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Motor Disease Alzheimer Disease

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Title: Motor Disease Alzheimer Disease


1
Motor DiseaseAlzheimer Disease
  • Charles S. Yanofsky MD
  • Susquehanna Physician Svcs
  • www. Susqneuro.com

2
Motor System Disese Alzheimer Disease
Charles S. Yanofsky, MD Susquehanna Health
Systems www.susqneuro.com
3
Motor Exam
  • Power
  • Tone
  • Flaccid
  • Spastic
  • Rigid
  • Bulk (atrophy)
  • Fatigue (myasthenia gravis)

4
Lower Motor Neuron
  • The nerve that goes to muscles is sick
  • Flaccidity
  • Atrophy
  • Fasciculations
  • Decreased reflexes
  • Loss of muscle mass and power

5
Atrophy
6
Lower Motor neuron Diseases
  • Nerve Injuries
  • ALS
  • Polio
  • ICU neuromyopathy
  • West Nile
  • Guillian Barre

7
Upper Motor Neuron
  • Cortico-spinal tract disease
  • The nerve that goes to the nerve that goes to
    muscle is sick
  • Spasticity (resistance to movt)
  • Increased reflexes
  • Little atrophy
  • Babinisky sign

8
Disease of Upper Motor Neuron
  • Stroke
  • ALS
  • Multiple sclerosis
  • Brain tumor

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12
Homunculus
13
Spasticity
  • Increased resistance to passive motion
  • Typically flexion or extension around a joint not
    both
  • Changes throughout excursion
  • Clasp Knife
  • Flexed in upper extremities
  • Extensor tone in lowers.
  • Increased deep tendon reflexes
  • Upgoing toes (Babinsky)
  • Cortico-spinal tract

14
Rigidity
  • Increased resistance to motion
  • Doesnt change through excursion
  • Cogwheel
  • No increased reflex or upgoing toe.
  • Slowness of motion
  • Refers to Basal Ganglia

15
Grading Strength
  • 5 full power
  • 4 - Gravity resistance but still weak
  • 3 - Barely against gravity
  • 2 - Moves limb but not against gravity
  • 1 - Flicker

16
Pronator Drift
17
UE Muscle Testing
18
LE Muscle Testing
19
Deep Tendon Reflexes
  • 4 Clonus
  • 3 Hyperactive
  • Crossed Adductor
  • Hoffman
  • Radiation of Reflexes
  • 2 Normal
  • 1 Inactive

20
Deep Tendon Reflexes -Findings
  • Hyperactive spacticity
  • Hypoactive Peripheral Neuropathy
  • Reflex Loss Nerve or root disease
  • Increased in LE spinal Cord
  • Increased on one side Stroke
  • Babinski sign Spasticity

21
Frontal Release Signs
  • Grasp
  • Snout
  • Suck
  • Root
  • Glabellar
  • Palmomental
  • Liberation from frontal inhibition

22
Motor systems
  • Pyramidal
  • Cortico-spinal tract
  • Extra-pyramidal
  • Basal ganglia
  • Cerebellum

23
Cerebellum
  • Big movement and balance Computer
  • The Hemispheres control the hands and speech
  • Midline controls Gait
  • Ataxia, nystagmus, wide based gait, dysarthria,
    intention tremor are words we connect with the
    cerebellum

24
Cerebellar Affections
  • Toxins
  • Alcohol, Mercury, sedatives
  • Vascular Strokes, hypoxia
  • Degenerations Many types
  • OPCA, Creutzfeldt-Jakob,
  • Inherited diseases Freidreichs Co
  • Demyelinations
  • Infections cerebellitis
  • Malignancy remote effect and metastatic, tumors
  • Endocrine Thyroid

25
Cerebellar Testing
  • Finger to nose
  • Heel-Knee-Shin
  • Fine movements
  • Handwriting
  • Rapid alternating movement dysdiadichokinesis
  • Wide based gait
  • Trunkal Titubation
  • Dysarthria
  • nystagmus

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28
Parkinson Tetrad
  • Tremor
  • Bradykindesia
  • Rigidity
  • Postural Instability

29
Tremor
  • Rhythmic alternating contraction of Agonist and
    antagonist

30
Parkinson Tremor
  • Rest tremor
  • Decreased with movement
  • Not present in sleep
  • Slow 5-7 Hz
  • High Amplitude
  • Typical Pronation-Supination
  • Pill rolling

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36
Tremors
37
Tremor in A. Spiral
38
Basal Ganglia
  • Striatum
  • Putamen
  • Caudate
  • Globus Pallidus
  • Subthalamic nucleus
  • Substantia nigra

