Cardioselective peripheral noradrenergic deficiency in Lewy body synucleinopathies

Abstract

Objective: Lewy body (LB) synucleinopathies such as Parkinson's disease (PD) entail profound cardiac norepinephrine deficiency. The status of sympathetic noradrenergic innervation at other extracranial sites has been unclear. Although in vivo neuroimaging studies have indicated a cardioselective noradrenergic lesion, no previous study has surveyed peripheral organs for norepinephrine contents in LB diseases. We reviewed 18 F-dopamine (18 F-DA) positron emission tomographic images and postmortem neurochemical data across several body organs of controls and patients with the LB synucleinopathies PD and pure autonomic failure (PAF) and the non-LB synucleinopathy multiple system atrophy (MSA). Methods: 18 F-DA-derived radioactivity in the heart, liver, spleen, pancreas, stomach, kidneys, thyroid, and submandibular glands were analyzed from 145 patients with LB synucleinopathies (112 PD, 33 PAF), 74 controls, and 85 MSA patients. In largely separate cohorts, postmortem tissue norepinephrine data were reviewed for heart, liver, spleen, pancreas, kidney, thyroid, submandibular gland, and sympathetic ganglion tissue from 38 PD, 2 PAF, and 5 MSA patients and 35 controls. Results: Interventricular septal 18 F-DA-derived radioactivity was decreased in the LB synucleinopathy group compared to the control and MSA groups (P < 0.0001 each). The LB and non-LB groups did not differ in liver, spleen, pancreas, stomach, or kidney 18 F-DA-derived radioactivity. The LB synucleinopathy group had markedly decreased apical myocardial norepinephrine, but normal tissue norepinephrine in other organs. The MSA group had normal tissue norepinephrine in all examined organs. Interpretation: By in vivo sympathetic neuroimaging and postmortem neurochemistry peripheral noradrenergic deficiency in LB synucleinopathies is cardioselective. MSA does not involve peripheral noradrenergic deficiency.

Pathophysiological significance of increased α-synuclein deposition in sympathetic nerves in Parkinson disease: A post-mortem observational study

“…Our results demonstrating sympathetic noradrenergic de ciency in myocardium but not in scalp skin or SMG in PD t with those from a recent organ survey of in vivo neuroimaging and post-mortem neurochemical data indicating that in Lewy body diseases peripheral noradrenergic de ciency is organselective and is most prominent in the heart (21). Understanding bases for the unusual susceptibility of cardiac noradrenergic neurons might provide clues as to the greater vulnerability of nigrostriatal than of other dopaminergic neurons in the brain.…”

“…This was an observational, retrospective, cross-sectional study of coded post-mortem samples from patients with autopsy-proven PD and from control (CTRL) subjects with similar age and sex distributions and no history of a neurodegenerative disease. The numbers of subjects in the two groups that would be required to test the main hypothesis of the study were determined based on previous publications about myocardial NE in Lewy body diseases (20,21). According to a power analysis, for 2 independent study groups, a dichotomous primary endpoint, alpha 0.05, and power 80%, a total of 10 data points per group would be needed.…”

Vagus Nerve Cross-Sectional Area in Patients With Parkinson's Disease—An Ultrasound Case-Control Study

“…Cardiac sympathetic neurons also reside in the vagus nerve and occupy up to 5% of the CSA (26, 27). Cardiac sympathetic neurons are particularly vulnerable in PD (28) and may also contribute to slight vagal atrophy. However, if vagal atrophy is mainly caused by sympathetic and parasympathetic (DMV) axonal loss, the reduction in CSA is probably very small and could explain why three studies failed to show vagal atrophy in PD (20)(21)(22).…”

Vagus nerve cross-sectional area in patients with Parkinson’s Disease – an ultrasound case-control study

“…Cardiac sympathetic neurons also reside in the vagus nerve and occupy up to 5% of the CSA [25, 26]. Cardiac sympathetic neurons are particularly vulnerable in PD and may also contribute to slight vagal atrophy [27]. However, if vagal atrophy is mainly caused by sympathetic and parasympathetic (DMV) axonal loss, the reduction in CSA is probably very small, and could explain why three studies failed to show vagal atrophy in PD [19-21].…”