Imaging inflammation and tau in elders with different clinical and biomarker profiles of Alzheimer’s disease

对具有不同阿尔茨海默病临床和生物标志物特征的老年人进行炎症和 tau 蛋白成像

基本信息

批准号：
9884705
负责人：
William Charles Kreisl
金额：
$ 15.78万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This grant application represents a proposed career development and research plan designed to accomplish my long-term career goals and my short-term training and research objectives. My long-term goal is to establish myself as an independent PI with a research program focused on developing effective treatment strategies for patients with diseases of aging. My training objectives are to refine my skills in clinical research methodology and ethics, refine my clinical expertise in evaluating patients with diseases of aging, develop expertise in PET imaging research, gain expertise in MRI analysis, learn to integrate biomarker analysis into clinical research, build a foundation in statistical analysis, and improve my grant writing skills. My research objectives are to determine 1) how inflammation and tau each relate to amyloidosis, neurodegeneration, and cognition, and 2) the spatial relationship among inflammation, tau, and amyloid. These objectives are designed to address an important knowledge gap in AD research. There is a critical need to determine how inflammation and tau develop in relation to amyloid deposition, neurodegeneration, and cognitive impairment and how they correlate with each other. My central hypothesis is that inflammation and tau increase in AD in a spatially related manner that is more closely associated with cognitive decline and brain atrophy than is amyloid burden. My preliminary clinical PET data suggests that inflammation is greater in AD than MCI and increases longitudinally, particularly in medial temporal cortex. This spatial and temporal progression is similar to that in autopsy studies that show tau pathology starts in medial temporal cortex and increases with degree of cognitive decline in AD. My rationale is that once it is known how inflammation and tau relate to risk of progression to AD, measuring these factors with PET can predict decline and serve as a biomarker for novel therapeutics. I will test my central hypothesis by performing inflammation and tau PET imaging in individuals with distinct clinical and biomarker profiles that define four different categories of cognitive aging: 1) Amyloid-positive elders who meet clinical criteria for amnestic MCI or mild AD (clinical AD group), 2) amyloid-positive elders without impairment (preclinical AD group), 3) amyloid-negative elders without impairment (normal aging group), and 4) amyloid-negative elders who meet clinical criteria for amnestic MCI or mild AD (suspected non-AD pathophysiology group). The specific aims are: 1) Determine the extent of inflammation and tau burden in different categories of cognitive aging. I postulate that within medial temporal, lateral temporal, and parietal regions a step-wise pattern will exist such that amyloid-positive elders with impairment will have greater inflammation and tau burden than amyloid- positive elders who are cognitively normal, who in turn will have greater inflammation and tau than amyloid- negative elders without cognitive impairment. Because I predict impairment and amyloid status to have an additive effect on inflammation, I hypothesize that amyloid-negative elders with impairment will have greater inflammation than cognitive controls but less inflammation than amyloid-positive elders with impairment. I also postulate that inflammation and tau burden measured with PET will correlate with clinical severity, brain atrophy, and CSF biomarkers for inflammation and tau. 2) Determine the spatial relationship between inflammation, tau, and amyloid. My working hypothesis is that inflammation and tau will correlate in a regionally dependent manner that is spatially distinct from amyloid. My approach is innovative in that it uses an improved radioligand for inflammation and will be the first study, to my knowledge, to combine inflammation and tau PET imaging in the same subjects. This contribution will be significant because it is the first step in a continuu of research that is expected to lead to development of neuroimaging strategies to predict future cognitive decline in elderly individuals and inform pharmacological studies targeting inflammation and tau pathology in AD. My environment is uniquely suited to maximize the chance of successfully completing the above training and research objectives. Through my appointment at the Taub Institute at Columbia University Medical Center and the collaborations established in this application, I will have sufficient resources to support my career development and research plan, including PET radiopharmaceutical production, imaging, subject recruitment, and all necessary laboratory analyses. I have secured commitment of institutional support from my Chairman, my advisory committee, and necessary collaborators.

