Keys to Care

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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
• 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

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Clock Drawing
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Life expectancy with Dementia

• 3.3 years, comparable to some malignancies
• In patients diagnosed with dementia
• Wolfson et al NEJM 20013441111-1116

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Alzheimer Brain Atrophy
From Whole Brain Atlas
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Neurodegenerative Diseases and Prions Stanley B.
Prusiner, M.D. Twenty-five years ago, little was
known about the causes of neurodegenerative
diseases.
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Stanley Prusiner Nobel 1997
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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

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Neurologic Diseases attributed to Protein
deposition

• Alzheimer disease Aß42
• Amyloid Angiopathy Aß42
• Huntington Disease Huntingtin
• Prion Disease PrP sc
• Tauopathies Picks, FT dementia, PSP
• Parkinson Disease, Lewy body Dementia (alpha
  synuclein)
• Spino-cerebellar Degenerations Ataxins
• ALS Neurofilament
• Macular Degeneration A2E

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Macular DegenerationAge 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 Alzheimers Disease

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Macular Degeneration
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Pathogenesis of Macular Degeneration
from Scientific American 10/2001
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First Hints to Causation

• Genetics
• Familial Alzheimer Disease
• Trisomy 21

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Alzheimer Genes Chromosome s

• 21 Abn APP Gene lt5
• 14 Presenilin 1 18-50
• 1 Presenilin 2
  lt1
• 19APOE-epsilon 4 Incr risk in Caucasions
• 19APOE-epsilon2 on Chr 19 decr risk
• of early-onset Disease

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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

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All have in Common

• Increased Accumulation of b Amyloid
• Abnormal Accumulation
• Defective Degradation

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Alzheimer Disease

• Cerebral Amyloidosis

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The Amyloid Hypothesis
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Pathogenesis

• Beta-Amyloid Accumulation
• Decrease in Acetylcholine, AchE
• Injury
• Free-Radical Formation
• Genetics
• Polygenic
• ApoE4
• FAD

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Characteristic Changes

• Pathology
• Tangles, plaques, Granulo-vacuolar degeneration,
  Atrophy,neuronal loss
• Biochemistry
• Decreased Ach, AchE
• Imaging
• Atrophy
• Decreased metab activity in postr cerebral
  association Cortices

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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.

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Amyloid Plaques

• Between Cells (extra-cellular)
• Appear before Tangles do
• Associated with Microglia (inflammation)
• (microglia are phagocytes of the brain)

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Amyloid Precursor Protein

• 695-770 Amino Acids
• Transmembrane protein
• Beta-Amyloid is snipped out precursor protein
• Beta-Amyloid- transmembrane component

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Cast of Characters

• Amyloid Precursor Protein (APP)
• Secretases alpha, beta, Gamma
• Enzymes that cut up Amyloid Precursor Protein
• Beta-Amyloid (or Aß42)
• Beta-Amyloid is the villain
• Setting The neuron cell membrane

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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 (Aß42)

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Presenilins

• Early Onset Alzheimer's
• Trans-membrane Protein Cleavers
• PreI Chr 14, PreIIChr 1
• Knockout for these proteins No Beta Amyloid
• Forms of Gamma-Secretase??

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Are Pre-Senilins forms of Secretase??
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Amyloid Plaque
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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

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Cutting ß-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

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Gamma Secretase a trans-membrane protease
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Beta Amyloid Mediated Damage

• Ca Deregulation
• Creation of Free Radicals
• Immune Aggregation

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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

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Mechanism of Amyloid destruction

• Liberating Calcium in Cells
• Damaging Mitochondria
• Enhancing inflammatory (Microglial) Response

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New Strategies

• Beta-Amyloid Vaccine
• Beta and Gamma Secretase Blockers
• Zinc and Copper Chelators

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Strategies to Prevent and treat Alzheimers

• 1. Inhibition of the proteases (enzymes) that
  produce Aß42 2. Inhibition of Aß42
  aggregation that precedes A deposition 3.
  Inhibition of Aß42 -induced neurotoxicity
• Vaccine or antibody to Aß42

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Dennis Selkoe Howard Weiner
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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

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Elan Pharmaceutical trial

• In PDAPP mouse (a genetically engineered mouse
  model with Alzheimers-like pathology)
• AN-1792, both reduces pre-existing deposits of
  amyloid and inhibits accumulation

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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

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Treatment Cornerstones

• Cholinesterase Inhibitors
• Ancillary Symptoms
• Anxiety
• Agitation
• Disorientation and Wandering
• Sleep Disturbance
• Placement
• Caring for Caretaker

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Other Pathology
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CSF in Alzheimers 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).

