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

本项目专注于多系统萎缩(MSA)的诊断、病理生理学和治疗，并有一个特定的自主神经焦点。基于我们在过去5年中取得的成功，我们准备实现几个独特的目标。在过去的5年中，我们收集了一大批MSA和帕金森病(PD)患者，这些患者都有完整的自主神经和神经学特征。我们将检验这一假设，即存在某些自主神经预测因子，可以预测MSA进展更快。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神经进展更快的速度，以及在第一次回访时自主神经功能障碍的增加是否记录在 1年末是MSA进展速度的预测指标。我们将通过增加50名早期MSA患者来加强研究。包括对MSA诊断的神经病理学确认的高度确认性将使我们能够利用尸检确诊病例来改进MSA的定义。我们应该能够 在MSA可能可以治疗的时候，开发一种算法来早期诊断MSA。我们将对100例早期MSA患者进行双盲安慰剂对照临床试验，观察利福平对神经和自主神经功能衰竭进展的影响。潜在的假设是，利福平，因为它的能力，抑制a-突触核蛋白纤维的形成和分解已经形成的纤维，将延缓或逆转MSA的神经和自主功能和症状。这项研究是与项目1和项目3合作完成的。神经源性直立性低血压(OH)是MSA的一个组成部分，治疗是有问题的，因为现有的治疗方法会加剧仰卧位高血压。在MSA中，Hwin问题存在节前神经传递失败及其神经递质去甲肾上腺素的节后神经元枯竭。我们提出了一项新的双盲、安慰剂对照的住院治疗试验，纳入了在不加重仰卧位高血压的情况下改善OH的策略。这个目标是用去甲肾上腺素(使用其前体LDOPS)填充节后轴突，并提高神经节神经传递的安全系数(使用吡斯的明)。

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).