There is growing recognition that Parkinson disease (PD) is a generalized disorder that, in addition to its well-characterized motor symptoms, involves prominent non-motor manifestations such as dementia, depression, anosmia, and autonomic nervous system failure. Indeed, approximately 90% of PD patients exhibit signs of failure of one or more components of the autonomic nervous system (1
); for example, post mortem neuropathologic studies have demonstrated profound sympathetic denervation within the cardiac tissues of a substantial proportion of PD patients (2
). Consistent with this, neuroimaging evidence of cardiac sympathetic denervation has been found in all PD patients with orthostatic hypotension (PD+OH; also known as PD with postural hypotension) analyzed (3
); however, a substantial proportion of PD patients without OH (PD-No-OH) lack evidence of such denervation and have near-normal myocardial neuron uptake of the sympathetic imaging agent 6-[18
). Since striatal dopaminergic and cardiac sympathetic denervation develop over the course of several years (5
), understanding the underlying pathologic processes could allow for early identification of individuals at risk for PD and therefore provide an opportunity for neuroprotective intervention.
Although genetic contributions to PD have been identified within familial disease, none account for the vulnerability of the very specific subset of central and peripheral neurons that utilize monoamine neurotransmitters. The selective loss of catecholaminergic striatal dopaminergic and cardiac noradrenergic neurons, however, suggests that a common pathophysiological process may be attacking both tissues.
Dopaminergic neurons in the brain can be studied in vivo using 18
F-labeled dihydroxyphenylalanine (18
F-DOPA). Although denervation implies a decreased overall 18
F-DOPA signal, it does not explain the results of kinetic studies that show faster removal of 18
F-DOPA–derived radioactivity in the putamen of PD patients (7
). A compensatory increase in pathway traffic to residual dopaminergic terminals, by acting to maintain transmitter delivery to dopamine receptors, has been proposed to explain these data (7
); however, we hypothesize that, instead, decreased vesicular sequestration results in increased deamination of cytosolic 18
F-DA. In this study, we have compared the existing model with our hypothesis using what we believe to be a novel combined neuroimaging-neurochemical approach capable of distinguishing between increased release and decreased vesicular uptake as determinants of accelerated loss of neuronal catecholamines.
Our technique monitors the alternative paths of 18
F-DA, an excellent substrate for uptake into neurons that express cell membrane catecholamine transporters, in cardiac noradrenergic nerves (Figure ). During a 3-minute i.v. administration of 18
F-DA, plasma levels of the tracer rapidly increase; and during a short interval after termination of the infusion, plasma levels rapidly decline (9
). Within this window, sympathetic nerves take up tracer from the circulation via the cell membrane norepinephrine transporter. Cytosolic 18
F-DA has only two fates: vesicular uptake via the vesicular monoamine transporter (VMAT) or oxidative deamination by monoamine oxidase (MAO) to form 18
F-dihydroxyphenylacetic acid (18
F-DOPAC), which is then rapidly extruded from the cell. Vesicular uptake normally predominates over oxidative deamination (Figure A) (10
). Radioactivity is thus retained in neurons due to (a) effective reuptake by the VMAT of any 18
F-DA that leaks passively into the cytosol, preventing its metabolism by MAO; and (b) neuronal reuptake of any released vesicular 18
F-DA, preventing its extra-neuronal metabolism or entry into the circulation.
Concept diagram for the effects of denervation and decreased vesicular sequestration on the uptake and fate of 18F-DA.
The ratio of retained 18F-DA to released 18F-DOPAC acts as an index of vesicular transport (IVT). Neuronal degeneration alone would decrease both measures proportionately (Figure B), yielding lower absolute signals but with a constant IVT. In contrast, decreased VMAT activity would be expected to diminish retention of 18F-DA and increase release of 18F-DOPAC (Figure C), decreasing the IVT. A combination of the two deficits would produce a decreased radioactive signal as well as a low IVT (Figure D).
Using this method, we compared patients with PD and patients with other diseases manifest by varying overlapping symptoms (Figure ) to determine whether the diseases involve cardiac sympathetic denervation or abnormal neuronal catecholamine handling. Two rare patients with PD+OH — one with an A53T mutation of the α-synuclein gene that is known as PARK1 and one with triplication of the normal α-synuclein gene that is known as PARK4 — were tested to look for correlation with α-synucleinopathy. To determine whether changes were more generally characteristic of Lewy body diseases, we tested patients with pure autonomic failure (PAF). PAF is a rare but scientifically important Lewy body disease (14
) that features cardiac and extracardiac sympathetic denervation (15
) and neurogenic OH without parkinsonism. In contrast, multiple system atrophy (MSA) is a non–Lewy body synucleinopathy that can resemble PD+OH clinically (16
). In MSA, aggregates of α-synuclein are characteristically found in glial cytoplasmic inclusions (17
); however, most MSA patients have intact sympathetic noradrenergic innervation (18
). As we describe here, application of our 18
F-DA tracer method to these different patient groups has provided insight into the pathogenesis of cardiac sympathetic denervation in PD.
Venn diagram showing relationships among some α-synucleinopathies.