Lecture #57: Parkinson Disease and its Variants

What is the core neuropathologic feature of Parkinson disease?

Degeneration of dopaminergic pigmented neurons in the ventrolateral substantia nigra leading to dopamine depletion in the striatum

What intracellular protein aggregate is characteristic of Parkinson disease?

Lewy bodies composed primarily of misfolded alpha synuclein

When do motor symptoms of Parkinson disease typically appear?

After approximately 60 percent of dopaminergic neurons have already been lost

What are the four cardinal motor symptoms of Parkinson disease?

Tremor, rigidity, akinesia or bradykinesia, and postural instability, often remembered as TRAP

What is the typical tremor seen in Parkinson disease?

An asymmetric resting tremor, 4 to 6 Hz, often described as pill rolling, involving supination and pronation of the hand

What is bradykinesia?

Slowness of movement with progressive decrement and fatigue during repetitive tasks such as finger tapping

What is rigidity in Parkinson disease?

Increased resistance to passive movement, often with cogwheeling due to superimposed tremor

What gait abnormalities are seen in Parkinson disease?

Reduced arm swing, shuffling gait, stooped posture, festination, and turning en bloc

What is freezing of gait?

A sudden inability to initiate movement, commonly triggered by doorways or crowds and a major cause of falls

What are early non motor symptoms of Parkinson disease?

Constipation, loss of smell, REM sleep behavior disorder, voice changes, and subtle stiffness years before motor signs

What neuropsychiatric symptoms are common in Parkinson disease?

Depression, anxiety, apathy, psychosis, hallucinations, impulse control disorders, and cognitive impairment

What autonomic symptoms occur in Parkinson disease?

Orthostatic hypotension, constipation, urinary urgency or incontinence, drooling, sexual dysfunction, and altered cardiac reflexes

What sleep disorders are associated with Parkinson disease?

REM sleep behavior disorder, insomnia, excessive daytime sleepiness, sleep attacks, and restless leg syndrome

What environmental exposures increase Parkinson disease risk?

Pesticides such as rotenone and paraquat, trichloroethylene, heavy metals, well water exposure, Agent Orange, MPTP, and head trauma

Which genetic mutation is associated with faster cognitive decline in Parkinson disease?

GBA mutation involving glucocerebrosidase

Which mutation is associated with slower motor progression?

LRRK2 mutation

Which gene mutations are commonly tested in early onset or familial Parkinson disease?

SNCA, PRKN, PINK1, PARK7, LRRK2, VPS35, and GBA

What are red flags suggesting atypical parkinsonism?

Early dementia with hallucinations, symmetrical signs, early falls, severe orthostatic hypotension, alien limb, inspiratory stridor, or markedly reduced eye movements

What features characterize dementia with Lewy bodies?

Fluctuating cognition, visual hallucinations, REM sleep behavior disorder, early dementia, and sensitivity to medications

What pathologic protein accumulates in dementia with Lewy bodies?

Alpha synuclein

What are key features of progressive supranuclear palsy?

Early postural instability, frequent falls, supranuclear gaze palsy, pseudobulbar palsy, and axial rigidity

What type of pathology is progressive supranuclear palsy?

A tauopathy involving 4 repeat tau protein

What are defining features of multiple system atrophy?

Parkinsonism with autonomic failure, urinary dysfunction, orthostatic hypotension, cerebellar signs, and laryngeal stridor

What proteinopathy underlies multiple system atrophy?

Alpha synuclein accumulation

What features distinguish corticobasal degeneration?

Asymmetric rigidity, hemidystonia, apraxia, alien limb phenomenon, and cortical deficits

What protein abnormality is seen in corticobasal degeneration?

Hyperphosphorylated 4 repeat tau inclusions

What is the classic triad of normal pressure hydrocephalus?

Urinary incontinence, dementia, and gait disturbance described as wet, wacky, and wobbly

What is the magnetic gait seen in normal pressure hydrocephalus?

A slow, wide based gait where feet appear stuck to the floor

How does a DaT scan assist in diagnosis?

It visualizes dopamine transporter uptake in the striatum and helps differentiate Parkinson disease from essential tremor

What does reduced uptake on PET scan indicate in Parkinson disease?

Loss of dopaminergic nerve terminals proportional to severity of degeneration

What is the gold standard medication for Parkinson disease?

Levodopa combined with carbidopa

Why is carbidopa given with levodopa?

To prevent peripheral conversion of levodopa to dopamine and reduce nausea

What are MAO B inhibitors used for in Parkinson disease?

To reduce dopamine breakdown and improve motor symptoms, examples include selegiline, rasagiline, and safinamide

What is a major adverse effect of dopamine agonists?

Impulse control disorders including hypersexuality and gambling

What are examples of dopamine agonists?

Pramipexole, ropinirole, rotigotine, and apomorphine

What do COMT inhibitors do?

Extend the plasma half life of levodopa to reduce wearing off motor fluctuations

What is a serious risk associated with tolcapone?

Hepatic necrosis

What medication is used for tremor in Parkinson disease?

Anticholinergics such as trihexyphenidyl or benztropine

What unique adverse effect is associated with amantadine?

Livedo reticularis

What is istradefylline?

An adenosine A2A receptor antagonist used as add on therapy to reduce off periods

Who is not a candidate for deep brain stimulation?

Patients with atypical parkinsonism, unstable psychiatric disease, advanced dementia, or significant medical comorbidities

What is the most important non pharmacologic therapy for Parkinson disease?

Exercise, which is the only intervention shown to slow disease progression

How can osteopathic manipulative treatment assist Parkinson patients?

It may improve balance, gait, posture, range of motion, autonomic dysfunction, and respiratory mechanics

What are proposed mechanisms linking COVID 19 to parkinsonism?

Vascular injury to the nigrostriatal system, neuroinflammation causing dopamine neuron loss, and viral neuroinvasion increasing alpha synuclein aggregation

What is the key principle in diagnosing Parkinson disease?

Recognize classic motor features, identify non motor symptoms, rule out red flags, and correlate clinical findings with supportive imaging when needed