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

描述(由申请人提供)：现有的一份由美国国立卫生研究院资助的合同(宪章)支持对600名艾滋病毒感染者(HIV+)样本的中枢神经系统改变的多地点纵向研究。这一样本代表了招募他们的社区中的感染群体：大多数人接受联合抗逆转录病毒药物治疗，相当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，这项研究还包括每年一次的神经成像检查，以使用磁共振形态测量技术评估大脑结构异常。在这份合同中以基线为基准接受检查的149名参与者中，脑白质的损害程度与疾病因素有关，如疾病预防控制中心分类和血清中丙型肝炎病毒抗体的存在。在这些参与者中测量到的神经认知障碍与白质损伤的增加和大脑皮层体积的丧失都相关，这两个因素仅显示出轻微的相关性，似乎与神经认知障碍的严重程度独立相关。研究结果表明，脑白质损伤是HIV相关神经认知损伤的重要中介，也可能是与丙型肝炎病毒混合感染相关的损伤增加的中介。多条证据表明，白质损伤和皮质变性在一定程度上反映了不同的发病机制。拟议的研究将利用宪章纵向研究的存在来确定UCSD站点中有证据表明脑白质损伤正在演变的20名个人(以及10名具有类似疾病特征的明显未受影响的个人)。然后，这些目标个体将每半年进行一次扩展高场(3T)神经成像研究，其中包括多光谱sMRI、计算形态计量学、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被用来解决以下问题：脑白质损伤随时间的演变；脑白质损伤与大脑皮层损伤之间的关系；以及免疫激活和病毒水平在调节这种损伤中的作用。

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.