INTRODUCTIONMultiple system atrophy (MSA) and Lewy body disorders, including dementia with Lewy bodies (DLB) and Parkinson'sdisease (PD), are synucleinopathies that may manifest with prominent autonomic failure. Over the past 5 years, we haveshown that in MSA there is loss of specific neuronal groups in the medulla, which is more severe than in PD and couldcontribute to the autonomic and respiratory manifestations of MSA. Whether the same occurs in DLB is stillundetermined. Involvement of hypothalamic autonomic neurons may contribute to the manifestations of MSA and othersynucleinopathies, but this possibility has not yet been systematically explored. Our central hypothesis is that (1) there isinvolvement of specific medullary and hypothalamic neuronal groups controlling autonomic and respiratory functions inMSA; (2) this involvement is more severe than in Lewy body disorders; and (3) this difference is reflected by the differentcharacteristics and degree of severity of autonomic and respiratory impairment in these synucleinopathies. To assess thesehypotheses, we plan to perform quantitative analysis of neurochemically defined cell groups in the medulla andhypothalamus of neuropathologically confirmed cases of MSA, DLB, PD and age-matched controls. We also plan toperform autonomic studies and assess the ventilatory responses to hypoxia and hypercapnia in patients with clinicaldiagnoses of MSA, DLB, or PD and age-matched controls.
Our specific aims are (1) to determine whether in DLB there isinvolvement of tyrosine hydroxylase (TH), tryptophan hydroxylase (TrOH), or neurokinin-1 (NK-1R) receptorimmunoreactive neurons in VLM and medullary raphe and compare this involvement with that seen in MSA; (2) tocorrelate the medullary neuropathological findings with the results of autonomic function and ventilatory drive in patientswith clinically diagnosed MSA, DLB, or PD; (3) to determine whether in MSA there is involvement of neuronsimmunoreactive for TH, arginine vasopressin (AVP), oxytocin (OXT) or corticotrophin releasing factor (CRF) in theposterior portion of the hypothalamic paraventricular nucleus (PVN), presumably involved in autonomic control; and (4)to determine whether in MSA there is sparing of magnocellular AVP neurons in the supraoptic nucleus (SON) and PVN. Ourstudies will provide further insight into the central neuropathological substrate for autonomic and respiratory manifestations ofMSA and Lewy body disorders and provide potential targets for therapeutic intervention.
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