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

脑成像和血液生物标志物在阿尔茨海默病中的比较效果

• 批准号: 7937994
• 负责人: Orly Lazarov
• 金额: $ 40.19万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937994
• 关键词: Adult; Affect; Age; Age-Months; Alzheimer disease detection; Alzheimer' s Disease; Amyloid deposition; Area; Atrophic; Biological Assay; Biological Markers; Biomedical Engineering; Blood; Blood specimen; Brain; Brain imaging; Censuses; Cerebrospinal Fluid; Chicago; Clinic; Clinical Research; Cognitive; Cognitive deficits; Data; Diagnosis; Diagnostic; Disease; Disease Progression; Doctor of Philosophy; Early Diagnosis; Effectiveness; Epigenetic Process; Evaluation; Event; Gene Expression; Genes; Geriatrics; Goals; Hippocampus (Brain); Human; Illinois; Image; Impaired cognition; Impairment; Individual; Investigation; Learning; Life; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Medial; Memory; Memory Disorders; Memory impairment; MicroRNAs; Molecular; Mus; Nerve Degeneration; Neurology; Neurons; Neuropsychology; Neurosciences; Nuclear; Participant; Pathology; Patients; Performance; Physics; Plasma; Play; Population; Protons; RNA; Radiology Specialty; Recruitment Activity; Research; Research Ethics Committees; Resolution; Role; Sampling; Screening procedure; Specificity; System; Techniques; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Universities; Untranslated RNA; Validation; Wild Type Mouse; aging population; base; comparative effectiveness; dentate gyrus; familial Alzheimer disease; human study; human subject; interest; medical specialties; mild neurocognitive impairment; mouse model; mutant; nerve stem cell; neurogenesis; neuroimaging; neuropathology; neuropsychological; neurosurgery; professor; public health relevance; research study; subventricular zone; success; tool

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.

描述（由申请人提供）：新神经元的形成在整个生命过程中发生在成人大脑的两个离散区域：脑室下区和齿状回的亚颗粒层。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。神经发生的损伤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的转基因小鼠中？E9淀粉样蛋白沉积在4-5个月大时开始，认知缺陷在8-9个月大时明显，而神经发生损伤在1-2个月大时检测到。这些观察结果表明，如果我们知道如何检测活体个体中的神经祖细胞，神经发生的改变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检测到健康人脑中的神经干细胞，并使用磁共振光谱（MRS）对其进行定量。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，我们在本研究中的目标是使用磁共振波谱和表观遗传验证来确定用于检测阿尔茨海默病的基于神经发生的诊断生物标志物。我们建议在健康和阿尔茨海默氏症的人脑神经发生进行彻底的调查。我们有一个强大的合作团队的专家在分子神经科学，神经发生和阿尔茨海默氏症的研究（博士Lazarov）;小鼠和人脑成像（博士小和博士X。Joe Zhou）;神经病学和老年医学专业的阿尔茨海默病患者诊断（分别为Pedalty博士和James博士）;老年人口、痴呆症患者和阿尔茨海默病患者的神经心理学评估（Neynhuis博士）。将使用9.4特斯拉MRI进行小鼠脑成像。携带APPswe/PS1的转基因小鼠脑中的神经发生？E9和野生型同窝仔将通过质子1H-MRS进行检查。本研究之后将立即进行一项人体研究，使用3 Tesla MRS定量轻度认知障碍（MCI）个体、AD患者和年龄匹配对照中的神经干细胞。我们将在MCI，AD患者和人口统计学上匹配的非痴呆个体的神经原性区域中放置感兴趣的区域，使用1H-MRS。目前，伊利诺伊大学芝加哥分校不仅拥有两个3特斯拉MRI系统，这两个系统都能够进行高分辨率MRS，而且还对AD患者进行了大量普查。此外，我们还获得了人类受试者机构审查委员会对该项目的批准。为了验证这些改变是阿尔茨海默氏病特异性的，我们将研究基因表达的改变，在神经原性领域，脑脊液和转基因小鼠和受疾病影响的个人的血浆。为此，将在MRS研究后从小鼠中收集样本。将采集所有研究受试者的脑脊液和血浆样本，即，我们将检查大脑，脑脊液和血浆中microRNA的变化，并将比较相同受试者的MRS数据和microRNA生物标志物，以评估它们在早期诊断或跟踪疾病进展方面的相对有效性。这项研究将提供关于阿尔茨海默病神经发生改变的关键和目前缺乏的信息，以及它可以用作这种疾病的诊断生物标志物的方式。 公共卫生相关性：利用脑成像和基因表达分析转基因小鼠、认知障碍的人类受试者和阿尔茨海默病患者的脑、脑脊液和血浆中的基因表达，该项目将确定用于诊断阿尔茨海默病的早期生物标志物。