Evaluating long non-coding RNA signatures as biomarkers for inflammatory pathway regulation and rehabilitative outcomes in Parkinson's disease: toward a precision medicine approach.

Approximately 2% of the human genome encodes proteins, while the remaining non-coding regions 19 may play critical roles in human diseases. Among these, long non-coding RNAs (lncRNAs) are 20 emerging as key regulators of gene expression through epigenetic, transcriptional, and post-21 transcriptional mechanisms, and may serve as potential biomarkers. In this pilot study, we investigated 22 lncRNAs in Parkinson's disease (PD) patients undergoing a six-week intensive multidisciplinary 23 rehabilitation program. Plasma samples from 26 PD patients were collected before (T0) and after (T1) 24 the intervention. Array profiling of 84 inflammation- and immunity-related lncRNAs revealed that 25 86% were differentially expressed post-intervention, with 55 upregulated (fold change >2) and 17 26 downregulated. Quantitative PCR confirmed significant upregulation of MALAT1, TUG1, and XIST 27 at T1 (p < 0.05). Plasma IL-1β levels were also significantly reduced after rehabilitation (p = 0.01). A 28 2 significant reduction in UPDRS-III scores was observed at T1 (p = 0.031), reflecting improved motor 29 function; however, no significant correlation was found between clinical changes and molecular 30 findings. These preliminary, hypothesis-generating results suggest that rehabilitation may modulate 31 immune-related lncRNAs and inflammatory markers in PD, providing insights into their regulatory 32 roles in neuroinflammation and potential as biomarkers of response to rehabilitative interventions.