Epidemiology, pathogenesis, genetics
Physiology
Diagnosis
Differentials
Treatment
100
Is Parkinson's inherited?
*for 1000 points: name 2 genes and 2 non-genetic factors (excluding age)
multi-factorial, polygenic and environmental interaction
genetic factors: LRRK2 (present in approximately 1 to 2% of all cases and up to 40% of familial cases), GBA1 (accounts for 39% of cases of Parkinson’s disease in persons of African ancestry), PRKN/ PINK1/DJ-1 (recessive, accounts for most cases in young age)
non-genetic factors: pesticides (dose-dependent, 40% or greater risk of Parkinson’s), solvents, drinking a lot of milk (increased brain concentrations of heptachlor)
also mild to moderate head trauma, DM, inflammatory disorders, infections, metals,
oxidative stress, mitochondrial dysfunction, inflammation, immune dysregulation, impaired autophagy, protein aggregation, and endolysosomal defects
100
Parkinson's onset can be slowed or stopped, T/F?
F
No therapy has been proved to slow progression. Dopaminergic therapies improve motor function, but loss of efficacy and side effects are common. Deep-brain stimulation surgery is effective for motor fluctuations.
100
Besides motor symptoms, what symptoms can we see in Parkinson's?
non-motor symptoms
sleep disorders, cognitive impairment, altered mood and affect, autonomic dysfunction (constipation, urogenital disorders, orthostatic hypotension), and sensory symptoms (hyposmia and pain).
Nonmotor symptoms — particularly hyposmia and rapid-eye-movement (REM) sleep behavior disorder, which is characterized by loss of normal atony during REM sleep and limb movements that simulate running or flailing — often predate the onset of motor symptoms by many years, which suggests that such symptoms may be prodromal. The burden of symptoms progresses, contributing to increasing disability and functional decline.
100
In a patient that doesn't respond to levodopa administration, what should be considered?
- parkinsonian plus syndromes (progressive supranuclear palsy (PSP), multiple-system atrophy (MSA), drug-induced)
100
These 4 things are the foundation for advising persons with Parkinson’s disease at any stage
Regular exercise
healthy diet
high-quality sleep
avoidance of adverse exposures
200
what are some other possible risk factors for PD, not mentioned in the 400/500 questions
Some studies have shown an association between a mild-to-moderate head injury and the onset of Parkinson’s disease or REM sleep behavior disorder decades later, with the disease risk increased by 31% to more than 400%.
Less consistently: exposure to metals, type 2 diabetes mellitus, certain inflammatory disorders, infections
200
Up to what percentage of substantia nigra dopaminergic neurons have lost function by the time classic motor symptoms manifest?
75%
200
In the cited cohort study, initial clinical-to-autopsy diagnostic concordance was 28 %, improving to 89 % after what condition?
What is longer disease duration (and expert diagnosis)?
200
This dementia subtype, often overlapping with Parkinson’s, presents early with visual hallucinations and cognitive fluctuations
Lewy body dementia
200
this surgical modality is used in treatment of PD
Mechanism & Indications: DBS involves placing leads in the subthalamic nucleus or globus pallidus connected to a chest neurostimulator; it modulates abnormal basal ganglia circuits to improve motor control in patients with medication-refractory motor fluctuations.
Clinical Benefits: Increases “on” time by ~3–4 hours/day, improves off-medication UPDRS III scores by 30–50%, and reduces medication needs by ~50%; benefits may last up to 15 years with low procedural risk.
Technology & Limitations: Modern DBS systems feature rechargeable batteries, imaging-guided programming, and emerging adaptive sensing; however, nonmotor symptoms (e.g., cognitive, mood, autonomic) and balance/freezing typically do not improve.
Alternatives & Experimental Therapies: Focused ultrasound thalamotomy offers incisionless tremor control but limited durability; gene and stem-cell therapies targeting dopamine production or neurotrophic factors remain experimental without regulatory approval
300
These 3 things have been associated with a lower risk of Parkinson's
cigarette smoking
caffeine consumption
increased physical activity
300
The primary motor symptoms of Parkinson’s arise from dysfunction of _____ neurons in this structure.
dopaminergic neurons in substantia nigra pars compacta (nigrostriatal pathway)
300
Which imaging modality helps identify structural changes typical of PSP or multiple-system atrophy rather than Parkinson’s?
MRI brain
300
This imaging technique/method can be used to differentiate PD from Essential Tremor and other disorders.
Although no imaging technique can confirm the diagnosis of Parkinson’s disease,
visualization of the striatal dopamine system (mainly with the use of 123I-ioflupane single-photon-emission computed tomography [SPECT] or 18F-labeled fluorodopa positron-emission tomography) can differentiate between Parkinson’s disease and disorders such as essential tremor. The sensitivity and specificity of 123I-ioflupane SPECT imaging are 90% or higher, and a systematic review showed that the use of these techniques led to changes in diagnosis in 31% of study participants and changes in management in 54%.
