project 1 - Autonomic Rare Diseases Clinical Research Consortium

项目 1 - 自主神经罕见疾病临床研究联盟

• 批准号: 7901210
• 负责人: HORACIO KAUFMANN
• 金额: $ 17.12万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901210
• 关键词: Affect; Area; Autonomic nervous system; Autonomic nervous system disorders; Biological Markers; Brain; Catechols; Categories; Characteristics; Clinical; Clinical Research; Cognition Disorders; Cognitive; Corpus striatum structure; Cytoplasmic Inclusion; DNA; Data; Deposition; Disease; Evaluation; Failure; Genes; Genetic; Heart; Hypotension; Instruction; Intervention; Lewy Bodies; Lewy Body Disease; Longitudinal Studies; Motor; Multiple System Atrophy; Natural History; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Orthostatic Hypotension; Parkinson Disease; Parkinson' s Dementia; Patients; Peripheral; Phenotype; Plasma; Proteins; Pure Autonomic Failures; Rare Diseases; Staging; Structure; Substantia nigra structure; Testing; Therapeutic; Time; alpha synuclein; clinical phenotype; cognitive function; neuroimaging; neuroprotection; noradrenergic; novel; prevent; prospective; synuclein; therapy development

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.

JECT 1 NYU项目摘要（请参阅说明）： 纯自主神经失败（PAF）是一种神经退行性疾病，在临床上以体位为特征 低血压（OH）和通过蛋白α突触核蛋白的细胞内沉积物在病理上。就像在帕金森氏症中一样 疾病（PD），在神经元胞质夹杂物中的PAFα突触蛋白聚集体中，称为Lewy体 （磅）。 PAF中的LB在周围自主神经元中有很多 散落在中枢神经系统中。 PAF是三种LB疾病之一，该类别包括PD和Lewy的痴呆症 身体（DLB）。这些疾病中的每一个都相对有选择地影响不同的神经元组，从而导致 独特但重叠的自主，运动和认知表型。由于数据很少 但是，PAF的自然历史尚不清楚纹状体和其他皮质区域是否完好无损 随着时间的流逝，PAF。该项目的具体目的1是进行一项前瞻性的纵向研究，以定义 PAF的自然历史并确定该疾病是否仅限于自主神经元或 最终发展成其他LB疾病之一，即PD或DLB。如果PAF患者维持“纯” 自主表型，PAF可能需要神经保护特征，以防止该疾病扩散到 大脑影响运动和认知功能。了解这种神经保护的机制 可以帮助开发所有LB疾病的治疗方法。特征的临床表现 PAF，神经源性体性低血压，也可能是多系统萎缩的初始表现 （MSA），一种神经退行性疾病，其中α突触核蛋白积聚在神经胶质细胞质内夹杂物中 而不是在路易的身体中。而三磅LB疾病涉及丢失后甲肾上腺素能的丧失 这些神经元中的神经元通常在MSA中幸免。因此，外周去甲肾上腺素能 神经流行病检测到的参与！或神经影像学研究，可能是PAF V的生物标志物。 早期的“前” MSA。在特定目标2中，我们将测试具有临床患者的假设 PAF的表型，但保留了旋格后的交感神经元没有PAF，但有早期 MSA或其他作为兽医疾病。