NEUROPATHOLOGY OF THE AGING SYMPATHETIC NERVOUS SYSTEM

老年人自主神经系统功能障碍日益严重， 认识到，但了解甚少，临床问题，病理基础， 其中大部分是未知的。 我们对人类衰老的初步研究 交感神经节已经证明：i）神经轴突营养不良 我们已经在老年实验动物中描述了这一点; ii） 椎前与椎旁交感神经优先损害 iii）营养不良轴突数量的年龄相关性增加; 和iv）含有NPY的神经末梢的选择性参与。 的 本研究计划中提出的研究代表了 我们对衰老的人类交感神经节的初步研究， 描述年龄对人类交感神经的病理影响 系统，将这些发现与衰老的动物模型相结合， 最终明确老年自主神经功能障碍的发病机制。 我们将描述人类神经节中的神经轴索营养不良，并确定 如果它与特定的临床实体或表现相关联。 其他的研究将调查老化的树突状结构 交感神经元和确定营养不良的神经末梢的起源 使用神经元内标记和亲脂性染料（di-I）， 人类神经节 为了确定人类最早的变化， 我们将使用免疫电子显微镜来集中研究 在人体中选择性靶向的含有NPY的神经末梢 衰老 RIA将用于定量NPY的神经节含量， 测量轴突病变的严重程度。 最后，我们将测试 提出了一个假说，即异常的神经丝代谢是 老化人类交感神经节中营养不良轴突的发育。 具体来说，e将：测试不寻常形式的神经节神经丝 蛋白质SDS-PAGE与蛋白质印迹法; 异常分布的神经丝蛋白和测定相关酶 神经丝降解（钙蛋白酶）;最后，试图模仿 用局部注射法观察幼年动物交感神经节轴突病变 钙蛋白酶抑制剂在体内的应用。 总的来说，这项研究计划 代表了一个多方面的调查年龄的影响， 交感神经系统 至少，这些调查将产生 丰富的数据老化人类交感神经节，并可能提供线索， 老年人植物神经功能障碍发病机制及治疗 人类

Dysfunction of the aged human autonomic nervous system is an increasingly recognized, but poorly understood, clinical problem, the pathologic basis of which is largely unknown. Our initial studies of aging human sympathetic ganglia have demonstrated: i) neuroaxonal dystrophy comparable to that we have characterized in aged experimental animals; ii) preferential damage of prevertebral versus paravertebral sympathetic ganglia; iii) an age-related increase in the number of dystrophic axons; and, iv) selective involvement of NPY containing nerve terminals. The studies proposed in this research plan represent a significant expansion of our initial investigation of aging human sympathetic ganglia to precisely characterize the pathologic effects of age on the human sympathetic nervous system, to integrate these findings with animal models of aging, and ultimately to define the pathogenesis of autonomic dysfunction in aging. We will characterize neuroaxonal dystrophy in human ganglia and determine if it is associated with a particular clinical entity or presentation. Other studies will investigate the dendritic structure of aging principal sympathetic neurons and identify the origin of dystrophic nerve terminals using intraneuronal labeling and lipophilic dyes (di-I) in both animal and human ganglia. In an attempt to identify the earliest alterations in human dystrophic axons we will use immunoelectron microscopy to concentrate on NPY containing nerve terminals, which are selectively targeted in human aging. RIAs will be used to quantitate the ganglionic content of NPY as a measure of the severity of the axonopathy. Finally, we will test the proposed hypothesis that abnormal neurofilament metabolism underlies the development of dystrophic axons in aging human sympathetic ganglia. Specifically, e will: test for unusual forms of ganglionic neurofilament proteins by SDS-PAGE with Western blotting; immunohistochemically probe for abnormally distributed neurofilament proteins and assay enzymes responsible for neurofilament degradation (calpains); and, finally, attempt to mimic the axonopathy in the sympathetic ganglia of young animals using local application of calpain inhibitors in vivo. Overall, this research proposal represents a multi-faceted investigation into the effects of age on the sympathetic nervous system. Minimally, these investigations will yield a wealth of data on aging human sympathetic ganglia and may provide clues to the pathogenesis (and possible treatment) of autonomic dysfunction in aged humans.