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

摘要 现代抗逆转录病毒疗法(ART)将艾滋病毒感染者(HIV)的存活期延长至晚年。 多年来，增加了与年龄相关的器官变化的可能性，包括神经变性和脑血管 疾病，可能会放大艾滋病毒对大脑的影响。到目前为止，关于过早或加速的中央 神经系统(CNS)的下降大多局限于对60岁以下人群的横断面研究 几年前。不再对进入第七个十年及以后的艾滋病毒感染者进行纵向研究 已经上报了。我们建议利用详细的神经医学和神经行为信息 适用于400名HIV成人，他们最初是作为CNS HIV抗逆转录病毒治疗的一部分进行评估的 2003至2007年间的效果研究(宪章)研究。对这一队列的后续行动，其中200人将是60岁 或年龄更大的患者，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下降的综合影响 以及由此导致的功能性残疾。主要目标将是建立在先前横断面结果的基础上进行比较 艾滋病毒和艾滋病毒-成年人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有更大的下降 在控制“正常衰老”对神经认知功能的影响的同时，比年轻的艾滋病毒成人(60岁)。 增加了这项研究的及时性和相关性：我们建议确定a)病毒、免疫力和 中枢神经系统衰退的代谢/血管和药理学相关性因年龄和b)程度不同而不同 生物老化指标解释了观察到的相关性。该项目将包括多个州- 最先进的评估包括HIV DNA测量(HIV整合的一个指标)、端粒长度 和线粒体DNA(作为生物衰老的指标)，以及ART的群体药代动力学模型 脑脊液中的药物浓度。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 山上医学院。纽约市西奈；加州大学圣地亚哥分校；UTMB加尔维斯顿大学；来自华盛顿的西雅图； 华盛顿大学圣路易斯分校)，由加州大学圣地亚哥分校的协调单位联合起来。建议数 该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 机械装置。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。

ABSTRACT Modern antiretroviral therapy (ART) has extended the survival of HIV infected (HIV+) adults into their later years, raising the possibility that age-related 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.