Age related determinants of HAND: A 12 year follow-up of CHARTER participants

 描述(申请人提供)：现代抗逆转录病毒疗法(ART)延长了艾滋病毒感染者(HIV+)成年人的寿命至晚年，增加了与年龄相关的器官变化，包括神经退行性变和脑血管疾病，可能会放大艾滋病毒对大脑的影响。到目前为止，有关中枢神经系统(CNS)过早或加速衰退的数据大多局限于对60岁以下人群的横断面研究。没有关于艾滋病毒携带者进入第七个十年及以后的长期纵向研究的报道。我们建议利用在2003年至2007年期间作为CNS HIV抗逆转录病毒治疗效果研究(CHECURE)研究的一部分对400名HIV+成年人进行初步评估的详细神经医学和神经行为信息。这一队列中有200人的年龄在60岁或以上，对该队列的后续研究将提供独特的12年纵向数据，说明艾滋病毒和抗逆转录病毒治疗对中枢神经系统功能衰退和由此导致的功能残疾的综合影响。主要目的将是建立在以前比较艾滋病毒+和艾滋病毒-成人的横断面研究结果的基础上，以确定老年艾滋病毒+成年人(≥60岁)在12年内中枢神经系统是否比年轻艾滋病毒+成年人(60岁)有更大的中枢神经系统衰退，同时控制“正常衰老”对神经认知功能的影响。增加这项研究的及时性和相关性：我们建议确定a)中枢神经系统衰退的病毒、免疫、代谢/血管和药物相关性如何随年龄变化，以及b)生物衰老指标的程度 解释了观察到的相关性。该项目将纳入多种最先进的评估，包括艾滋病毒DNA测量(艾滋病毒整合的一个指标)、端粒长度和线粒体DNA(作为生物老化的指标)，以及脑脊液中ART药物浓度的群体药代动力学模型。Charge由6个美国学术网站组成(约翰·霍普金斯大学，巴尔的摩；伊坎医学院纽约市西奈；加州大学圣地亚哥分校；UTMB加尔维斯顿大学；华盛顿，西雅图，华盛顿大学，圣路易斯)，由加州大学圣地亚哥分校的协调单位联合起来。拟议的项目将提供第一个关于神经艾滋病和老龄化的大规模结果数据，并将这些数据与可能的机制联系起来。此外，这项研究将向科学界提供数据和样本，延续我们启动新研究的强劲记录，并进一步利用这项研究的投资价值。

 DESCRIPTION (provided by applicant): Modern antiretroviral therapy (ART) has extended the survival of HIV infected (HIV+) adults into their later years, raising the possibility that age-relted organ changes, including neurodegeneration and cerebrovascular disease, might amplify the effects of HIV on the brain. Thus far, data on premature or accelerated central nervous system (CNS) decline have been mostly limited to cross-sectional studies of persons younger than 60 years of age. No longer-term longitudinal studies of HIV+ individuals entering their 7th decade and beyond have been reported. We propose to take advantage of the detailed neuromedical and neurobehavioral information available on 400 HIV+ adults who were initially evaluated as part of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study between 2003 and 2007. Follow-up of this cohort, 200 of whom will be 60 or older, will provide unique 12-year longitudinal data on the combined effects of HIV and ART on CNS decline and resultant functional disability. The major aim will be to build on prior cross-sectional findings comparing HIV+ and HIV- adults to determine if older HIV+ adults (≥ 60 years) have greater CNS decline over 12 years than younger HIV+ adults (< 60 years), while controlling for effects of "normal aging" on neurocognitive function. Adding to the timeliness and relevance of this study: We propose to determine a) how the viral, immune, metabolic/vascular, and pharmacologic correlates of CNS decline differ with age and b) the extent to which indicators of biological aging account for the observed correlations. The project will incorporate multiple state-of-the-art assessments including HIV DNA measurements (an indicator of HIV integration), telomere length and mitochondrial DNA (as indicators of biological aging), and population pharmacokinetic modeling of ART drug concentrations in CSF. CHARTER consists of 6 U.S. academic sites (Johns Hopkins, Baltimore; Icahn School of Medicine at Mt. Sinai, NYC; UC San Diego; UTMB Galveston; Univ. of Washington, Seattle; Washington Univ., St. Louis) that are united by a Coordinating Unit based at UC San Diego. The proposed project will provide the first large scale outcome data on neuroAIDS and aging, and link these to possible mechanisms. In addition, this study will make data and samples available to the scientific community, continuing our strong record of jumpstarting new research and further leveraging the value of the investment in this study.