Validation of Novel Plasma Biomarkers for Mixed Etiology Dementia

混合病因痴呆的新型血浆生物标志物的验证

• 批准号: 10283888
• 负责人: Lawren VandeVrede
• 金额: $ 20.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10283888
• 关键词: Address; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease blood test; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Area Under Curve; Autopsy; Behavioral; Benchmarking; Biological Assay; Biological Markers; Blood; Blood Tests; California; Cerebrospinal Fluid; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Clinical dementia rating scale; Communities; Data; Dementia; Development Plans; Diagnostic; Disease; Disease Progression; Early Diagnosis; Environment; Etiology; Frontotemporal Lobar Degenerations; Future; Generations; Goals; Gold; Image; Isomerism; K-Series Research Career Programs; Light; Liquid substance; Measures; Mentors; Mentorship; Modality; Nerve Degeneration; Neurodegenerative Disorders; Neurologist; Observational Study; Parents; Participant; Pathology; Pathway interactions; Patient Recruitments; Patient Representative; Patients; Performance; Physicians; Plasma; Population; Population Heterogeneity; Positron-Emission Tomography; Public Health; Race; Receiver Operating Characteristics; Research; Sampling; San Francisco; Scanning; Scientist; Screening procedure; Senile Plaques; Site; Specimen; Sum; Syndrome; Testing; Therapeutic; Time; Training; Translations; Underrepresented Minority; Universities; Validation; advanced disease; base; biomarker discovery; biomarker validation; career; career development; clinical Diagnosis; clinical application; clinical phenotype; clinically relevant; cohort; comorbidity; cost; design; diagnostic accuracy; diagnostic screening; improved; mixed dementia; multidisciplinary; multimodality; neurofilament; neuroimaging; neuroimaging marker; neuropathology; novel; novel marker; patient population; population based; professor; prospective; racial diversity; recruit; research study; screening; tau Proteins; tau aggregation; tau-1; tool

PROJECT SUMMARY In this K23 career development award, Dr. Lawren VandeVrede, a behavioral neurologist and Assistant Professor at the University of California, San Francisco (UCSF), will obtain training in the use, validation, and translation of multimodal biomarkers for Alzheimer's Disease (AD) and related dementias (ADRD). This project supports his long-term career goal to become a leader in ADRD biomarker translation and novel clinical trial design, and to establish a lab that paves the way for a new generation of clinical trials that will evaluate and refine treatment approaches for patients with dementia. Through this K23 and the enriched multidisciplinary training environment at UCSF, Dr. VandeVrede aims to accomplish the following specific training goals: 1) gain expertise in the use of clinical, neuropathological, biofluid, and neuroimaging biomarker modalities, 2) develop specialized proficiency in validation of novel plasma AD biomarkers benchmarked to gold-standard neuropathology and current-generation positron emission tomography (PET) neuroimaging, and (3) develop a pathway for translation of biomarkers into clinical settings for use as large-scale screening and diagnostic tools for ADRD. To achieve these goals, Dr. VandeVrede has assembled an exemplary mentorship team, including his primary mentor, Dr. Adam Boxer, a leader in ADRD fluid biomarker discovery and clinical trial design, and co-mentors, Drs. Lea Grinberg and Gil Rabinovici, experts in ADRD neuropathology and PET imaging respectively. In addition, he has two collaborators with expertise in relevant plasma biomarker assays, Drs. Michelle Mielke and Jeff Dage, and a biostatistician, Dr. John Kornak, with significant expertise in ADRD biomarker validation and clinical trial design. The overarching goal of the project is to better characterize the diagnostic performance of several novel AD plasma biomarkers in an important and clinically relevant patient population: mixed etiology dementia. The central rationale is that blood tests are critically needed for large-scale diagnostic screening for AD, and whereas several proposed plasma biomarkers in the research world show promise as future clinical tools, key validation data and comparisons between biomarkers are missing in real-world dementia patients with mixed etiology. Therefore, in this project, novel plasma biomarkers of ADRD will be validated (1) in Aim I against gold-standard neuropathology in autopsy cohorts that include comorbid and alternative neuropathologies; (2) in Aim II against current-generation PET biomarkers in several prospective observational studies that include early, mixed, and atypical clinical phenotypes; and (3) in Aim III in a large community-based study specifically designed to recruit under-represented minorities. This project provides critical data that would support translation of these specific blood tests into clinical use, and establishes a platform for future discovery and validation projects for ADRD biomarkers.

项目摘要 在这个K23职业发展奖，Lawren VandeVrede博士，行为神经学家和助理 加州大学旧金山分校弗朗西斯科（UCSF）的教授将接受使用、验证和 阿尔茨海默病（AD）和相关痴呆（ADRD）的多模式生物标志物的翻译。这个项目 支持他的长期职业目标，成为ADRD生物标志物翻译和新型临床试验的领导者 设计，并建立一个实验室，为新一代的临床试验铺平道路， 完善痴呆症患者的治疗方法。通过K23和丰富的多学科 在UCSF的培训环境中，VandeVrede博士旨在实现以下具体的培训目标：1）获得 在临床，神经病理学，生物流体和神经成像生物标志物模式的使用方面的专业知识，2）开发 专业熟练验证以金标准为基准的新型血浆AD生物标志物 神经病理学和当代正电子发射断层扫描（PET）神经成像，和（3）开发一个 将生物标志物转化为临床环境以用作大规模筛查和诊断工具的途径 对于ADRD。为了实现这些目标，VandeVrede博士组建了一个模范导师团队，包括 他的主要导师Adam Boxer博士是ADRD液体生物标志物发现和临床试验设计的领导者， 共同导师，莱亚格林伯格和吉尔Rabinovici博士，ADRD神经病理学和PET成像专家 分别此外，他还有两名在相关血浆生物标志物测定方面具有专业知识的合作者。 Michelle Mielke和Jeff Dage，以及生物统计学家John Kornak博士，在ADRD方面具有重要的专业知识 生物标志物验证和临床试验设计。 该项目的总体目标是更好地表征几种新型AD的诊断性能 一个重要的和临床相关的患者群体的血浆生物标志物：混合病因痴呆。的 主要理由是，血液检查对于AD的大规模诊断筛查至关重要， 尽管研究界提出的几种血浆生物标志物显示出作为未来临床工具的前景， 验证数据和生物标志物之间的比较在现实世界的痴呆患者中缺失， 病因学因此，在本项目中，ADRD的新型血浆生物标志物将在目标I中进行验证（1）， 尸检队列中的金标准神经病理学，包括共病和替代神经病理学;（2）在 Aim II在几项前瞻性观察性研究中针对当前一代PET生物标志物，包括 早期、混合和非典型临床表型;（3）在Aim III中，在一项大型社区研究中， 旨在招募代表性不足的少数民族。该项目提供了关键数据， 将这些特定的血液检测转化为临床应用，并为未来的发现和 ADRD生物标志物的验证项目。