Validation of Novel Plasma Biomarkers for Mixed Etiology Dementia

项目总结 在这个K23职业发展奖中，行为神经学家兼助理Lawren VandeVrede博士 加州大学旧金山分校(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)多模式生物标志物的翻译。这个项目 支持他成为ADRD生物标记物翻译和新临床试验的领导者的长期职业目标 设计，并建立一个实验室，为新一代临床试验铺平道路，将评估和 完善痴呆症患者的治疗方法。通过这个K23和丰富的多学科 在加州大学旧金山分校的培训环境中，VandeVrede博士的目标是实现以下具体的培训目标：1)获得 在临床、神经病理学、生物体液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 以黄金标准为基准的新型血浆AD生物标志物验证的专业熟练程度 神经病理学和当代正电子发射断层扫描(PET)神经成像，以及(3)发展一种 将生物标志物转化为临床环境用作大规模筛查和诊断工具的途径 为了ADRD。为了实现这些目标，VandeVrede博士组建了一支模范导师团队，包括 他的主要导师，ADRD液体生物标记物发现和临床试验设计的领导者Adam Boxer博士，以及 共同导师Lea Grinberg博士和Gil Rabinovici博士是ADRD神经病理学和PET成像方面的专家 分别进行了分析。此外，他还有两位在相关血浆生物标记物检测方面具有专业知识的合作者。 米歇尔·米尔克和杰夫·达奇，以及在ADRD方面拥有丰富专业知识的生物统计学家约翰·科尔纳克博士 生物标记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 重要且临床相关的患者群体中的血浆生物标记物：混合性病因痴呆。这个 主要的理由是，血液测试是大规模AD诊断筛查的关键，以及 鉴于研究界提出的几种血浆生物标记物有望成为未来的临床工具，关键 混合型痴呆患者缺少验证数据和生物标记物之间的比较 病因学。因此，在本项目中，将验证(1)针对ADRD的新型血浆生物标志物 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；(2) 在几项前瞻性观察研究中，AIM II与当前一代的PET生物标志物进行了对比，这些研究包括 早期的、混合的和非典型的临床表型；以及(3)在AIM III的一项大型社区研究中 旨在招募代表性不足的少数族裔。该项目提供的关键数据将支持 将这些特定的血液测试转化为临床使用，并为未来的发现和 ADRD生物标记物验证项目。

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.