A 58-year-old man with Parkinson disease exhibits bradykinesia and rigidity, while a 62-year-old woman with Huntington disease presents with chorea and dystonia. Which neurophysiological feature best distinguishes the pathology of these two conditions in terms of basal ganglia circuit dysfunction?

Question

Accepted Answer

A. Loss of dopaminergic neurons in the substantia nigra pars compacta in Parkinson disease versus selective neuronal loss in the striatum in Huntington disease. ## Distinguishing Pathophysiology of Parkinson vs Huntington Disease

### Anatomical Basis of Difference

**Key Point:** The fundamental distinction between Parkinson disease (PD) and Huntington disease (HD) lies in the **primary site of neuronal loss** within the basal ganglia circuit, not merely in the direction of pathway dysregulation.

### Pathological Hallmark Comparison

| Feature | Parkinson Disease | Huntington Disease |
|---------|-------------------|--------------------|
| **Primary pathology** | Loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) | Selective loss of medium spiny neurons (MSNs) in the striatum |
| **Neurotransmitter deficit** | Dopamine depletion | GABA and enkephalin depletion |
| **Circuit consequence** | Unopposed indirect pathway activity | Unopposed direct pathway activity |
| **Clinical result** | Hypokinetic (bradykinesia, rigidity) | Hyperkinetic (chorea, dystonia) |

### Circuit Mechanism Explanation

1. **In Parkinson Disease:**
   - Loss of dopamine from SNpc removes inhibition of indirect pathway MSNs
   - Indirect pathway becomes overactive → excessive inhibition of globus pallidus externus (GPe) → disinhibition of subthalamic nucleus (STN) → excessive inhibition of globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr)
   - Result: **excessive thalamic inhibition** → bradykinesia and rigidity

2. **In Huntington Disease:**
   - Selective loss of indirect pathway MSNs (which express D2 receptors and enkephalin)
   - Direct pathway MSNs (D1 receptors) remain relatively preserved
   - Result: **reduced thalamic inhibition** → involuntary movements (chorea)

**High-Yield:** The **anatomical lesion** (SNpc in PD vs. striatum in HD) is the most fundamental and clinically relevant discriminator. This explains why the two conditions produce opposite motor phenotypes despite both involving basal ganglia dysfunction.

**Clinical Pearl:** This is why dopamine replacement (levodopa) helps PD but worsens HD — it strengthens the already-overactive direct pathway in HD.

[cite:Harrison 21e Ch 428]

Answer

B. Excessive inhibition of the thalamus via the direct pathway in Parkinson disease versus reduced inhibition via the indirect pathway in Huntington disease

Answer

C. Hyperactivity of the subthalamic nucleus in Parkinson disease versus hypoactivity of the globus pallidus internus in Huntington disease

Answer

D. Increased GABA release from striatal neurons in Parkinson disease versus decreased GABA release in Huntington disease

A 58-year-old man with Parkinson disease exhibits bradykinesia and rigidity, while a 62-year-old woman with Huntington disease presents with chorea and dystonia. Which neurophysiological feature best distinguishes the pathology of these two conditions in terms of basal ganglia circuit dysfunction?

Explanation

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