A1259875835BowbP - PowerPoint PPT Presentation

Title: A1259875835BowbP


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The Age-Specific Prevalence of Dementia in Taiwan
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Dementia Definition

• Multiple Cognitive Deficits
• Memory dysfunction
• especially new learning, a prominent early
  symptom
• At least one additional cognitive deficit
• aphasia, apraxia, agnosia, or executive
  dysfunction
• Cognitive Disturbances
• Sufficiently severe to cause impairment of
  occupational or social functioning and
• Must represent a decline from a previous level of
  functioning

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DIAGNOSTIC CRITERIA FOR DEMENTIA OF THE
ALZHEIMER TYPE(DSM-IV, APA, 1994)
A. DEVELOPMENT OF MULTIPLE COGNITIVE
DEFICITS 1. MEMORY IMPAIRMENT 2, OTHER
COGNITIVE IMPAIRMENT B. THESE IMPAIRMENTS
CAUSE DYSFUNCTION IN IN SOCIAL OR
OCCUPATIONAL ACTIVITIES C. COURSE SHOWS
GRADUAL ONSET AND DECLINE D. DEFICITS ARE
NOT DUE TO 1. OTHER CNS
CONDITIONS 2. SUBSTANCE INDUCED CONDITIONS
F. DO NOT OCCUR EXCLUSIVELY DURING
DELIRIUM G. ARE NOT DUE TO OTHER
PSYCHIATRIC DISORDER
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AD risk and protective factors

• Risk factors
• Age
• Family History of AD
• (ApoE-4)
• Head trauma
• Low educational level
• Downs syndrome
• Small brain volume
• Vascular disease
• high homocysteine

• Protective factors
• Genetic (ApoE-2)
• High educational level
• Long-term anti-
• inflammatory drug use
• Long-term use of
• estrogens (in women)
• Statin
• Low fat diet

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Proposed Causes for AlzheimersDisease

• Hereditary
• Vascular problems
• Infectious agents
• Toxic exposures
• Inflammatory response

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Alzheimer Genes

• 21 Abnormal APP Gene
• 14 Presenilin 1 (PS1)
• 1 Presenilin 2 (PS2)
• 19APOE-epsilon 4 Incr risk
• 19APOE-epsilon2 on Chr 19 decr risk

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Genes and Alzheimers disease
(all known genes relate to bamyloid)

• Familial AD (onset lt 60 y/o) (lt5)
• Presenilin I, II (ch 14, 1)
• APP (ch 21)
• Non-familial (late onset)
• APOE
• Clinical studies suggest 40 50 due to e4
• If e2 is considered, may be 95 of causation
• Population studies suggest 10 20 cause
• Evolution over last 300,000 to 200,000 years
• At least 20 other genes

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Genetics of AD
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PS1 PS2

• PS 1 (and likely PS 2) is the g-secretase (Vassar
  and Citron, Neuron 27, 419422, 2000)
• Role of presenilins-alterations in cellular
  calcium metabolism (Yoo et al., Neuron 27,
  561572, 2000)

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APP

• APP is the precursor for amyloid peptides
  produced by the action of a-, b-, and
  g-secretases.
• The cleavage of partially processed APP (the
  b-secretase product) by g-secretase normally
  yields a 40 amino acid peptide termed Ab.

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APP in AD

• Missense mutations in APP
• Yielding a 42 amino acid product
• Ab1-42, or ab42
• Much more adhesive than Ab
• Amyloid plaques

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Amyloid Precursor Protein
g49
g40
b1
a
Bace2
g42
b11

Bace2
670
693
709
724





KM DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVI
TLVMLKKK
V
1
11
16
40
42
19
21
22
A I
T
Q G
E
M
V
L
P
I
L
V
F
KM
NL
A
G
G
I
V
b-secretase
a-secretase
g-secretase
Flemish
Swedish
Australian
London
French
Florida
Austrian-Iranian
Dutch-Italian-Arctic
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Statin and AD

• Controversial
• Case-controlled study lower risk for AD
• Prospective cohort study not confirmed
• 2 randomized treatment trial (simvastatin,
  pravastatin)-no benefit
• Surrogate marker of good health?

