Role of evolving white matter damage in neurocognitive effects of HIV and HCV

描述（由申请人提供）：现有的美国国立卫生研究院资助的合同（CHARTER）支持对600名HIV感染者（HIV+）样本的中枢神经系统变化进行多点纵向研究。该样本代表了招募他们所在社区的感染群体：大多数人接受联合抗逆转录病毒药物治疗，很大一部分人同时感染丙型肝炎病毒。除了全面的神经医学和神经行为评估外，本研究还包括使用MR形态测量技术进行年度神经影像学检查，以评估脑结构异常。在149名受试者中，脑白质损伤程度与疾病因素相关，如CDC分类和血清中HCV抗体的存在。在这些参与者中测量的神经认知障碍与大脑皮层白质损伤增加和体积损失有关，这两个因素仅显示出适度的相关性，似乎独立地影响了神经认知障碍的严重程度。结果表明，脑白质损伤是hiv相关神经认知障碍的重要中介，也可能介导与HCV合并感染相关的损伤增加。多种证据表明，白质损伤和皮质退化在一定程度上反映了不同的发病机制。拟议的研究将利用CHARTER纵向研究的存在，在UCSD地点确定20个有证据表明白质损伤的个体（以及10个具有类似疾病特征的明显未受影响的个体）。这些目标个体将每半年进行一次扩展高场（3T）神经成像调查，包括多光谱sMRI、计算形态测量、扩散张量成像（DTI）和化学位移成像（CSI）。这些额外的神经成像数据将用于解决有关白质损伤随时间演变的问题；脑白质损伤与大脑皮层损伤的关系以及免疫激活和病毒水平在介导这种损伤中的作用。

DESCRIPTION (provided by applicant): An existing NIH-funded contract (CHARTER) supports a multi-site longitudinal study of CNS alterations in a sample of 600 HIV-infected (HIV+) individuals. This sample is representative of infected groups in the communities where they are recruited: most are treated with combination ARVs and a significant proportion are co-infected with HCV. In addition to comprehensive neuromedical and neurobehavioral assessments this study involves annual neuroimaging examinations for assessment of structural brain abnormalities using MR morphometry techniques. Within 149 participants examined in this contract at baseline, the degree of damage in cerebral white matter is associated with disease factors such as CDC classification and the presence of HCV antibodies in serum. The neurocognitive impairment measured in these participants is associated with both increased white matter damage and volume loss in cerebral cortex, and the two factors, which show only modest correlation, appears to contribute independently to severity of neurocognitive impairment. The pattern of the results suggests that damage to the cerebral white matter is an important mediator of HIV-related neurocognitive impairment and may also mediate increases in impairment associated with co-infection with HCV. Multiple lines of evidence suggest that white matter damage and cortical degeneration to some extent reflect distinct pathogenetic mechanisms. The proposed study would take advantage of the existence of the CHARTER longitudinal study to identify 20 individuals at the UCSD site in whom there is evidence of evolving white matter damage (and 10 apparently unaffected individuals with comparable disease characteristics). These targeted individuals would then be studied semiannually with an extended high field (3T) neuroimaging investigation which would include multispectral sMRI, computational morphometry, diffusion tensor imaging (DTI), and chemical shift imaging (CSI). These additional neuroimaging data would be used to address questions about the evolution of white matter damage over time; about the relationship between the white matter damage and the damage to cerebral cortex; and about the role of immune activation and viral levels in mediating this damage.