Differential patterns of central synucleinopathy and catecholaminergic abnormalities in Lewy body diseases and multiple system atrophy

Introduction: Parkinson's disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA) feature intracellular deposition of alpha-synuclein and catecholamine deficiency in the putamen or heart. This retrospective, cross-sectional, observational study assessed relationships of cerebrospinal fluid alpha-synuclein seed amplification assay (CSF SAA) data with catecholamine deficiency indicated by positron emission tomography (PET). Methods: In groups with PD, PAF, parkinsonian MSA (MSA-P), or cerebellar MSA (MSA-C) SAAs were conducted by Rocky Mountain Laboratories (RML) and Amprion, Inc. using different assay conditions. ¹⁸F-DOPA PET examined putamen dopaminergic innervation, and ¹⁸F-dopamine PET assessed cardiac noradrenergic innervation. Results: CSF SAAs by both RML and Amprion separated PD or PAF from MSA. The Amprion assay detected type 1 seeding associated with Lewy body diseases (LBDs) in 22/24 (92%) PD patients and 15/16 (94%) PAF patients and type 2 seeding associated with MSA in 9/10 (90%) MSA-P and 3/4 (75%) MSA-C patients (p < 0.0001). All of 24 PD and all of 9 MSA-P patients had low putamen/occipital cortex ratios of ¹⁸F-DOPA-derived radioactivity, while 11/13 (85%) PAF patients and 4/4 (100%) MSA-C patients had normal ratios. Contingency analyses of CSF SAA and brain ¹⁸F-DOPA PET efficiently separated the 4 groups (p < 0.0001). Conclusion: CSF SAAs and cardiac ¹⁸F-dopamine PET distinguish LBDs from MSA but not PAF from PD or MSA-P from MSA-C. ¹⁸F-DOPA PET separates PAF from PD and MSA-P from MSA-C. Combining biomarkers differentiates among these synucleinopathies.