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Inflammation and AD

• Activated microglia and inflammatory protein are
  found in AD brain
• Elevated plasma levels of the inflammatory
  proteinsa1-antichymotrypsin, interleukin-6 and
  CRP
• Some NSAID shift the cleavage product of APP to
  less fibrillogenic forms of the amyloidogenic
  peptide Aß
• Almost all clinical trials of NSAID in AD-null
  findings

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CSF constituents that are altered in AD

• Tau
• Aß
• Isoprostanes-putative markers of lipid
  peroxidation and oxidative damage in the brain
• Sulfatide-a prominent component of cerebral white
  matter

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Neuropathology of AD

• Senile plaques
• beta-amyloid protein (? Primary problem)
• Neurofibrillary tangles
• hyper-phosphorylated tau (loss of synapses,
  dementia)
• Neurotransmitter losses
• Acetylcholine (Ach) major loss of nicotinic
  receptors
• Norepinephrine, serotonin, glutamate, GABAss
• Inflammatory responses

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Dementias Are Proteinopathies
Principal Protein Disease
Alpha-synuclein protein Parkinson's disease and dementia with Lewy bodies
Tau protein Frontotemporal dementias and related conditions
Amyloid beta protein Alzheimers disease
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Alzheimers Disease is aTriple Proteinopathy

• Aßpeptide
• Tau
• a-synuclein

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a- synuclein is the main component of Lewy body
HE stain
immunoperoxidase stain for ubiquitin
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Synucleinopathy

• Parkinson disease
• Dementia with Lewy bodies
• Multiple system atrophy
• Hallervorden-Spatz syndrome (neurodegeneration
  with iron accumulation type 1)

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a-synuclein in AD

• a-Synuclein immunostaining is common in senile
  plaques
• a-synuclein deposits are found in the amygdala

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Neurofibrillary Tangles

• On H and E, the neuron contains a basophilic
  filamentous condensation and thickening along the
  edge of the cell body - extending up into the
  apical dendrite.

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Neurofibrillary Tangles

• These filaments within the neuron are well seen
  on Bielschowsky (silver) stain where they often
  assume a "flame" shape.
• These filaments represent hyperphosphorylated
  tau, a microtubule associated protein.

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Preferential Regional Involvement by
Neurofibrillary Tangles

• limbiclimbic and limbiccortical
  connections including
• neurons of layers II and IV of the entorhinal
  cortex
• perirhinal cortex
• subiculum of the hippocampus
• inferior temporal gyrus
• Amygdala
• posterior hippocampal gyri
• cholinergic basal forebrain
• dorsal raphe of the brainstem

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Tauopathy

• selective involvement of neurons in frontal and
  temporal cortex and frontal-subcortical systems
• tau is a microtubule associated protein that is
  involved in microtubular assembly and
  stabilization
• Tau function depends on its phosphorylation state
• hyperphosphorylated tau is less effective in
  microtubular polymerization, leading to failure
  of normal transport of vesicles and cell
  organelles and aberrant assembly of tau filaments
  to form tau-positive inclusions.

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Tauopathies

• Frontotemporal lobar degeneration
• progressive supranuclear palsy
• corticobasal degeneration

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Plaque and Tangles
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Amyloid precursor protein
there are 150 different mutations in presenilin
and APP, and they all lead to the same common
culprit, A-beta 42. A-beta 42 is a peptide that
has 2 extra amino acids on the end making it
extra prone to amyloid formulation and extra
toxic to nerve cells.
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Amyloid Processing in AD
Gamma-secretase
Cell membrane
Beta-secretase
Amyloid precursor protein (APP)
Beta- amyloid
Neuritic plaque
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Beta-Amyloid Deposition

• ?-amyloid may be slowly deposited throughout
  life.
• Necessary, but not sufficient to cause AD
• Interacts with endothelium
• May interact with cholinergic system
• May have an immune effect
• May accelerate aging

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Preferential Regional Involvement by Amyloid
Plaques

• Hippocampal formation
• entorhinal cortex of the parahippocampal gyrus
• the amygdala
• olfactory bulb
• layers II and II of the neocortex regions

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Synapes and Dementia

1. Synapse loss causes dementia, not plaques!
   Cholinergic loss is a major contributor
   especially re memory.
2. Hyperphosphorylation of Tau (even when not
   polymerized as PHF) causes instability of
   microtubules, so axoplasmic transport is reduced
   resulting in loss of synapses.
3. Most of the shrunken neurons in normal aging and
   most of the lost neurons in AD are glutamatergic.
4. Microglia are activated throughout the cortex,
   perhaps in response to degeneration of synapses,
   which is also diffuse.
5. Synapse loss can cause neuron loss because
   trophic factors get to perikaryon via the synapse
   and retrograde through the axon.

