Fluorodopamine-derived Radioactivity Research Articles

Sympathetic innervation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson's disease.

Cardiac sympathetic denervation occurs commonly in Parkinson's disease. This study explored whether analogous denervation occurs in primates with Parkinsonism from systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 6-[18F]Fluorodopamine positron emission tomographic scanning and plasma levels of catecholamines and their deaminated metabolites were used to assess sympathetic and adrenomedullary function in rhesus monkeys, in the untreated state (n = 3), 2 weeks after a series of four MPTP injections, before establishment of Parkinsonism (acute phase, n = 1); a month later, after four more MPTP doses, associated with severe Parkinsonism (subacute phase, n = 1); or more than 2 years from the last dose (remote phase, n = 3), with persistent severe Parkinsonism. A positive control received i.v. 6-hydroxydopamine 1 week before 6-[18F]fluorodopamine scanning. Acute MPTP treatment increased cardiac 6-[18F]fluorodopamine-derived radioactivity, whereas 6-hydroxydopamine markedly decreased cardiac radioactivity, despite similarly low plasma levels of catecholamines and metabolites after either treatment. Subacutely, plasma catecholamines remained decreased, but now with myocardial 6-[18F]fluorodopamine-derived radioactivity also decreased. Remotely, MPTP-treated monkeys had lower plasma catecholamines and higher myocardial 6-[18F]fluorodopamine-derived radioactivity than did untreated animals. The results indicate that in nonhuman primates, systemic MPTP administration produces multiphasic effects on peripheral catecholamine systems, with nearly complete recovery by 2 years. MPTP- and 6-hydroxydopamine-induced changes differ markedly, probably from ganglionic or preganglionic neurotoxicity with the former and more severe cardiac sympathetic neurotoxicity with the latter. Because of multiphasic sympathetic and adrenomedullary effects, without cardioselective sympathetic denervation at any time, the primate MPTP model does not mimic the changes in peripheral catecholamine systems that characterize the human disease.

Neurotransmitter specificity of sympathetic denervation in Parkinson's disease.

In PD, orthostatic hypotension reflects sympathetic noradrenergic denervation. The authors assessed sympathetic cholinergic innervation by the quantitative sudomotor axon reflex test (QSART) in 12 patients who had sympathetic neurocirculatory failure, markedly decreased cardiac 6-[18F] fluorodopamine-derived radioactivity, and subnormal plasma norepinephrine increments during standing. All 12 had normal QSART results. The sympathetic nervous system lesion in PD involves loss of postganglionic catecholaminergic but not cholinergic nerves.

Local sympathetic denervation in painful diabetic neuropathy.

This study assessed whether painful diabetic neuropathy is associated with abnormal sympathetic nervous function in the affected limbs. Nine patients with diabetes (four men, five women; age 61 +/- 7 years) and painful peripheral neuropathy of the feet, but without evidence of generalized autonomic neuropathy, underwent intravenous infusion of tritiated norepinephrine (NE) and sampling of arterial and venous blood in both feet and in one arm to quantify the rate of entry of NE into the local venous plasma (NE spillover). In the same patients, positron emission tomography (PET) scanning after intravenous injection of the sympathoneural imaging agent 6-[(18)F]fluorodopamine was used to visualize sympathetic innervation and after intravenous [(13)N]ammonia to visualize local perfusion. The results were compared with those in the feet of normal volunteers and in an unaffected foot of patients with unilateral complex regional pain syndrome (CRPS). In addition, neurochemical results obtained in painful diabetic neuropathy were compared with those obtained in diabetic control patients with painless neuropathy and diabetic control patients without neuropathy. Local arteriovenous difference in plasma NE levels (DeltaNE(AV)) and NE spillover in the arms did not differ across the groups. However, DeltaNE(AV) in the feet was significantly less in the group with painful diabetic neuropathy than in the control groups. Also NE spillover in the feet tended to be lower in painful neuropathy. DeltaNE(AV) of diabetic control patients without neuropathy (n = 6) resembled values in the control groups without diabetes, whereas patients with painless diabetic neuropathy (n = 6) had evidence suggesting partial loss of sympathetic innervation. PET scanning revealed decreased flow-corrected 6-[(18)F]fluorodopamine-derived radioactivity in patients with painful diabetic neuropathy, compared with values in normal volunteers and patients with CRPS. The results provide neurochemical and neuroimaging evidence for regionally selective sympathetic denervation in the painful feet of patients with diabetic neuropathy.

