Neuropsychiatric and clinical correlates to miRNA expression in the frontal cortex of HIV-infected individuals

Objective: To elucidate molecular mechanisms of neurocognitive dysfunction in long-term HIV-infected individuals by assessing the microRNA (miR) profile and determining clinical and neurocognitive correlates to miR expression. Design: Analysis of miR profile in frontal cortex of retrospectively-identified autopsy cases of longitudinally-followed subjects with HIV-infection and age/sex-matched controls. HIV-subjects had semi-annual neuropsychiatric and clinical testing, at autopsy, tissue was archived. Methods: MiR repertoires were profiled from frontal cortices. Analysis of variance (ANOVA) and Tukey Honestly Sigificant Difference (HSD) tests with Benjamini-Hochberg correction for multiple comparisons were used to compare expression among the three groups. Pairwise correlations were used to identify neuropsychiatric variable that correlatee with expression of miRs. Results: MiRs were significantly different by HIV-status: miR-103, miR-125a, miR-380, miR-422a, miR-515, miR-520b, miR0618, miR-886, and miR-9. Many miRs correlated with neuropsychiatric outcomes like Learning, Memory, Executive, Verbal, and Motor deficit scores. Conclusions: MiRs are clearly dysregulated in the frontal cortex of HIV-positive individuals. Only a few miRs were significantly dysregulated in only the methamphetamine group. Our study identifies miRs that form rational targets for further inquiry on biochemical mechanisms of HIV-related neurocognitive deficits. Learning deficit score correlates with expression of more miRs than other parameters. A total of 11 HIV positive individuals were analyzed, 5 of which had a past history of methamphetamine ABUSE, and 5 age-matched HIV-negative normal Controls. Technical duplicates are included. Included are clinical and neuropsychiatric data from most recent visit before time of death. This is a retrospective autopsy study of longitudinally-followed subjects on miRNA levels in the frontal cortex.

研究目的：本研究旨在通过分析人类免疫缺陷病毒（Human Immunodeficiency Virus, HIV）长期感染者的微小RNA（microRNA, miR）表达谱，明确其神经认知功能障碍的分子机制，并探究miRNA表达与临床及神经认知指标的相关性。
研究设计：本研究对经回顾性确认的纵向随访HIV感染者尸检样本，以及年龄、性别匹配的对照样本的前额叶皮层（frontal cortex）miRNA表达谱进行分析。所有HIV感染者均接受每半年一次的神经精神及临床评估，尸检时留存脑组织样本。
研究方法：从前额叶皮层样本中完成miRNA表达谱分析。采用方差分析（Analysis of Variance, ANOVA）结合图基诚实显著差异（Tukey Honestly Significant Difference, HSD）检验，并辅以本杰明尼-霍赫贝格（Benjamini-Hochberg）多重比较校正法，对三组样本的miRNA表达水平进行比较。采用两两相关性分析筛选与miRNA表达水平相关的神经精神变量。
研究结果：不同HIV感染状态下的miRNA表达存在显著差异，涉及miR-103、miR-125a、miR-380、miR-422a、miR-515、miR-520b、miR-0618、miR-886及miR-9。大量miRNA的表达与学习、记忆、执行功能、语言及运动功能缺损评分等神经精神结局指标存在相关性。
研究结论：HIV感染者前额叶皮层中的miRNA表达明显失调。仅甲基苯丙胺（methamphetamine）暴露组存在少量显著失调的miRNA。本研究筛选出可作为HIV相关神经认知缺损生化机制后续研究的合理靶点miRNA。与其他指标相比，学习功能缺损评分与更多miRNA的表达水平存在相关性。本研究共纳入11名HIV阳性感染者进行分析，其中5名有甲基苯丙胺滥用史，另设5名年龄匹配的HIV阴性健康对照。研究包含技术重复样本，同时纳入了受试者死亡前最后一次随访的临床及神经精神评估数据。本研究为一项针对纵向随访受试者前额叶皮层miRNA水平的回顾性尸检研究。