Dec 4, 2024

Deep brain stimulation halts Parkinson‘s disease-related immune dysregulation in the brain and peripheral blood.

McFleder RL, Musacchio T, Keller J, Knorr S, Petschner T, Chen JZ, Muthuraman M, Badr M, Harder-Rauschenberger L, Kremer F, Asci S, Steinhauser S, Karl AK, Brotchie JM, Koprich JB, Volkmann J, Ip CW.

*equal contribution

Brain Behav Immun. 2025; 123: 851-862.
doi: 10.1016/j.bbi.2024.10.039.
Download summary: ReTune PoM 2024 Nov

Deep brain stimulation (DBS) has long been established as an effective symptomatic treatment for Parkinson’s disease (PD), but its potential impact on immune dysregulation, a significant driver of neurodegeneration, has remained unclear. Our study explored this connection by combining longitudinal patient data from the Parkinson’s Progression Marker Initiative (PPMI) with experiments in a rodent model of PD. We demonstrated that DBS has a broader role beyond motor symptom control, potentially altering the trajectory of PD by addressing immune dysregulation in both the brain and peripheral blood.
We began by analyzing immune cell changes in the PPMI dataset, confirming that circulating lymphocytes progressively decline in PD patients over time. This decline correlated strongly with motor dysfunction severity and could predict future motor symptom progression with an accuracy of 85%. Notably, we discovered that patients receiving DBS exhibited a stabilization in lymphocyte levels, halting the progressive decline observed in non-DBS patients. Detailed flow cytometry analysis revealed that DBS reversed the pro-inflammatory shift in CD4+ T helper cells, particularly reducing the proportion of Th17 cells and restoring the balance between pro-inflammatory Th17 cells and anti-inflammatory regulatory T cells (Tregs). These findings suggest that DBS may counteract systemic immune dysregulation in PD patients.
To extend these observations to the brain, we utilized an AAV-A53T α-synuclein rat model of PD, which replicates the progressive neurodegeneration seen in humans. DBS not only mitigated dopaminergic neuronal loss in the substantia nigra but also reduced neuroinflammation, as evidenced by a significant decrease in the infiltration of CD4+ and CD8+ T cells and the activation of microglia. Bulk RNA sequencing further revealed that DBS suppressed immune-related gene expression in the substantia nigra, shifting the transcriptomic profile away from inflammation and toward homeostasis. Interestingly, these immunomodulatory effects were accompanied by changes in neurotransmitter-related pathways, hinting at complex neuroimmune interactions mediated by DBS. Together, these findings highlight DBS’s dual role in reducing neuroinflammation and restoring peripheral immune balance, suggesting a potential disease-modifying effect. By linking peripheral lymphocyte levels with neurodegeneration and demonstrating that DBS can stabilize both systemic and central immune dysregulation, our findings highlight the potential of utilizing circulating immune cells as biomarkers for assessing the disease-altering effects of PD treatments.

Prof. Rhonda McFleder

Rhonda McFleder is a Junior Professor in Translational Medicine at the Universitätsklinikum Würzburg (UKW). Her research is focused on immune dysregulation in PD and utilizing transcriptomics and molecular techniques to develop treatment strategies to target these immune cells.

Dr. Thomas Musacchio

Thomas Musacchio is a senior physi cian at the Department of Neurology. In addition to his clinial interest in rare genetic movement disorders, his basic research focuses on the translational aspects of DBS from rodents to humans.