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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
  followingLoss 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 themstroke, 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.

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Granulo-vacuolar Degeneration
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Granulo-vacuolar degeneration

• 5 m clear intracytoplasmic vacuole
• Argyrophillic core
• Pyramidal cell region of hippocampus

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Neurofibrillary Tangles
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Neurofibrillary Tangles
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Neurofibrillary Tangle
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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

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Neurofibrillary Tangle

• Tau protein Assd with microtubules
• Correlates more with degree of dementia
• Appear after than Senile plaque
• Not Specific for Alzheimer Disease

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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.

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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 Medl School

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Causes of Dementia

• Alzheimer 55
• Vascular - 20
• Lewy Body 15
• Picks and lobar atrophy 5
• Other 5
• Small,GW et al JAMA 1997,2781363-71, APA, Am J
  Psychiatry 1997,154 (suppl)1-39
• Morris JC Clin GeriatrMed. 1994,10257-76

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Multi-infarct dementia
Whole brain Atlas
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Hachinski Score for Dx of Vascular Dementia

• Abrupt onset
• Stepwise deterioration  
• Fluctuating course improvement between
  strokes  
• Relative preservation of personality 
• Nocturnal confusion   
    
• Depression   

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Hachinski Score (contd)

• Somatic complaints
• Emotional incontinence
• History of hypertension
• Evidence of atherosclerosis
• Pvd, MI
  
• Focal Neurological symptoms (TIA)   Focal
  neurological signs

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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 Infarctsaphasia, agnosia,
  apraxia

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Behavior contd

• 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

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Agitation and Dementia

• Structure and routine.
• Follow regular, predictable routines. 
• Keep things simple. 
• Distract. 

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Behavior

• Why is depression relatively uncommon??
• Anosognosia for dementia

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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

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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. 

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Sleep and Anxiety

• Nonpharmacologic Daytime stimulation, adequate
  supervision, avoidance of napping.
• Neuroleptics may be helpful for delusion and
  agitation. 20 may get worse.

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Preventing Alzheimer Disease
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Alzheimers 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
  cost174000

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Alzheimers Burden (contd)

• 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

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Neurological Diseases

• Alzheimers 4 Million
  110 Bn
• Affective Disorders 17 Million 44Bn
• Drug etoh 15Million
  240Bn
• Intractable Pain
  65 Bn
• Parkinsons 500,000
  5.6Bn
• Schizophrenia 2 Million
  30Bn
• Stroke 700,000/yr
  30Bn
• MS 350,000
• SourceJAMA 285594(2001)

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Neurological Disease(Prevalence)

• Alzheimer Disease 4 million
• Stroke 3-4 Million
• Traumatic Brain Inj 2.5-3.7 Million
• Epilepsy 1.75 Million
• Parkinsons 1.5 Million
  

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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

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Risks

• Advanced Age
• Half of those gt85 1/10 of those gt65
• Female Sex
• Mild Cognitive Impairment
• Head Injury
• APOE4
• Family History
• Low Education
• Downs
• ?Race
• ?Homocysteine?

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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

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Estrogen

• 3 studies in Neurology 200054 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 1996348429-432
• Jury Still Out
• Prospective treatment trials

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Estrogen Reviews

• NEJM 3441242-1244 April 19, 2001 Number 16
  Richard Mayeux
• Neurology 2000542035-2037 Marder and Sano

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Womens 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.

