HIV-1 Infection: Central Dopamine and Cognition

描述(申请人提供)：艾滋病毒感染与皮质下类型的认知功能障碍和运动障碍有关。一些证据表明，人类中枢性多巴胺缺乏在这些功能障碍的发展中起着重要作用。这些观察结果导致了一种概念，即中枢性多巴胺缺乏发生在HIV-1感染中。我们早期的研究表明，HIV-1+患者脑脊液(CSF)中的多巴胺水平下降支持这一概念。然而，中枢性多巴胺缺乏与HIV-1感染中认知功能障碍的关系还没有得到充分的研究。最近NIH赞助的国家神经艾滋病组织联盟(NNTC)的成立提供了一个机会来检验这一假说，即大脑不同区域的多巴胺水平下降将与HIV-1感染的认知障碍有关。这项应用建议通过量化艾滋病毒-L+患者和艾滋病毒-1-患者大脑不同区域中多巴胺及其代谢物高香草酸的水平来检验这一假设。建议调查来自三个民族(高加索人、非裔美国人、西班牙裔)的共60名成年男性和女性的脑和脑脊液样本，年龄19-50岁(HIV-I+病例40例，HIV-1病例N=20例)。来自HIV-1阳性患者(N=40)的脑组织将包括10名被诊断为HAD、MCMD、NPI和无认知障碍的人。从NNTC获得的基底节(尾状核和壳核、苍白球)、黑质和额叶皮质以及脑脊液的组织样本将被检测多巴胺及其代谢物HVA的水平。据推测，与HIV-1携带者相比，HIV-1阳性者认知功能障碍患者脑区的多巴胺和HVA水平将降低。这项应用还将研究中枢病毒载量与多巴胺/HVA水平之间的关系，以及探索HAART干预与HIV-1+个体中多巴胺/HVA水平的关系。这些发现将有助于制定干预的治疗策略。

DESCRIPTION (provided by applicant): HIV-infection is associated with subcortical type of cognitive dysfunctions and motor disorders. Several lines of evidence suggest that central dopamine deficiency in humans plays an important role in the development of these dysfunctions. These observations have lead to the concept that central dopamine deficiency occurs in HIV-1 infection. Our earlier studies showing a decrease in the levels of dopamine in the cerebrospinal fluid (CSF) of HIV-1+ individuals support this concept. However, the relationship between central dopamine deficiency and cognitive dysfunctions in HIV-1 infection has not been fully investigated. The recent establishment of the NIH sponsored National NeuroAIDS Tissue Consortium (NNTC) has provided an opportunity to test the hypothesis that decreased dopamine levels in various areas of the brain will be related to the cognitive deficits in HIV-1 infection. This application proposes to test this hypothesis by quantifying levels of dopamine and its metabolite, homovanillic acid (HVA), in different areas of the brain of HIV-l+ cases with known cognitive status during life and in HIV-1- cases. It is proposed to investigate samples of brain and CSF obtained from a total of 60 adult men and women, age 19-50 (HIV-I+ cases, N=40; and HIV-1- cases, N=20), belonging to three ethnic groups (Caucasian, African-Americans, Hispanics). The brain tissue from HIV-1+ cases (N=40) will include 10each from those diagnosed with HAD, MCMD, NPI and no cognitive impairment. Tissue samples of the basal ganglia (caudate nucleus and putamen, globus pallidus), substantia nigra, and the frontal cortex, as well as CSF of obtained from the NNTC, and will be assayed for the levels of dopamine and its metabolite, HVA. It is hypothesized that the levels of dopamine and HVA will be decreased in the brain regions ofHIV-1+ cases with cognitive dysfunctions compared to that in HIV-1- cases. This application will also investigate the relationship between central viral load and dopamine/HVA levels, as well as explore the relationship of HAART intervention with dopamine/HVA levels in HIV-1+ individuals. These findings will be helpful in developing therapeutic strategies for interventions.