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

• 批准号: 9251712
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/9251712
• 关键词: Academic Medical Centers; Address; Advisory Committees; Aging; Agreement; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid deposition; Amyloidosis; Animal Model; Applications Grants; Appointment; Autopsy; Binding; Biological Markers; Categories; Cerebrospinal Fluid; Chairperson; Clinical; Clinical Research; Cognition; Cognitive; Cognitive aging; Collaborations; Data; Dementia; Development; Disease; Elderly; Environment; Foundations; Functional disorder; Future; Goals; Grant; Human; Image; Impaired cognition; Impairment; In Vitro; Individual; Inflammation; Institutes; Knowledge; Laboratories; Lateral; Lead; Learning; Magnetic Resonance Imaging; Measures; Medial; Mission; Nerve Degeneration; Neuroimmune; Parietal; Participant; Pathologic; Pathology; Patients; Pattern; Pharmacology Study; Positron-Emission Tomography; Production; Public Health; Radiopharmaceuticals; Recruitment Activity; Research; Research Ethics; Research Methodology; Resources; Risk; Secure; Severities; Societies; Statistical Data Interpretation; Temporal Lobe; Testing; Training; Writing; amnestic mild cognitive impairment; amyloid imaging; career; career development; cerebral atrophy; clinical biomarkers; cognitive control; critical period; design; effective therapy; fluorodeoxyglucose positron emission tomography; improved; innovation; insight; mild cognitive impairment; neuroimaging; normal aging; novel marker; novel therapeutics; pre-clinical; prevent; programs; prospective; public health relevance; radioligand; research and development; skills; spatial relationship; targeted treatment; tau Proteins; tau aggregation; treatment strategy

 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（由申请人提供）：此资助申请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。我的长期目标是使自己成为一名独立的 PI。我的培训目标是提高我在临床研究方法和伦理方面的技能，提高我在评估老年疾病方面的临床专业知识，发展 PET 成像研究的专业知识。 ，获得 MRI 分析方面的专业知识，学习将生物标志物分析融入临床研究，奠定统计分析基础，并提高我的资助写作技巧 我的研究目标是确定 1) 炎症和 tau 蛋白与淀粉样变性、神经退行性变和认知之间的关系，以及 2) 之间的空间关系。这些目标旨在解决 AD 研究中的一个重要知识空白，迫切需要确定炎症和 tau 蛋白与淀粉样蛋白沉积、神经变性和认知障碍之间的关系以及它们之间的关系。我的中心假设是，AD 中的炎症和 tau 蛋白以空间相关的方式增加，与认知能力下降和脑萎缩的关系比淀粉样蛋白负荷更密切，我的初步临床 PET 数据表明，AD 中的炎症比 MCI 中的炎症更严重。并且纵向增加，特别是在内侧颞叶皮层，这种空间和时间进展与尸检研究中的情况相似，尸检研究表明tau蛋白病理学始于内侧颞叶皮层，并随着AD认知能力下降的程度而增加。炎和 tau 与进展为 AD 的风险相关，用 PET 测量这些因素可以预测衰退并作为新疗法的生物标志物，我将通过在具有不同临床和生物标志物特征的个体中进行炎症和 tau PET 成像来测试我的中心假设。认知衰老的四种不同类别：1）符合遗忘性MCI或轻度AD临床标准的淀粉样蛋白阳性老年人（临床AD组），2）无损伤的淀粉样蛋白阳性老年人（临床前AD组），3）没有损伤的淀粉样蛋白阴性老年人（正常衰老组），以及4）符合遗忘性MCI或轻度AD临床标准的淀粉样蛋白阴性老年人（疑似非AD病理生理组）具体目的是：1）确定炎症程度。我假设，在内侧颞叶、外侧颞叶和顶叶区域中，将存在逐步模式，从而导致淀粉样蛋白阳性的老年人出现损伤。与认知正常的淀粉样蛋白阳性老年人相比，他们的炎症和 tau 蛋白负担更大，而认知功能正常的淀粉样蛋白阴性老年人又比没有认知障碍的淀粉样蛋白阴性老年人有更多的炎症和 tau 蛋白负担，因为我预测损伤和淀粉样蛋白状态会对炎症产生附加影响，所以我帮助了他们。淀粉样蛋白阴性的有损伤的老年人会比认知对照有更大的炎症，但比淀粉样蛋白阳性的有损伤的老年人有更少的炎症，我还假设用 PET 测量的炎症和 tau 蛋白负荷将与临床严重程度、大脑相关。萎缩，以及炎症和 tau 蛋白的脑脊液生物标志物 2) 确定炎症、tau 蛋白和淀粉样蛋白之间的空间关系 我的工作假设是，炎症和 tau 蛋白将以与淀粉样蛋白在空间上不同的方式相关。据我所知，它使用改进的放射性配体来治疗炎症，并且将是第一项将炎症和 tau PET 成像结合在同一受试者中的研究。一系列研究预计将导致神经影像学策略的发展，以预测老年人未来的认知能力下降，并为针对 AD 炎症和 tau 病理学的药理学研究提供信息。通过我在哥伦比亚大学医学中心 Taub 研究所的任命以及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 放射性药物生产、成像、受试者招募以及所有必要的资源。实验室我已获得主席、顾问委员会和必要合作者的机构支持承诺。