Parkinsons + Drugs Flashcards
rigidity, bradykinesia (slowed movements), tremor (usually resting), mask facies, stooped posture, festinating gait (progressively shortened accelerated steps)
Parkinsonism
DDX for Parkinsonism
– Parkinson’s disease (idiopathic) – most common cause
– Multiple system atrophy
– Progressive supranuclear palsy
– Corticobasal degeneration
– Intoxication with MPTP
– Post-encephalitic Parkinson’s disease
Prevelance of Parkinsons Disease
Prevalence:500,000-1,000,000patientsinU.S.
– 1-in-40 lifetime risk of having PD
– Slight male predominance
– Prevalence increases with age (peak onset: 55-65 yrs)
• Age is the strongest risk factor
– Positive family history in 6-16% of PD cases: If have 1 first degree relative with PD, 3 times greater risk for getting PD and If have 2 or more: 10 times the risk
Possible mechanism for Parkinsons
*Misfolded protein/stress response triggered by protein aggregation
*Defective proteosomal function
*Altered mitochondrial function
PD genetics: most are sporadic, but there is some familial cases that are the _____gene thats located on chromosome ____ and seen in YOUNGER people with parkinsons
Parkin gene
chromosme 6
Very rare mutation present in families with auto. dom. familial PD and subsequently discovered to be a major component of Lewy bodies
***NOT present in sporadic PD
α-synuclein
POssible Environment and pestacides involved in PD
Manganese
Carbon monoxide
Rural living
– Well-water drinking
Paper mills
Hydrocarbons (petroleums, plastics)
Residential use of pesticides
Symptoms of Parkinsons
TRAPS body
Tremor (at rest; pill rolling)
Rigidity (cogwheeling)
Akineisa or Bradykinesia
Postural instability
Shuffling gait
Most common presenting syndrome in Parkinsons
Tremor
It is typically **asymmetric and low frequency **( 4Hz to 6 Hz)
Pill-rolling type of movements
Most often affects the distal upper extremities
Chin tremor specific for PD
• Slowness or lack of movement
- Micrographia
- Hypophonia
- Hypomimia
• Decreased blink rate
• Decreased arm swing with walking
**• Shortened stride length **
Bradykinesia
Increased resistance to passive movement of skeletal muscle across a joint
Rigidity seen in Parkinsons
How does posturea and gait present in parkinsons early and late?
- Early on, it can manifest as dragging of one leg or stooped posture
- Later in the course of the disease gait problems can be severe
What are some nonmotor symptoms seen during the PREmotor phase of PD
• Sleep: REM behavior disorder
- Olfactory Loss
- Dysautonomia
What are some supportive criteria for a Parkinsons Dx?
• Unilateral onset
• Rest tremor present
• Excellent response to levodopa
• Clinical course for 10y or more
How do we confirm dx of Parkinsons?
• No lab tests
• No blood tests
• No x-rays or MRI scans
_• Must be a response to L-DOPA _
What is the pathology we see in the brain associated with Parkinsons?
– Pallor of substantia nigra
– Neuronal loss and Lewy bodies in substantia nigra
– Lewy bodies - Eosinophilic cytoplasmic neuronal inclusions • Contain alpha-synuclein
What is this indicitivie of?
Lewy body seen in Parkinsons:
• Eosinophilic cytoplasmic neuronal inclusions • Contain alpha-synuclein
characterized by dementia associated with any two the following three core clinical features:
• Fluctuating cognition or level of consciousness
- Visual hallucinations
- Parkinsonian motor signs
Dementia with Lewy Body (DLB)
What are ‘suggestive’ features for DLB diagnosis?
Rapid eye movement (REM) sleep behavior disorder
Neuroleptic sensitivity
Low dopamine transporter uptake in the basalganglia
*If one or more of these suggestive features is present along with one or more core features, a diagnosis of probable DLB can be made *
How are Parkinsons and dementia with Lewy Body simular and different?
Both have substantia nigra degeneration and Lewy bodies
Different clincal presentaiton:
PD
– Patients present with parkinsonism signs and symptoms
– Most eventually develop dementia – 5x more frequent than in controls (age-matched)
– Pathologic correlate of dementia is Lewy body presence in cortex (cortical Lewy bodies)
Neuronal loss and Lewy bodies in substantia nigra AND
Lewy bodies in the cerebral cortex
Lewy Body Dementia has LB in the subnigra + cerebral cortex
*this image is of a Lewy body in cortex (note there is none of the brown shit you see in substantia nigra)
Focus of Pharmacotherapy in Parkinsons
Primarily targeted to restoring the neurotransmission in the circuit that regulates the extrapyramidal system
Understanding role of dopamine in parkinsons
the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement
Why are dopaminergic cells vulnerable?
Due to MAO breakdown of dopamine; we end up with OH and OH- free radicals and iron; as cellls age, they accumulate free radicals and reduce number of DA cells
What is the lifecycle of Dopamine
Tryosine –> tyrosine hydroxylase–> DOPA–> (L-AAAD)–> DA
DA gtes a methyl group added via COMT
then broken down by MAO
OR uptake back into the terminal