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: 8593003
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593003
• 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; 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; 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）：公共卫生需要最早，无症状的阶段来检测阿尔茨海默氏病（AD）。这将极大地促进有针对性的临床试验的行为，改善疾病的治疗剂的发展，并最终减少AD构成的迫在眉睫的流行病。这样的努力必然需要一个具有互补专业领域的调查员团队。这项面向蜜蜂的衰老培养业研究职业发展奖（K23）提案的目标是为候选人提供经验，知识和技能，以进行高质量，临床相关的老龄化研究所需的经验，知识和技能，以便他可以在未来有效地参与并领导这样一个多学科小组。因此，该提案包括一组统一的研究和培训活动，这些活动对候选人从K23培训生的过渡到了独立研究员的过渡。该培训计划无缝地结合了与导师，正式课程，教学活动，动手培训，领导培训和专业发展的会议。具体的培训目标包括：（1）对衰老和老年认知障碍的更细微的了解，（2）接受神经影像学方法的专门培训，（3）发展高级神经成像数据分析专业知识，（4）（4）在负责任的研究中接受持续的培训，并获得研究领导者的持续研究，并（5）（5）（5）（5）（5）（5）（5）（5）（5）（5）（5）（5）（5）临床前AD的神经影像学。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 阶段3临床前AD（假设阶段是赋予未来AD进展的最大风险），然后确定表现出这种大脑变化的无症状，中年成年人是否更有可能经历未来的认知能力下降。这些目标与全球努力通过早期检测到高位的人而停止广告的努力直接相关 进步广告的风险。这是因为目前的国家指南检测AD I无症状人士要求进行广泛的评估（例如，核成像和腰椎穿刺），这些评估价格昂贵，并不总是受到研究志愿者的耐受性，而且更重要的是，不广泛使用。相比之下，该项目将使用常规，无创和可广泛的磁共振成像（MRI）测量大脑结构和血流的测量值严格评估大脑变化I阶段3临床前AD。该项目的特定可交付是派生的单一，定量，异常得分，可以与相关的健康信息结合使用，从而在个人级别上识别出无症状的AD风险较高的人。然后，当此类药物可用时，此类人可能会受益于更广泛的AD生物标志物测试，更仔细的监测以及通过疾病改良药物进行治疗。该项目的成功具有重要的物质潜力，可以显着扩大拟议临床前广告指南的公共卫生覆盖范围。该项目中解决的三个具体目的是：（1）指定MRI上的大脑变化模式，这是第3阶段临床前AD的特征，（2）前瞻性评估中期结构功能性MRI大脑的总体测量的预后效用，（3）预先评估个人差异与认知能力的差异和遗传变化之间的差异，并将遗传变化如何变化。在本k23中提出的相互关联的研究和培训活动的完成将大大促进候选人的发展成独立的临床医生 - 科学家，并在进行转化和多学科神经影像学研究方面的专业知识。