project 1 - Autonomic Rare Diseases Clinical Research Consortium

对象1纽约大学项目总结(见说明)： 单纯自主神经衰竭(PAF)是一种以立位为特征的神经退行性疾病。 低血压(OH)和病理上由蛋白α突触核蛋白在细胞内沉积所致。就像帕金森症 帕金森病(PD)，PAFα突触核蛋白聚集在神经元胞浆内，称为路易小体 (磅)。PAF中的Lb在外周自主神经细胞中大量存在，仅在黑质和 散布在中枢神经系统。PAF是三种LB病之一，包括帕金森病和路易斯病痴呆 身体(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、运动和认知表型。由于数据的稀缺性， 然而，PAF的自然历史，尚不清楚纹状体和其他皮质区域是否保持完好 随着时间的推移，PAF。该项目的具体目标1是进行前瞻性的纵向研究，以确定 PAF的自然病史，并确定该病是否仅限于自主神经元或 最终发展成另一种LB病，即PD或DLB病。如果房颤患者持续“纯净” 自主神经表型，PAF可能需要神经保护功能，防止疾病扩散到 影响运动和认知功能的大脑。了解这种神经保护的机制 可以帮助开发治疗所有LB病的方法。多发性硬化症的典型临床表现 PAF，神经源性直立性低血压，也可以是多系统萎缩的最初表现 (MSA)，一种神经退行性疾病，阿尔法突触核蛋白在胶质细胞胞浆内积聚 而不是在路易体中。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，外周去甲肾上腺素能 神经化学检测到了牵连！或神经成像研究，可能是PAF与 早期的“前驱运动”MSA。在特定的目标2中，我们将检验这样的假设，即有临床症状的患者 PAF的表型但保留了节后交感神经元没有PAF但有早期 MSA或其他作为兽医不明原因的疾病。

JECT 1 NYU PROJECT SUMMARY (See instructions): 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 neurochemica! 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.