Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases

Several neuro&generative disorders, including Parkinson disease (PD), are characterized by the presence of Lewy bodies cytoplasmic inclusions containing a-synuclein protein aggregates in the affected neurons. A poorly understood feature of Lewy body diseases is loss of sympathetic nerves in the heart and other organs, manifesting as orthostatic hypotension (OH; also known as postural hypotension). We asked whether sympathetic denervation is associated with decreased uptake of catecholamines, such as dopamine and norepinephrine, into storage vesicles within sympathetic neurons. We used 6-[F-18]-dopamine (F-18-DA) to track myocardial uptake and retention of catecholamines. Concurrently, the fate of intra-neuronal F-18-DA was followed by assessment of arterial plasma levels of the F-18-DA metabolite F-18-dihydroxyphenylacetic acid (F-18-DOPAC). The ratio of myocardial F-18-DA to arterial F-18-DOPAC provided an index of vesicular uptake. Tracer concentrations were measured in patients with PD with or without orthostatic hypotension (PD+OH, PD-No-OH); in patients with pure autonomic failure (PAF, a Lewy body disease without parkinsonism); in patients with multiple system atrophy (MSA, a non-Lewy body synucleinopathy); and in normal controls. Patients with PD+OH or PAF had decreased vesicular F-18-DA uptake and accelerated F-18-DA loss, compared with MSA and control subjects. PD-No-OH patients could be subtyped into one of these categories based on their initial F-18-DA uptake. We conclude that sympathetic denervation in Lewy body diseases is associated with decreased vesicular uptake of neuronal catecholamines, suggesting that vesicular monoamine transport is impaired. Vesicular uptake may constitute a novel target for diagnosis, treatment, and prevention.