Multiple System Atrophy - Novel Targets in Early Diagnosis, Pathophysiology, and Therapeutic Approach

 描述（由申请方提供）：多系统萎缩（MSA）是一种进行性和致死性神经系统疾病，其特征为自主神经功能衰竭、帕金森综合征和/或小脑共济失调。MSA诊断的共识标准提高了诊断的准确性，但也将诊断推迟到疾病的后期。MSA的治疗试验在很大程度上是负面的，因为这种疾病直到疾病的晚期才能被明确诊断。因此，一个重要的目标是在疾病活动可以被阻止并且有意义的恢复是可能的阶段识别早期的、仍在发展的MSA。我们的建议集中在开发新的生物标志物，使我们能够在如此早期的阶段识别MSA。首先，我们将在目前可能的最早疾病阶段（将共识标准与临床自主诊断测试相结合）诊断后研究MSA。在该队列中，我们将推导并跟踪一组选定的生物标志物，包括用于神经元丢失的MRI形态测量和用于中央轴突和神经元变性的脊髓液生物标志物，以确定早期MSA的生物标志物（具体目标#1）。我们的第二种方法涉及纯自主神经功能衰竭（PAF），一种以严重的进行性自主神经功能衰竭为特征的突触核蛋白病。大多数PAF患者存活数十年，无临床中枢神经系统受累，但有些患者转为MSA。在我们的发现队列中，我们已经确定了在两到三年的时间范围内转换为MSA的高度预测性临床指标。我们将把我们的生物标志物方法应用于预测从PAF演变为MSA（特定目标#2）的患者，随时间随访患者，并比较临床病程和生物标志物与稳定的PAF。这种方法使我们能够评估所提出的生物标志物的价值，并在比以前更早的阶段研究MSA。我们处于独特的位置进行这些研究，因为我们的项目可以接触到大量患有这两种罕见疾病的患者。我们的自主神经疾病数据库目前有300多名PAF患者和600多名MSA患者，包括我们在过去10年中研究的受试者。这项建议的结果应导致MSA诊断在一个更早的阶段比以前可能的。我们认为，这种方法的见解可能最终使我们能够在疾病的早期发展或临床前阶段诊断MSA。使用一套新的标准和生物标志物的随机临床试验应该有更大的可能性证明疗效。对于本提案的具体目标#3，我们将使用与其他两个目标密切相关的MRI形态测定法识别选定脑结构萎缩的模式和进展。

 DESCRIPTION (provided by applicant): Multiple system atrophy (MSA) is a progressive and fatal neurologic disorder characterized by autonomic failure, parkinsonism, and/or cerebellar ataxia. Consensus criteria for the diagnosis of MSA have improved certitude of diagnosis but have also deferred diagnosis to a later stage of disease. Treatment trials of MSA have been negative in significant part because the disorder could not be diagnosed with certainty until a late stage of disease. An important goal is therefore to identify early, still evolving MSA at a stage when disease activity can be arrested and meaningful recovery is possible. Our proposal is focused on the development of novel biomarkers that will allow us to identify MSA at such an early stage. Firstly, we shall study MSA following diagnosis at the earliest disease stage currently possible (combining consensus criteria with clinical autonomic testing for diagnosis).In this cohort, we will derive and follow a selected set of biomarkers, including MRI morphometry for neuronal loss and spinal fluid biomarkers for central axonal and neuronal degeneration, to identify biomarkers of early MSA (Specific Aim #1). Our second approach involves pure autonomic failure (PAF), a synucleinopathy characterized by severe, progressive autonomic failure. Most patients with PAF survive for decades without clinical central nervous system involvement, but some patients convert to MSA. In our discovery cohort, we have identified highly predictive clinical indicators of conversion to MSA within a two to three year timeframe. We will apply our biomarker approach to patients predicted to evolve from PAF to MSA (Specific Aim #2), follow patients over time, and compare clinical course and biomarkers with stable PAF. This approach enables us to assess the value of the proposed biomarkers and study MSA at an earlier stage than has previously been possible. We are uniquely situated to undertake these studies since our program has access to a large number of patients with both of these rare conditions. Our Autonomic Disorders database, currently has over 300 patients with PAF and over 600 patients with MSA, comprising subjects we have studied over the last 10 years. The findings from this proposal should result in MSA diagnosis at a much earlier stage than has been previously possible. We posit that insights from this approach might eventually allow us to diagnose MSA at an even earlier evolving or preclinical stage of disease. Randomized clinical trials using a novel set of criteria and biomarkers should stand a greater probability of demonstrating efficacy. With Specific Aim #3 of this proposal we shall identify pattern and progression of atrophy of selected brain structures using MRI morphometry which is tightly interconnected with the other two aims.