PET imaging of alpha-synuclein pathology

About This Grant

Project Summary/Abstract Fibrillar alpha-synuclein (αSyn) aggregates accumulate in dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and multiple systems atrophy (MSA), with distinct topological spread in association with the progression of each disease. While DLB and PD fibrils are structurally similar, MSA fibrils are distinct. PET molecular imaging of amyloid plaques and tau tangles has revolutionized diagnosis, understanding, and clinical trials in Alzheimer’s disease (AD), and PET imaging of αSyn pathologic changes in life has similar potential for these αSyn-associated ADRD that can arise in isolation as well as in association with AD co-pathology. We previously identified SY08 as a molecule that selectively binds αSyn fibrils outside of the ThioT binding site and does not bind αSyn monomer, amyloid-42, or tau fibrils. SY08 binds Lewy body disease brain tissue homogenates with high affinity and with high selectivity over AD tissue, with no significant off target binding to more than 50 CNS targets. Brain [11C]SY08 retention was increased in rodent PD αSyn models. In non-human primates, [11C]SY08 PET imaging showed rapid CNS entry across brain regions; plasma radioactivity analysis showed rapid clearance from blood with limited brain uptake of radiometabolites. In the first-in-human [11C]SY08 PET study (NCT06098612), we detected increased brainstem and cortical binding in PD and DLB, yet limited binding in MSA participants, compared to aged-matched healthy control (HC) participants. Building on these results, the overall goals of this proposal are to 1) evaluate whether fibrillar αSyn burden measured with [11C]SY08 differentiates DLB, PD, and MSA from each other and from HC and AD, and 2) to relate regional [11C]SY08 binding to the expected topology of αSyn pathologic changes and clinical features. As an exploratory aim, we will evaluate if [11C]SY08 binding is increased in isolated REM sleep behavioral disorder (iRBD), a prodromal synucleinopathy state. We hypothesize that [11C]SY08 PET imaging will distinguish DLB, PD, and MSA from HC and from AD participants; that binding in DLB and PD will be higher than in MSA; and that the pattern of [11C]SY08 retention will reflect the distinct topographies of αSyn pathology and the clinical features of each synucleinopathy, without impact of co-morbid amyloid- when present. We also hypothesize that brainstem [11C]SY08 retention will be elevated in iRBD. To accomplish these objectives, we will acquire neurologic exams, detailed cognitive testing, simultaneous [11C]SY08 PET-MRI, and biomarkers of brain amyloid deposition in PD, DLB, and MSA participants with evidence of αSyn pathology on skin biopsy, AD, HC, and participants with isolated RBD. Together, these efforts will establish the potential for developing [11C]SY08 PET as an imaging marker of αSyn pathology in PD, DLB, MSA, and iRBD.