39
Basal ganglia
  • Rigidity
  • resistance increased in agonist and antagonist
    throughout whole excursion
  • Tremor
  • Rest, Action, Sustension, Intention. Rhythmic
    alternate spont. contraction of agonist
  • Chorea Dancing movement
  • Dystonia and toritcollis
  • Myoclonus random rapid contraction
  • Brady/akinesia

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41
Basal Ganglia
42
Basal Ganglia
43
Treatment of PD
  • Increase Dopamine
  • Block Acetylcholine (Ach)
  • Tweaking

44
Parkinson Medicines
  • Sinemet Carbidopa/L-Dopa
  • Dopamine Agonists
  • Mirapex (pramipexole), Requip ( ropinerole)
  • Eldepryl (selegilene)
  • Comtan (entacapone)
  • Stalveo (L-DOPA, carbidopa, entacapone)
  • Deep brain Stimulation

45
Deep Brain Stimulation
46
Genetics
  • Alpha Synuclein accumulation
  • Aharon-Peretz et al NEJM mutations in
    glucocerebrosidase (Gaucher heterozygotes) and PD

47
Gait
  • Hemiparetic
  • Ataxic (lurching) etoh and Cbllm
  • Spastic (scissors) spinal cord
  • Elderly
  • Parkinsonian (festinating, shuffling, stooped)
  • Frontal Lobe
  • Steppage, slapping peripheral nerve
  • Choreic
  • Veering vestibular
  • Multi-sensory deficit
  • Astasia-Abasia fashion model, hysterical

48
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49
Cholinergic Hypothesis
  • Diffusely projecting area Nucleus Basalis of
    Meynert
  • Layers I and II major cholinergic cortical
    innervation
  • Amygdala and hippocampus lgest innervation

50
Acetylcholine
  • Correlation with Dementia and markers of ACh
    metabolism
  • CAT choline acetyl transferase
  • AChE acetylcholinesterase (breaks down ACh)

51
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52
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

53
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?

54
Alzheimer Disease
  • Dissolution of the Personality
  • Inexorable Progression

55
Keys of Therapy
  • Early Recognition of Disease
  • Cholinesterase Blockers
  • Treatment of Ancillary Symptoms
  • Maintaining Patient in own Environment
  • Family Support

56
Diagnosis
  • Index of Suspicion
  • Age!
  • Sensitivity to Patients and Family

57
10 Warning Signs
  • Dysfunction on Job
  • Problem with Language function
  • Difficulty performing Familiar Tasks
  • Disorientation
  • Poor Judgment
  • Altered Abstract thinking

58
More Signs
  • Misplacing Objects
  • Personality Change
  • Altered Mood and Behavior
  • Loss of initiative

59
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

60
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

61
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!!

62
Alzheimer Dementia
  • Often anosognosia unawareness of problem on
    part of sufferer
  • Also denial

63
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

64
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

65
Pseudo-Dementia
  • Associated with severe depression
  • Lack of reactivity psychomotor retardation
  • More abrupt onset
  • Some old folks have combined organic dementia and
    severe depression

66
MCI
  • 6-25 progress to Alzheimers disease per year.

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68
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

69
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

70
Late Stage
  • Weight loss
  • Seizures, skin infections, difficulty swallowing
  • Groaning, moaning, or grunting
  • Increased sleeping
  • Lack of bladder and bowel control

71
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??

72
Evaluation compare betw visits
  • Folstein Mini-Mental Status
  • Clock-drawing
  • Scale of level of Function as reported by family
    member
  • Language function

73
Rule Out
  • Alcohol
  • Depression
  • Drug s
  • Metabolic Derangement
  • Nutritional Deficiencies
  • Infection

74
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

75
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

76
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

77
Picks
  • Fronto-temporal atrophy on imaging or SPECT or
    PET scans show decr metabolism
  • Tau opathy
  • Grouped with PSP etc
  • May be familial

78
UCSF. edu Web site
Fronto-Temporal Dementia MRI
79
Others
  • Creutzfeldt-Jakob
  • Cortico-Basal Degen
  • Progressive Supranuclear Palsy
  • Frontal Lobe Dementia

80
Parkinson Related Dementia
  • Late consequence of Parkinson Disease
  • Hallucination prominent
  • Dopaminergic Meds, anticholinergics are
    hallucinogenic
  • Parkinson and age related perceptual changes

81
Parkinsons and Dementia
  • Diffuse Lewy Body Disease
  • Alzheimer changes in the aged
  • Parkinson-dementia complex
  • Parkinson related diseases
  • Anti-esterases seem effective here too

82
Treatment Cornerstones
  • Cholinesterase Inhibitors
  • Ancillary Symptoms
  • Anxiety
  • Agitation
  • Disorientation and Wandering
  • Sleep Disturbance
  • Placement
  • Caring for Caretaker

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

85
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

86
Agitation and Dementia
  • Structure and routine.
  • Follow regular, predictable routines. 
  • Keep things simple. 
  • Distract. 

