Cardiac sympathetic denervation preceding motor signs in Parkinson disease*

DISCUSSION

In this patient, results of 6-[¹⁸F]fluorodopamine PET scanning indicated cardiac sympathetic denervation 4 years before the clinical onset of PD. Considering that in PD loss of cardiac noradrenergic innervation progresses slowly over years,¹³ and that the patient already had evidence for markedly decreased cardiac noradrenergic innervation at the time of initial evaluation, loss of cardiac sympathetic nerves probably preceded the movement disorder by many more than the 4 years between initial testing and the onset of PD.

The findings in this case fit with previous reports of cardiac noradrenergic denervation in de novo PD and with the concept of a peripheral-to-central and caudal-to-rostral pathogenetic sequence. Orimo and co-workers have noted loss of noradrenergic terminal innervation of the myocardium before loss of cell bodies in sympathetic ganglia in PD.¹⁶

Our patient also had evidence for decreased baroreflex-cardiovagal function 4 years before the movement disorder. The baroreflex is a homeostatic arc, and abnormalities of afferent neurotransmission, central integration by brainstem centers, or vagal efferent pre-ganglionic or post-ganglionic fibers could result in the same clinical laboratory finding of low baroreflex-cardiovagal gain. In particular, the extent to which baroreflex-cardiovagal failure in PD reflects a brainstem lesion, as opposed to an afferent lesion or loss of parasympathetic cholinergic efferents, remains unknown. The results in our patient are consistent with the view that baroreflex-cardiovagal function worsens over years before the onset of PD.

Chronic constipation, which also preceded parkinsonism in our case, would be consistent with early dysregulation of gastrointestinal autonomic function. Accumulations of alpha-synuclein in enteric neurons and in the dorsal motor nucleus of the vagus nerve, the central neural site of origin of parasympathetic innervation of much of the gastrointestinal tract, has been reported to be an early pathological finding.³ As noted above, however, the occurrence of central neural pathology would not exclude a concurrent afferent or efferent lesion, and studies have found Lewy bodies in the myenteric plexus of both the esophagus and colon,⁹ as well as loss of enteric dopaminergic neurons in PD with chronic constipation.¹⁹

Evidence for abnormalities of the sympathetic norad renergic and parasympathetic cholinergic components of the autonomic nervous system in our patient occurred without evidence for compromised adrenomedullary function. On the contrary, the patient had augmented plasma epinephrine responses to glucagon injection, both upon initial evaluation and at follow-up. The patient therefore did not appear to have diffuse loss of catecholaminergic cells. Although studies have noted decreased adrenomedullary catecholamine concentrations in patients with severe PD,^7,20,21 plasma levels of epinephrine and its O-methylated metabolite, metanephrine, have been reported to be normal.¹⁰

Combined cardiac sympathetic denervation (with attendant denervation supersensitivity), baroreflex-cardiovagal hypofunction, and adrenomedullary hyper-responsiveness might explain the symptoms and signs of cardiovascular instability, such as episodic hypertensive paroxysms, tachycardia, palpitations, and chest pain despite normal coronary arteries, that led to clinical suspicion of pheochromocytoma in this patient.

The results in this case lead us to propose that cardiac sympathetic denervation and decreased baroreflex-cardiovagal gain may be biomarkers of early autonomic involvement in PD. Studies in progress about autonomic function in relatives of patients with familial PD should help test this hypothesis.