DEMENTIA, MYELOPATHY, AND NEUROPATHY IN AIDS

艾滋病引起的痴呆、脊髓病和神经病

• 批准号: 3760868
• 负责人: JUSTIN CHARLES. MCARTHUR
• 金额: --
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3760868
• 关键词: 2'3' dideoxycytidine; 2'3' dideoxyinosine; AIDS; AIDS dementia complex; AIDS therapy; HIV infections; antiAIDS agent; brain imaging /visualization /scanning; central nervous system disorders; cytomegalovirus; dosage; drug administration rate /duration; drug adverse effect; fiber cell; histopathology; human subject; human therapy evaluation; immunocytochemistry; longitudinal human study; neuropsychological tests; nutrition; nutrition related tag; patient /disease registry; postmortem; questionnaires

Infection with human immunodeficiency virus (HIV) is associated with the development of distinct neurological disorders, including dementia, myelopathy, and sensory neuropathy. Usually occurring in advanced HIV infection, the clinical features and temporal progression of these disorders remains incompletely characterized. Unanswered issues include the discordance between the clinical expression of dementia and the absence of HIV-related neuropathological changes; the timing of development of HIV-related neuropathological change with respect to systemic disease and immunodeficiency; the influence of antiretroviral therapy on neuropathological abnormalities; and the characterization of the sensory neuropathies in AIDS. The proposed studies will test four hypotheses: First, that quantitative differences in neuronal loss, astrocyte and microglial/macrophage proliferation, and expression of viral antigens in the brain determine the clinical course of HIV dementia. Second, despite entry of HIV into the brain relatively early in infection, the neuropathological changes associated with productive HIV infection develop only with advanced immune deficiency. Third, that specific antiretroviral therapies attenuate the neuropathological changes in dementia and myelopathy. Fourth, that the clinical expression of sensory neuropathy is related to changes in unmyelinated fiber densities and is provoked by certain antiretrovirals and nutritional deficiencies. By using well-characterized patients with advanced HIV infection, our studies will use state of the art stereological techniques to determine regional distribution of neuronal, astrocyte, and microglial numbers, and correlate these findings with patterns of neurocognitive decline, clinical features, and temporal progression of dementia and myelopathy. In patients with sensory neuropathy, the neuropathic pain will be characterized and related to changes in the structure and function of unmyelinated nerve fiber. Skin biopsy will be used to measure the degree of distal nerve fiber loss and will be validated by the study of nerve obtained by biopsy and autopsy. The studies will correlate the clinical expression of HIV-associated neurological disease with neuropathological abnormalities in brain, spinal cord, and peripheral nerve. The information from these projects will be applicable to the exploration of pathogenetic mechanisms and the rational design of therapies.

人类免疫缺陷病毒 (HIV) 感染与 不同神经系统疾病的发展，包括痴呆症， 脊髓病和感觉神经病。 通常发生在艾滋病毒晚期 感染、临床特征和时间进展 疾病的特征仍不完全。 未解答的问题包括 痴呆症的临床表现与 不存在与 HIV 相关的神经病理学变化；的时间安排 与 HIV 相关的神经病理学变化的发展 全身性疾病和免疫缺陷；抗逆转录病毒药物的影响 神经病理异常的治疗；和表征 艾滋病中的感觉神经病。 拟议的研究将检验四个假设：首先，定量 神经元损失、星形胶质细胞和小胶质细胞/巨噬细胞的差异 大脑中病毒抗原的增殖和表达决定了 HIV痴呆的临床过程。 其次，尽管艾滋病毒已进入 大脑在感染相对早期，神经病理学变化 与生产性 HIV 感染相关的仅在晚期才发生 免疫缺陷。 三、具体的抗逆转录病毒疗法 减轻痴呆和脊髓病的神经病理变化。 四、感觉神经病的临床表现与 无髓纤维密度的变化是由某些因素引起的 抗逆转录病毒药物和营养缺乏。 通过使用特征明确的晚期 HIV 感染患者，我们的 研究将使用最先进的体视学技术来确定 神经元、星形胶质细胞和小胶质细胞数量的区域分布，以及 将这些发现与神经认知能力下降的模式联系起来， 痴呆和脊髓病的临床特征以及时间进展。 感觉神经病患者会出现神经性疼痛 与结构和功能的变化有关的特征 无髓神经纤维。 将使用皮肤活检来测量程度 远端神经纤维损失，并将通过神经研究来验证 通过活检和尸检获得。 这些研究将把临床 HIV相关神经系统疾病与神经病理学的表达 大脑、脊髓和周围神经的异常。 这 这些项目的信息将适用于勘探 发病机制和治疗方案的合理设计。