Cardiac Sympathetic Denervation in Parkinson Disease

Orthostatic hypotension is common in Parkinson disease (1). Although earlier studies implicated L-dopa treatment as the cause (2), more recent studies have shown that orthostatic hypotension may result from deficient cardiovascular reflexes that depend on release of the sympathetic neurotransmitter norepinephrine in the heart and blood vessels (3-5). We call this phenomenon sympathetic neurocirculatory failure. Several recent studies have reported decreased myocardial concentrations of radioactivity after injection of the sympathoneural imaging agent 123I-metaiodobenzylguanidine (123I-MIBG) in patients with Parkinson disease (6-13). This finding is consistent with but does not prove cardiac sympathetic denervation. In addition, studies have not specifically considered the possible association between cardiac sympathetic denervation and sympathetic neurocirculatory failure in Parkinson disease. Measures of autonomic function have included blood pressure during tilt-table testing (abnormalities of which can have several causes), heart rate responses to the Valsalva maneuver (which are determined mainly by changes in parasympathetic cholinergic outflow to the heart), or skin conductance or sweating responses (which are determined mainly by alterations in sympathetic cholinergic outflow to the skin). These measures may not allow assessment of sympathetic noradrenergic function. One way to detect sympathetic neurocirculatory failure in a patient with orthostatic hypotension is by analyzing beat-to-beat blood pressure associated with performance of the Valsalva maneuver (Figure 1). In patients with sympathetic neurocirculatory failure, blood pressure decreases progressively during phase II of the maneuver, whereas normally blood pressure plateaus or increases at the end of phase II (phase II-L). In patients with sympathetic neurocirculatory failure, phase IV blood pressure increases slowly back to baseline after release of the maneuver, whereas normally blood pressure overshoots. These abnormalities are a direct result of deficient cardiovascular reflexes that depend on sympathetically mediated release of norepinephrine. In our study, we defined sympathetic neurocirculatory failure as chronic, reproducible orthostatic hypotension associated with abnormal blood pressure responses in both phase II-L and phase IV of the Valsalva maneuver. Figure 1. Heart rate and blood pressure responses to the Valsalva maneuver in a control patient with a history of neurocardiogenic syncope ( left ) and a patient with Parkinson disease and orthostatic hypotension ( right ). Previous studies also have not independently confirmed that a low myocardial concentration of 123I-MIBGderived radioactivity actually reflects cardiac sympathetic denervation in Parkinson disease. Neurochemical findings indicating decreased norepinephrine release, neuronal uptake, turnover, and synthesis in the heart could provide such confirmation. In humans, 6-[18F]fluorodopamine can be used to visualize cardiac sympathetic innervation by positron emission tomographic (PET) scanning (14), which provides excellent spatial and temporal resolution. Since 6-[18F]fluorodopamine is a catecholamine handled in the heart in a manner similar to the way in which norepinephrine is handled (15), PET scanning may allow functional and anatomic assessments of sympathetic cardiac innervation (16). We used PET scanning after injection of 6-[18F]fluorodopamine and neurochemical measurements during cardiac catheterization to answer the following questions: 1) What proportions of patients with Parkinson disease, with or without sympathetic neurocirculatory failure, have decreased myocardial 6-[18F]fluorodopaminederived radioactivity? 2) Does decreased myocardial 6-[18F]fluorodopaminederived radioactivity in Parkinson disease actually reflect cardiac sympathetic denervation, as identified by indices of cardiac norepinephrine release, neuronal uptake, turnover, and synthesis? 3) Does the frequency of cardiac sympathetic denervation differ between groups of patients with Parkinson disease who have sympathetic neurocirculatory failure and those who do not? 4) Does cardiac sympathetic denervation also occur in patients with multiple-system atrophy, a progressive neurodegenerative disease of adults that features autonomic dysfunction and has parkinsonian, cerebellar, or mixed forms (17)? [The diagnosis of multiple-system atrophy is clinical and, except for a typically poor response to L-dopa treatment, can be difficult to distinguish from Parkinson disease.] 