Clinical Movement Disorders 2: Parkinsonian Disorders Flashcards
What are the chief motor signs of Parkinson’s disease?
TRAP Tremor - resting tremor Rigidity - Cogwheel Akinesia / bradykinesia Postural instability
Define cogwheel rigidity and resting tremor?
Cogwheel rigidity - inconsistent resistance, patient resists hard and then lets you then resists hard again
Resting tremor - 4-6 Hz slow pill-rolling tremor better with movement
What is bradykinesia vs hypokinesia? When else could these occur?
Bradykinesia - Slowness of movement, also caused by psychomotor retardation or deliberate slowing if you’re ataxic
Hypokinesia - Reduction in number of movements and AMPLITUDE of movement - can also occur in lethargy or frontal akinesis
What are the features of postural instability in Parkinsonism?
- Flexed posture - shoulders bent over
- Festination - shuffling gait, walking forward quickly to catch weight
- Retropulsion - difficulty balancing oneself when pulled backward, need to take a few steps back (walking backward)
How does the onset of Parkinsonian tremor differ from essential tremor?
Parkinsonian tremor begins unilaterally and remains asymmetric
Other than the motor features, what are some other broad functional deficits which occur in Parkinson’s? When do these occur in relation to motor symptoms?
- Cognitive disturbances - depression and dementia
- Autonomic dysfunction
- Altered senses
- Sleep disorders
These can occur before motor symptoms
What autonomic dysregulation occurs in Parkinsonism?
Constipation (super common)
Nocturia
Orthostatic hypotension
Problems with temperature regulation
What senses are altered in Parkinsonism?
- Anosmia - loss of smell is very common
2. Pain - lowered pain threshold, and muscles often ache from rigidity
What sleep problems does Parkinsonism cause?
Insomnia, sleep apnea
REM sleep behavior syndrome - disinhibited movements related to dream activity which can be violent
What does the pathology of Parkinson’s look like? Is it just substantia nigra pars compacta that is affected?
Neural degeneration with gliosis and Lewy body formation
-> no, other nuclei in the ventral mesencephalic tegmentum are also affected
What is the pattern of spread of neuronal loss in Parkinson’s? What symptoms does this explain?
“Braak Stages” - Starts in medulla and moves its way up to eventually involve the cortex.
Parkinson’s development exists on a spectrum, and at least 50% of dopaminergic neurons need to be lost in order to have disease
Explains early symptoms
- > anosmia - anterior olfactory nucleus involved early
- > constipation - dorsal motor nucleus of X affected early in medulla
In what ways is Parkinsonism like CJD?
Spread of synuclein is via protein misfolding, forming neurotoxic fibrils, which can spread from cell to cell in a prion-like manner causing more misfolding and neural degeneration
What compound is known to induce Parkinson’s and how?
MPTP - a contaminant in the production of the opiate drug MPPP
MPTP is converted by MAO-B to MPP+ in dopaminergic neurons, which is toxic and causes their death.
What other information suggests Parkinson’s might have an environmental cause?
There is an ALS/Parkinson’s syndrome occurring only in Guam, probably due to diet
Also, rural life increases change of Parkinson’s (probably due to agricultural chemicals)
What was the first discovered cause of Familial Parkinson’s disease? What is the function of the malfunctioning protein?
Autosomal dominant mutations in synuclein on chromosome 4
- synucleins are abundant in neurons at presynaptic terminals
- bind lipid vesicles and integrate signalling and membrane trafficking
- important in dopamine vesicle organization, and plays are role in other neurodegenerative diseases
What gene is mutated in autosomal recessive Parkinson’s inheritance and what is the clinical picture?
Parkin gene - functions as an E3 ubiquitin ligase and proteasome regulator
- Early Parkinson’s (20s) but slow progression
- Patients do NOT have Lewy bodies
What is the most common cause of inherited PD? Clinical progression?
LRRK-2 mutations - Lysine-Rich Repeat Kinase -> has GTPase and Kinase domains
- > Patients present clinically exactly the same as idiopathic Parkinson, with low penetrance
- > can be viewed as a “super risk factor”
Why is the proteasome thought to be involved in even sporadic cases of Parkinsonism? And what is the function of E3?
Involved because ubiquinated alpha-synuclein can be seen in Lewy Bodies
E1 - activates ubiquitin (via ATP)
E2 - Carries ubiquitin, will do the conjugation
E3 - Brings substrate in proximity of E2 carrying ubiquitin so ubiquitin can be attached (ligating enzyme)
Do twin studies show a major role of genetics in the development of Parkinson’s disease?
No - after age 50 there is no correlation
Early onset forms yes
What are the non-pharmacologic interventions which can be used for Parkinson’s disease?
Deep brain stimulation -> stimulate subthalamic nucleus (to release pallidum control of thalamus) or GPi
Stem cell replacement may have some efficacy
How can Huntington’s cause Parkinsonism?
If you have severe Juvenile Huntington’s, you can develop Parkinson’s late in the disease because it progresses so quickly, the direct pathway also degrades
What Parkinson plus syndrome is characterized by more severe autonomic dysfunction and what is this dysfunction? What are its subclassifications?
Severe orthostatic hypotension and urinary incontinence, preceding movement disorder
- Multiple System Atrophy with predominant parkinsonian features (MSA-P)
- Multiple System Atrophy with predominant cerebellar features (MSA-C)
What are the clinical features of the Parkinsonism of MSA? Other motor signs?
No resting tremor, early gait disorder, may or may not response to levadopa.
Often associated with hyperreflexia, cervical dystonia and limb dystonia, etc
What are the cerebellar signs of MSA? What one does it occur in?
Gait disorder with limb ataxia
Mostly in MSA-C, but can happen in MSA-P as well
