Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA.
Department of Psychiatry, University of California San Diego School of Medicine, San Diego, CA, USA.
J Neurovirol. 2020 Aug;26(4):496-508. doi: 10.1007/s13365-020-00846-z. Epub 2020 May 11.
HIV-associated neurocognitive disorders (HAND) describe a spectrum of neuropsychological impairment caused by HIV-1 infection. While the sequence of cellular and physiological events that lead to HAND remains obscure, it likely involves chronic neuroinflammation. Host genetic markers that increase the risk for HAND have been reported, but replication of such studies is lacking, possibly due to inconsistent application of a behavioral phenotype across studies. In the current study, we used histopathologic phenotypes in order to validate putative risk alleles for HAND. The National NeuroAIDS Tissue Consortium, a longitudinal study of the neurologic manifestations of HIV. Data and specimens were obtained from 175 HIV-infected adults. After determining several potential covariates of neurocognitive functioning, we quantified levels of six histopathological markers in the frontal lobe in association with neurocognitive functioning: SYP, MAP 2, HLA-DR, Iba1, GFAP, and β-amyloid. We then determined alleles of 15 candidate genes for their associations with neurocognitive functioning and histopathological markers. Finally, we identified the most plausible causal pathway based on our data using a multi-stage linear regression-based mediation analysis approach. None of the genetic markers were associated with neurocognitive functioning. Of the histopathological markers, only MAP 2 and SYP were associated with neurocognitive functioning; however, MAP 2 and SYP did not vary as a function of genotype. Mediation analysis suggests a causal pathway in which presynaptic degeneration (SYP) leads to somatodendritic degeneration (MAP 2) and ultimately neurocognitive impairment. This study did not support the role of host genotype in the histopathology underlying HAND. The findings lend further support for synaptodendritic degeneration as the proximal underlying neuropathological substrate of HAND.
HIV 相关神经认知障碍 (HAND) 描述了由 HIV-1 感染引起的一系列神经心理障碍。虽然导致 HAND 的细胞和生理事件序列仍然不清楚，但它可能涉及慢性神经炎症。已经报道了宿主遗传标记物增加 HAND 的风险，但由于缺乏对研究的复制，这些研究可能由于研究之间行为表型的不一致应用而缺乏。在当前的研究中，我们使用组织病理学表型来验证 HAND 的假定风险等位基因。国家神经艾滋病组织联盟是一项关于 HIV 神经系统表现的纵向研究。数据和标本取自 175 名 HIV 感染成年人。在确定了几个可能影响神经认知功能的协变量后，我们在额叶中定量了与神经认知功能相关的六种组织病理学标志物的水平：SYP、MAP2、HLA-DR、Iba1、GFAP 和 β-淀粉样蛋白。然后，我们确定了 15 个候选基因的等位基因与神经认知功能和组织病理学标志物的关联。最后，我们使用基于多阶段线性回归的中介分析方法，根据我们的数据确定最合理的因果途径。没有遗传标记与神经认知功能有关。在组织病理学标志物中，只有 MAP2 和 SYP 与神经认知功能有关；然而，MAP2 和 SYP 并没有随着基因型的变化而变化。中介分析表明，一种因果途径是，突触前退化 (SYP) 导致树突体退化 (MAP2)，最终导致神经认知障碍。这项研究不支持宿主基因型在 HAND 潜在组织病理学中的作用。研究结果进一步支持突触树突退化作为 HAND 潜在神经病理学基质的近端基础。
