3,4-Dihydroxyphenylglycol levels separate multiple system atrophy from Parkinson disease with orthostatic hypotension

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 < 0.0001) compared to the controls but also tended to be decreased in PD + OH (N = 16, p = 0.0598). Antecubital venous plasma DHPG was decreased in PD + OH (N = 40, p < 0.0001) but also in MSA (N = 59, p = 0.0458). CSF/plasma concentration ratios of DHPG were lower in MSA than in PD + OH (p < 0.0001). Cardiac arteriovenous increments in plasma DHPG and cardiac norepinephrine spillovers were strikingly decreased in PD + OH (N = 6) and were lower than in MSA (N = 20, p < 0.0001 each). Combining cardiac arteriovenous increments in plasma DHPG with norepinephrine spillovers completely separated PD + OH from MSA. Conclusions CSF/plasma ratios of DHPG, cardiac venous-arterial differences in plasma DHPG, and cardiac norepinephrine spillovers separate MSA from PD + OH. From our results we propose that biomarker combinations involving DHPG in biofluids may enable a pathophysiological differential diagnosis of MSA vs. PD + OH.