Hippocampal Structure and Function in Cognitive Impairment

描述(由申请人提供)：在保罗·B·比森以患者为导向的老年研究职业发展奖的申请中，候选人寻求5年的工资和研究支持，以获得培训并从事与神经成像和临床前阿尔茨海默病(AD)相关的研究项目。长期目标是成为一名独立的研究人员，并建立一个致力于研究AD和其他神经退行性疾病的实验室。具体的希望是使用先进的神经成像技术来创造新的、敏感的生物标记物，用于AD的早期诊断和疾病监测。尽管到目前为止，他的训练取得了实质性进展，但他的知识和技能仍然存在差距。旨在填补这些空白的短期目标包括：(1)扩大以前的7-特斯拉(7T)磁共振成像(MRI)培训；(2)开发设计、执行和解释功能磁共振实验的新技能；(3)获得临床流行病学和统计学方面的新技能；以及(4)巩固临床研究设计方面的技能。与他的导师团队一起，他制定了一个全面的培训计划，其中包括以下概述的研究项目、课程作业和与他的导师的定期会议。他在这项提案中的总体目标是发展技能和初步数据，以便在获奖的第4-5年期间提交成功的RO1申请。 这项拟议的研究旨在满足对生物标记物的迫切需求，这些生物标记物可以在遗忘性轻度认知损害(AMCI)期间检测AD的最早临床前迹象。这些生物标志物可能有助于最终将新的疾病修正疗法提供给受影响最小的患者，他们将受益最大。神经成像技术前景看好，但传统技术对早期疾病不敏感。尸检研究显示，在患者开始经历早期记忆障碍的时候，海马体的特定亚区，包括CA1顶神经纤维，会发生病理变化。因此，为了最大限度地敏感于早期疾病，神经成像生物标记物应该能够分析局灶性海马区的完整性。在这里，候选人建议应用两种互补的、高分辨率的先进成像技术来解决这个问题：(1)7T MRI，它可以在~200？m的分辨率下揭示海马区的微结构；(2)高分辨率3T fMRI结合与事件相关的面名配对任务，以研究与记忆或遗忘相关的海马区激活模式。他将汇集30名aMCI患者和30名年龄匹配的正常对照的队列，在目标1中，他将使用神经成像工具来发现记忆障碍的结构和功能相关性。他将每年跟踪受试者(平均跨度为40个月)，并在目标2中确定最能预测随后认知能力下降的基线结构和功能成像指标。除了有助于临床前AD生物标记物的开发外，这项工作还有望揭示aMCI和AD中海马依赖记忆丧失的结构和功能基础的基本细节。 与公共卫生相关：阿尔茨海默病是一种流行病。除了需要能够阻止或减缓疾病的新的治疗方法外，还需要能够在疾病的最早阶段识别疾病的生物标记物，以便促进将新的治疗方法均匀地提供给损失最大的患者。拟议的工作重点是两项先进的神经成像技术，它们可能有助于填补这一关键空白。

DESCRIPTION (provided by applicant): In this application for a Paul B. Beeson Patient-Oriented Research Career Development Award in Aging, the candidate seeks 5 years of salary and research support to obtain training and to pursue a research project related to neuroimaging and preclinical Alzheimer's disease (AD). The long term goal is to become an independent investigator and to establish a laboratory dedicated to the study of AD and other neurodegenerative diseases. The specific hope is to use advanced neuroimaging technologies to create novel, sensitive biomarkers for early AD diagnosis and disease monitoring. Despite substantial progress in his training so far, gaps remain in his knowledge and skills. Short term goals, aimed at filling these gaps, include: (1) to expand upon previous training in 7-Tesla (7T) magnetic resonance imaging (MRI); (2) to develop new skills in designing, performing, and interpreting fMRI experiments; (3) to achieve new skills in clinical epidemiology and statistics; and (4) to solidify skills in clinical research design. With his mentorship team, he has developed a comprehensive training program, which includes the research project outlined below, coursework, and regular meetings with his mentors. His overall goal in this proposal is to develop the skills and preliminary data needed to submit a successful RO1 application during Years 4-5 of the award. The proposed research seeks to fill a critical need for biomarkers that can detect the earliest, preclinical signs of AD, during a period of amnestic Mild Cognitive Impairment (aMCI). Such biomarkers may facilitate the eventual delivery of novel disease-modifying therapeutics to the minimally affected patients who stand the most to benefit. Neuroimaging holds great promise, but conventional technologies are insensitive to early disease. Post-mortem studies reveal that specific subfields of the hippocampus, including the CA1 apical neuropil, develop pathology around the time that patients begin to experience early memory impairment. Therefore, to be maximally sensitive to early disease, neuroimaging biomarkers should be able to assay the integrity of focal hippocampal subfield areas. Here, the candidate proposes to apply two complementary, highresolution, advanced imaging technologies to the problem: (1) 7T MRI, which can reveal hippocampal microstructure at ~200 ¿m resolution; and (2) high-resolution 3T fMRI coupled with an event-related face-name pairing task, to study patterns of hippocampal subfield activation that correlate with remembering or forgetting. He will assemble cohorts of 30 patients with aMCI and 30 age-matched normal controls, and in Aim 1 will use the neuroimaging tools to discover the structural and functional correlates of memory impairment. He will follow subjects annually (average span 40 months), and in Aim 2 will identify the baseline structural and functional imaging metrics that are most predictive of subsequent cognitive decline. In addition to contributing to preclinical AD biomarker development, this work promises to reveal basic details of the structural and functional underpinnings of hippocampal-dependent memory loss in aMCI and AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is epidemic. In addition to the need for new treatments that can stop or slow the disease, there is a parallel need for biomarkers capable of identifying the illness in its earliest possible stages, in order to facilitate the evenual delivery of new treatments to patients with the most to lose. The proposed work focuses on two advanced neuroimaging technologies that may help to fill this critical gap.