Physiology · Year 1 · from Physiology
Case 3: Parkinson's Disease - Dopaminergic Transmission Deficit
Clinical Image
Source: Clinical illustration of dopaminergic pathway dysfunction
Patient Presentation
A 65-year-old male is brought by his wife to the neurology clinic because she has noticed progressive changes over the past 2 years. He has become slower in his movements, his handwriting has become smaller (micrographia), and he shuffles when walking. She also notes that his right hand shakes when resting but stops when he reaches for objects. He has become less expressive facially and his voice is softer. He reports constipation, loss of smell (anosmia), and vivid dreams with movement during sleep (REM sleep behavior disorder) that preceded the motor symptoms.
Demographics
- Age: 65 years
- Sex: Male
- Duration: Prodromal symptoms for years; motor symptoms for 2 years
Chief Complaint
Progressive slowness, resting tremor, shuffling gait, and reduced facial expression
Physical Examination
- General: Masked facies (hypomimia), reduced blinking
- Speech: Hypophonic (soft), monotonous
- Motor:
- Tremor: 4-6 Hz resting tremor, right hand > left, "pill-rolling" quality, resolves with action
- Rigidity: Cogwheel rigidity in right arm and leg
- Bradykinesia: Reduced finger tapping amplitude and speed, difficulty with rapid alternating movements
- Postural instability: Positive pull test with retropulsion (multiple steps backward)
- Gait: Shuffling, reduced arm swing (right > left), festination, difficulty initiating movement
- Writing: Micrographia demonstrated on writing sample
Workup
- Clinical diagnosis based on cardinal features (bradykinesia plus tremor or rigidity)
- DaTscan (dopamine transporter SPECT): Reduced uptake in putamen bilaterally (left > right), consistent with nigrostriatal degeneration
- MRI brain: No structural abnormalities, rules out vascular parkinsonism
- Response to levodopa trial: Marked improvement in motor symptoms (positive)
Diagnosis
Idiopathic Parkinson's Disease (Hoehn & Yahr stage 2)
Treatment
- Levodopa/carbidopa (Sinemet) - most effective symptomatic treatment
- Dopamine agonist (pramipexole or ropinirole) as adjunct or initial monotherapy in younger patients
- MAO-B inhibitor (rasagiline or selegiline) for mild symptom control and possible neuroprotection
- COMT inhibitor (entacapone) to extend levodopa effect
- Physical therapy for gait training and balance
- Speech therapy for hypophonia
- Treatment of non-motor symptoms: Constipation (fiber, laxatives), RBD (melatonin, clonazepam), depression, cognitive changes
- Consider deep brain stimulation (DBS) for motor fluctuations refractory to medications
Physiological Principles Demonstrated
- Dopaminergic neurotransmission: Dopamine is synthesized from tyrosine via tyrosine hydroxylase (rate-limiting) and DOPA decarboxylase. It is released from synaptic vesicles and acts on D1-D5 G-protein coupled receptors.
- Nigrostriatal pathway: Dopaminergic neurons in the substantia nigra pars compacta project to the striatum (caudate and putamen). Loss of these neurons (>60-80%) produces the motor symptoms of PD.
- Direct and indirect pathways: The basal ganglia modulate movement through two pathways. Dopamine facilitates movement by stimulating D1 receptors on the direct (go) pathway and inhibiting D2 receptors on the indirect (stop) pathway. Dopamine loss results in excessive inhibition of movement.
- Levodopa mechanism: Levodopa (L-DOPA) is the precursor to dopamine that can cross the blood-brain barrier (dopamine itself cannot). Carbidopa inhibits peripheral decarboxylation, ensuring more levodopa reaches the brain.
- MAO-B inhibitors: Monoamine oxidase B degrades dopamine in the brain. MAO-B inhibitors (rasagiline, selegiline) prolong dopamine action by preventing its breakdown.
- Signal termination: Dopamine action is terminated primarily by reuptake via the dopamine transporter (DAT) and degradation by MAO and COMT. Understanding these pathways guides pharmacotherapy.