Transcript Involuntary with lessened muscle power in parts, not in

PARKINSON’S DISEASE
“Involuntary with lessened muscle power in
parts, not in action even when supported; with
the propensity to bend the trunk forwards and
to pass from a walking to running pace; the
senses and intellect being uninjured”
Dr. James Parkinson, 1817
PARKINSON’S DISEASE SYMPTOMS
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Bradykinesia
Tremor
Rigidity
Postural instability
Gait disturbance
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Other features:
 Dementia
 Psychiatric disturbance
Autonomic dysfunction
Dystonia
Eye movement
abnormalities
PD EPIDEMIOLOGY
~ 1,000,000 patients in the United States
 Annual incidence of about 50,000 – 60,000
 Net prevalence increase of 15,000 patients
annually
 Average age of onset: 50 – 65 years old
 85% of patients over age 65
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COGNITIVE CHANGES IN
PARKINSON’S DISEASE
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Estimates range from 30% - 90%
Important to distinguish “dementia” from
specific cognitive changes:
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Dementia: global deterioration of intellect –
occurs in about 10% - 20% of PD patients
Specific pattern of cognitive impairment seen
in a majority of PD patients
COGNITIVE CHANGES IN PD
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General findings:
 Slowed information processing
 Difficulty starting or stopping mental activity
 Delayed response times
Memory impairment:
– Reduced attention span
– Impaired spontaneous recall of information
– Relatively preserved recognition memory
 Impairment of “working memory”
– Capacity to hold information in brief, short-term storage
in order to perform a mental manipulation
COGNITIVE CHANGES IN PD
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Other Cognitive Findings:
 Mental Inflexibility
– Tendency to get “stuck” on a thought or action
– Inability to shift attention or thought process
– Decreased planning/organizational ability
– Tendency to repeat things over and over
 Visuospatial impairment
– Independent of motor component
– Deficits in visual analysis and integration
– Difficulty with visual discrimination and matching
– Intact abilities: perceptual orientation, mental rotation
DEPRESSION IN PD
 Can
occur in 20% to 40% of PD patients
 Major reactive depression (initial diagnosis)
 Adjustment disorder (physical/cognitive
limitations)
 May be part of the clinical spectrum of PD
ANXIETY IN PD
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ANXIETY: A state characterized by a vague
and unpleasant sense of apprehension, often
accompanied by physical symptoms such as
sweating and dry mouth
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IN PD: Anxiety is often caused by lack of
effectiveness of PD medications, dyskinesias,
motor fluctuations, fear of freezing/falling. Panic
attacks are common
ANXIETY DISORDERS IN PD
1. Generalized anxiety disorder
2. Panic Attacks/Disorder – tend to occur when PD
medications become less effective or patients
experience various motor fluctuations
3. Social Phobias – fear of an inability to function in
social settings
4. Obsessive-Compulsive Disorder (fear of disabling
physical capacity, excessive worry about taking
medication, fear of freezing or falling, repetitive
checking (e.g., pill box, clock)
PSYCHOSIS IN PD
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Relatively uncommon in PD
Occurs in about 20% of patients with advanced PD and
on chronic anti-PD medications
Almost always drug-induced (e.g., Sinemet)
Often characterized by visual hallucinations, vivid
dreams or nightmares
Usually accompanied by a clear sensorium (e.g., the
patient is alert and not delirious)
Older patients with cognitive impairment at higher risk
Most common reason for nursing home placement
PUTATIVE CAUSES OF PD
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Environmental risk factors:
 Pesticides
 Living in a rural environment
 Consumption of well water
 Exposure to herbicides, pesticides
 Proximity to industrial plants or quarries
Drug addicts who developed parkinsonism after injection of 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
 Patients developed bradykinesia, rigidity, and tremor, which
progressed over several weeks and improved modestly with
dopamine replacement therapy
 A chemical resemblance between MPTP and some
herbicides and pesticides suggest an MPTP-like
environmental toxin, but no specific agent has been
identified
Neuronal Loss in Parkinson's Disease
Loss of substantia nigra pars compacta cells cause
reduced nigral-striatal dopamine input to the
putamen:
1. Loss of striatal excitatory dopamine input
(D1-mediated direct pathway):
• Loss of dopamine-mediated excitation of an
inhibitory GABA pathway causes GPi
hyperactivity which leads to excessive thalamic
inhibition (GPi output is inhibitory - GABA)
Neuronal Loss in Parkinson's Disease
Loss of substantia nigra pars compacta cells cause reduced
nigral-striatal dopamine input to the putamen:
2. loss of an striatal inhibitory dopamine input (D2mediated, indirect pathway)
• loss of dopamine-mediated inhibition of a GABA
inhibitory pathway; more GABA release and GPe
hypoactivity
• GPe hypoactivity decreases GABA (inhibitory) output
to subthalamic nuclei.
• Increased subthalamic nuclei excitatory output
(glutamate-mediated) further increases GPi
hyperactivity leading to further thalamic inhibition.
Neuronal Loss in Parkinson's Disease
3. Decreased activity of direct pathway (less
GPi inhibition) increased GPi activity
increased thalamic inhibition
• increased activity of the indirect
pathway (more GPe inhibition)
less subthalamic nuclei inhibition
increased GPi activity increased
thalamic inhibition
OXIDATIVE HYPOTHESIS OF PD
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The oxidative metabolism of dopamine by MAO leads to the formation
of hydrogen peroxide. Hydrogen peroxide normally is cleared rapidly by
glutathione.