300
treatment of non-motor symptoms in PD
Nonmotor symptoms cause substantial morbidity, but evidence for treatment is sparse. Off-label medications are commonly used. Comprehensive multidisciplinary care, guided by the patient’s input and implemented by a team that includes a neurologist, mental health professional, neurosurgeon, and physical, occupational, and speech therapists, among others, is ideally introduced early. The needs of the patient, family members, and caregivers should be reassessed regularly, including advanced care planning and, in some severe cases, referral to hospice.
400
Residential or occupational exposure to these 2 things has been associated with a dose-dependent, 40% or greater risk of Parkinson’s disease in most studies.
pesticides (e.g., paraquat, rotenone, 2,4-dichlorophenoxyacetic acid, and several organochlorines and organophosphates)
chlorinated solvents (e.g., trichloroethylene and perchloroethylene)
400
Carbidopa has this drug effect modification on Levodopa
Potentiation
- drug B (with no therapeutic action alone) enhances the therapeutic action of drug A
- Carbidopa only blocks enzyme to prevent peripheral conversion of levodopa “2 + 0 > 2”
400
The symptoms of PD can we remembered by this 4 letter mnemonic
TRAP
Tremor (pill-rolling tremor at rest)
Rigidity (cogwheel or leadpipe)
Akinesia/bradykinesia --> shuffling gait, small handwriting (micrographia)
Postural instability (tendency to fall)
Dementia is usually a late finding.
400
Which reversible or non-degenerative causes of parkinsonism must be excluded before confirming idiopathic Parkinson’s disease?
- drug-induced (antipsychotics), vascular, metabolic, toxin-related
400
These two medications (started in younger vs older patients) are the most effective treatments for PD
MOA and adverse effects
non-ergot dopamine agonists are usually started in younger patients
- pramipexole, ropinirole
- toxicity includes nausea, impulse control disorder (eg, gambling), postural hypotension, hallucinations, confusion, sleepiness, edema
levodopa (with carbidopa) is usually started in older patients
- increase dopamine in brain. Unlike dopamine, l-DOPA can cross BBB and is converted by DOPA decarboxylase in the CNS to dopamine. Carbidopa, a peripheral DOPA decarboxylase inhibitor that cannot cross BBB, is given with l-DOPA to increase bioavailability of l-DOPA in the brain and to limit peripheral adverse effects.
- Nausea, hallucinations, postural hypotension. With progressive disease, l-DOPA can lead to “on-off” phenomenon with improved mobility during “on” periods, then impaired motor function during “off” periods when patient responds poorly to l-DOPA or medication wears off.
500
These genes are thought to be involved in or at least associated with the pathogenesis of PD
Name 2
LRRK2 (present in approximately 1 to 2% of all cases and up to 40% of familial cases)
GBA1 (accounts for 39% of cases of Parkinson’s disease in persons of African ancestry)
PRKN/ PINK1/DJ-1 (recessive, accounts for most cases in young age)
VPS35 and SNCA (<1% of cases)
500
These 3 neurotransmitters are affected in PD
Name them and explain how they are affected
where is each produced?
Acetylcholine (Basal nucleus of Meynert (forebrain)): increased via Loss of Inhibition (dopamine normally inhibits the release of acetylcholine from cholinergic interneurons in the striatum)
Dopamine (Ventral tegmentum, SNc (midbrain)): decreased
Serotonin (raphe nuclei of brainstem): decreased
500
diagnostic criteria for PD
At a minimum, bradykinesia plus either tremor or rigidity must be present to consider the diagnosis of PD.
In addition, an unequivocal, beneficial response to dopaminergic therapy is an important supportive feature of the diagnosis, while the absence of an observable response to high-dose levodopa therapy (>1000 mg daily) in patients with at least a moderate severity of parkinsonism makes the diagnosis of PD extremely unlikely.
Postural instability is also a feature of PD but usually does not appear until later in the course of the disease. Thus, patients with parkinsonian signs who exhibit postural instability early in the course of the illness most likely have another form of parkinsonism.
500
What is this? What's it made of? How would you describe them?
What conditions are they found in? How do you tell which one's which?
Lewy Bodies
a-synuclein
intracellular eosinophilic inclusions
Parkinson disease and Lewy body dementia:
Called Lewy body dementia if cognitive and motor symptom onset < 1 year apart, otherwise considered dementia 2° to Parkinson disease.
500
what are 5 strategies (drug classes, actions) employed in the treatment of Parkinson Disease
1) dopamine agonists (non-ergot, ergot)
2) increase dopamine availability (amantadine)
3) increase L-Dopa availability (levodopa/carbidopa, entacapone, tolcapone)
4) prevent dopamine breakdown (MAO-B inhibitors, Tolcapone)
5) curb excess cholinergic toxicity (antimuscarinics like benztropine and trihexyphenidyl)