Marcotte Thomas D, Deutsch Reena, Michael Benedict Daniel, Franklin Donald, Cookson Debra Rosario, Bharti Ajay R, Grant Igor, Letendre Scott L
Department of Psychiatry, UC San Diego, San Diego, CA, 92093, USA.
J Neuroimmune Pharmacol. 2013 Dec;8(5):1123-35. doi: 10.1007/s11481-013-9504-2. Epub 2013 Oct 8.
Neurocognitive (NC) impairment (NCI) occurs commonly in people living with HIV. Despite substantial effort, no biomarkers have been sufficiently validated for diagnosis and prognosis of NCI in the clinic. The goal of this project was to identify diagnostic or prognostic biomarkers for NCI in a comprehensively characterized HIV cohort. Multidisciplinary case review selected 98 HIV-infected individuals and categorized them into four NC groups using normative data: stably normal (SN), stably impaired (SI), worsening (Wo), or improving (Im). All subjects underwent comprehensive NC testing, phlebotomy, and lumbar puncture at two timepoints separated by a median of 6.2 months. Eight biomarkers were measured in CSF and blood by immunoassay. Results were analyzed using mixed model linear regression and staged recursive partitioning. At the first visit, subjects were mostly middle-aged (median 45) white (58 %) men (84 %) who had AIDS (70 %). Of the 73 % who took antiretroviral therapy (ART), 54 % had HIV RNA levels below 50 c/mL in plasma. Mixed model linear regression identified that only MCP-1 in CSF was associated with neurocognitive change group. Recursive partitioning models aimed at diagnosis (i.e., correctly classifying neurocognitive status at the first visit) were complex and required most biomarkers to achieve misclassification limits. In contrast, prognostic models were more efficient. A combination of three biomarkers (sCD14, MCP-1, SDF-1α) correctly classified 82 % of Wo and SN subjects, including 88 % of SN subjects. A combination of two biomarkers (MCP-1, TNF-α) correctly classified 81 % of Im and SI subjects, including 100 % of SI subjects. This analysis of well-characterized individuals identified concise panels of biomarkers associated with NC change. Across all analyses, the two most frequently identified biomarkers were sCD14 and MCP-1, indicators of monocyte/macrophage activation. While the panels differed depending on the outcome and on the degree of misclassification, nearly all stable patients were correctly classified.
神经认知（NC）障碍（NCI）在HIV感染者中很常见。尽管付出了巨大努力，但在临床上尚无生物标志物能得到充分验证用于NCI的诊断和预后评估。本项目的目标是在一个全面特征化的HIV队列中识别NCI的诊断或预后生物标志物。多学科病例审查选取了98名HIV感染者，并使用标准化数据将他们分为四个NC组：稳定正常（SN）、稳定受损（SI）、恶化（Wo）或改善（Im）。所有受试者在两个时间点接受了全面的NC测试、静脉穿刺和腰椎穿刺，两个时间点的间隔中位数为6.2个月。通过免疫测定法在脑脊液和血液中测量了八种生物标志物。使用混合模型线性回归和逐步递归划分对结果进行分析。在首次就诊时，受试者大多为中年（中位数45岁）白人（58%）男性（84%），患有艾滋病（70%）。在接受抗逆转录病毒治疗（ART）的73%的受试者中，54%的血浆HIV RNA水平低于50拷贝/mL。混合模型线性回归确定，只有脑脊液中的MCP-1与神经认知变化组相关。旨在诊断（即正确分类首次就诊时的神经认知状态）的递归划分模型很复杂，需要大多数生物标志物才能达到错误分类限度。相比之下，预后模型更有效。三种生物标志物（sCD14、MCP-1、SDF-1α）的组合正确分类了82%的Wo和SN受试者，包括88%的SN受试者。两种生物标志物（MCP-1、TNF-α）的组合正确分类了81%的Im和SI受试者，包括100%的SI受试者。对特征明确的个体进行的这项分析确定了与NC变化相关的简洁生物标志物组。在所有分析中，最常确定的两种生物标志物是sCD14和MCP-1，它们是单核细胞/巨噬细胞活化的指标。虽然生物标志物组因结果和错误分类程度而异，但几乎所有稳定患者都被正确分类。