87
Behavior
  • Why is depression relatively uncommon??
  • Anosognosia for dementia

88
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

89
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.

90
Amyloid
91
Amyloid Plaque
92
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.

93
Neurofibrillary Tangles
94
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

95
Alzheimer Manifestations
Activity of Daily Living
Behavior
Cognitive Dysfunction
All aided by Anti-esterases
96
Anti-esterases
97
Cholinesterase Blockers
98
Acetylcholine
  • Formation ChAT and Acetyl-CoA
  • Degradation AchE and Butyryl-cholinesterase

99
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

100
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).

101
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

102
Rivastigmine
  • Shown to improve Global function, behavior, and
    Cognition

103
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.

104
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

105
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.

106
Upshot
  • Many of the same anathemas as in Atherosclerosis
    (stroke)
  • B vitamins, vitamin E, NSAIDs, Ginkgo,
    Cholinesterase blockers.

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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

111
Clock Drawing
112
Alzheimer Brain Atrophy
From Whole Brain Atlas
113
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

114
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

115
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

116
Macular Degeneration
117
Pathogenesis of Macular Degeneration
from Scientific American 10/2001
118
First Hints to Causation
  • Genetics
  • Familial Alzheimer Disease
  • Trisomy 21

119
Delirium
  • Delirium or acute confusional state is a
    transient global disorder ofcognition. The
    condition is a medical emergency associated with
    increasedmorbidity and mortality rates. Early
    diagnosis and resolution of symptoms
    arecorrelated with the most favorable
    outcomes.Delirium is not a disease but a
    syndrome with multiple causes that result in
    asimilar constellation of symptoms. Delirium is
    defined as a transient, usuallyreversible, cause
    of cerebral dysfunction and manifests clinically
    with a widerange of neuropsychiatric
    abnormalities. The clinical hallmarks are
    decreasedattention span and a waxing and waning
    type of confusion.

120
Causes of Delirium The usual suspects
  • Metabolic e.g. hyponatremia
  • Infectious e.g. meningitis, other infection
  • Intoxication e.g. cocaine, stimulants
  • Endocrine hypothyroidism, hypoglycemia
  • Post ictal
  • Mass lesion
  • Drug withdrawal
  • Advanced age Cerebral reserve
  • Psychiatric Mania

121
Workup for Delirium
  • Thorough history and exam
  • Complete metabolic screen
  • Drug screen
  • Blood gas
  • CT scan
  • EEG
  • LP if meningismus or FUO

122
EEG in Delirium
  • Is it normal or not? If normal consider
    psychiatric cause, or chronic dementia
  • Generalized slowing encephalopathy
  • Certain specific abnormalities
  • Seizure activity
  • Periodic Lateralized Epileptiform Discharges
  • Periodic discharges

123
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

124
All have in Common
  • Increased Accumulation of b Amyloid
  • Abnormal Accumulation
  • Defective Degradation

125
Alzheimer Disease
  • Cerebral Amyloidosis

126
The Amyloid Hypothesis
127
Pathogenesis
  • Beta-Amyloid Accumulation
  • Decrease in Acetylcholine, AchE
  • Injury
  • Free-Radical Formation
  • Genetics
  • Polygenic
  • ApoE4
  • FAD

128
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

129
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.

130
Amyloid Plaques
  • Between Cells (extra-cellular)
  • Appear before Tangles do
  • Associated with Microglia (inflammation)
  • (microglia are phagocytes of the brain)

131
Amyloid Precursor Protein
  • 695-770 Amino Acids
  • Transmembrane protein
  • Beta-Amyloid is snipped out precursor protein
  • Beta-Amyloid- transmembrane component

132
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

133
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)

134
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??

135
Are Pre-Senilins forms of Secretase??
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137
Amyloid Plaque
138
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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140
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

141
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142
Gamma Secretase a trans-membrane protease
143
Beta Amyloid Mediated Damage
  • Ca Deregulation
  • Creation of Free Radicals
  • Immune Aggregation

144
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

145
Mechanism of Amyloid destruction
  • Liberating Calcium in Cells
  • Damaging Mitochondria
  • Enhancing inflammatory (Microglial) Response

146
New Strategies
  • Beta-Amyloid Vaccine
  • Beta and Gamma Secretase Blockers
  • Zinc and Copper Chelators

147
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

148
Dennis Selkoe Howard Weiner
149
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

150
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

151
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

152
Treatment Cornerstones
  • Cholinesterase Inhibitors
  • Ancillary Symptoms
  • Anxiety
  • Agitation
  • Disorientation and Wandering
  • Sleep Disturbance
  • Placement
  • Caring for Caretaker
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