If hydrogen peroxide is not cleared adequately, it may lead to the
formation of highly reactive hydroxyl radicals that can react with cell
membrane lipids to cause lipid peroxidation and cell damage. In PD,
levels of reduced glutathione are decreased, suggesting a loss of
protection against formation of free radicals. Iron is increased in the
substantia nigra and may serve as a source of donor electrons, thereby
promoting the formation of free radicals.
Indices of lipid peroxidation are increased in PD.
Thus, PD is associated with increased dopamine turnover, decreased
protective mechanisms (glutathione), increased iron (a pro-oxidation
molecule), and evidence of increased lipid peroxidation. This hypothesis
raises concern that increased dopamine turnover due to levodopa
administration could increase oxidative damage and accelerate loss of
dopamine neurons.
GENETIC FACTORS IN PD
 Twin Studies
• In a study of 193 twins, overall concordance for MZ and DZ pairs
was similar.
• In 16 pairs of twins in whom PD was diagnosed at or before age 50
years, all 4 MZ pairs, but only 2 of 12 DZ pairs, were concordant.
 Family Studies
• One large family with highly penetrant, autosomal-dominant,
autopsy-proven PD originated in the town of Contursi in southern
Italy. Of 592 family members, 50 were affected by PD.
• Linkage analysis incriminated a region in chromosome 4 and
sequencing revealed an A-for-G substitution at the alpha-synuclein
gene.
HUNTINGTON’S DISEASE
 Named for Long Island, NY physician who
described disorder in 1872
 Autosomal dominant neurodegenerative disorder
 Determined by genetic mutation on short arm of
chromosome 4
 Mutation is an expanded and unstable
trinucleotide repeat of cytosine-adenosineguanine (CAG);
  34
Normal Range
  39
Positive Inheritance
 35–38
Indeterminate
Age of Onset and CAG Repeat Length
CAG repeat length on normal
and HD chromosomes and age at
onset in HD. The CAG repeat
length distribution of alleles
found on normal (blue line) and
HD (red line) The mean age at
onset associated with each CAG
repeat length is plotted as a red
square (against the left axis). The
pink area surrounding the mean
age at onset denotes the range of
ages at onset associated with any
given repeat length, with
deviations presumably being due
to the effects of genetic or
environmental modifiers.
HUNTINGTON’S DISEASE
 Estimated 30,000 Americans with HD
 200,000 individuals at-risk
 Onset is usually between ages 30-45 although there is a
juvenile variant
 Progressive loss of functional ability and death within
10-30 yrs from onset
 Key clinical features:
Motor impairment
Cognitive impairment
Psychiatric manifestations
Decline in ADL’s
HUNTINGTON’S DISEASE
Cognitive Changes
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100% of patients experience progressive cognitive
decline
Pattern of cognitive decline:
 “Subcortical” - slowed information processing,
encoding and retrieval deficits (intact recognition
memory)
 Anterior cortical – mental inflexibility, impaired
planning, organization, sequencing and decreased
judgement, reasoning and problem-solving
Late Stage HD – global dementia
HUNTINGTON’S DISEASE
Behavioral and Psychiatric Features
Can be initial presenting symptom in HD
 Prevalence of psychiatric symptoms ranges from
35% - 75%
 Most common psychiatric disorder is depression
(30% - 50% prevalence)
 Modestly increased suicide rate in HD
 No increased risk in presymptomatic
individuals who test gene positive
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HUNTINGTON’S DISEASE
Behavioral and Psychiatric Features
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Psychosis
Paranoid ideation and persecutory delusions
most common
 Auditory and visual hallucinations commonly
reported in patients with psychosis
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Anxiety and OCD
 Shared pathophysiology between HD and OCD
 Anxiety symptoms typically secondary to worry and
concern about financial difficulty, guilt about passing
gene to offspring
HUNTINGTON’S DISEASE
Behavioral and Psychiatric Features
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Other Psychiatric/Behavioral Problems
 Changes in personality (irritability, apathy, antisocial,
intermittent explosive)
 Change in sexual behavior (hypo- and hypersexuality)
 Restlessness and agitation
 Apathy (? link to frontal dysfunction)
 Increased risk for alcohol and drug dependency
 Bipolar disorder and/or manic episodes reported but
less common
Effect of the HD Mutation on Huntingtin
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Huntingtin is a large protein of more than 3,100 amino acids that
bears no close similarity to any other protein
Normal and mutant huntingtin proteins are both expressed
widely, inside and outside the nervous system
CAG in HD gene is translated into an uninterrupted stretch of
glutamine residues – leads to alteration of structural and
biochemical properties of neurons
Polyglutamine tracts result in insoluble and toxic precipitates
creating “cellular” aggregates similar to amyloid deposits seen in
senile plaques
Similar aggregates have been found in HD brains, brains of
transgenic mice (with 115-156 CAG repeats), and in cultured
cells
HUNTINGTON’S DISEASE
Pathophysiology
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Excitotoxicity
 NMDA receptor mediated glutamatergic
neurotransmission
 Neuronal loss confined to GABA striatal neurons
“Energetic”
 Mitochondrial energy defects lead to  production of
free-radicals,  lactate levels
 Results in DNA, RNA and protein damage, and
ultimately, neuronal death
HD Treatment
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Currently no pharmacological treatment available
 Can treat psychiatric manifestations
 Use of DA blocking agents will  chorea
NMDA receptor antagonists (data disappointing thus far)
Free Radical Scavengers
 Coenzyme Q10
 Creatine
Caspase Inhibition – Minocycline
Inhibition of acetyltransferases – HDAC inhibitors reverse
neuronal degeneration in drosophila model of HD
Ongoing investigation of huntingtin
 Agents that prevent nuclear aggregation
 Agents that “cleave” protein rendering non-toxic