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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
• RR1.6 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 346476-483 February
  14, 2002

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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
  3451515-1521, Nov 22, 2001

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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 199748626-632

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Alzheimer Genes

• 21 Abn APP Gene
• 14 Presenilin 1
• 1 Presenilin 2
• 19APOE-epsilon 4 Incr risk in Caucasions
• 19APOE-epsilon2 on Chr 19 decr risk

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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 ADLs, Incontinent

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Ongoing Studies From May 16, 2002 ELEENA DE
LISSER, The Wall Street Journal
PATHWAYS TO PREVENTION?
Ongoing clinical trials related to
Alzheimeraposs disease and possible modes of
prevention
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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

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Prevent AD with Estrogen

• National Institute on Aging
• Mary Sano, PhD
• 5 year study

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Strategies

• Vitamin E and Selegeline or donepezil
• Estrogens
• NSAIDs
• B12,B6,Folate (homocysteine)
• Statins
• Valproate ?Neuroprotective
• IPA (Indole-3-Propionic Acid) anti-oxidant

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Homocysteine

• Does this mean that lowering H. levels will
  prevent As Disease?
• No one knows

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Homocysteine

• 50 Mg pyridoxine
• Up to 4 mg. of Folate
• 500 mcg of B12

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NSAIDs

• Inflammation is part of Aß Accumulation
• Longitudinal Studies show dose related effect of
  NSAIDs
• Nature Nov. 8, 2001 NSAIDs directly decrease
  deposition of Aß42
• ASA,Celebrex, Naprosyn no effect
• Others at very high doses decreased production in
  cells up to 80

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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 19973361216-1222

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Gingko Biloba

• 1 year
• 120 mg.
• 2.4 decrease in Alzheimers disease Assessment
  scale Cognitive subscale
• Very little other evidence
• Le Bars PL et al.JAMA 19972781327-1332

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Alzheimer Disease

• Dissolution of the Personality
• Inexorable Progression

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Keys of Therapy

• Early Recognition of Disease
• Cholinesterase Blockers
• Treatment of Ancillary Symptoms
• Maintaining Patient in own Environment
• Family Support

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Diagnosis

• Index of Suspicion
• Age!
• Sensitivity to Patients and Family

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Vigilance

• Now Important because there are now early
  treatments that help.

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10 Warning Signs

• Dysfunction on Job
• Problem with Language function
• Difficulty performing Familiar Tasks
• Disorientation
• Poor Judgment
• Altered Abstract thinking

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More Signs

• Misplacing Objects
• Personality Change
• Altered Mood and Behavior
• Loss of initiative

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Diagnostic Criteria for Dementia

• Multiple Cognitive Deficits with Both
• Memory Impairment plus one or more of follg
• Aphasia, Apraxia, Agnosia, Executive function
• Impaired abstraction, judgement
• Impaired Social or Occupational Function
• DSM IV (1994), 133-35

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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

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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!!

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Alzheimer Dementia

• Often anosognosia unawareness of problem on
  part of sufferer
• Also denial

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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

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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

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Pseudo-Dementia

• Associated with severe depression
• Lack of reactivity psychomotor retardation
• More abrupt onset
• Some old folks have combined organic dementia and
  severe depression

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MCI

• 6-25 progress to Alzheimers disease per year.

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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 ADLs

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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 ADLs

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Evaluation

• Thorough Hx/Pex
• Mental Function Evaluation
• CBC, Chems, RPR, LFTs,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??

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Evaluation compare betw visits

• Folstein Mini-Mental Status
• Clock-drawing
• Scale of level of Function as reported by family
  member
• Language function

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Rule Out

• Alcohol
• Depression
• Drug s
• Metabolic Derangement
• Nutritional Deficiencies
• Infection

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Causes of Dementia

• Alzheimer 55
• Vascular - 20
• Lewy Body 15
• Picks and lobar atrophy 5
• Other 5
• Small,GW et al JAMA 1997,2781363-71, APA, Am J
  Psychiatry 1997,154 (suppl)1-39
• Morris JC Clin GeriatrMed. 1994,10257-76

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Hachinski Score for Dx of Vascular Dementia

• Abrupt onset
• Stepwise deterioration  
• Fluctuating course improvement between
  strokes  
• Relative preservation of personality 
• Nocturnal confusion   
    
• Depression   

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Hachinski Score (contd)

• Somatic complaints
• Emotional incontinence
• History of hypertension
• Evidence of atherosclerosis
• Pvd, MI
  
• Focal Neurological symptoms (TIA)   Focal
  neurological signs

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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 Infarctsaphasia, agnosia,
  apraxia

