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

 描述（由申请人提供）：现代抗逆转录病毒疗法（ART）延长了HIV感染（HIV+）成人的生存期，使其进入晚年，增加了与年龄相关的器官变化（包括神经变性和脑血管疾病）可能放大HIV对大脑的影响的可能性。到目前为止，关于中枢神经系统（CNS）过早或加速衰退的数据大多仅限于对60岁以下人群的横断面研究。目前还没有关于进入第七个十年及以后的HIV阳性个体的长期纵向研究报告。我们建议利用400名HIV阳性成人的详细神经医学和神经行为信息，这些成人最初是作为2003年至2007年CNS HIV抗逆转录病毒治疗效果研究（CHARTER）研究的一部分进行评估的。该队列的随访，其中200人将是60岁或以上，将提供独特的12年的纵向数据，艾滋病毒和ART对中枢神经系统下降和由此产生的功能障碍的综合影响。主要目的是建立在先前的横断面研究结果的基础上，比较HIV+和HIV-成人，以确定老年HIV+成人（≥ 60岁）在12年内是否比年轻HIV+成人（< 60岁）有更大的CNS下降，同时控制“正常衰老”对神经认知功能的影响。增加本研究的及时性和相关性：我们建议确定a）CNS衰退的病毒、免疫、代谢/血管和药理学相关性如何随年龄而不同，以及B）生物老化指标 解释观察到的相关性。该项目将纳入多项最先进的评估，包括HIV DNA测量（HIV整合的指标），端粒长度和线粒体DNA（作为生物老化的指标），以及CSF中ART药物浓度的群体药代动力学建模。宪章由6个美国学术网站（约翰霍普金斯，巴尔的摩;伊坎医学院在山。西奈，纽约;加州大学圣地亚哥分校; UTMB加尔维斯顿;华盛顿大学，西雅图;华盛顿大学，圣路易斯），由总部设在加州大学圣地亚哥分校的协调单位统一。拟议的项目将提供关于神经艾滋病和衰老的第一个大规模结果数据，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，继续我们在启动新研究方面的良好记录，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.