project 1 - Autonomic Rare Diseases Clinical Research Consortium

项目1纽约大学 纯自主神经功能衰竭（PAF）是一种神经退行性疾病，其临床特征为直立性低血压（OH），病理特征为α-突触核蛋白在细胞内沉积。如在帕金森病（PD）中，在PAF中，α突触核蛋白聚集在称为路易体（LB）的神经元胞质内含物中。PAF中的LB在外周自主神经元中数量较多，在黑质中数量较少，在中枢神经系统中呈散在分布。PAF是三种LB疾病之一，包括PD和路易体痴呆（DLB）。这些疾病中的每一种相对选择性地影响不同的神经元组，导致不同但重叠的自主神经、运动和认知表型。然而，由于缺乏关于PAF自然史的数据，不知道PAF中的纹状体和其他皮质区域是否随着时间的推移而保持完整。该项目的具体目标1是进行前瞻性纵向研究，以确定PAF的自然史，并确定该疾病是否仍然局限于自主神经元或最终发展为其他LB疾病之一，即，PD或DLB。如果PAF患者维持“纯”自主表型，PAF可能需要神经保护功能，防止疾病扩散到大脑，影响运动和认知功能。了解这种神经保护机制有助于开发所有LB疾病的治疗方法。PAF的特征性临床表现，神经源性直立性低血压，也可能是多系统萎缩（MSA）的初始表现，MSA是一种神经退行性疾病，其中α突触核蛋白积聚在胶质细胞胞质内含物中，而不是路易体中。而这三种LB疾病涉及节后去甲肾上腺素能神经元的丢失， 心脏中的神经元，这些神经元通常在MSA中幸免。因此，通过神经化学或神经影像学研究检测到的外周去甲肾上腺素能参与可能是有用的PAF与早期“运动前”MSA的生物标志物。在具体目标2中，我们将检验以下假设：具有PAF临床表型但保留了节后交感神经元的患者不具有PAF，但具有早期MSA或其他兽医未定义的疾病。

PROJECT 1 NYU Pure autonomic failure (PAF) is a neurodegenerative disorder characterized clinically by orthostatic hypotension (OH) and pathologically by intracellular deposits of the protein alpha synuclein. As in Parkinson disease (PD), in PAF alpha synuclein aggregates in neuronal cytoplasmic inclusions called Lewy bodies (LBs). LB in PAF are numerous in peripheral autonomic neurons with only a few in the substantia nigra and scattered in the CNS. PAF is one of three LB disorders, a category that includes PD and dementia with Lewy bodies (DLB). Each of these disorders affects different neuronal groups relatively selectively, resulting in distinct but overlapping autonomic, motor, and cognitive phenotypes. Because of paucity of data on the natural history of PAF, however, it is not known whether the striatum and other cortical areas remain intact in PAF over time. Specific Aim 1 of this project is to conduct a prospective, longitudinal study to define the natural history of PAF and determine whether the disease remains confined to autonomic neurons or develops eventually into one of the other LB disorders, i.e., PD or DLB. If PAF patients sustain the "pure" autonomic phenotype, PAF might entail neuroprotective features that prevent the disorder from spreading to the brain affecting motor and cognitive function. Understanding the mechanisms of this neuroprotection could aid in the development of treatments for all LB disorders. The characteristic clinical manifestation of PAF, neurogenic orthostatic hypotension, can also be the initial manifestation of multiple system atrophy (MSA), a neurodegenerative disorder in which alpha synuclein accumulates in glial cytoplasmic inclusions rather than in Lewy bodies. Whereas the three LB disorders involve loss of postganglionic noradrenergic neurons in the heart, these neurons are usually spared in MSA. Therefore, peripheral noradrenergic involvement detected by neurochemical or neuroimaging studies, might be useful as a biomarker of PAF vs. early "premotor" MSA. In Specific aim 2 we will test the hypothesis that patients who have the clinical phenotype of PAF but have preserved postganglionic sympathetic neurons do not have PAF but have early MSA or other as vet undefined disorders.