Early detection of asymptomatic middle-age adults at risk for AD

早期发现有 AD 风险的无症状中年人

• 批准号: 8867116
• 负责人: OZIOMA C OKONKWO
• 金额: $ 16.28万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867116
• 关键词: Address; Adult; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloidosis; Area; Atrophic; Biological Assay; Biological Markers; Blood flow; Brain; Cerebrospinal Fluid; Characteristics; Classification; Clinical; Clinical Trials; Cognition Disorders; Cognitive; Complex; Data; Derivation procedure; Development; Discrimination; Disease; Disease Marker; Early Diagnosis; Early identification; Elderly; Enrollment; Epidemic; Evaluation; Exhibits; Fostering; Frequencies; Functional Magnetic Resonance Imaging; Future; Genetic Risk; Goals; Guidelines; Health; Image; Impaired cognition; Individual; Individual Differences; K-Series Research Career Programs; Knowledge; Lead; Leadership; Link; MRI Scans; Machine Learning; Magnetic Resonance Imaging; Measurement; Measures; Mentors; Methods; Modality; Modification; Monitor; Nerve Degeneration; Neuronal Injury; Nuclear; Pathology; Pattern; Persons; Pharmaceutical Preparations; Positron-Emission Tomography; Procedures; Protocols documentation; Public Health; Publishing; Registries; Relative (related person); Reporting; Research; Research Activity; Research Personnel; Research Project Grants; Research Proposals; Risk; Scanning; Scientist; Specific qualifier value; Spin Labels; Spinal Puncture; Staging; Structure; Symptoms; Techniques; Temporal Lobe; Testing; Therapeutic Agents; Training; Training Activity; Weight; Wisconsin; base; career; clinical risk; clinically relevant; cognitive reserve; cohort; experience; high risk; hippocampal atrophy; hypoperfusion; improved; meetings; middle age; multidisciplinary; neuroimaging; novel; patient oriented research; peer; pre-clinical; preclinical study; prognostic; prospective; responsible research conduct; success; volunteer

DESCRIPTION (provided by applicant): There is a pressing public health need to detect Alzheimer's disease (AD) in its earliest, asymptomatic, stages. This would immensely facilitate the conduct of targeted clinical trials, the development of disease-modifying therapeutic agents, and, ultimately, the curtailment of the looming epidemic that AD poses. Such an endeavor necessarily requires a multidisciplinary team of investigators with complementary areas of expertise. The goal of this Beeson Patient-Oriented Research Career Development Award in Aging (K23) proposal is to provide the candidate with the experience, knowledge, and skillset necessary to carry out high quality, clinically- relevant, aging research so that he might effectively participate in and lead such a multidisciplinary group in the future. The proposal, therefore, comprises a unified set of research and training activities that are well-tuned to the candidate's transition from a K23 trainee to an independent investigator. The training plan seamlessly combines meetings with mentors, formal coursework, didactic activities, hands-on training, leadership training, and professional development. Specific training goals include: (1) cultivate a more nuanced understanding of aging and geriatric cognitive disorders, (2) receive dedicated training in neuroimaging methods, (3) develop advanced neuroimaging data analytic expertise, (4) receive ongoing training in the responsible conduct of research, and (5) obtain the career guidance needed for successful transition from the K23 to an independent research career, and maturation into a future leader in the neuroimaging of preclinical AD. In turn, the overall objectives of the research project are to use novel multi-modality machine learning techniques to specify the characteristic pattern of brain changes that is distinctive of persons in Stage 3 preclinical AD (the stage hypothesized to impart the greatest risk of future progression to AD), and then determine whether asymptomatic, middle-aged adults who exhibit such brain changes are more likely to experience future cognitive decline. These objectives are directly relevant to the global effort to halt AD via early detection of cognitively-healthy persons at high risk for progressing to AD. This is because current national guidelines for detecting risk for AD i asymptomatic persons call for extensive evaluations (e.g., nuclear imaging and lumbar puncture) that are expensive, not always well-tolerated by research volunteers and, more importantly, not widely available. In contrast, this project will rigorously assess brain changes i Stage 3 preclinical AD using routine, non-invasive, and broadly-deployable magnetic resonance imaging (MRI) measurements of brain structure and blood flow. A specific deliverable of this project is the derivation of a single, quantitative, abnormality score that can be used-in combination with pertinent health information-for identifying, on an individual level, asymptomatic persons at heightened risk for AD. Such persons may then benefit from more extensive AD biomarker testing, closer monitoring, and treatment with disease-modifying drugs when such drugs become available. The project's success has material potential to significantly extend the public health reach of the proposed guidelines for defining preclinical AD. The three specific aims addressed in this project are: (1) specify the pattern of brain changes on MRI that is characteristic of Stage 3 preclinical AD, (2) prospectively assess the prognostic utility of an aggregate measure of midlife structural-functional MRI brain changes, and (3) preliminarily evaluate how individual differences related to cognitive reserve and genetic risk modify the association between early brain changes and future decline. Completion of the interrelated set of research and training activities proposed in this K23 will greatly foster the candidate's development into an independent clinician-scientist with expertise in conducting translational and multidisciplinary neuroimaging studies of preclinical AD.

