Objective: To explore the potential for an immunologically based intervention to slow evolution of symptoms in persons with prodromal or Stage 2b (Simuni et al. 2024) synucleinopathy.

Background: REM Sleep Behavior Disorder (RBD), a parasomnia characterized by dream enactment, almost universally progresses to Parkinson’s disease or related synucleinopathy (Postuma et al. 2019). There is mounting evidence that synucleinopathic neurodegeneration may be immunologically mediated: brains of persons with synucleinopathies contain activated microglia, CD4 and CD8 T cells (Weiss et al 2022); synuclein-reactive T cells can be found in PD patient blood, even years before diagnosis (Sulzer et al 2017); and increased TNFα levels are seen in PD and RBD (Kim et al. 2020, Zhang et al 2020). Finally, persons treated with TNFα blockers for autoimmune diseases have a reduced PD risk (Peter et al 2017).

Method: We studied 81 subjects, 34 PSG-confirmed RBD; 32 PD (14 without and 18 with RBD); and 15 healthy controls. Clinical assessments included MDS-UPDRS, MoCA and UPSIT; RBD subjects had DaT scans. Single-cell RNA sequencing (scRNA-seq) was performed on blood and CSF leukocytes. Data was used to support the design of a clinical trial.

Results: Subjects’ mean age was 67.7 years; 62% male. There was a mild CSF pleocytosis in CSF of RBD subjects compared to controls (4.2 vs 1.6/μL; p < 0.002). scRNA-seq revealed a novel CSF monocyte population and increased TNFα pathway gene expression. TNFα was elevated in PD and RBD CSF (2.5 vs. 1.9 pg/mL; p < 0.03) compared to controls. Based on these data we designed PRISMS, a proof-of-concept clinical trial to test the hypothesis that TNFα inhibition can slow progression in prodromal PD. 100 subjects will be randomized 1:1 to receive adalimumab or placebo biweekly for two years. Outcomes will include time to achieve milestones of motor or cognitive function loss, rate of change in the Parkinson’s Disease Related Pattern (PDRP) and DaT SPECT imaging studies, other clinical measures, imaging, and fluid biomarkers.

Conclusion: CNS inflammation and activation of the TNFα pathway are important factors in the earliest stages of synucleinopathies. PRISMS will be the first clinical trial to test the hypothesis that inhibition of TNFα can slow evolution of disease signs and symptoms.

References: 1. Kim R, Lee J-Y, Kim H-J, et al. Parkinsonism and Related Disorders 2020;81:1
2. Pervonik M, Rus T, Schindelbeck KA, Eidelberg D. Nature Reviews Neurology 2022;19:73
3. Peter, I. Dubinsky M, Bressman S. et al. JAMA neurology 75, 939
4. Postuma RB, Iranzo A, Nu M et al. Brain 2019: 142; 744
5. Simuni T, Chahine LM, Poston K et al. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024;23:178
6. Sulzer D, Alcalay RN, Garretti F et al. Nature 2017;546:656
7. Weiss F. Garrido AL, Dzamko N, Halliday G. Neurobiology of Disease 2022; 168:105700
8. Zhang H, Wang T, Li Y et al. Parkinsonism and Related Disorders 2020;78:145

« Back to 2024 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/the-potential-for-rational-immune-system-manipulation-to-prevent-emergence-of-synucleinopathy-manifestations-in-persons-with-rem-sleep-behavior-disorder-rbd/