Longitudinal dynamics of clinical and neurophysiological changes in parkinson’s disease over four and a half years

Parkinson's disease (PD) is a clinically heterogeneous neurodegenerative disorder whose trajectory is shaped by progressive motor impairment and cortical dysfunction. However, longitudinal studies integrating clinical scales with direct neurophysiological assessments remain scarce. In this 4.5-year cohort study, we conducted one of the longest clinical-electrophysiological follow-ups in PD to date, evaluating 22 patients across early and advanced stages using both Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores and transcranial magnetic stimulation (TMS). We demonstrate that the cortical silent period (CSP), a marker of GABAergic inhibition, progressively lengthens over time and is associated with motor decline, suggesting its potential as a dynamic biomarker of disease progression. Resting motor threshold (rMT) and motor asymmetry also deteriorated longitudinally, with changes most pronounced following the COVID-19 pandemic-suggesting that environmental stressors may accelerate PD pathophysiology. Unlike prior short-term studies, our findings reveal persistent cortical reorganization over several years, independent of sex, and underscore the clinical relevance of TMS-derived metrics in tracking disease progression. These findings suggest that CSP may serve as a non-invasive and scalable biomarker for monitoring Parkinson's disease progression and informing neurophysiological endpoints in future therapeutic studies.