NEUROPATHOLOGY OF THE AGING SYMPATHETIC NERVOUS SYSTEM

老年人自主神经系统功能障碍日益严重 公认的，但了解很少的临床问题，病理基础 其中有哪些在很大程度上是未知的。我们对老龄化人类的初步研究 交感神经节表现出：1)神经轴索营养不良可比 对于这一点，我们已经在老年实验动物中进行了表征；ii) 椎前交感神经优先于椎旁交感神经损伤 神经节；iii)营养不良轴突的数量随年龄增加； 4)选择性累及含NPY的神经末梢。这个 这项研究计划中提出的研究代表着对 我们对人类交感神经节老化的初步研究 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，以及 最终明确衰老自主神经功能障碍的发病机制。 我们将描述人类神经节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。 其他研究将调查老化校长的树突结构 交感神经元和营养不良神经末梢的起源 在动物和动物中使用神经元内标记和亲脂染料(di-i) 人类神经节。试图确定人类最早的变化 营养不良的轴突我们将使用免疫电子显微镜来集中研究 含有神经肽Y的神经末梢，在人类体内具有选择性靶向 衰老。RIAS将被用来定量神经节细胞的NPY含量作为 测量轴突病变的严重程度。最后，我们将测试 提出的假说是神经丝代谢异常是 老年人交感神经节营养不良轴突的发育。 具体地说，e将：测试不寻常形式的神经节细胞神经丝 蛋白质的SDS-PAGE和Western blotting；免疫组织化学检测 异常分布的神经丝蛋白和相关的检测酶 用于神经丝降解(钙痛)；最后，尝试模仿 局部应用于幼年动物交感神经节的轴突病变 钙蛋白酶抑制剂在体内的应用。总体而言，这项研究建议 代表了对年龄影响的多方面的调查 交感神经系统。最低限度，这些调查将产生一个 关于人类交感神经节老化的丰富数据，并可能提供线索 老年人自主神经功能障碍的发病机制(及可能的治疗方法) 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.