Immunologic and Imaging studies with TNF Therapy in Prodromal Synucleinopathies - Project Summary Immunologic and Imaging studies with TNF Therapy in Prodromal Synucleinopathies is a pioneering, prospective, randomized, double-blind parallel group study designed to assess the potential of anti- TNF (adalimumab) to slow or prevent the emergence of motor and cognitive symptoms of synucleinopathy. The trial is based on data from our ASAP grant where we integrated single-cell genomics analysis and observed T-cell pleocytosis in the CSF of RBD patients and an increase in circulating inflammatory central memory Th17 cells in RBD similar to other autoimmune diseases. In CSF of RBD and PD patients, we observed increases in activated non-classical monocytes with upregulated TNFR2 and TNF-mediated signaling pathways indicating increased CNS inflammation. Core funding for PRISMS was provided by a grant from the Marcus Foundation, AbbVie is providing drug, and the study is being carried out with the Parkinson Study Group. 100 subjects with polysomnographically-proven RBD who have not been diagnosed with either PD or DLB will be randomized 1:1 to receive anti-TNF or placebo for two years. In addition to clinical assessments, subjects will undergo multimodal neuroimaging studies and will be given a body-attached wearable biosensor. The core trial funding for PRISMS is sufficient to support conduct of site activities, including clinical outcome measures, MRI and dopamine transporter (DaT) scans, collection of biological samples, trial operations, oversight and regulatory reporting. In this proposal, we are requesting funding to support novel interrogation of the immune cell populations (in vivo perturb seq) and clinical imaging. Specifically, we propose to perform: Aim 1) immunophenotyping with single-cell RNA-Seq, characterization of FoxP3 regulatory CD4 T cells, and evaluation of the soluble markers of inflammation and neurodegeneration in CSF of a subset of 30 subjects and in blood of the entire study population; Aim 2) FDG-PET scans for assessment of brain metabolic activity using the statistical parametric methods, structural integrity of brain dopaminergic systems using Dopamine Transporter SPECT imaging to evaluate dopamine nerve cell terminals, and neuromelanin-MRI to assess catecholaminergic cell bodies. While the clinical trial will test the hypothesis that prodromal PD as manifest with RBD is inflammatory mediated by TNF whether the treatment approach is successful, the proposal will provide deep mechanistic insight into the role of the TNF pathway in the progression of synucleinopathies.