描述（由申请人提供）：公共卫生部门迫切需要在阿尔茨海默氏病 (AD) 的早期、无症状阶段进行检测。这将极大地促进有针对性的临床试验的进行、改善疾病的治疗药物的开发，并最终遏制 AD 带来的迫在眉睫的流行病。这样的努力必然需要一个由具有互补专业领域的多学科研究人员组成的团队。 Beeson 面向患者的老龄化研究职业发展奖 (K23) 提案的目标是为候选人提供开展高质量、临床相关的老龄化研究所需的经验、知识和技能，以便他能够有效地参与未来加入并领导这样一个多学科小组。因此，该提案包括一套统一的研究和培训活动，这些活动非常适合候选人从 K23 实习生到独立调查员的过渡。培训计划将与导师的会议、正式课程、教学活动、实践培训、领导力培训和专业发展无缝结合起来。具体培训目标包括：(1) 培养对衰老和老年认知障碍的更细致的了解，(2) 接受神经影像方法的专门培训，(3) 发展先进的神经影像数据分析专业知识，(4) 接受负责任行为的持续培训(5) 获得从 K23 成功过渡到独立研究职业所需的职业指导，并成熟为临床前 AD 神经影像学的未来领导者。反过来，该研究项目的总体目标是使用新颖的多模态机器学习技术来指定不同人群的大脑变化的特征模式。 第 3 阶段临床前 AD（假设该阶段具有未来进展为 AD 的最大风险），然后确定表现出此类大脑变化的无症状中年人是否更有可能经历未来的认知能力下降。这些目标与全球通过早期发现认知健康的高水平人群来阻止 AD 的努力直接相关。 进展为 AD 的风险。这是因为，目前用于检测无症状人群 AD 风险的国家指南要求进行广泛的评估（例如核成像和腰椎穿刺），这些评估费用昂贵，而且研究志愿者并不总是能很好地耐受，更重要的是，这些评估并不广泛可用。相比之下，该项目将使用常规、非侵入性且可广泛部署的大脑结构和血流磁共振成像 (MRI) 测量来严格评估临床前 AD 第三阶段的大脑变化。该项目的具体成果是得出单一的定量异常评分，该评分可与相关健康信息结合使用，以在个人层面上识别 AD 风险较高的无症状人群。当这些药物可用时，这些人可能会受益于更广泛的 AD 生物标志物测试、更密切的监测以及疾病缓解药物的治疗。该项目的成功具有显着扩大拟议的临床前 AD 定义指南的公共卫生影响范围的巨大潜力。该项目的三个具体目标是：(1) 明确 MRI 上大脑变化的模式，这是第 3 阶段临床前 AD 的特征，(2) 前瞻性评估中年结构功能 MRI 大脑变化的总体测量的预后效用，（3）初步评估与认知储备和遗传风险相关的个体差异如何改变早期大脑变化和未来衰退之间的关联。完成本 K23 中提出的一系列相互关联的研究和培训活动将极大地促进候选人发展成为一名独立的临床医生科学家，拥有进行临床前 AD 的转化和多学科神经影像研究的专业知识。