Parkinson's Disease

Definition

• Robbins & Kumar Basic Pathology, p. 854
• Goldman-Cecil Medicine, Chapter 378

Epidemiology

• Symptoms typically emerge between 55–65 years of age
• Second most common neurodegenerative disease after Alzheimer's
• A 2024 systematic review (Lancet Healthy Longev, PMID 38945129) documented rising global prevalence of PD from 1980 to 2023, with increasing incidence linked to aging populations

Pathogenesis

1. α-synuclein accumulation — normally involved in synaptic transmission; in PD it misfolds, aggregates, and forms Lewy bodies (cytoplasmic eosinophilic inclusions containing α-synuclein, neurofilaments, and ubiquitin)
2. Defective autophagy/lysosomal clearance — mutations in Parkin, LRRK2 (most common autosomal dominant mutation), and glucocerebrosidase all impair protein/organelle clearance
3. Mitochondrial dysfunction — toxins (MPTP in synthetic heroin, pesticides) selectively injure dopaminergic neurons via mitochondrial inhibition
4. Nigrostriatal pathway disruption — dopaminergic neurons project from substantia nigra → striatum; their loss removes inhibitory dopamine input to the neostriatum, causing relative cholinergic overactivity

Morphology

• Loss of pigmented catecholaminergic neurons with reactive gliosis
• Remaining neurons contain Lewy bodies — round, eosinophilic cytoplasmic inclusions with a dense pink center and lighter halo
• Lewy neurites — dystrophic neurites containing aggregated α-synuclein

Clinical Features

Cardinal Motor Features (TRAP)

Non-Motor Features (also diagnostically important)

• Autonomic: Orthostatic hypotension, constipation, urinary dysfunction, sialorrhea
• Neuropsychiatric: Depression, anxiety, apathy, dementia (late), visual hallucinations
• Sleep: REM sleep behavior disorder (may precede motor symptoms by years), excessive daytime sleepiness
• Olfactory: Hyposmia/anosmia — often an early pre-motor symptom
• Dysphagia: Present subjectively in ~35%, objectively in ~82%; silent aspiration occurs in 15–33%

Disease Course

Diagnosis

• Bradykinesia + at least one of: resting tremor, rigidity
• Asymmetric onset
• Good response to levodopa

• DaT-SPECT scan — reduced dopamine transporter uptake in striatum (useful when clinical diagnosis uncertain)
• MRI brain — mainly to exclude other causes (vascular, structural)
• No blood or CSF biomarker is diagnostic in routine practice

Management

Pharmacological

• Levodopa is a metabolic precursor of dopamine; crosses the blood-brain barrier
• Carbidopa inhibits peripheral DOPA decarboxylase → reduces peripheral dopamine side effects, increases CNS availability
• Standard starting dose: carbidopa/levodopa 25/100 mg three times daily
• Limitation: long-term use causes motor fluctuations ("wearing-off", "on-off" phenomenon) and dyskinesias (~50% by 5 years)

• Entacapone, opicapone, tolcapone — inhibit peripheral COMT, reducing conversion of levodopa to 3-O-methyldopa
• Increase levodopa CNS availability; reduce "wearing-off"

• Non-ergot: ropinirole, pramipexole, rotigotine, apomorphine (injectable)
• Longer duration of action than levodopa; used in early disease or for motor fluctuations
• Less dyskinesia risk as initial therapy vs. levodopa
• Side effects: hallucinations, impulse control disorders (especially in elderly)

• Selegiline, rasagiline — inhibit monoamine oxidase B, reducing dopamine catabolism
• Used as monotherapy in early disease or adjunct to levodopa

• Trihexyphenidyl, benztropine — reduce cholinergic overactivity
• Useful mainly for tremor, especially in younger patients
• Avoid in elderly (cognitive side effects)

• Mechanism: enhances dopamine release, NMDA antagonism
• Used for dyskinesias and mild early disease

Surgical

• Electrodes implanted in the subthalamic nucleus or globus pallidus interna
• Modulates basal ganglia circuitry; allows significant reduction in levodopa dose
• Indicated when medical therapy fails to control motor symptoms
• Improves quality of life, reduces dyskinesias and motor fluctuations

