Plasma Phosphorylated-Tau, Neurodegeneration, and Clinical Outcomes

血浆磷酸化 Tau、神经变性和临床结果

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要阿尔茨海默氏病引起的痴呆是一场全球健康危机，如果没有疾病，这种危机就会加剧过去阿尔茨海默病临床试验的失败部分归因于晚期。在临床环境中，治疗的启动和研究纳入的筛选不准确。衰老过程中认知能力下降的原因以及治疗和预后因潜在病因而异。目前筛查阿尔茨海默病病理的方法包括脑脊液分析和正电子发射断层扫描对于研究实验室和诊所来说都尚未广泛使用。开发一种可获取且准确的阿尔茨海默病病理学早期标记物至关重要。高灵敏度单分子阵列技术的技术进步创造了机会准确测量血液中的磷酸化 tau (p-tau)，这是阿尔茨海默病的病理标志。血浆 p-tau 已成为一种主要的血液阿尔茨海默病生物标志物，与阿尔茨海默病病理学的其他标志物，将临床阿尔茨海默病与其他痴呆症区分开来亚型，并准确预测死后阿尔茨海默病的病理学，血浆 p-tau 已显示出巨大的作用。潜力，但现有的研究主要集中于确定这一点的敏感性和特异性阿尔茨海默病的生物标志物；其能够预测更具临床意义的纵向结果拟议的研究将在队列纵向研究中检查基线血浆 p-tau。衰老与纵向神经退行性变和 9 年随访期间的临床结果有关。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、认知能力下降，日常生活主观活动的功能能力下降，以最大限度地发挥这种潜力生物标志物有意义地融入临床护理中。拟议的研究将利用丰富的资源。范德比尔特记忆与阿尔茨海默病中心、范德比尔特大学影像科学研究所的资源，瑞典萨尔格伦斯卡大学医院临床神经化学实验室将进行这项研究。由跨学科导师团队指导，其中包括老年神经心理学、阿尔茨海默病专家疾病、磁共振成像、主观认知能力下降、液体生物标志物、临床管理异常的认知老化和统计分析将有助于候选人的训练。获得必要的知识和技能来研究基于血液的阿尔茨海默病生物标志物并推动他作为一名独立的临床医生科学家，您将获得成功的职业生涯。了解血浆的预测有效性。 p-tau 的临床相关结果将提供进一步研究所需的重要信息。开发这种生物标志物作为临床试验登记、准确观察研究的工具阿尔茨海默病和痴呆症的临床护理。