Separable, symptom specific alterations in brain microstructure associated with early-stage Parkinsons Disease

Introduction: Parkinson's Disease (PD) is diagnosed based on motor symptoms (bradykinesia, resting tremor, rigidity); yet non-motor symptoms, including sleep abnormalities, autonomic dysfunction, and cognitive changes, often precede motor signs and fulfill the criteria for prodromal PD. How motor and non-motor symptoms emerge from dopamine depletion and whether they involve separable neural substrates remains unclear. Methods: We used correlational tractography based on multi-shell diffusion-weighted magnetic resonance imaging to assess microstructural changes throughout the brain associated with early-stage PD. Eight participants with early-stage PD and 5 healthy controls underwent motor, mood, and cognitive assessments, followed by structural and multi-shell, diffusion-weighted magnetic resonance imaging. Their groupwise differences in white matter integrity associated with PD status were quantified using correlational tractography, with and without age correction. Results: Changes in local microstructure throughout the brain were found to be significantly positively and negatively associated with PD status, with each statistical map being differentially related to the degree of motor and non-motor symptoms. Regression found that quantitative anisotropy (QA) extracted from positively and negatively associated fibers was significantly related to cognitive and motor function, respectively, and robust to participant age. Depressive mood, however, was only related to QA extracted from positively associated fibers in age-uncorrected analyses, suggesting a strong age-related effect. Conclusion: In early-stage PD, motor and non-motor symptoms are mapped to anatomically distinct pathways, suggesting separable pathophysiological mechanisms. These findings further suggest that correlational tractography is appropriate to evaluate changes in structural connectivity in neurodegenerative diseases and, potentially, their therapeutic interventions.