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: David S Goldstein, Courtney Holmes, Irwin J Kopin, Yehonatan Sharabi
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 121 Issue 8 Pg. 3320-30 (Aug 2011) ISSN: 1558-8238 [Electronic] United States
• PMID: 21785221 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Catecholamines
• Fluorine Radioisotopes
• 3,4-Dihydroxyphenylacetic Acid
• Desipramine
• Dopamine

Topics

• 3,4-Dihydroxyphenylacetic Acid (pharmacology)
• Aged
• Catecholamines (metabolism)
• Cytosol (metabolism)
• Desipramine (pharmacology)
• Dopamine (pharmacology)
• Female
• Fluorine Radioisotopes (pharmacology)
• Humans
• Lewy Body Disease (metabolism)
• Male
• Middle Aged
• Models, Biological
• Myocardium (metabolism)
• Neurons (metabolism, pathology)