Effect of a multidisciplinary intensive outpatient rehabilitation program on plasma neurofilaments and myokines in Parkinson’s disease: an exploratory analysis

Physical exercise is increasingly recognized as a supportive intervention for people with Parkinson’s disease (PwPD), yet the biological mechanisms underlying its effects remain unclear. This study investigated whether exercise-based rehabilitation modulates circulating biomarkers associated with neuroaxonal integrity, inflammation, and muscle–brain communication. In this randomized controlled substudy, 40 PwPD were assigned to a multidisciplinary intensive outpatient rehabilitation program (experimental group, EXP; n = 20) or a home-based self-managed intervention (control group, CTRL; n = 20). Assessments were performed at baseline (T0), post-treatment (T1), and 3-month follow-up (T2). Clinical outcomes included motor function (UPDRS-III), cognition (MoCA), and functional status (ADL, IADL). Plasma levels of neurofilament light chain (NFL), irisin, interleukin-6 (IL-6), and soluble IL-6 receptor (sIL-6R) were measured. No significant changes over time or between groups were observed in motor or cognitive outcomes. In contrast, significant biomarker modulation was detected. Irisin levels increased in the EXP group at T1 and T2, while decreasing in the CTRL group ( p < 0.01). NFL levels significantly decreased in the EXP group at both time points, whereas an increase was observed at follow-up in the CTRL group. IL-6 remained stable in both groups. sIL-6R levels decreased over time, with a significant group-by-time interaction at T1 ( p = 0.038). No significant correlations emerged between clinical outcomes and biomarkers. Intensive multidisciplinary rehabilitation was associated with significant modulation of circulating biomarkers, despite the absence of clinical changes. Decreased NFL and increased irisin suggest potential neuroprotective and exercise-responsive effects. These findings support the use of plasma biomarkers as sensitive indicators of neurobiological adaptations to rehabilitation in PwPD. Trial registration The original randomized controlled trial (RCT) was registered at ClinicalTrials.gov (Study ID: NCT05452655)