Hypothesis

We propose that a specific decline in the striatal D1/D2 receptor ratio marks the transition from compensatory network reorganization to functional impairment in habit learning, preceding detectable regional atrophy and predicting Parkinson's disease conversion within three years in individuals with REM sleep behavior disorder.

Mechanistic Basis

• Age‑related D2R loss accelerates in prodromal PD, reducing rebound acetylcholine signaling after stimulus‑evoked pauses (D2R inactivation shortens stimulus-evoked acetylcholine decreases and enhances rebound levels).
• D1R preserves excitatory drive for model‑based action selection, whereas D2R supports automatic stimulus‑response encoding (Putamen tissue iron concentration correlates with habitual decision‑making).
• When D2R falls faster than D1R, the D1/D2 ratio rises, shifting corticostriatal balance toward goal‑directed circuits and weakening habit formation.
• Compensatory volumetric expansions in thalamus and cerebellum initially preserve performance by increasing afferent drive, but this reserve is exhausted once the D1/D2 ratio exceeds a critical point (Distributed volumetric patterns across interconnected motor circuits rather than isolated regional atrophy; D2 receptor expression declines at 0.6% per year in healthy aging but accelerates to 1.8-3% per year in PD patients).

Predictions

1. In a longitudinal RBD cohort, baseline D1/D2 PET ratio will correlate negatively with habit learning accuracy (serial reaction time task) and positively with model‑based behavior scores.
2. Individuals whose baseline ratio exceeds the empirically derived threshold (~1.2) will show a significant decline in habit learning over 12‑month follow‑up, whereas those below the threshold will remain stable.
3. The ratio threshold will predict conversion to clinically definite Parkinson's disease within 36 months with higher sensitivity and specificity than volumetric measures of putamen or thalamic atrophy.
4. Thalamic and cerebellar volumes will show a quadratic relationship with habit learning: increase at low‑to‑moderate ratio (compensation) followed by decline after the ratio passes the threshold.

Experimental Design

• Recruit 120 polysomnography‑confirmed RBD patients without motor symptoms.
• Acquire baseline [^11C] raclopride (D2R) and [^11C] SCH23390 (D1R) PET, structural MRI, and administer a probabilistic classification task to quantify habit versus model‑based learning.
• Follow participants annually for up to three years, repeating PET/MRI and behavioral assessments.
• Define conversion as emergence of two cardinal motor signs confirmed by neurologist blinded to imaging.
• Statistical plan: logistic regression with baseline D1/D2 ratio, habit learning slope, and thalamic/cerebellar volume as predictors of conversion; ROC analysis to determine optimal ratio cutoff; mixed‑effects models to test trajectory differences between high‑ and low‑ratio groups.

Potential Outcomes

• If the high‑ratio group shows accelerated habit learning decline and higher conversion rates, the hypothesis is supported, establishing the D1/D2 ratio as a prodromal biomarker and mechanistic link between receptor loss and network compensation failure.
• If no difference is observed, the hypothesis is falsified, suggesting that either compensatory mechanisms are independent of receptor ratio or that other neurotransmitter systems dominate the pre‑atrophy phase.