Motor Disease Alzheimer Disease

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Motor DiseaseAlzheimer Disease

• Charles S. Yanofsky MD
• Susquehanna Physician Svcs
• www. Susqneuro.com

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Motor System Disese Alzheimer Disease
Charles S. Yanofsky, MD Susquehanna Health
Systems www.susqneuro.com
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Motor Exam

• Power
• Tone
• Flaccid
• Spastic
• Rigid
• Bulk (atrophy)
• Fatigue (myasthenia gravis)

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Lower Motor Neuron

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

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Atrophy
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Lower Motor neuron Diseases

• Nerve Injuries
• ALS
• Polio
• ICU neuromyopathy
• West Nile
• Guillian Barre

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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

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Disease of Upper Motor Neuron

• Stroke
• ALS
• Multiple sclerosis
• Brain tumor

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Homunculus
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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

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Rigidity

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

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Grading Strength

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

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Pronator Drift
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UE Muscle Testing
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LE Muscle Testing
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Deep Tendon Reflexes

• 4 Clonus
• 3 Hyperactive
• Crossed Adductor
• Hoffman
• Radiation of Reflexes
• 2 Normal
• 1 Inactive

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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

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Frontal Release Signs

• Grasp
• Snout
• Suck
• Root
• Glabellar
• Palmomental
• Liberation from frontal inhibition

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Motor systems

• Pyramidal
• Cortico-spinal tract
• Extra-pyramidal
• Basal ganglia
• Cerebellum

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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

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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

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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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Parkinson Tetrad

• Tremor
• Bradykindesia
• Rigidity
• Postural Instability

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Tremor

• Rhythmic alternating contraction of Agonist and
  antagonist

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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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Tremors
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Tremor in A. Spiral
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Basal Ganglia

• Striatum
• Putamen
• Caudate
• Globus Pallidus
• Subthalamic nucleus
• Substantia nigra

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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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Basal Ganglia
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Basal Ganglia
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Treatment of PD

• Increase Dopamine
• Block Acetylcholine (Ach)
• Tweaking

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Parkinson Medicines

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

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Deep Brain Stimulation
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Genetics

• Alpha Synuclein accumulation
• Aharon-Peretz et al NEJM mutations in
  glucocerebrosidase (Gaucher heterozygotes) and PD

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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

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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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Acetylcholine

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

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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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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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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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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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Late Stage

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

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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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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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UCSF. edu Web site
Fronto-Temporal Dementia MRI
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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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Behavior Problems

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

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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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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
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Amyloid Plaque
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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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Neurofibrillary Tangles
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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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Alzheimer Manifestations
Activity of Daily Living
Behavior
Cognitive Dysfunction
All aided by Anti-esterases
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Anti-esterases
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Cholinesterase Blockers
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Acetylcholine

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

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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).

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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

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Rivastigmine

• Shown to improve Global function, behavior, and
  Cognition

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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.

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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

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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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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

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Clock Drawing
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Alzheimer Brain Atrophy
From Whole Brain Atlas
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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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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.

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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

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Workup for Delirium

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

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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

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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