title: Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases.
abstract: Several neurodegenerative disorders, including Parkinson disease (PD), are characterized by the presence of Lewy bodies - cytoplasmic inclusions containing α-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-[18F]-dopamine (18F-DA) to track myocardial uptake and retention of catecholamines. Concurrently, the fate of intra-neuronal 18F-DA was followed by assessment of arterial plasma levels of the 18F-DA metabolite 18F-dihydroxyphenylacetic acid (18F-DOPAC). The ratio of myocardial 18F-DA to arterial 18F-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 18F-DA uptake and accelerated 18F-DA loss, compared with MSA and control subjects. PD-No-OH patients could be subtyped into one of these categories based on their initial 18F-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.
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland 20892-1620, USA. goldsteind@ninds.nih.gov
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.forename: Courtney
authors.initials: C
authors.lastname: Holmes
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Kopin
authors.forename: Yehonatan
authors.initials: Y
authors.lastname: Sharabi
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D000368:Aged; D002395:Catecholamines / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D005260:Female; D005462:Fluorine Radioisotopes / Q000494:pharmacology; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
chemical_list: D002395:Catecholamines; D005462:Fluorine Radioisotopes; D015102:3,4-Dihydroxyphenylacetic Acid; D003891:Desipramine; D004298:Dopamine