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

MSA 自主神经衰竭的诊断、病理生理学和治疗研究

• 批准号: 8330333
• 负责人: PHILLIP A LOW
• 金额: $ 26.99万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8330333
• 关键词: Algorithms; Anhidrosis; Autopsy; Axon; Cessation of life; Clinic; Collaborations; Controlled Clinical Trials; Cytoplasmic Inclusion; Diagnosis; Disease; Double-Blind Method; Evaluation; Failure; Functional disorder; Generations; Goals; Hypertension; Image; Inpatients; Multiple System Atrophy; Natural History; Neurologic; Neurons; Neurotransmitters; Norepinephrine; Orthostatic Hypotension; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Patients; Pharmaceutical Preparations; Placebo Control; Prospective Studies; Rifampin; Role; Safety; Severities; Staging; Sweat test; Symptoms; Synaptic Transmission; Testing; Time; Visit; Weight; alpha synuclein; base; clinical phenotype; cohort; follow-up; improved; indexing; instrument; neuron loss; neurotransmission; novel; novel strategies; outcome forecast; prevent; pyridostigmine; success; treatment trial

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).

该项目的重点是多系统萎缩（MSA）的诊断、病理生理学和治疗，并以特定的自主神经为重点。基于我们在过去5年的成功，我们准备实现几个独特的目标。我们在过去的5年中收集了一个大型的MSA和帕金森病（PD）患者队列，具有完整的自主神经和神经特征。我们将测试的假设，有一定的自主神经预测更迅速的进展过程中MSA。我们将评估入组研究时自主神经功能衰竭的严重程度和分布是否可预测MSA的神经系统进展速度更快，以及首次随访时记录的自主神经功能缺损的增加是否与患者的年龄相关。 1年结束时，可预测MSA的进展率。我们将通过增加50例早期MSA患者来加强研究。高度确定性，包括对MSA诊断的神经病理学确认，将使我们能够利用尸检确诊病例改进MSA的定义。我们应该能够 开发一种算法，用于MSA的早期诊断，在他们可能适合治疗的时候。我们将在100例早期MSA患者中进行一项关于利福平对神经和自主神经功能衰竭进展的影响的双盲安慰剂对照临床试验。潜在的假设是，利福平，由于其抑制α-突触核蛋白原纤维的形成和解聚已形成的原纤维的能力，将延迟进展或逆转MSA的神经和自主神经功能和症状。本研究与项目1和项目3合作进行。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，因为现有的治疗会加重仰卧位高血压。在MSA中，存在着节前神经传递障碍和节后神经元的神经递质去甲肾上腺素耗竭的问题。我们提出了一个新的双盲，安慰剂对照的住院治疗试验，纳入战略，将改善OH不加重仰卧位高血压。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（使用吡啶斯的明）。