Separable, symptom specific alterations in brain microstructure associated with early-stage Parkinson's disease

Parkinson's Disease (PD) is diagnosed based on motor symptoms (bradykinesia, resting tremor, rigidity); yet non-motor symptoms such as sleep abnormalities, autonomic dysfunction, and cognitive changes often precede motor signs, fulfilling the criteria for prodromal PD. How motor and non-motor symptoms emerge from dopamine depletion and whether they involve separable neural substrates remains unclear.

We applied correlational tractography based on multi-shell, diffusion-weighted magnetic resonance imaging in early-stage PD to assess microstructural changes throughout the brain. Eight participants with early-stage PD and 5 healthy controls underwent motor, cognitive, and mood 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.

Correlational tractography delineated both microstructural changes that held either a significant positive or negative association with PD status, where the statistical maps of these changes linked differentially to motor and non-motor symptoms. Quantitative anisotropy (QA) extracted from positively associated fibers significantly correlated with cognitive function, while QA of negatively associated fibers correlated with motor function-independent of the effect of age. Of note, QA of positively associated fibers correlated with depressive mood only in the age-uncorrected analyses, suggesting a strong age-related effect.

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.