描述（由应用程序提供）：本赠款应用程序代表了一项拟议的职业发展和研究计划，旨在实现我的长期职业目标以及我的短期培训和研究目标。我的长期目标是将自己确立为独立的PI，其研究计划着重于为衰老疾病制定有效的治疗策略。我的培训目标是完善我在临床研究方法和伦理方面的技能，完善我在评估衰老疾病，在PET成像研究方面发展专业知识，在MRI分析方面获得专业知识的临床专业知识，学会将生物标志物分析整合到临床研究中，建立统计分析的基础，并提高我的赠款写作技能。我的研究目标是确定1）如何与淀粉样变性，神经变性和认知的每种关系以及2）炎症，TAU和淀粉样蛋白之间的空间关系。这些目标旨在解决广告研究中的重要知识差距。迫切需要确定感染和TAU如何与淀粉样蛋白沉积，神经退行性和认知障碍以及它们之间如何相互关联有关。我的中心假设是，与淀粉样蛋白伯嫩相比，与认知能力下降和脑萎缩更紧密相关的AD感染和TAU的AD增加。我的初步临床PET数据表明，AD的感染比MCI更大，并且纵向增加，尤其是内侧临时皮层。这种空间和暂时的进展与尸检研究相似，该研究表明，tau病理学始于内侧临时皮层，并且随着AD的认知能力下降而增加。我的理由是，一旦知道感染和TAU如何与进展为AD的风险有关，用PET测量这些因素就可以预测下降并成为新型治疗的生物标志物。我将通过对具有独特临床和生物标志物概况的个体进行感染和TAU PET成像来检验我的中心假设，这些临床和生物标志物概况定义了四个不同类别的认知衰老：1）淀粉样蛋白阳性长老，他们符合羊膜MCI或轻度AD AD（临床AD组）的临床标准，而无需模仿型amylig spositive-Amyly-Elderical-3 3）损害（正常衰老组）和4）符合Amnestic MCI或轻度AD临床标准的淀粉样蛋白阴性长老（Surped non-AD非AD病理生理学组）。具体目的是：1）确定不同类别的认知衰老中的炎症和tau伯嫩的程度。我假设在内侧临时，侧面临时和顶区域内，将存在逐步的模式，使得淀粉样蛋白阳性阳性的长老会比认知正常的淀粉样蛋白阳性长老会更大，而淀粉样蛋白阳性的长老则比淀粉样蛋白更大，而不是淀粉样蛋白的淀粉样蛋白，而不是淀粉样蛋白，而不是淀粉样蛋白。因为我预测损伤和淀粉样蛋白状况会对感染产生额外的影响，所以我假设淀粉样蛋白阴性长老的感染将比认知对照更大，但感染比淀粉样蛋白阳性长老较少。我还假设，用PET测量的感染和Tau燃烧将与临床严重程度，脑萎缩和CSF生物标志物进行感染和TAU相关。 2）确定感染，TAU和淀粉样蛋白之间的空间关系。我的工作假设是，感染和TAU将以区域依赖的方式与淀粉样蛋白不同。我的方法具有创新性，因为它使用改进的放射性物质进行感染，据我所知，将是第一个研究，将感染和Tau PET成像结合在同一受试者中。这项贡献将是重要的，因为它是一项连续研究的第一步，预计会导致神经影像学策略的发展，以预测老年人的未来认知能力下降，并为针对AD中的感染和TAU病理学的药物研究提供了信息。我的环境非常适合成功完成上述培训和研究目标的机会。通过我在哥伦比亚大学医学中心的TAUB研究所的任命以及在本申请中建立的合作，我将拥有足够的资源来支持我的职业发展和研究计划，包括PET放射性药物制作，成像，学科招聘以及所有必要的实验室分析。我已经获得了主席，咨询委员会和必要合作者的机构支持的承诺。