Parkinson's Disease - 10 Marker (MBBS Standard)

Definition

Epidemiology

• Peak onset: 6th decade (45-70 years); rare before 30 years
• Affects ~1% of population over 65 years
• Slightly more common in males
• Universal in all ethnic groups; incidence in Asians is one-third to one-half that in whites

Etiology / Causes

1. Idiopathic (Most Common)

• No identifiable cause; multifactorial (genetic + environmental)

2. Genetic Causes (Familial PD)

3. Environmental / Toxic Causes

• MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine): A meperidine analogue used by drug addicts; converted by MAO-B to MPP+, which selectively destroys dopaminergic neurons in substantia nigra
• Pesticides / organophosphates: Slight increased incidence in agrarian regions
• Heavy metals, iron deposition in substantia nigra

4. Post-encephalitic Parkinsonism

• Following encephalitis lethargica; neurofibrillary tangles rather than Lewy bodies

Pathology

Gross

• Pallor of substantia nigra (visible to naked eye) due to loss of neuromelanin-containing pigmented neurons

Microscopic

1. Loss of pigmented dopaminergic neurons in the substantia nigra pars compacta - reduced to 30% or less of age-matched controls (>66% reduction in absolute numbers)
2. Lewy bodies: Eosinophilic cytoplasmic inclusions with a faint halo, seen in practically all idiopathic cases - the hallmark of PD

Lewy body: round eosinophilic inclusion in the cytoplasm of a nigral neuron (H&E stain) - Adams & Victor's, 12th Ed.

1. Neuronal loss also occurs in: locus ceruleus, dorsal motor nucleus of vagus, sympathetic ganglia, putamen, pallidum

Pathophysiology

Normal Basal Ganglia Circuit

• Substantia nigra pars compacta → releases dopamine → acts on striatum (putamen + caudate)
• Direct pathway: D1 receptors → facilitates movement (excitatory)
• Indirect pathway: D2 receptors → inhibits movement

In Parkinson's Disease

Loss of nigral dopaminergic neurons
        ↓
Reduced dopamine in striatum
        ↓
Direct pathway UNDERACTIVE + Indirect pathway OVERACTIVE
        ↓
Globus pallidus internus (GPi) becomes HYPERACTIVE
        ↓
Thalamus INHIBITED (excessive inhibition)
        ↓
Reduced thalamocortical drive
        ↓
BRADYKINESIA + AKINESIA + RIGIDITY

Molecular Mechanism - α-Synuclein Toxicity

• Mutant/misfolded α-synuclein aggregates form Lewy bodies
• Normal α-synuclein is degraded by ubiquitin-proteasome system
• Dysfunction of parkin (E3 ubiquitin ligase) → impaired protein clearance → accumulation
• Mitochondrial dysfunction (PINK1, DJ-1 mutations) → oxidative stress → neuronal death

Clinical Features

Cardinal Motor Features (TRAP)

Non-Motor Features

• Autonomic: Constipation, orthostatic hypotension, sialorrhea (drooling), urinary dysfunction, sexual dysfunction
• Neuropsychiatric: Depression (most common non-motor feature), anxiety, dementia (late), psychosis
• Sleep: REM sleep behavior disorder (can precede motor symptoms by years), insomnia
• Sensory: Anosmia (often an early sign), pain
• Speech: Hypophonia (soft voice), dysarthria, dysphagia

Early vs Late Features

• Early: Unilateral tremor, anosmia, constipation, depression, REM sleep disorder
• Late: Bilateral involvement, dementia, falls, autonomic failure, dysphagia

Gait in PD

• Short shuffling steps, reduced arm swing
• Festination: involuntary acceleration of gait
• Freezing of gait: sudden inability to initiate steps
• Difficulty turning; en-bloc turning

Hoehn and Yahr Staging

Diagnosis

Summary Box (for quick recall)

PD = Progressive loss of dopaminergic neurons in substantia nigra pars compacta → reduced dopamine → overactive indirect pathway → TRAP (Tremor, Rigidity, Akinesia, Postural instability). Pathological hallmark = Lewy bodies (α-synuclein aggregates). Mainly idiopathic; genetic causes include SNCA, PARK2, LRRK2.