Motor fluctuations in Parkinson's disease leave a distinct immune fingerprint in blood

Neuroinflammation is increasingly implicated in PD. Peripheral immune alterations are well described, but their link to motor complications, particularly ON-OFF fluctuations, remains unstudied. We hypothesized that such fluctuations act as intermittent stressors, transiently modulating peripheral immunity.

To investigate the immunological impact of motor fluctuations in PD by analyzing blood transcriptomic signatures during motor state transitions.

Whole-blood transcriptomic profiling with Clariom D arrays was performed in fluctuating PD (PD-Fluc) patients during OFF and ON dopaminergic states to identify relevant genes and pathways. Four natural killer (NK) cell-related genes were validated by qPCR in an expanded cohort: PD-Fluc, non-fluctuating PD (PD-NonFluc), and controls. Motor status (MDS-UPDRS III) was evaluated before each blood draw.

Transcriptomic analysis identified 737 transcripts differentially expressed in ON vs. OFF states in PD-Fluc patients, with NK cell-related genes among the most prominently downregulated in the ON state. Gene set enrichment analysis (GSEA) further supported the downregulation of NK cell-mediated cytotoxicity pathways. qPCR validation confirmed state-dependent modulation of ADGRG1 and PRF1 genes in PD-Fluc patients, an effect absent in PD-NonFluc patients following dopaminergic treatment. Moreover, the expression levels of these genes were able to discriminate PD-Fluc from PD-NonFluc patients, highlighting their potential as molecular markers for disease stratification.

Motor fluctuations in PD drive dynamic changes in peripheral immunity, including up-regulation of NK cell-related genes in the OFF state, which reflects fluctuating immune activation states. These findings underscore the need for early and sustained control of motor fluctuations to protect neurological and immune integrity.