Plasma Phosphorylated-Tau, Neurodegeneration, and Clinical Outcomes

血浆磷酸化 Tau、神经变性和临床结果

• 批准号: 10389666
• 负责人: Corey Bolton
• 金额: $ 6.72万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389666
• 关键词: Activities of Daily Living; Affect; Age; Aging; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid beta-Protein; Autopsy; Biological Markers; Biometry; Blood; Brain; Caring; Cerebrospinal Fluid; Clinic; Clinical; Clinical Management; Clinical Research; Clinical Trials; Cognition; Cognitive aging; Collaborations; Data; Data Collection; Dementia; Deposition; Development; Diagnostic Specificity; Disease; Disease Progression; Elderly; Enzyme-Linked Immunosorbent Assay; Episodic memory; Epitopes; Etiology; Failure; Future; Impaired cognition; Inferior; Institutes; International; Knowledge; Laboratories; Letters; Liquid substance; Literature; Longitudinal cohort study; Magnetic Resonance Imaging; Measurement; Measures; Medial; Memory; Mentors; Mentorship; Methods; Nerve Degeneration; Neuropsychology; Observation in research; Observational Study; Outcome; Outcomes Research; Pathologic; Patient Care; Pattern; Phosphorylation; Plasma; Population; Positioning Attribute; Positron-Emission Tomography; Predictive Value; Prevention; Prognosis; Proteins; Protocols documentation; Public Health; Questionnaires; Reporting; Research; Research Personnel; Resources; Scientist; Sensitivity and Specificity; Site; Specificity; Spinal Puncture; Statistical Data Interpretation; Stroke; Structure; Sweden; Techniques; Temporal Lobe; Thick; Thinness; Threonine; Training; Training Activity; Universities; University Hospitals; Venous; angular gyrus; base; biomarker development; biomarker validation; brain dysfunction; brain magnetic resonance imaging; career; clinical care; clinical trial enrollment; clinically relevant; cohort; dementia care; effective therapy; experience; follow-up; global health; imaging science; informant; innovation; insight; instrumental activity of daily living; multi-atlas segmentation; neurochemistry; neuroimaging; novel marker; potential biomarker; regional atrophy; screening; single molecule; skills; specific biomarkers; tau Proteins; tau phosphorylation; tau-1; tool

PROJECT SUMMARY Dementia due to Alzheimer’s disease is a global health crisis that is intensified by the absence of disease modifying treatments. The failure of past clinical trials in Alzheimer’s disease has been due in part to late initiation of treatment and inaccurate screening for study inclusion. In clinical settings, there are numerous causes of cognitive decline in aging and treatment and prognosis vary depending on the underlying etiology. Current methods of screening for Alzheimer’s pathology include cerebrospinal fluid analysis and positron emission tomography, both of which are not widely accessible. For both the research lab and the clinic, development of an accessible and accurate early marker of Alzheimer’s pathology is essential. Recent technological advances in highly sensitive single-molecule array techniques have created the opportunity to accurately measure phosphorylated tau (p-tau), a pathological hallmark of Alzheimer’s disease, in the blood. Plasma p-tau has emerged as a leading blood-based Alzheimer’s biomarker, showing strong correlations with other markers of Alzheimer’s pathology, distinguishing clinical Alzheimer’s disease from other dementia subtypes, and accurately predicting post-mortem Alzheimer’s pathology. Plasma p-tau has shown tremendous potential, yet existing research has largely focused on establishing the sensitivity and specificity of this biomarker for Alzheimer’s disease; its ability to predict more clinically meaningful longitudinal outcomes remains in question. The proposed research will examine baseline plasma p-tau in a longitudinal cohort study of aging as it relates to longitudinal neurodegeneration and clinical outcomes over a 9-year follow-up period. Highly clinically relevant outcomes were selected, including neurodegeneration, domain-based cognition, subjective cognitive decline, and functional abilities for activities of daily living, to maximize the potential of this biomarker being meaningfully integrated into clinical care. The proposed research will leverage the rich resources of the Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Institute of Imaging Science, and the Clinical Neurochemistry Laboratory of Sahlgrenska University Hospital, Sweden. The research will be guided by an interdisciplinary mentorship team, including experts in geriatric neuropsychology, Alzheimer’s disease, magnetic resonance imaging, subjective cognitive decline, fluid biomarkers, clinical management of abnormal cognitive aging, and statistical analysis. The parallel training plan will facilitate the candidate’s acquisition of the necessary knowledge and skills to study blood-based Alzheimer’s biomarkers and propel him into a successful career as an independent clinician-scientist. Understanding the predictive validity of plasma p-tau for clinically relevant outcomes would provide essential information that is necessary for the further development of this biomarker as a tool for clinical trial enrollment, accurate observational research in Alzheimer’s disease, and clinical care of dementia.

项目总结 阿尔茨海默病引起的痴呆症是一种全球性的健康危机，没有疾病会加剧这种危机 修改治疗方法。过去治疗阿尔茨海默病的临床试验的失败在一定程度上是由于 开始治疗和对研究纳入的筛选不准确。在临床环境中，有许多 衰老和治疗中认知能力下降的原因和预后因潜在的病因而异。 目前阿尔茨海默病的筛查方法包括脑脊液分析和正电子分析 发射断层扫描，这两种技术都不是很普遍。无论是对研究实验室还是临床， 开发一种可获得的、准确的阿尔茨海默氏病病理早期标志物是至关重要的。近期 高灵敏单分子阵列技术的技术进步创造了 精确测量血液中的磷酸化tau(p-tau)，这是阿尔茨海默病的一个病理标志。 血浆p-tau已成为主要的血液阿尔茨海默氏症生物标志物，显示出与 阿尔茨海默病病理的其他标记物，区分临床阿尔茨海默病和其他痴呆 亚型，并准确预测死后阿尔茨海默氏症的病理。血浆p-tau显示出巨大的 潜在的，但现有的研究主要集中在建立这种敏感性和特异性 阿尔茨海默病的生物标记物；其预测更具临床意义的纵向结果的能力 仍然存在疑问。拟议的研究将在纵向队列研究中检查基线血浆p-tau。 由于它与纵向神经退行性变和9年随访期的临床结果有关，因此与衰老有关。 选择了高度临床相关的结果，包括神经退行性变，基于领域的认知， 主观认知能力下降，日常生活活动的功能能力，最大限度地发挥这种潜能 生物标记物正在有意义地整合到临床护理中。拟议中的研究将对富人产生影响 范德比尔特大学影像科学研究所范德比尔特记忆和阿尔茨海默氏症中心的资源， 和瑞典萨尔格伦斯卡大学医院的临床神经化学实验室。这项研究将是 在包括老年神经心理学专家在内的跨学科指导团队的指导下，阿尔茨海默氏症 疾病，磁共振成像，主观认知能力下降，体液生物标志物，临床处理 认知功能异常老化，并进行统计分析。平行培训计划将有助于应聘者 获得必要的知识和技能来研究基于血液的阿尔茨海默氏症生物标志物并推动他 成为一名成功的独立临床医生兼科学家。了解血浆的预测有效性 临床相关结果的P-tau将提供进一步研究所必需的基本信息。 开发这种生物标志物作为临床试验登记、准确的观察性研究的工具 阿尔茨海默病和痴呆症的临床护理。