety1
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
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
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
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 cont1
Agitation (Cont)

Anxiolytics: for short term use, long term use may worsen cognitive functionLorazepam 0.5 - 2 mg

Buspar: Takes long to act.

Anticonvulsants: Use is common, but questionable. May ameliorate mood fluctuations, impulsivenessCarbamazepine 100 mg bid, titrateDepakene 125 mg bid, titrate

Beta blockers: ?behavioral outbursts

vit e selegiline
Vit E + Selegiline
  • Slow the progression of AD (Sano et al, 1997).
  • Rate of progression -25% less than the rate in placeboDose 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
pathogenesis1
Pathogenesis
  • Beta-Amyloid Accumuation
  • Decrease in Acetylcholine, AchE
  • Injury
  • Free-Radical Formation
  • Genetics
    • Polygenic
    • ApoE4
    • FAD
characteristic changes1
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 plaque1
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.
neurofibrillary tangle3
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.
beta amyloid1
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 strategies1
New Strategies
  • Beta-Amyloid Vaccine
  • Beta and Gamma Secretase Blockers
  • Zinc and Copper Chelators
evolving therapies
Evolving Therapies
  • Vaccine
  • Secretin inhibitors
  • Blocking Amyloid Accumulation
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