Complications

Key Points for Exam

• Lewy body = pathological hallmark (α-synuclein inclusions)
• Substantia nigra depigmentation = gross hallmark
• TRAP = classic motor tetrad
• Levodopa remains the most effective drug; carbidopa prevents peripheral conversion
• DBS targets subthalamic nucleus or globus pallidus interna
• Non-motor features (anosmia, constipation, REM sleep disorder) may predate motor symptoms by years

Parkinson's Disease

(B. Pharm — Pharmacology, 4th Semester | PCI Syllabus)

1. Definition

• Tremors
• Muscular rigidity
• Bradykinesia (slowness of movement)
• Postural and gait abnormalities

2. Etiology / Pathophysiology

• The substantia nigra sends inhibitory dopaminergic neurons to the neostriatum
• The neostriatum also contains excitatory cholinergic (ACh) neurons
• Normally, dopamine (DA) and acetylcholine (ACh) are balanced

1. Dopaminergic neurons in the substantia nigra are destroyed
2. Less dopamine → less inhibition of cholinergic neurons in the neostriatum
3. Relative excess of ACh → triggers abnormal motor signaling → loss of movement control

Lippincott Illustrated Reviews: Pharmacology — Fig. 15.4

3. Treatment Strategy

• Increasing dopamine (or its effects), OR
• Decreasing acetylcholine (anticholinergics)

4. Drugs Used in Parkinson's Disease

A. Levodopa + Carbidopa (First-line, most effective)

• Metabolic precursor of dopamine
• Dopamine itself cannot cross the blood–brain barrier (BBB), but levodopa can
• Converted to dopamine in surviving neurons of the substantia nigra → restores dopaminergic transmission

• Carbidopa = peripheral DOPA decarboxylase inhibitor
• Prevents conversion of levodopa to dopamine in the periphery
• More levodopa reaches the CNS → better effect with lower dose
• Reduces peripheral side effects (nausea, vomiting, cardiac arrhythmias)

"Wearing-off" phenomenon: after years of use, drug effect diminishes before next dose; ~50% of patients develop dyskinesias within 5 years.

B. MAO-B Inhibitors

• Inhibit monoamine oxidase type B (MAO-B) — the enzyme that breaks down dopamine in the brain
• Inhibition → increased dopamine concentration in the striatum
• Used as monotherapy in early PD or as adjunct to levodopa to reduce "wearing-off"
• Adverse effects: insomnia, nausea, dizziness (selegiline metabolized to amphetamine)

C. COMT Inhibitors

• Inhibit catechol-O-methyltransferase (COMT) — a peripheral enzyme that converts levodopa to inactive 3-O-methyldopa
• When added to levodopa/carbidopa → more levodopa reaches the CNS
• Reduce "wearing-off" symptoms
• Tolcapone — risk of fulminant hepatic necrosis; only used if other options fail
• Entacapone/Opicapone — safer; have replaced tolcapone in routine practice

D. Dopamine Receptor Agonists

• Directly stimulate D2 dopamine receptors in the striatum (do not require enzymatic conversion)
• Longer duration of action than levodopa
• Used: early PD, or as adjuncts in motor fluctuations
• Less risk of dyskinesias than levodopa

E. Amantadine

• Originally an antiviral drug (accidentally found to have antiparkinsonian action)
• Mechanism:
  • Increases dopamine release
  • Blocks NMDA (glutamate) receptors
  • Mild anticholinergic effect
• Used in early/mild PD; also reduces levodopa-induced dyskinesias
• Less efficacious than levodopa; tolerance develops readily
• Adverse effects: restlessness, agitation, hallucinations, orthostatic hypotension, urinary retention, livedo reticularis

F. Anticholinergic (Antimuscarinic) Agents

• Block muscarinic receptors → reduce excess cholinergic activity → restore DA/ACh balance
• Mainly useful for tremor and rigidity; less effective for bradykinesia
• Used as adjuncts; preferred in younger patients with tremor-predominant PD
• Contraindicated: glaucoma, prostatic hyperplasia, pyloric stenosis
• Adverse effects (peripheral): Dry mouth, constipation, urinary retention, blurred vision
• Adverse effects (central): Mood changes, confusion, memory impairment (avoid in elderly)

5. Summary Table of Drugs