Early Onset AD Consortium - the LEAD Study (LEADS)

早发性 AD 联盟 - LEAD 研究 (LEADS)

基本信息

批准号：
10219685
负责人：
LIANA G APOSTOLOVA
金额：
$ 107.21万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219685
关键词：
Administrative Supplement Age Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk American Amyloid Amyloid beta-Protein Atrophic Autopsy Biological Markers Blood Brain Cerebrospinal Fluid Characteristics Clinical Clinical Trials Clinical assessments Cognitive Collection DNA Data Diagnosis Disease Disease Progression Elderly Episodic memory Etiology Funding Future Genes Genetic Genotype Goals Heritability Image Impaired cognition Impairment Individual Inflammation Inherited Italy Language Late Onset Alzheimer Disease Life Light Lipids Liquid substance Magnetic Resonance Imaging Measures Medial Memory Methods Mutation Nerve Degeneration Neurodegenerative Disorders Observational Study Outcome Outcome Measure Participant Pathogenicity Pathology Pathway interactions Patients Pattern Performance Peripheral Blood Mononuclear Cell Plasma Population Positron-Emission Tomography Presenile Alzheimer Dementia Psychometrics RNA Research Signal Transduction Site Suggestion Symptoms Testing Therapeutic Trials Thinking Time Visuospatial Work apolipoprotein E-4 autosomal dominant Alzheimer&apos s disease biomarker development brain tissue clinical biomarkers clinical outcome measures clinical phenotype cognitive function cohort comorbidity design fluorodeoxyglucose fluorodeoxyglucose positron emission tomography genetic risk factor gray matter imaging biomarker machine learning algorithm meetings neurofilament neuroimaging next generation sequencing novel patient population predictive modeling presenilin-1 recruit serial imaging sex tau Proteins treatment trial

项目摘要

Project Summary While the risk of Alzheimer’s disease (AD) increases with advancing age, approximately 5% of AD patients develop symptoms before age 65 (~280,000 Americans). The vast majority (90%-95%) of EOAD patients do not have a known mutation in APP or PSEN1/2, and only ~50% are APOE4 carriers. Unlike late-onset AD (LOAD), 30-64% of EOAD have non-amnestic presentations, leading to missed or delayed diagnosis. Despite being highly motivated and having few comorbidities, EOAD patients are commonly excluded from large scale observational biomarker studies (e.g. ADNI and DIAN) and therapeutic trials due to their young age, non- amnestic deficits, or absence of known pathogenic mutations. Furthermore, studies suggest high heritability in EOAD in the absence of known mutations or APOE4, signifying that this population may be enriched for novel genetic risk factors. Emerging biomarkers of amyloid and tau have not been systematically characterized in this population. Clinical and neuroimaging measures employed in LOAD may be insensitive to baseline deficits and disease progression in EOAD, which predominantly involve non-memory cognitive domains and posterior cortical neurodegeneration. To fill this gap in AD research, we plan to recruit and longitudinally follow 400 amyloid PET-positive EOAD subjects meeting NIA-AA criteria for MCI due to AD or probable AD dementia (including primary amnestic, dysexecutive, language and visuospatial presentations), 200 subjects meeting clinical criteria with negative amyloid PET (EOnonAD) and 100 age-matched controls. Participants in the Longitudinal Early-onset Alzheimer’s Disease Study (LEADS) will undergo clinical assessments, psychometric testing, MRI, amyloid ([18F]Florbetaben) and tau ([18F]AV1451) PET, CSF and blood draw for collection of DNA, RNA, plasma, serum and peripheral blood mononuclear cells (PBMC). EOnonAD participants and controls will also receive [18]FDG PET. All participants are followed annually (controls up to 24 months; impaired participants up to 48 months). Methods will be harmonized with ADNI and DIAN. We will comprehensively characterize cognitive, imaging and biofluid changes over time in EOAD and EOnonAD and compare to age-matched controls and sex and stage- matched LOAD participants identified in ADNI. We will employ machine learning algorithms to develop sensitive clinical and imaging measures of EOAD progression. Additionally, we will characterize demographic, clinical, neuroimaging, and fluid biomarker measures in EOnonAD cases to explore the possible etiologies of cognitive impairment. An exploratory aim will apply next generation sequencing to assess for novel genetic risk factors for disease. The study will also establish a network of EOAD research sites and set the stage for the launch of clinical trials in this population.

项目概要虽然患阿尔茨海默病 (AD) 的风险随着年龄的增长而增加，但大约 5% 的 AD 患者 65 岁之前出现症状（约 280,000 名美国人）绝大多数 (90%-95%) EOAD 患者不会出现症状。 APP 或 PSEN1/2 存在已知突变，并且只有约 50% 是 APOE4 携带者，与迟发性 AD (LOAD) 不同， 30-64% 的 EOAD 具有非遗忘性表现，导致漏诊或延迟诊断。 EOAD 患者有积极性且几乎没有合并症，因此通常被排除在大规模观察之外由于年龄小、非遗忘缺陷或此外，研究表明，在不存在已知致病突变的情况下，EOAD 具有较高的遗传力。已知突变或 APOE4，表明该人群可能富含新的遗传风险因素。淀粉样蛋白和 tau 蛋白的新兴生物标志物尚未在该人群中进行系统的临床表征。 LOAD 中采用的神经影像学测量可能对基线缺陷和疾病进展不敏感 EOAD，主要涉及非记忆认知领域和后皮质神经变性。为了填补 AD 研究的这一空白，我们计划招募并纵向跟踪 400 名淀粉样蛋白 PET 阳性 EOAD 因 AD 或可能的 AD 痴呆（包括原发性遗忘、执行障碍、语言和视觉空间表现），200 名受试者符合临床标准，结果为阴性淀粉样蛋白 PET (EOnonAD) 和 100 名年龄匹配的纵向早发型参与者。阿尔茨海默病研究 (LEADS) 将接受临床评估、心理测试、MRI、淀粉样蛋白 ([18F]Flobetaben) 和 tau ([18F]AV1451) PET、CSF 和抽血用于收集 DNA、RNA、血浆、血清 EOnonAD 参与者和对照组也将接受 [18]FDG。 PET。每年对所有参与者进行随访（对照长达 24 个月；受损参与者长达 48 个月）。方法将与 ADNI 和 DIAN 相协调，我们将全面描述认知、成像和诊断的特征。 EOAD 和 EOnonAD 中生物体液随时间的变化，并与年龄匹配的对照、性别和阶段进行比较我们将使用机器学习算法来开发敏感的 ADNI 中确定的匹配 LOAD 参与者。此外，我们还将描述 EOAD 进展的临床和影像学特征。 EOnonAD 病例中的神经影像学和液体生物标志物测量，以探讨认知障碍的可能病因探索性目标将应用下一代测序来评估新的遗传风险因素。该研究还将建立一个 EOAD 研究地点网络，并为启动 EOAD 奠定基础。对该人群进行的临床试验。