CSF Molecular Marker Study Consortium

本项目拟在瑞典哥德堡、意大利米兰、美国旧金山和澳大利亚悉尼建立一个国际性、多中心的联盟，以促进脑脊液（CSF）分子标记的合理使用，以管理（预防、诊断和治疗）和了解HIV-1脑感染的发病机制及其主要临床后果——艾滋病痴呆复合物（ADC）。所要求的资金将用于：发展合作联盟的基础设施、方法和程序，以促进一个机构可以完成的对艾滋病毒感染CSF变化的连续、更迅速的分析方法；2. 对一组初步的候选脑脊液标记物进行初步筛选，其成分评估病毒学、宿主免疫学、神经和血脑屏障对脑脊液成分的贡献，并使用约160个定义良好的横断面脑脊液和血液样本对的矩阵将其减少到更小的初始核心脑脊液标记物电池；3. 通过额外的(a)横断面研究来测试个体和组合标记物与更复杂的真实样本和患者光谱的诊断价值，以及(b)开始停止抗逆转录病毒治疗后标记物动态的短期纵向研究，进一步评估和完善该电池，使其成为特征良好的次级核心CSF标记物电池；4. 继续扩大脑脊液/血浆样本库，评估其他标记物作为补充或替代次级电池成分标记物的候选物，并解决发病机制问题；5. 发展个体市场动态及其相互作用的正式模型；6. 利用从这些研究中获得的信息，为临床试验设计制定一套CSF标记物指南。此外，在这项研究的5年中，将采取措施，通过与其他模式的研究相结合，包括功能神经影像学和遗传分析，为这项研究做准备并随后扩展这项研究。

This application proposes to establish an international, multi-centered consortium with sites in Goteborg Sweden, Milan Italy, San Francisco USA, and Sydney Australia to advance the rational use of cerebrospinal fluid (CSF) molecular markers to manage (prevent, diagnose and treat) and understand the pathogenesis of HIV-1 brain infection and its major clinical consequence, the AIDS dementia complex (ADC). The requested funding will be used to: 1. Develop the infrastructure, methodologies and procedures of the cooperative consortium that facilitate a sequential, more expeditious approach to analysis of CSF changes in HIV infection that could be accomplished by a single institution; 2. Carry out initial screening of a preliminary group of candidate CSF markers, with components assessing virological, host immunological, neural and blood-brain barrier contributions to CSF composition, and to reduce this to a smaller initial core CSF marker battery using a matrix of about 160 well-defined, cross-sectional CSF and blood sample pairs; 3. Further assess and refine this battery into a well-characterized secondary core CSF marker battery by additional (a) cross-sectional study to test the diagnostic value of the individual and combined markers with a more complex, real-world spectrum of samples and patients and (b) short-term longitudinal studies of marker dynamics after initiation of cessation of anti-retroviral therapy; 4. Continue to enlarge to enlarge CSF/plasma sample repositories and to assess additional markers as candidates to add to or replace component markers of the secondary battery and to address questions of pathogenesis; 5. Develop formal models of individual marker dynamics and their interactions; 6. Use the information derived from these studies to formulate a set of CSF marker guidelines for the design of clinical trials. Additionally, throughout the 5 years of this study, measures will be taken to prepare for and subsequently extend this study through integration with studies using other modalities, including functional neuroimaging and genetic analyses.