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Abstract Background The autonomic synucleinopathy multiple system atrophy (MSA) can be difficult to distinguish clinically from Parkinson disease with orthostatic hypotension (PD + OH). 18F-Dopamine positron emission tomography separates these conditions based on cardiac noradrenergic deficiency in PD + OH and not in MSA but is available only at the NIH Clinical Center. 3,4-Dihydroxyphenylglycol (DHPG) is the main neuronal metabolite of norepinephrine. This retrospective observational study examined whether DHPG levels in cerebrospinal fluid (CSF) or plasma differentiate MSA from PD + OH. Methods We reviewed CSF and plasma neurochemical data from all patients referred for evaluation at the NIH Clinical Center between 1995 and 2024 for chronic autonomic failure or parkinsonism. A concurrently studied comparison group were healthy volunteers or patients with orthostatic intolerance. Results CSF DHPG was decreased in MSA (N = 46, p
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