Synucleinopathy-like clinical features and biologically defined synuclein seeding in PSP-Parkinsonism: an imperfect match.

Whether synucleinopathy-like (syn-like) symptoms match biologically defined synuclein seeding in PSP-parkinsonism (PSP-P) vs. Parkinson's disease (PD) remains unexplored. We studied 80 subjects: 20 PSP-P, 20 PSP-Richardson-syndrome(PSP-RS), 20 PD, and 20 controls(CS). Procedures included specific smell-testing, structured interview by a sleep specialist, orthostatic-stress test, specific dysautonomia scale, CSF-α-synuclein seed-amplification-assay (asyn-SAA) and neurofilament-levels (NfL). Frequency of syn-like symptoms was low in CS and PSP-RS, intermediate in PSP-P, and high in PD. Premotor probable-RBD and orthostatic hypotension favoured PD, whereas probable-RBD after motor onset and higher pupillomotor dysautonomia scale scores predominated in PSP groups. NfL peaked in PSP-RS, not differing among PSP-P, PD and CS. asyn-SAA was 100% positive in PD, 100% negative in CS and PSP-RS, and positive in 24% PSP-P. Not all clinically syn-like PSP-P cases were asyn-SAA positive, and vice versa. In summary, while partly overlapping with PD (including mild neurodegeneration as per NfL), syn-like symptoms do not always match biologically defined synuclein seeding in PSP-P.