project 1 - Autonomic Rare Diseases Clinical Research Consortium

项目1纽约大学 单纯自主神经衰竭(PAF)是一种神经退行性疾病，临床上以直立性低血压(OH)为特征，病理上以蛋白α突触核蛋白在细胞内沉积为特征。与帕金森病(PD)一样，在PAFα中，突触核蛋白聚集在神经元胞浆内，称为路易小体(Lbs)。PAF中的Lb在周围自主神经细胞中大量存在，仅在黑质有少量分布，散在分布于CNS。PAF是三种LB病之一，包括帕金森病和路易体痴呆(DLB)。这些障碍中的每一种都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，由于缺乏有关PAF自然病史的数据，尚不清楚PAF的纹状体和其他皮质区域是否随着时间的推移而保持完好。这个项目的具体目标1是进行一项前瞻性的纵向研究，以确定PAF的自然病史，并确定该病是否仍局限于自主神经元，或最终发展为其他LB病之一，即PD或DLB型。如果PAF患者保持“纯”自主神经表型，PAF可能需要神经保护功能，以防止疾病扩散到大脑，影响运动和认知功能。了解这种神经保护的机制有助于开发治疗所有LB病的方法。PAF的特征性临床表现-神经源性直立性低血压-也可以是多系统萎缩(MSA)的初始表现，MSA是一种神经退行性疾病，在这种疾病中，α突触核蛋白聚集在胶质细胞质包涵体中，而不是路易体。而三种LB病涉及节后去甲肾上腺素能的丧失 心脏中的神经元，这些神经元在MSA中通常是幸免的。因此，通过神经化学或神经成像研究检测到的外周去甲肾上腺素参与，可能是PAF与早期运动前MSA的生物标记物。在特定的目的2中，我们将检验这样一种假设，即具有PAF临床表型但保留了节后交感神经元的患者没有PAF，但有早期的MSA或其他VET不明疾病。

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.