Defining the clinical utility of CSF biomarkers of neurodegeneration in HIV+ elders

摘要 这是K23奖的申请书，申请人是大学的行为神经学研究员， 位于加州旧金山弗朗西斯科（UCSF）的记忆和衰老中心（MAC）。赫尔南德斯博士正在树立自己的形象 一名初级研究员，在老年神经艾滋病方面进行以患者为导向的临床研究，包括 HIV相关性神经认知障碍（HAND）的神经发病机制以及准确 诊断，治疗和预防这种情况。这个K23将为赫尔南德斯博士提供资源和支持 必须实现以下目标：（1）熟练掌握脑脊液（CSF）生物标志物 分析和方法;（2）促进她对神经退行性变指标的理解， 包括解释脑脊液（CSF）神经退行性生物标志物和淀粉样蛋白PET扫描;（3） 获得纵向神经成像技术和统计分析的高级技能，解决多变量 和纵向建模;（5）临床研究操作中的主要指导。实现这些 为了实现这些目标，Hellhill博士组建了一个由主要导师维克托瓦尔库尔博士（艾滋病毒相关 认知障碍;艾滋病毒的多模式神经成像;老年神经艾滋病毒的临床研究）;和两个共同的， 导师Gil Rabinovici博士（阿尔茨海默病（AD）的多模态神经成像;改善阿尔茨海默病的生物标志物） AD的诊断准确性）和Henrik Zetterberg博士（临床神经化学; 包括AD在内的神经退行性疾病的早期诊断）。 拟议的研究项目解决了如何准确诊断艾滋病毒+老年人的诊断困境 认知障碍，因为他们的年龄增加了阿尔茨海默病（AD）诊断的风险，然而， 这些症状可能反映了HIV相关的神经认知障碍（HAND）。赫尔南德斯医生将检查 AD的CSF生物标志物的纵向面板，在HIV患者的一些报告中受到干扰的那些，在 独特的临床样本：患有AD的轻度症状性认知障碍的HIV阳性老年人 通过淀粉样PET扫描排除了神经病理学，并通过抗逆转录病毒治疗抑制了病毒。通过 为此，她将建立这些CSF AD生物标志物在HIV+老年人治疗中的效用， 这些CSF AD生物标志物与持续性CSF免疫激活标志物之间的相关性，参见 AD和免疫激活标志物如何预测HAND中加速的脑萎缩。Hellhill博士的 K23培训将使她做好准备，使用CSF对老年神经HIV进行独立的临床研究 生物标志物和神经成像，并将准备她成功申请R01，并成为一个领导者， 老年神经艾滋病领域。

ABSTRACT This is an application for a K23 award for Dr. Joanna Hellmuth, a behavioral neurology fellow at the University of California, San Francisco (UCSF) Memory and Aging Center (MAC). Dr. Hellmuth is establishing herself as a junior investigator conducting patient-oriented clinical research in geriatric neuroHIV, including the neuropathogenesis of HIV-Associated Neurocognitive Disorder (HAND) and approaches to accurately diagnose, treat and prevent this condition. This K23 will provide Dr. Hellmuth with the resources and support essential to accomplish the following goals: (1) to gain proficiency in cerebrospinal fluid (CSF) biomarker analysis and methodologies; (2) to advance her understanding of the indicators of neurodegeneration, including interpretation of cerebrospinal (CSF) neurodegenerative biomarkers and amyloid PET scans; (3) to gain advanced skills in longitudinal neuroimaging techniques and statistical analyses addressing multivariable and longitudinal modeling; and (5) primary mentorship in the operations of clinical research. To achieve these goals, Dr. Hellmuth has assembled a mentoring team of a primary mentor, Dr. Victor Valcour (HIV-associated cognitive disorders; multimodal neuroimaging in HIV; clinical research in geriatric neuroHIV); and two co- mentors, Dr. Gil Rabinovici (multi-modal neuroimaging in Alzheimer’s disease (AD); biomarkers that improve diagnostic accuracy of AD) and Dr. Henrik Zetterberg (clinical neurochemistry; CSF and plasma biomarkers for the early diagnosis of neurodegenerative disorders, including AD). The proposed research project addresses the diagnostic dilemma of how to accurately diagnose HIV+ elders with cognitive impairment, as their age increases the risk for an Alzheimer’s disease (AD) diagnosis, however the symptoms could reflect HIV-Associated Neurocognitive Disorder (HAND). Dr. Hellmuth will examine a longitudinal panel of CSF biomarkers of AD, ones that are perturbed in some reports of HIV patients, in a unique clinical sample: HIV+ elders with mild symptomatic cognitive impairment who have had AD neuropathology ruled out by amyloid PET scan, and are virally suppressed with antiretroviral therapy. Through this, she will establish the utility of these CSF AD biomarkers in HIV+ elders on treatment, explore the associations between these CSF AD biomarkers and markers of persistent CSF immune activation, and see how both AD and immune activation markers can predict accelerated brain atrophy in HAND. Dr. Hellmuth’s K23 training will prepare her to conduct independent, clinical research in geriatric neuroHIV using CSF biomarkers and neuroimaging, and will prepare her to successfully apply for an R01, and become a leader in the field of geriatric neuroHIV.