5) Is cardiac sympathetic denervation in patients with Parkinson disease related to L-dopa treatment or to disease duration or severity? Methods The Intramural Research Board of the National Institute of Neurological Disorders and Stroke approved the study protocol. All participants provided written informed consent. Participants We included patients with Parkinson disease or multiple-system atrophy who were studied at the National Institutes of Health Clinical Center in Bethesda, Maryland. Twenty-nine patients had Parkinson disease, including 10 who were not receiving or had never received L-dopa. Twenty-four patients had multiple-system atrophy, including 8 who were taking L-dopa at the time of evaluation. For comparison, we used 6-[18F]fluorodopamine PET scan data and, in most cases, cardiac neurochemical data from 7 patients with pure autonomic failure (5 men, 2 women [mean age SE, 60 6 years]) and 33 controls. Of these 33 controls, 22 had a history of neurocardiogenic syncope (4 men, 18 women [mean age, 35 3 years]) and 11 had a history of postural tachycardia syndrome (1 man, 10 women [mean age, 42 4 years]). 6-[18F]fluorodopamine PET scan data were also obtained from 19 normal volunteers. All patients with Parkinson disease were referred by neurologists or movement disorder clinics and fulfilled accepted clinical criteria (18). Parkinson disease was staged by using the HoehnYahr classification. All affected patients had bradykinesia, cogwheel rigidity, and one or more additional parkinsonian features (pill-roll tremor, stooped posture, festinating gait, difficulty initiating movement, masklike face, micrographia, or marked improvement in motor function during treatment with L-dopa). Patients with multiple-system atrophy had at least two parkinsonian features but were not classified in terms of cerebellar, parkinsonian, or mixed subtypes (17). All had gradually progressive parasympathetic failure (manifested by impotence in men, urinary retention or incontinence, constipation, or constant pulse rate) and had one or more additional features of multiple-system atrophy (heat or cold intolerance and decreased sweating, intention tremor or other evidence of cerebellar dysfunction, slurred speech or a history of aspiration, or no or only slight improvement during an adequate trial of L-dopa treatment). Sympathetic neurocirculatory failure was defined as reproducible, chronic orthostatic hypotension (decrease in diastolic pressure of at least 10 mm Hg and in systolic pressure of at least 20 mm of Hg after 3 to 5 minutes of standing), coupled with abnormal responses of beat-to-beat blood pressure associated with the Valsalva maneuver (19). As noted previously, patients with sympathetic neurocirculatory failure usually exhibit a progressive decrease in blood pressure in phase II-L of the maneuver and an absence of a pressure overshoot in phase IV after release of the maneuver. Valsalva Maneuver For the Valsalva maneuver, the patient lay supine with his or her head on a pillow and blew into a plastic or rubber tube connected to a sphygmomanometer, keeping a pressure of 30 mm Hg for 10 to 12 seconds. The response of beat-to-beat blood pressure during phase II-L of the Valsalva maneuver was considered to be normal if the diastolic and mean arterial pressure increased before the end of the straining and abnormal if they decreased. The response during phase IV was considered to be normal if the systolic blood pressure increased progressively to a value exceeding the baseline (measured just before the patient inhaled and then began straining) and abnormal if the systolic pressure did not exceed the baseline. Sympathetic Neuroimaging Patients were positioned in a GE Advance scanner (General Electric, Milwaukee, Wisconsin), with their thoraxes in the gantry. 6-[18F]fluorodopamine (specific activity, 7.4 to 37 MBq/mmol; dose in most cases, 0.037 MBq) was dissolved in approximately 10 mL of normal saline and infused intravenously at a constant rate for 3 minutes. Thoracic PET scanning was performed for up to 3 hours. The tomographic data were divided into intervals of 5 to 30 minutes. Data acquisition was not gated to the electrocardiogram. In most patients, PET scanning was also used to delineate the left ventricular myocardium and assess myocardial perfusion after administration of the perfusion imaging agent 13 N-ammonia. Intravenously injected 13 N-ammonia exits the bloodstream rapidly and enters cells nonspecifically. A few minutes after the injection, the concentration of 13 N-ammoniaderived radioactivity in the left ventricular myocardium exceeds that in the left ventricular chamber, enabling visualization of the myocardium. Myocardial tissue concentrations of 13 N-ammoniaderived radioactivity depend on local perfusion (20). Neurochemical Testing Patients underwent right-heart catheterization for measurements of norepinephrine spillover into coronary sinus plasma and of venousarterial differences in plasma levels of dihydroxyphenylglycol (DHPG) and L-dopa. After placement of arm and right internal jugular venous catheters (the latter advanced into the coronary sinus), a tracer amount of [3H]norepinephrine (levo- [2, 5, 6] [3H]norepinephrine, New England Nuclear, Boston, Massachusetts) was infused intravenously. Coronary sinus blood flow was measured by thermodilution, and arterial and great cardiac venous or coronary sinus blood was sampled