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

 描述(申请人提供)：多系统萎缩(MSA)是一种进行性和致命性神经系统疾病，以自主神经衰竭、帕金森综合症和/或小脑性共济失调为特征。诊断MSA的共识标准提高了诊断的确定性，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阴性的，因为直到疾病的晚期才能肯定地诊断出这种疾病。因此，一个重要的目标是在疾病活动可以停止和有意义的恢复可能的阶段及早发现仍在发展的MSA。我们的建议集中在开发新的生物标记物，使我们能够在如此早期阶段识别MSA。首先，我们将在目前可能的最早疾病阶段对MSA进行研究(结合共识标准和临床自主神经测试进行诊断)。在这个队列中，我们将衍生并遵循一组精选的生物标记物，包括神经元丢失的MRI形态测量和中枢轴突和神经元变性的脊液生物标记物，以识别早期MSA的生物标记物(特定目标1)。我们的第二种方法涉及纯自主神经衰竭(PAF)，这是一种以严重的进行性自主神经衰竭为特征的联核症。大多数PAF患者在没有临床中枢神经系统受累的情况下存活数十年，但也有部分患者转为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框架内转换为MSA的高度预测的临床指标。我们将把我们的生物标记物方法应用于预计将从PAF演变为MSA的患者(特定目标2)，随时间跟踪患者，并将临床病程和生物标记物与稳定的PAF进行比较。这种方法使我们能够评估建议的生物标记物的价值，并比以前更早地研究MSA。我们处于进行这些研究的独特位置，因为我们的计划可以接触到大量患有这两种罕见疾病的患者。我们的自主神经障碍数据库目前有300多名PAF患者和600多名MSA患者，包括我们在过去10年中研究的对象。这项建议的结果应该会导致MSA的诊断比以前更早的阶段。我们假设，这种方法的洞察力最终可能使我们能够在疾病的更早发展阶段或临床前阶段诊断MSA。使用一套新的标准和生物标志物的随机临床试验应该更有可能证明疗效。根据本提案的具体目标#3，我们将使用与其他两个目标紧密相关的MRI形态计量学来识别选定的大脑结构的萎缩模式和进展。

 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.