Cardiac sympathetic denervation preceding motor signs in Parkinson disease

Abstract

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-[ 18 F]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.In Parkinson disease (PD), by the time the movement disorder develops, most of the nigrostriatal dopamine terminals have been lost. Identification of biomarkers of PD should improve early diagnosis and spur development of effective treatments.Correspondence: David S. Goldstein, MD, PhD, Clinical Neurocardiology Section, NINDS, NIH, 10 Center Drive MSC-1620, Building 10, Room 6N252, Bethesda, MD 20892-1620; goldsteind@ninds.nih.gov. No author conflicts of interest were reported in the original publication of this article. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptBraak has proposed a pathogenetic sequence beginning outside the brain, with invasion of peripheral, vulnerable autonomic neurons, followed by alpha-synucleinopathy in lower brainstem nuclei and then by alpha-synucleinopathy in the midbrain substantia nigra and then finally in the cerebral cortex. 3,4 Consistent with early involvement of peripheral autonomic or lower brainstem centers, several studies of de novo PD have reported evidence of cardiac noradrenergic denervation 5,8,14,22 or of decreased baroreflex-cardiovagal function. 1,2,6,14,18 Whether these abnormalities can actually precede symptomatic PD has been unknown. Here we report the case of a patient who had cardiac noradrenergic denervation, detected by 6-[ 18 F]fluorodopamine positron emission tomography, and decreased baroreflex-cardiovagal gain, detected by abnormal beat-to-beat blood pressure and heart rate responses to the Valsalva maneuver, 4 years before the clinical onset of PD. CASE REPORTA 56-year-old man was referred for possible pheochromocytoma, based on episodic hypertensive episodes and symptoms suggesting excessive catecholamine effects.He had no serious health problems until about 1998, when he began to experience malaise and exercise intolerance and episodes of hypertension or hypotension, palpitations, and chest tightness. He also had a long history of constipation and dyspepsia, a tendency to urinary retention, and complained of a sense of fullness in the left neck. The patient's career was in marketing and business development, until he quit work due to his symptoms. His mother had died of PD. Cardiac catheterization showed normal coronary arteries. Gastrointestinal endoscopy was unrevealing. Biochemical testing showed elevated plasma levels and urinary excretion of epin...

Arterial Baroreflex Dysfunction Fails to Mimic Parkinson’s Disease in Rats

“…Previous investigators have observed ABR dysfunction in PD, which may precede the development of behavioral and motor symptoms of PD (14,15). These clinical observations provided the impetus for our current investigation of the potential for SAD-induced ABR dysfunction to cause PD.…”

“…For example, orthostatic hypotension is a common symptom of cardiovascular dysfunction in patients with PD, which appears to arise from a combination of vasomotor-, cardiac sympathetic-, and baroreflex-dysfunction (13). Importantly, attenuated baroreflex function in PD may even precede the behavioral and motor symptoms of PD (14,15). To our knowledge, no studies have focused on the effects of ABR dysfunction on behavior and motor function.…”

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“…A way to test the catecholaldehyde hypothesis would be to determine if inhibiting MAO-A slows catecholaminergic neurodegeneration, as assessed by neuroimaging (Goldstein et al, 2007) or neurochemical (Goldstein et al, 2012a) biomarkers.…”

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“…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 F]-dopamine ( 18 F-DA) (4). Since striatal dopaminergic and cardiac sympathetic denervation develop over the course of several years (5,6), understanding the underlying pathologic processes could allow for early identification of individuals at risk for PD and therefore provide an opportunity for neuroprotective intervention.…”