Predicting Brain Changes in HIV/AIDS

描述（由申请人提供）：在广泛使用联合抗逆转录病毒疗法（CART）的富裕国家，艾滋病毒感染者的预期寿命已大大超过10年，但这大大增加了艾滋病毒/艾滋病感染者的人数。目前有4000万人面临进行性HIV相关脑损伤的风险（Navia 2011），40%的人表现出一些神经或认知障碍。基于我们最近在MRI和扩散张量成像方面的发现和创新，我们的项目绘制了大脑中HIV疾病的动态，揭示了预测临床衰退和大脑衰退的因素。通过分析来自艾滋病毒和艾滋病全国委员会的数据，（HIV神经影像学联盟）队列（218名HIV+受试者每26-32周进行一次MRI纵向扫描，持续3年; 900次扫描），我们将使用我们敏感的图像分析方法，基于张量的形态测量学来（1）绘制随时间推移的脑组织损失率，确定哪些脑系统组织损失最快;（2）将这些丢失模式与神经认知功能障碍（NCI）联系起来;（3）确定哪些宿主和疾病相关因素在基线时预测3年随访期间的萎缩率较高。为了深入探讨功能障碍的原因，我们将在267名受试者中使用基于弥散张量成像的全脑纤维束成像，以确定HIV+患者的纤维完整性降低。我们将使用每个患者的DTI扫描来计算全脑连接矩阵，基于我们开发的最先进的全脑纤维束成像方法。我们将联合收割机将目标1和2的最佳神经影像学指标结合到我们的支持向量机方法中，以预测（1）未来萎缩率，以及（2）3年随访期间的认知下降。利用我们对目标1和2的下降的最佳预测因子，我们将预测哪些HIV+患者将显示即将下降。我们将估计基于神经影像学的药物试验所需的样本量，以检测萎缩速度减缓5%，10%或25%，以及认知下降速度减缓的相同结果。我们将测试我们的预测器是否推广到HIVNC之外的大型独立Charter和Miriam数据集（参见Igor Grant和罗恩科恩博士的支持信），以及我们的许多HIV研究合作者现在使用我们的方法时;参见试点数据）。如新的试点数据所示，我们评估了成像协议差异如何影响测量;我们减少扫描协议混淆的创新（例如，调整后的FA）将指导选择最稳健的预测器。我们将评估这些新的测量方法在预测认知能力下降和增强抗逆转录病毒药物试验中的作用。换句话说，DTI扫描和基于MRI的萎缩图在多大程度上有助于对即将发生的认知障碍进行临床预测？他们能帮助选择药物试验的样本吗？我们的活动将通过选择对未来治疗有更大反应潜力的受试者，使临床试验设计更有效。与往常一样，我们将向医学、神经科学、工程学领域的专家和学员以及我们的100多个合作实验室网络（包括两个国家艾滋病毒联盟：HIVNC、CHARTER和Miriam HIV队列）传播我们的方法，以加速他们的工作。

DESCRIPTION (provided by applicant): In affluent countries where combination anti-retroviral therapy (CART) is widely used, life expectancy with HIV has increased well beyond 10 years, but this has greatly increased the number of people living with HIV/AIDS. 40 million people are now at risk for progressive HIV-related damage to the brain (Navia 2011), and 40% show some neurological or cognitive impairment. Building on our recent discoveries and innovations in MRI and diffusion tensor imaging, our project charts the dynamics of HIV disease in the brain, revealing factors that predict clinical decline and brain decline. By analyzing data from the HIVNC (HIV Neuroimaging Consortium) cohort (218 HIV+ subjects scanned longitudinally with MRI every 26-32 weeks for 3 years; 900 scans), we will use our sensitive image analysis method, tensor-based morphometry to (1) map rates of brain tissue loss over time, determining which brain systems lose tissue fastest; (2) relate these loss patterns to neurocognitive impairment (NCI); and (3) determine which host and disease-related factors, at baseline, predict higher atrophic rates over the 3-year follow-up interval. To deeply probe the causes of dysfunction, we will use whole-brain tractography based on diffusion tensor imaging in 267 subjects to determine where HIV+ patients have reduced fiber integrity. We will use each patient's DTI scan to compute a whole-brain connection matrix, based on a state-of-the-art whole-brain tractography method we developed. We will combine the best neuroimaging measures from Aims 1 and 2 into our support vector machine method to predict (1) future rates of atrophy, and (2) cognitive decline over the 3-year follow-up. With our best predictors of decline from Aims 1 and 2, we will predict which HIV+ patients will show imminent decline. We will estimate the sample sizes needed for a neuroimaging-based drug trial to detect a 5%, 10%, or 25% slowing in the rate of atrophy, and the same percents of slowing in the rate of cognitive decline. We will test whether our predictors generalize to the large, independent Charter and Miriam datasets beyond HIVNC (see Support Letters from Drs. Igor Grant and Ron Cohen), and when used by our many HIV research collaborators now using our methods; see Pilot Data). As shown in new pilot data, we assess how imaging protocol differences affect the measures; our innovations to reduce scan protocol confounds (e.g., adjusted FA) will guide selection of the most robust predictors. We will evaluate how useful these new measures are for predicting cognitive decline, and boosting power in an antiretroviral drug trial. In other words, to what extent can a DTI scan, and an MRI-based map of atrophy, help to make clinical predictions of imminent cognitive impairment? Can they help select a sample for a drug trial? Our activities will make clinical trial design more efficient by selecting subjects with greater potential to respond t future therapies. As always, we will disseminate our methods to both experts and trainees in medicine, neuroscience, engineering, and to our network of over 100 collaborating labs (including two national HIV consortia: HIVNC, CHARTER, and the Miriam HIV cohort), to accelerate their work.