Studies on Diagnosis, Pathophysiology, and Treatment of Autonomic Failure in MSA

本项目聚焦于多系统萎缩（MSA）的诊断、病理生理和治疗，并以特定的自主神经为重点。在过去5年的成功基础上，我们准备实现几个独特的目标。我们收集了过去5年MSA和帕金森病（PD）患者的大型队列，具有完整的自主神经和神经特征。我们将检验这一假设，即在MSA中存在某些更快速进展过程的自主预测因子。我们将评估进入研究时自主神经功能衰竭的严重程度和分布是否预示着MSA神经系统进展速度更快，以及首次复诊时是否记录了自主神经功能障碍的增加

This project is focused on the diagnosis, pathophysiology, and treatment of multiple system atrophy (MSA), with a specific autonomic focus. Based on our success in the prior 5 years, we are poised to achieve several unique goals. We have assembled a large cohort in the previous 5 years of patients with MSA and Parkinson's disease (PD), with full autonomic and neurological characterization. We will test the hypothesis that there are certain autonomic predictors of a more rapidly progressive course in MSA. We will evaluate if the severity and distribution of autonomic failure at entry into the study is predictive of a more rapid rate of neurologic progression of MSA and if the increase in autonomic deficit documented at the first return visit, at the end of 1 year, is predictive of the rate of progression of MSA. We will enhance the study by adding 50 patients with eariy MSA. The high ascertainment, including neuropathological confirmation of the diagnosis of MSA will permit us to improve the definition of MSA, using autopsy confirmed cases. We should be able to develop an algorithm for the eariy diagnosis of MSA, at a time when they may be amenable to treatment. We will undertake a double-blind placebo controlled clinical trial on the effect of Rifampicin on progression of neurological and autonomic failure in 100 patients with eariy MSA. The underlying hypothesis is that Rifampicin, because of its ability to inhibit the formation of a-synuclein fibrils and disaggregate fibrils already formed, will delay progression or reverse neurologic and autonomic functions and symptoms in MSA. This study is done in collaboration with Projects 1 and 3. Neurogenic orthostatic hypotension (OH) is an integral component of MSA and treatment is problematic since available treatments will aggravate supine hypertension. In MSA, the hwin problem exists of failure of preganglionic neurotransmission and depletion of postganglionic neurons of its neurotransmitter, norepinephrine. We propose a novel double-blind, placebocontrolled inpatient treatment trial, incorporating strategy that will improve OH without aggravating supine hypertension. This goal is to replete the postganglionic axon with norepinephrine (using its precursor, LDOPS) and improving the safety factor of ganglionic neurotransmission (with pyridostigmine).