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: 10643885
• 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/10643885
• 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; Image; Isomerism; K-Series Research Career Programs; Light; Liquid substance; Measures; Mentors; Mentorship; Modality; Nerve Degeneration; Neurodegenerative Disorders; Neurologist; Observational Study; PET positivity; 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; biomarker discovery; biomarker validation; career; career development; clinical application; clinical diagnosis; clinical phenotype; clinically relevant; cohort; comorbidity; cost; design; diagnostic accuracy; diagnostic screening; diagnostic strategy; diagnostic tool; improved; mixed dementia; multidisciplinary; multimodality; neurofilament; neuroimaging; neuroimaging marker; neuropathology; novel; novel marker; patient population; population based; professor; prospective; racial diversity; racial population; 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职业发展奖中，行为神经科医生兼助理Lawren Vandevrede博士 加利福尼亚大学旧金山大学教授（UCSF）将获得使用，验证和 阿尔茨海默氏病（AD）和相关痴呆症（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颖临床试验的领导者 设计，并建立一个为新一代临床试验铺平道路的实验室，该试验将评估和 痴呆症患者的优化治疗方法。通过这个K23和丰富的多学科 UCSF的培训环境，Vandevrede博士旨在实现以下具体培训目标：1） 在临床，神经病理学，生物流体和神经影像学生物标志物模态的使用方面的专业知识，2）发展 专门熟练验证新型等离子体AD生物标志物的基准为金标准 神经病理学和电流产生正电子发射断层扫描（PET）神经影像学，（3）发展 将生物标志物转换为临床环境的途径，以用作大规模筛查和诊断工具 对于Adrd。为了实现这些目标，Vandevrede博士组建了一个模范的指导团队，包括 他的主要导师Adam Boxer博士，Adrd Fluid生物标志物发现和临床试验设计的领导者， 联合官员，博士。 Lea Grinberg和Gil Rabinovici，ADRD神经病理学和宠物成像专家 分别。此外，他还有两个合作者在相关等离子生物标志物分析方面具有专业知识，Drs。 米歇尔·米尔克（Michelle Mielke）和杰夫·戴奇（Jeff Dage），生物统计学家约翰·科纳克（John Kornak）博士，在ADRD中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描述几种新型广告的诊断性能 重要且与临床相关的患者人群中的血浆生物标志物：混合病因痴呆。这 中心理由是大规模诊断筛查AD和 研究界的几个提议的血浆生物标志物显示出作为未来临床工具的希望 在现实世界中，验证数据和生物标志物之间的比较混合患者中缺少 病因。因此，在这个项目中，ADRD的新颖血浆生物标志物将在AIM I中得到验证（1） 尸检队列中的金标准神经病理学，包括合并和替代神经病理学； （2）英寸 AIM II反对当前的几项前瞻性观察研究，包括 早期，混合和非典型临床表型； （3）在一项大型社区研究中，在AIM III中 旨在招募代表性不足的少数民族。该项目提供了支持的关键数据 将这些特定的血液检查转换为临床使用，并建立了一个未来发现的平台 ADRD生物标志物的验证项目。

项目成果

Scientific commentary on: "Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer's disease and primary tauopathies".

• DOI: 10.1007/s00401-023-02656-z
• 发表时间: 2024-02-03
• 期刊: Acta neuropathologica
• 影响因子: 12.7

Hepatic and renal function impact concentrations of plasma biomarkers of neuropathology.

• DOI: 10.1002/dad2.12321
• 发表时间: 2022
• 期刊: ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING
• 影响因子: 5.3
• 作者: Berry, Kacey;Asken, Breton M.;Grab, Joshua D.;Chan, Brandon;Lario Lago, Argentina;Wong, Randi;Seetharaman, Srilakshmi;LaHue, Sara C.;Possin, Katherine L.;Rojas, Julio C.;Kramer, Joel H.;Boxer, Adam L.;Lai, Jennifer C.;VandeVrede, Lawren
• 通讯作者: VandeVrede, Lawren

Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning.

• DOI: 10.1093/braincomms/fcad048
• 发表时间: 2023
• 期刊: Brain communications
• 影响因子: 4.8