Multiple system atrophy (MSA) is characterized by severe autonomic failure and life-threatening respiratory manifestations. We have shown that there is a marked depletion of catecholaminergic (tyrosine hydroxylase, TH, positive) neurons in the rostral and caudal ventrolateral medulla (VLM) in patients with MSA. The objective of this project is to test the hypothesis that other neurochemically defined neuronal groups in the VLM, implicated in sympathetic, cardiovagal and respiratory control, are also affected in patients with MSA. We will perform quantitative analysis of VLM neuronal populations reactive for TH, NADPH diaphorase, acetylcholinesterase, choline-acetyltransferase (CAT), angiotensin II type I (AT1R) and mu opioid receptors (MOR) in medullae obtained at postmortem from patients evaluated at the Mayo Clinic for autonomic failure, and possible MSA, as compared to age- and sex- matched controls and patients with other forms of parkinsonism. The three specific aims are: (1) to determine whether loss of AT1R neurons in the VLM correlates with the presence of orthostatic hypotension; (2) to determine whether loss of CAT neurons in the nucleus ambiguus correlates with cardiovagal failure; and (3) to determiner whether MSA patients with respiratory dysfunction have loss of NADPH- and MOR- reactive neurons in the VLM. We plan to study approximately 5-7 cases/year, including (1) 2-4 cases with no history of neurologic disease (controls); (2) 1-3 cases with clinical and autonomic laboratory diagnosis of MSA; (3) 1-3 cases with Parkinson's disease; and (4) 1-2 cases with other forms of parkinsonism. These studies will provide insight into the medullary circuits involved in human cardiorespiratory control and the pathophysiology of MSA.
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