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Picks 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

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Picks

• Fronto-temporal atrophy on imaging or SPECT or
  PET scans show decr metabolism
• Tau opathy
• Grouped with PSP etc
• May be familial

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Others

• Creutzfeldt-Jakob
• Cortico-Basal Degen
• Progressive Supranuclear Palsy
• Frontal Lobe Dementia

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Parkinson Related Dementia

• Late consequence of Parkinson Disease
• Hallucination prominent
• Dopaminergic Meds, anticholinergics are
  hallucinogenic
• Parkinson and age related perceptual changes

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Parkinsons and Dementia

• Diffuse Lewy Body Disease
• Alzheimer changes in the aged
• Parkinson-dementia complex
• Parkinson related diseases
• Anti-esterases seem effective here too

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Treatment Cornerstones

• Cholinesterase Inhibitors
• Ancillary Symptoms
• Anxiety
• Agitation
• Disorientation and Wandering
• Sleep Disturbance
• Placement
• Caring for Caretaker

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Cholinergic hypothesis

• Diffusely projecting area Nucleus Basalis of
  Meynert
• Layers I and II major cholinergic cortical
  innervation
• Amygdala and hippocampus lgest innervation

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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.

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AChEs Contd

• 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. 

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Alzheimer Manifestations
Activity of Daily Living
Behavior
Cognitive Dysfunction
All aided by Anti-esterases
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Cholinesterase Blockers
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Cholinesterase blockers
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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

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Acetylcholine

• Formation ChAT and Acetyl-CoA
• Degradation AchE and Butyryl-cholinesterase

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Butyrylcholinesterase

• Role is minor in normal brain
• Proportionate activity increases in Alzheimer
  brain

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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

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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).

139
Reminyl

• Average approx. 4 pts on ADAS-Cog Scores

140
Galantamine

• Common snowdrop (Galanthus nivalis)
• Binds AChE
• Modulator of Nicotinic Receptors
• ?Enhanced Sexual Fxn
• Mythology
• Iliad, Circe, Atropine, Jimsonweed

141
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

142
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

143
Rivastigmine

• Shown to improve Global function, behavior, and
  Cognition

144
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.

145
Alzheimer Scales

• CIBIC-Plus 1-7
• Clinicians interview-based impression of change
  with caregiver input
• 1marked improvement, 4nc, 7marked worsening
• ADAS-Cog0-70
• Higher scoresgreater cognitive impairment
• Mild to moderate15-25
• 6-12 points/yr average deterioration

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Rivastigmine GI Effects

• 18 Men, 26 Women at Max dose

147
ADAS-Cog Effects
148
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. 

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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

151
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.

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153
Behavior Problems

• Personality change apathetic or more impulsive
• Anxiety
• apprehension over upcoming events
• Aggression
• physical or verbal

154
Behavior contd

• 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

155
Agitation and Dementia

• Structure and routine.
• Follow regular, predictable routines. 
• Keep things simple. 
• Distract. 

156
Behavior

• Why is depression relatively uncommon??
• Anosognosia for dementia

157
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

158
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. 

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Sleep and Anxiety

• Nonpharmacologic Daytime stimulation, adequate
  supervision, avoidance of napping.
• Neuroleptics may be helpful for delusion and
  agitation. 20 may get worse.

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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)

161
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

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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

163
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

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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

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Time course in deterioration
166
Pathogenesis

• Beta-Amyloid Accumuation
• Decrease in Acetylcholine, AchE
• Injury
• Free-Radical Formation
• Genetics
• Polygenic
• ApoE4
• FAD

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Characteristic Changes

• Pathology
• Tangles, plaques, Hirano bodies, Atrophy,neuronal
  loss
• Biochemistry
• Decreased Ach, AchE
• Imaging
• Atrophy
• Decreased metab activity in postr cerebral
  associaation Corices

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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.

169
Amyloid
170
Amyloid Plaque
171
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.

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Neurofibrillary Tangles
173
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

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New Strategies

• Beta-Amyloid Vaccine
• Beta and Gamma Secretase Blockers
• Zinc and Copper Chelators

175
Evolving Therapies

• Vaccine
• Secretin inhibitors
• Blocking Amyloid Accumulation