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

描述(由申请人提供)：有迫切的公共卫生需求来检测阿尔茨海默病(AD)的最早、无症状的阶段。这将极大地促进进行有针对性的临床试验，开发疾病修改治疗剂，并最终减少AD引起的迫在眉睫的流行病。这样的努力必然需要一个多学科的调查小组，他们具有互补的专业领域。毕生以患者为导向的老年研究职业发展奖(K23)计划的目标是为候选人提供开展高质量、与临床相关的老龄研究所需的经验、知识和技能，以便他能够在未来有效地参与和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，这些活动与候选人从K23实习生向独立调查员的转变相适应。培训计划将与导师的会议、正式课程作业、教学活动、动手培训、领导力培训和专业发展无缝地结合在一起。具体的培训目标包括：(1)培养对衰老和老年认知障碍的更细微的理解，(2)接受神经成像方法的专门培训，(3)开发高级神经成像数据分析专业知识，(4)接受负责任的研究进行的持续培训，以及(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的神经成像领域的未来领导者。反过来，研究项目的总体目标是使用新颖的多模式机器学习技术来指定大脑变化的特征模式，这是 第三阶段临床前AD(假设未来进展为AD的风险最大的阶段)，然后确定无症状的中年成年人是否更有可能经历未来的认知能力下降。这些目标直接关系到全球通过早期发现认知健康的人来阻止阿尔茨海默病的努力 进展为AD的风险。这是因为目前检测无症状阿尔茨海默病患者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术)，这些评估成本高昂，研究志愿者并不总是能很好地耐受，更重要的是，无法广泛获得。相比之下，该项目将使用常规的、非侵入性的、可广泛部署的脑部结构和血流磁共振成像(MRI)测量来严格评估第三阶段临床前AD的脑部变化。该项目的一个具体成果是得出一个单一的、定量的异常评分，该评分可以与相关的健康信息结合使用，在个人层面上识别无症状的AD高危人群。然后，这些人可能会受益于更广泛的AD生物标记物测试、更密切的监测，以及当疾病修改药物可用时进行治疗。该项目的成功具有显著扩大拟议的临床前AD定义指南的公共卫生覆盖面的巨大潜力。本项目涉及的三个具体目标是：(1)明确临床前AD阶段3的MRI脑变化模式，(2)前瞻性评估中年结构-功能MRI脑变化综合指标的预后效用，以及(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脑变化与未来衰退之间的联系。完成本K23中建议的相关研究和培训活动将极大地促进候选人发展为一名独立的临床医生兼科学家，拥有进行临床前AD的转化性和多学科神经成像研究的专业知识。

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.