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-[ 18 F]-dopamine ( 18 F-DA) to track myocardial uptake and retention of catecholamines. Concurrently, the fate of intra-neuronal 18 F-DA was followed by assessment of arterial plasma levels of the 18 F-DA metabolite 18 F-dihydroxyphenylacetic acid ( 18 F-DOPAC). The ratio of myocardial 18 F-DA to arterial 18 F-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 18 F-DA uptake and accelerated 18 F-DA loss, compared with MSA and control subjects. PD-No-OH patients could be subtyped into one of these categories based on their initial 18 F-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.

Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration

“…We used peak arterial F-DOPAC:DHPG as a biomarker of decreased vesicular sequestration in the sympathetic nervous system as whole. We predicted that in PAF and PD+OH, peak arterial F-DOPAC:DHPG would be increased [11], whereas in PD No OH, MSA-P, status post SNS-x, or AAG, peak arterial F-DOPAC:DHPG would be normal. If generalized loss of sympathetic noradrenergic nerves were associated with a vesicular storage defect, regardless of the specific disease, then across conditions peak F-DOPAC:DHPG in arterial plasma would be related inversely to arterial plasma DHPG. In PD without orthostatic hypotension (PD No OH), noradrenergic denervation seems to be localized to the heart, whereas PD+OH and PAF involve generalized noradrenergic denervation. We therefore predicted normal peak arterial plasma F-DOPAC:DHPG in PD No OH.…”

“…We used peak arterial F-DOPAC:DHPG as a biomarker of decreased vesicular sequestration in the sympathetic nervous system as whole. We predicted that in PAF and PD+OH, peak arterial F-DOPAC:DHPG would be increased [11], whereas in PD No OH, MSA-P, status post SNS-x, or AAG, peak arterial F-DOPAC:DHPG would be normal.…”

“…In PD, indices of catecholaminergic denervation and decreased vesicular storage are linked, both in putamen dopaminergic terminals [8, 10, 11] and in sympathetic nerves [5, 12, 13]. …”

“…Moreover, although most MSA patients have intact cardiac noradrenergic innervation [19], a minority have denervation [20–22], and a recently reported case of MSA-P with cardiac sympathetic denervation had post-mortem neurochemical evidence for a vesicular storage defect both in the putamen and myocardium [23]. Pure autonomic failure (PAF), a rare but scientifically important Lewy body disease [24, 25] manifesting with neurogenic orthostatic hypotension, also features deficient vesicular storage in the residual noradrenergic nerves [13]. …”

Recognition and treatment of autonomic disturbances in Parkinson’s disease

“…Cardiac MIBG can reliably discriminate PD from MSA, even between PD with profound autonomic dysfunction and MSA with predominant Parkinsonism [62,63]. In addition, cardiac 18F-DA uptake has also been proven an effective tool in differentiating PD from MSA [64].…”