Progressive loss of cardiac sympathetic innervation in Parkinson's disease.

This study addressed whether cardiac sympathetic denervation progresses over time in Parkinson's disease. In 9 patients without orthostatic hypotension, 6-[(18)F]fluorodopamine positron emission tomography scanning was repeated after a mean of 2 years from the first scan. 6-[(18)F]fluorodopamine-derived radioactivity was less in the second scan than in the first scan, by 31% in the left ventricular free wall and 16% in the septum. In Parkinson's disease, loss of cardiac sympathetic denervation progresses in a pattern of loss suggesting a dying-back mechanism.

Kinetic model for the fate of 6-[18F]fluorodopamine in the human heart: a novel means to examine cardiac sympathetic neuronal function.

After injection of 6-[18F]fluorodopamine, thoracic positron emission tomographic scanning visualizes the sympathetic innervation of the heart. This report introduces a kinetic model that relates 6-[18F]fluorodopamine positron emission tomographic scanning results to specific aspects of cardiac sympathoneural function. Inputs were the 6-[18F]fluorodopamine concentration in arterial blood and the estimated contribution of circulating metabolites of 6-[18F]fluorodopamine. All of the three compartments in the model were intraneuronal. Two compartments corresponded to vesicles in sympathetic nerves, consistent with the "multiple vesicular pool" hypothesis from preclinical studies. The model successfully fit the empirical time-activity curve for myocardial 6-[18F]fluorodopamine-derived radioactivity and predicted correctly the effects of several neuropharmacological and physiological manipulations on the time-activity curve. Myocardial cell uptake of metabolites of 6-[18F]fluorodopamine from the circulation could explain an immediate peak of 6-[18F]fluorodopamine-derived radioactivity. The model seems useful in predicting effects of altered cardiac sympathetic function on time-activity curves for myocardial 6-[18F]fluorodopamine-derived radioactivity in humans.

Sympathetic innervation and function in reflex sympathetic dystrophy

Patients with reflex sympathetic dystrophy have posttraumatic pain disproportionate to the injury and spreading beyond the distribution of any single peripheral nerve. We examined sympathetic neurocirculatory function and the role of sympathetic postganglionic nerve traffic in maintaining the pain in 30 patients with reflex sympathetic dystrophy. Most had had the condition for more than 1 year, and 14 had undergone sympathectomy for the pain. Positron emission tomographic scanning after administration of 13N-ammonia was used to assess local perfusion, and 6-[18F]fluorodopamine was used to assess sympathetic innervation. Rates of entry of norepinephrine in the regional venous drainage (spillovers) and regional plasma levels of L-dihydroxyphenylalanine (the immediate product of the rate-limiting enzymatic step in norepinephrine biosynthesis) and dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) were measured with and without intravenous trimethaphan for ganglion blockade. 13N-Ammonia-derived radioactivity was less on the affected side than on the unaffected side, whereas 6-[18F]fluorodopamine-derived radioactivity was symmetrical. Thus, perfusion-adjusted 6-[18F]fluorodopamine-derived radioactivity was higher on the affected side. Norepinephrine spillover and arteriovenous increments in plasma levels of L-dihydroxyphenylalanine and dihydroxyphenylglycol did not differ significantly between affected and unaffected limbs, although 4 patients had noticeably less norepinephrine spillover and smaller arteriovenous increments in plasma dihydroxyphenylglycol on the affected side. Trimethaphan decreased the pain in only 2 of 12 nonsympathectomized patients. The results indicate that patients with chronic unilateral reflex sympathetic dystrophy have decreased perfusion of the affected limb, symmetrical sympathetic innervation and norepinephrine synthesis, variably decreased release and turnover of norepinephrine in the affected limb, and failure of ganglion blockade to improve the pain in most cases. These findings suggest augmented vasoconstriction, intact sympathetic terminal innervation, possibly impaired sympathetic neurotransmission, and pain usually independent of sympathetic neurocirculatory outflows.

Sympathetic cardioneuropathy in dysautonomias.

