MRSI and DKI Evaluation of HIV-1 Clade C Infection in the Whole Brain

摘要摘要 人类免疫缺陷病毒(HIV-1)感染已成为一种慢性病 联合抗逆转录病毒疗法(CART)。然而，大多数抗逆转录病毒药物要么不通过血脑屏障，要么有 有限的渗透率。因此，艾滋病毒-1感染继续对中枢神经系统产生不利影响。 在相当大比例的HIV-1感染者中，该系统会导致神经认知功能障碍。这个 在印度最流行的基因分支是HIV-1分支C。该分支中的Tat蛋白具有丝氨酸基序 C30-31，与分支B中含有半胱氨酸基序的TAT相比，没有神经毒性。 已知在HIV-1感染中产生的细胞因子和gp120具有神经毒性，无论其分支类型如何。 因此，包括我们在内的最近的报告表明，神经认知功能障碍确实发生在 印度的C分支感染者。 充分了解HIV-1 C分支感染对大脑的不利影响与神经认知 功能障碍，有必要对C分支感染者的大脑进行检查。据推测，微妙的 感染HIV-1 C分支的人的大脑会发生实质性和其他变化。受到以下激励 我们正在与印度昌迪加尔的PGIMER进行研究合作，并收购了3T MRI 扫描仪，在本申请中建议使用以下方法评估感染HIV-1分支C亚型的个体 先进的脑成像技术。我们将研究神经代谢物、组织微结构、 C分支感染者和人口统计匹配的当地人群的全脑水平的形态 健康正常受试者。这些变化可能是导致神经认知的潜在神经底物。 感染C分支的受试者中有相当大比例存在缺陷。 在这项为期5年的横断面研究中，我们建议招收220名社区居住科目， 男性和女性，年龄18至45岁，110名艾滋病毒阳性(CD4350和Cart-≤)和151名艾滋病毒对照组。我们 建议实施一系列已翻译成当地语言的标准神经心理测试 (印地语)，并使用一套先进的磁共振成像技术，包括磁共振光谱成像和扩散 峰度成像。收集的大脑成像数据将使我们能够评估组织结构的差异， 两组之间的形态、代谢物水平。这项研究的指标将包括N-乙酰- 天冬氨酸/肌酸、胆碱/肌酸、肌醇/肌酸、各向异性分数、平均扩散系数、轴向 弥散率、径向扩散率、平均峰度、轴向峰度、径向峰度、皮质灰质厚度 结构、灰质和白质亚结构的体积，以及神经认知领域的得分。 这一应用将使我们能够表征组织结构、形态和代谢物的差异 在C分支感染者和对照组的大脑中，使用多模式全脑成像技术。 这些发现还将使我们能够将这些差异与两组人的神经认知功能联系起来。

SUMMARY ABSTRACT Human immunodeficiency virus (HIV-1) infection has become a chronic illness after the introduction of combination antiretroviral therapy (cART). However, most antiretrovirals either do not cross the BBB or have a limited permeability. As a result, HIV-1 infection continues to exert its adverse effects on the central nervous system leading to neurocognitive dysfunctions in a significant percentage of HIV-1 infected individuals. The genetic clade that is most prevalent in India is HIV-1 clade C. The tat protein in this clade has a serine motif at C30-31 that is not neurotoxic as compared to tat containing cysteine motif in clade B. However, inflammatory cytokines produced in HIV-1 infection, irrespective of the clade types, and gp120 are known to be neurotoxic. Consequently, recent reports including from us have shown that neurocognitive dysfunctions indeed occur in clade C infected individuals in India. To fully understand the adverse effects of HIV-1 clade C infection on the brain vis-à-vis neurocognitive dysfunctions, it is necessary to examine the brain of clade C infected individuals. It is hypothesized that subtle parenchymal and other changes occur in the brain of individuals with HIV-1 clade C infection. Encouraged by our ongoing research collaboration with PGIMER, Chandigarh, in India and their acquisition of 3T MRI scanners, it is proposed in this application to evaluate individuals infected with HIV-1 clade C subtype using advanced brain imaging techniques. We will investigate changes in neurometabolites, tissue microstructures, and morphology at the whole-brain level in clade C infected individuals and demographically-matched local healthy normal subjects. These changes may be the underlying neural substrates causing neurocognitive deficits in a significant proportion of subjects living with clade C infection. In this 5-year cross-sectional study, we propose to enroll a total of 220 community residing subjects, men and women, age 18 to 45 years, 110 HIV+ (CD4 ≤350 and cART-naive) and 151 HIV- controls. We propose to administer a standard battery of neuropsychological tests already translated into a local language (Hindi), and to use a suite of advanced MRI techniques that includes MR spectroscopic imaging and diffusion kurtosis imaging. The brain imaging data collected will allow us to evaluate differences in the tissue structure, morphology, and metabolite levels between the two groups. The metrics of this study will include N-acetyl- aspartate/creatine, choline/creatine, myo-inositol/creatine, fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity, mean kurtosis, axial kurtosis, and radial kurtosis, thickness of cortical gray matter structures, volume of gray matter and white matter sub-structures, and neurocognitive domain scores. This application will allow us to characterize tissue structural, morphological and metabolite differences in the brain of clade C infected individuals and controls using multi-modal whole-brain imaging techniques. Findings will also allow us to relate these differences to neurocognitive functions in the two groups.