Comparative effectiveness of Brain Imaging and Blood Biomarkers in Alzheimer??s d

描述(由申请人提供)：新神经元的形成发生在成人大脑的两个独立区域：齿状回的脑室下区和亚颗粒层。越来越多的证据表明，新形成的神经元整合在特定的大脑区域，并在学习和记忆的许多方面发挥作用。我们对家族性阿尔茨海默病(FAD)小鼠模型的研究表明，这些小鼠的神经发生严重受损。神经发生的损害在生命的早期就很明显，在淀粉样蛋白沉积和记忆缺陷之前。例如，在携带FAD连锁突变APPswe/PS1？E9的转基因小鼠中，淀粉样蛋白沉积的开始时间是4-5个月，认知障碍在8-9个月时明显，而神经发生的损害在1-2个月大时被检测到。这些观察表明，如果我们知道如何在活体个体中检测神经前体细胞，神经发生的变化可能为我们提供早期诊断生物标志物。最近的一项研究成功地在健康的人脑中检测到了神经干细胞，并使用磁共振波谱(MRS)对它们进行了量化。受我们在健康个体中重现这些研究结果的初步能力的鼓舞，我们在这项研究中的目标是找出一种基于神经发生的诊断生物标记物，用于使用磁共振波谱和表观遗传学验证来检测阿尔茨海默病。我们建议对健康和阿尔茨海默病患者的人脑中的神经发生进行彻底的调查。我们拥有强大的协作专家团队，包括分子神经科学、神经发生和阿尔茨海默病研究(Lazarov博士)；鼠和人脑成像(Little Little博士和周乔X.Joe博士)；诊断具有神经学和老年学专业专长的阿尔茨海默氏症患者(分别为Pedalty博士和James博士)；以及对老龄化人口、痴呆患者和阿尔茨海默氏症患者进行神经心理评估(Neynhuis博士)。小鼠的大脑成像将使用9.4特斯拉核磁共振进行。携带APPswe/PS1、E9基因的转基因小鼠和野生型小鼠脑内的神经发生将通过质子1H-MRS进行检测。在这项研究之后，将立即进行一项人类研究，利用3Tesla的MRS对轻度认知障碍(MCI)患者、AD患者和年龄匹配的对照组的神经干细胞进行量化。我们将使用1H-MRS在MCI、AD患者和人口统计学上匹配的非痴呆患者的神经源性区域放置感兴趣区域。目前，伊利诺伊大学芝加哥分校不仅拥有两个3-特斯拉磁共振成像系统，这两个系统都能够进行高分辨率的MRS，而且还对AD患者进行了大规模普查。此外，我们还为这个项目获得了人类受试者机构审查委员会的批准。为了验证这些变化是阿尔茨海默氏病特有的，我们将检测神经源性区域、脑脊液以及转基因小鼠和受该疾病影响的个人血浆中基因表达的变化。为此，将在MRS研究后从小鼠身上收集样本。脑脊液和血浆样本将从所有研究参与者，即MCI、AD患者和接受MRS的年龄匹配的对照组中收集。我们将检测大脑、脑脊液和血浆中microRNA的变化，并将同一受试者的MRS数据和microRNA生物标志物进行比较，以评估它们在能够提供早期诊断或跟踪疾病进展方面的比较有效性。这项研究将提供有关阿尔茨海默病神经发生变化的关键信息，以及如何将其用作这种疾病的诊断生物标记物。 公共卫生相关性：该项目将利用脑成像和转基因小鼠、认知障碍患者和阿尔茨海默病患者的脑、脑脊液和血浆中的基因表达分析，确定诊断阿尔茨海默病的早期生物标记物。

DESCRIPTION (provided by applicant): Formation of new neurons takes place throughout life in two discrete areas in the adult brain: the subventricular zone and the subgranule layer of the dentate gyrus. Increasing evidence suggests that newly formed neurons integrate in specific brain areas and play a role in numerous aspects of learning and memory. Our studies in mouse models of Familial Alzheimer's disease (FAD) revealed that neurogenesis is severely compromised in these mice. Impairments in neurogenesis are apparent very early in life, preceding amyloid deposition and memory deficits. For example, in transgenic mice harboring FAD- linked mutant APPswe/PS1?E9 onset of amyloid deposition is 4-5 months of age and cognitive deficits are apparent at 8-9 months, while impairments in neurogenesis are detected at 1-2 months of age. These observations suggest that alterations in neurogenesis may provide us with an early diagnostic biomarker, if we know how to detect neural progenitor cells in live individuals. A recent study successfully detected neural stem cells in the healthy human brain and quantified them using Magnetic Resonance Spectroscopy (MRS). Encouraged by our preliminary ability to reproduce the results of these studies in healthy individuals, our goal in this study is to identify a neurogenesis-based diagnostic biomarker for the detection of Alzheimer's disease using magnetic resonance spectroscopy and epigenetic validation. We propose to perform a thorough investigation of neurogenesis in the healthy and Alzheimer's human brain. We have a strong collaborative team of experts in molecular neuroscience, neurogenesis and Alzheimer's disease research (Dr. Lazarov); Mouse and human brain imaging (Dr. Little and Dr. X. Joe Zhou); Diagnosis of Alzheimer's patients with specialty in Neurology and Geriatrics (Dr. Pedalty and Dr. James, respectively); Neuropsychological evaluation of the aging population, demented individuals and Alzheimer's patients (Dr. Neynhuis). Mouse brain imaging will be performed using a 9.4-Tesla MRI. Neurogenesis in the brains of transgenic mice harboring APPswe/PS1?E9 and in wild type littermates will be examined by proton 1H-MRS. This study will be immediately followed by a human study for the quantification of neural stem cells in individuals with mild cognitive impairments (MCI), AD patients and age-matched controls, using MRS at 3Tesla. We will place regions of interest in the neurogenic areas of MCI, AD patients and demographically-matched non-demented individuals, using 1H-MRS. At present, the University of Illinois at Chicago not only has two 3-Tesla MRI systems both of which are capable of high resolution MRS but also a large census of patients with AD. Additionally, we also have human subjects institutional review board approval for this project. To validate that these alterations are Alzheimer's disease-specific, we will examine alterations in gene expression in neurogenic areas, cerebrospinal fluid and in the plasma of transgenic mice and individuals affected with the disease. For this purpose, samples will be collected from mice following MRS study. Cerebrospinal fluid and plasma samples will be collected from all study participants, i.e., MCI, AD patients and age-matched controls undergoing MRS. We will examine alterations in microRNA in brain, Cerebrospinal fluid and plasma, and will compare MRS data and microRNA biomarkers in the same subjects to evaluate their comparative effectiveness at being able to provide for the early diagnosis or for following the progression of the disease. This study will provide critical and currently absent information concerning alterations in neurogenesis in Alzheimer's disease and the ways by which it can be used as a diagnostic biomarker for this disorder. PUBLIC HEALTH RELEVANCE: Using brain imaging and gene expression analysis in brain, cerebrospinal fluid and plasma of transgenic mice, human subjects with cognitive impairments and Alzheimer's disease patients, this project will determine early biomarkers for the diagnosis of Alzheimer's disease.