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Causes of Dementia
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Other Dementias

• Infections Creutzfeldt-Jakob Disease
  sporadicfamilialiatrogenic vCJD HIV (Aids
  Dementia Complex) Syphillis
• Genetics Picks Disease Huntingtons Disease
• Pseudo-dementia (depression)
• Treatable causes of dementia-like conditions
  deficiences in diet, intoxications,raised
  intra-cranial pressure

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Differentiating Normal Agingfrom Dementia

• Normal cognitive changes
• Age-associated memory impairment (AAMI)
• Age-related cognitive decline
• Slowing in speed of thought processing
• Slight decline in memory
• Slight decline in ability to manage multiple
  tasks simultaneously

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Differentiating Normal Agingfrom Dementia

• Mild cognitive impairment (MCI)
• Transitional phase between normal cognition and
  dementia
• Memory complaint
• Normal ADLs
• Normal cognitive function
• Abnormal memory for age

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Mild cognitive impairment (MCI)

• Annual conversion rate of 10-15 vs. 1-2 for
  non-demented elderly aged 80 years or less
• Amnestic MCI, single domain
• Amnestic MCI, multiple domain
• Non-amnestic MCI, single domain
• Non-amnestic MCI, multiple domain

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MCI CRITERIA (Amer. Acad. Neurology)(Petersen
et al., 2001 Neurology 561133)

• Memory complaint, preferably corroborated by an
  informant
• Objective memory impairment
• Normal general cognitive function
• Intact activities of daily living
• Not demented
• - Earlier descriptions by
• Jonker, Hooyer, 1990
• Flicker, Ferris, Reisberg, 1991
• Zaudig, 1992

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Assessment

• History Of The Development Of The Dementia
• Ask the Patient What Problem Has Brought Him to
  See You
• Ask the Family, Companion about the Problem
• Specifically Ask about Memory Problems
• Ask about the First Symptoms
• Enquire about Time of Onset
• Ask about Any Unusual Events Around the Time of
  Onset, e.g., stress, trauma, surgery
• Ask about Nature and Rate of Progression
• Physical Examination
• Neurological Examination
• Laboratory Tests
• Neuropsychological / Cognitive Assessment

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Laboratory Evaluation

• Rule out toxic, metabolic, infectious
• dementias
• CBC, lytes, calcium, glucose, renal
• function, liver function, B12 , TSH,
• serologic test for syphilis
• CT or MRI (consider stage)

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Hierarchical topography of neuronal involvement
and loss in AD

• Entorhinal cortex and hippocampus
• Neocortex with preferential involvement of higher
  order association cortex
• High resolution MRI-gray matter loss in the
  cingulate gyrus and in posterior cortical area
• MRS-a decrease of NAA in the posterior cingulate
  gyrus
• PET-hypometabolism in temporoparietal lobes

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Baark staging of AD pathology

• medial pole of the temporal lobe, affecting most
  severely the entorhinal cortex and hippocampus.
• other cortical regions, esp. in high-order
  association regions
• cerebral cortex

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PET in the Evaluation of Dementia

• 284 dementia patients(138 autopsy-confirmed
  diagnosis)
• Sensitivity 93 specificity 76
• Negative PET scan indicated chance of cognitive
  progression lt20 over 3 years

Silverman DH, Small GW, Chang CY, et al. JAMA.
2001 Nov 7286(17)2120-2127
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Common Clinical Features of AD
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Common Clinical Features of AD
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Stages of AD
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Noncognitive Symptoms

• Delusions and Hallucinations
• About one third of AD
• Delusions often paranoia
• Hallucinations often visual
• Depressive symptoms
• Up to 40 of AD
• May be first presenting symptom
• May cause acceleration if not treated

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Noncognitive Symptoms

• Agitation or Aggression
• Up to 80
• Leading cause of NH admission
• Consider delirium or pain as trigger
• Anxiety
• Sleep/wake disturbance
• Disinhibition
• Sundowning

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The Prevalence of Neuropsychiatric Symptoms of
Alzheimers Disease among Chinese and American
Patients
Abe.Motor
Agitation
Anxiety
Apathy
Appetite
Delusion
Depression
Disinhibation
Euphoria
Hallucination
Irritability
Sleep
Chow et.al. Int J Geriatr Psychiatry 2002
1722-28
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Ann Neurol 200354147154
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Cholinesterase Inhibitors
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Memantine

• Symptomatic treatment of moderate to severe AD
• Inhibit cytotoxic overstimulation of
  glutamatergic neuron

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Memantine

• NMDA-receptor antagonist
• Protect against the effects of glutamate and
  calcium mediated neurotoxicity
• First drug for moderate to severe AD
• Can be used in combination with any of the
  anticholinergics

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Memantine

• Dosing
• 5 mg /day for 1 week
• Increase to 10 mg/day for 1 week
• 15-20 mg/day in third week
• Indications for vascular and alcohol dementia
• New treatment for those beyond the mild-moderate
  stage

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Agitation Treatment Guidelines

• Use nonpharmacologic approaches first
• Look for underlying source of agitation
  (infection, pain, constipation)
• Agitation in nonacute psychosis (Risperdol
  0.5-1.0 mg Zyprexa 2.5 mg)
• Agitation in context of depression (SSRI)

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Alzheimers Disease