Parkinson's Disease

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LECTURE 4 NEUROPATHOLOGY
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PARKINSONS DISEASE
James Parkinson, 1817
...involuntary tremulous motion, with lessened
muscular power, in parts not in action and even
when supported with a propensity to bend the
trunk forwards, and to pass from a walking to a
funning pace, the senses and the intellects
uninjured.
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CLINICAL SYMPTOMS
rhythmic tremor at rest rigidity with cog-wheel
characteristic akinesia
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STAGES OF PARKINSON'S DISEASE
DOPAMINE
( control)
100
80
ADAPTIVE
60
CAPACITY
40
COMPENSATION
-no symptoms
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MILD SYMPTOMS
DECOMPENSATION
MARKED SYMPTOMS
0
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EPIDEMIOLOGY
fifth or sixth decade of life 85
idiopathic prevalence 3 per 1000 cumulative
life-time risk 1 in 40 approximately 1 million
patients no cure
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ETIOLOGY
Genetic Factors 1999 - examined 17,000 twins
gt 50 years old no genetic effect
lt 50 years old 10 genetic defect Diet ?
vitamins, antioxidants ? ? incidence Smoking ?
? incidence Environment ? incidence in rural
areas dopamine neuron toxins
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MPTP A Neurotoxin for Dopamine Neurons

• Methylphenyltetrahydropyridine
• contaminant in synthetic heroin
• inhibits electron transport chain

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TREATMENT
Pharmacology Restore Dopamine
Function Dopamine precursor L-DOPA Dopamine
agonists apomorphine, bromocriptine Inhibitors
of Dopamine degradation selegiline, tolcapone
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TREATMENT
Neural Transplants Chromaffin cells fetal
dopamine neurons genetically engineered
cells Surgery Pallidotomy and
Thalamotomy Deep Brain Stimulation
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Pathophysiology of Parkinsons Disease
Normal
STRIATUM
MOTOR CORTEX
PALLIDUM
THALAMUS
SUBSTANTA NIGRA
Pathology
STRIATUM
MOTOR CORTEX
PALLIDUM
THALAMUS
SUBSTANTA NIGRA
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Deep Brain Stimulation
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Huntingtons Disease

• first described by George Huntington in 1872
• onset of disease in fourth or fifth decade of
  life
• inherited

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Symptoms

• General
• chorea, dementia
• First signs
• absentmindedness, irritability
• depression, fidgeting, clumsiness
• Later signs
• uncontrolled (i.e., choreiform) movements
• confinement to wheel chair or bed
• speech first slurred than incomprehensible
• mental functions deteriorate

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Epidemiology

• incidence 5 per 100,000
• 150,000 at risk in US
• affects men and women equally
• each child of an affected parent has
• 50 chance of inheritance
• no current treatment

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Etiology

• autosomal dominant trait
• HD patients in eastern US from two ancestors
• - emigrated to salem, MA in 1630
• HD patients in Venezuela from single ancestor
  (1630)

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Biochemistry
General 1. Loss of cholinergic and GABAergic
neurons in striatum 2. Disinhibition of
nigrostriatal dopamine neurons
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Comparison
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Criteria for Diagnosis of Schizophrenia
1. continuously ill for at least six months 2.
one or more of the following a. bizarre
delusions (1) persecution, control by outside
force b. auditory hallucinations (1) hearing
voices c. disorder of thought (1) loss of
association between ideas (2) poverty of
speech (3) loss of emotional responsiveness
("flattening of affect")
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Two Overlapping Syndromes
1. positive-syndrome a. delusions,
hallucinations, psychotic episodes b. respond
well to antipyschotic drugs 2. negative-syndromes
a. flattening of affect, poverty of speech,
poor social adjustment b. respond less well to
antipsychotic drugs
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Epidemiology

• rate varies throughout the world
• - 1 of population in the US
• - slightly higher in Ireland, Yugoslavia and
  Scandinavia
• typically affects patients in their twenties and
  thirties

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Etiology

• genetic component
• non-Mendelian
• perhaps due to
• 10 different genes

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Etiology

• problem with fetal brain development
• - due to viral infection in prenatal second
  trimester

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Treatment
Neuroleptics - bind dopamine receptors
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Neuroleptics

• Problems with classical or typical neuroleptics
• extrapyramidal side effects
• - tardive dyskinesia - involuntary movements
• - Parkinson-like movements

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Schizoid Personality

• Symptoms
• suspicious
• preference for isolation
• preoccupation with unusual beliefs
• vague and digressive speech
• eccentric dress
• Etiology
• common in families of schizophrenics
• fewer number of schizophrenic genes

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Criteria for Diagnosis of Depression

• Abnormal sense of sadness, despair and
• bleak feelings about the future
• disordered eating and weight control
• disordered sleeping
• diminished sexual interest

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Epidemiology

• 5 to 8 of the US population
• 10 if include manic depression

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Etiology

• Genetic predisposition ??
• Non-Mendelian
• higher incidence in
• - monozygotic compared to dizygotic twins
• - in children adopted from depressed patients

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Neurobiology

• Biogenic Amine Hypothesis
• dopamine, norepinephrine and serotonin

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Treatment of Depression
1. Electroconvulsive therapy - full remission or
marked improvement in 90 of well defined
depression - short lasting? 2. Antidepressant
pharmacology - effectively treat 70 of all
patients
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Pharmacology of Depression

• Tricyclic antidepressants - block
• amine uptake
• 1. Desipramine (NE)
• 2. Imipramine (5-HT and NE)
• Atypical antidepressants
• 1. Nomifensine (DA and NE)
• 2. Buproprion (DA, 5-HT and NE)

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Pharmacology of Depression

• monoamine oxidase inhibitors
• (MAO-A)
• 1. Phenelzine
• 2. Pargyline
• specific serotonin uptake inhibitors (SSI)
• 1. Fluoxetine (Prozac)

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