The classification of dysautonomias has been confusing, and the pathophysiology obscure. We examined sympathetic innervation of the heart in patients with acquired, idiopathic dysautonomias using thoracic positron-emission tomography and assessments of the entry rate of the sympathetic neurotransmitter norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover). We related the laboratory findings to signs of sympathetic neurocirculatory failure (orthostatic hypotension and abnormal blood-pressure responses associated with the Valsalva maneuver), central neural degeneration, and responsiveness to treatment with levodopa-carbidopa (Sinemet). Cardiac scans were obtained after intravenous administration of 6-[18F]fluorodopamine in 26 patients with dysautonomia. Fourteen had sympathetic neurocirculatory failure--three with no signs of central neurodegeneration (pure autonomic failure), two with parkinsonism responsive to treatment with levodopa-carbidopa, and nine with central neurodegeneration unresponsive to treatment with levodopa-carbidopa (the Shy-Drager syndrome). The rates of cardiac norepinephrine spillover were estimated on the basis of concentrations of intravenously infused [3H]norepinephrine during catheterization of the right side of the heart. Patients with pure autonomic failure or parkinsonism and sympathetic neurocirculatory failure had no myocardial 6-[18F]fluorodopamine-derived radioactivity or cardiac norepinephrine spillover, indicating loss of myocardial sympathetic-nerve terminals, whereas patients with the Shy-Drager syndrome had increased levels of 6-[18F]fluorodopamine-derived radioactivity, indicating intact sympathetic terminals and absent nerve traffic. Patients with dysautonomia who did not have sympathetic neurocirculatory failure had normal levels of 6-[18F]fluorodopamine-derived radioactivity in myocardium and normal rates of cardiac norepinephrine spillover. The results of 6-[18F]fluorodopamine positron-emission tomography and neurochemical analyses support a new clinical pathophysiologic classification of dysautonomias, based on the occurrence of sympathetic neurocirculatory failure, signs of central neurodegeneration, and responsiveness to levodopa-carbidopa.

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There is substantial interest in identifying biomarkers to detect early Parkinson disease (PD). Cardiac noradrenergic denervation and attenuated baroreflex-cardiovagal function occur in de novo PD, but whether these abnormalities can precede PD has been unknown. Here we report the case of a patient who had profoundly decreased left ventricular myocardial 6-[18F]fluorodopamine-derived radioactivity and low baroreflex-cardiovagal gain, 4 years before the onset of symptoms and signs of PD. The results lead us to hypothesize that cardiac noradrenergic denervation and decreased baroreflex-cardiovagal function may occur early in the pathogenesis of PD.

Positron emission tomographic imaging of cardiac sympathetic Innervation using 6-[18F]Fluorodopamine: Initial findings in humans

Objectives. This study evaluated the safety, efficacy and validity of 6-[18F]fluorodopamine positron emission tomographic scanning of cardiac sympathetic innervation and function in humans.Methods. Positron emission tomographic (PET) scans, arterial blood and urine were obtained after a 3-min intravenous infusion of 6-[18F]fluorodopamine (1 to 4 mCi, 188 to 809 mCi/mmol) in healthy volunteers, with or without pretreatment with oral desipramine to inhibit neuronal uptake of catecholamines.Results. 6-[18F]Fluorodopamine PET scanning visualized the left ventricular myocardium. Blood pressure increased slightly and transiently. The estimated absorbed radiation dose to the main target organ, the wall of the urinary bladder, was 0.8 to 1.0 rad/mCi of injected 6-[18F]fluorodopamine. By 24 h after the injection, the main 6F-compound in urine was 6F-vanillylmandelic acid, a metabolite of 6F-norepinephrine. Desipramine attenuated accumulation of myocardial 6-[18F]fluorodopamine-derived radioactivity and plasma 6Fdihydroxyphenylacetic acid.Conclusions. 6-[18F]Fluorodopamine produces negligible hemodynamic effects and acceptable radiation exposure at doses that visualize the left ventricular myocardium. Sympathetic nerves take up 6-[18F]fluorodopamine, which is translocated from the axoplasm into storage vesicles, where is it beta-hydroxylated to the fluorinated analogue of the sympathetic neurotransmitter norepinephrine. Therefore, the basis for visualization of myocardium after 6-[18F]fluorodopamine injection in humans is radiolabeling by 6-[18F]fluorodopamine and 6-[18F]fluoronorepinephrine of vesicles in sympathetic terminals. 6-[18F]Fluorodopamine PET scanning provides a novel means for assessing sympathetic innervation and function noninvasively in the human heart.