Plasma Proteome and Risk of Alzheimer Dementia and Related Endophenotypes in the Framingham Study

弗雷明汉研究中的血浆蛋白质组和阿尔茨海默氏痴呆症及相关内表型的风险

基本信息

批准号：
9763974
负责人：
ROBERT E GERSZTEN
金额：
$ 273.01万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763974
关键词：
Accounting Address Adult Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid Area Biological Biological Assay Biological Markers Biology Blood Blood - brain barrier anatomy Blood Proteins Blood Vessels Brain Brain imaging Case-Control Studies Cerebrospinal Fluid Cerebrum Clinical Clinical Trials Cognition Cognitive Communities Comorbidity Data Dementia Disease Elderly Enrollment Epidemiology Evolution Funding Grant Heart Heterogeneity Impaired cognition Impairment Incidence Individual Kidney Laboratories Life Style Liver Longitudinal Studies Lung Magnetic Resonance Imaging Mass Spectrum Analysis Measures Methods Minority Molecular Profiling Natural History Nerve Degeneration Neurocognition Neurocognitive Neurology Outcome Participant Pathway interactions Patient Selection Pattern Persons Pharmaceutical Preparations Phase Phenotype Plasma Plasma Proteins Population Positron-Emission Tomography Proteins Proteome Proteomics Research Research Personnel Risk Risk Factors Risk stratification Sampling Set protein Standardization Stream Stroke Structure Subjects Selections Systems Biology Testing Time Tissues United States Validation Vascular Dementia Woman aging brain aptamer base body system bone cognitive function cohort design endophenotype follow-up improved middle age mild cognitive impairment molecular imaging multidisciplinary neurocognitive test neurotoxic normal aging novel offspring population based pre-clinical prevent prospective protein aggregate protein misfolding protein profiling proteomic signature proteostasis screening tau Proteins trait vascular risk factor

项目摘要

Abstract The burden of cognitive impairment and Alzheimer disease (AD) is increasing rapidly with the aging of the US population. Accordingly, it is critical to identify molecular signatures of the long pre-symptomatic phase of AD to identify and target its clinically silent phase. New criteria of preclinical AD use structural and molecular imaging (MRI and PET) and cerebrospinal fluid (CSF) assays, which are expensive, invasive and not scalable for population-based screening. Hence, there is a quest for blood biomarkers of pre-symptomatic stages, mild cognitive impairment (MCI), and dementia that could (i) elucidate the biology of `normal' brain aging, AD and AD-related dementias (ADRD), (ii) improve risk prediction of AD, and iii) permit risk stratification and subject selection for enrollment in targeted clinical trials of early preclinical disease. AD is an archetypal proteinopathy characterized by protein misfolding and formation of neurotoxic protein aggregates. Damaged cerebral proteins leak into the CSF and can enter the blood. Therefore, ultra-sensitive proteomic profiling has been used to identify blood biomarkers of pre-dementia and AD. Yet, initial studies have been small, limited by suboptimal designs, and an absence of analytical validation and replication. We will characterize the plasma proteome (1310 SomaScan proteins) at two critical time points (mid-life and older age) in 1874 middle-aged-to-elderly individuals in the Framingham Offspring Study (FOS) spanning the spectrum of normal and abnormal cognition. Participants have serial neurocognitive and brain imaging data (including PET scans in a subset) and are under surveillance for AD. We hypothesize that the plasma proteome changes with the aging and with early changes in cognition. We posit that longitudinal patterns of blood biomarkers can distinguish normal aging from presence of comorbidities, pre-dementia, MCI and AD. Our specific aims are: Aim 1. Characterize the plasma proteome in 1874 elderly FOS participants at their tenth exam (2019-2021), and relate the proteome cross-sectionally to risk factors, lifestyle and medications; function of body systems and comorbidities; and structural/cognitive endophenotypes of AD. Aim 2. Evaluate longitudinal changes in plasma proteins with aging over a 25-yr follow-up period (between the 5th and 10th exams; using extant protein data at former), and relate protein changes to longitudinal trajectories of neurocognitive and brain imaging measures. Aim 3. Relate the plasma proteome at exam 10 (and changes between exams) to the incidence of cognitive decline, stroke and AD prospectively. Aim 4. Relate the top proteomic findings in Aims 1-3 to brain amyloid and tau on PET scans in a subset. We will validate our findings with mass spectrometry, and replicate them in independent cohorts. Our multidisciplinary team will identify novel longitudinal proteomic signatures of AD and ADRD; construct biological protein networks associated with AD that may be targeted in clinical trials for preventing cognitive decline and AD in middle age and beyond.

抽象的随着美国的衰老，认知障碍和阿尔茨海默氏病（AD）的负担正在迅速增加人口。因此，至关重识别和针对其临床沉默阶段的AD。临床前广告的新标准使用结构和分子成像（MRI和PET）和脑脊液（CSF）测定，它们昂贵，侵入性且不可扩展用于基于人群的筛查。因此，有一个追求症状阶段的血液生物标志物，轻度认知障碍（MCI）和痴呆症可能（i）阐明“正常”脑衰老的生物学和与广告相关的痴呆症（ADRD），（ii）改善AD的风险预测，iii）允许风险分层和对临床前疾病的有针对性临床试验入学的受试者选择。 AD是一种原型蛋白质病，其特征是蛋白质错误折叠和神经毒性蛋白的形成聚合。受损的脑蛋白会渗入CSF，并可能进入血液。因此，超敏感蛋白质组学分析已用于鉴定止动物和AD的血液生物标志物。但是，初步研究很小，受到次优设计的限制，并且没有分析验证和复制。我们将在两个关键时间点（中年和中间生活）表征血浆蛋白质组（1310 somascan蛋白）年龄较大）1874年，弗雷明汉后代研究（FOS）中的中年至较高的人正常和异常认知的频谱。参与者具有串行神经认知和大脑成像数据（包括子集中的PET扫描），并正在监视AD。我们假设血浆蛋白质组随老化和认知的早期变化而变化。我们认为这种纵向模式血液生物标志物可以将正常衰老与合并症，诱导前，MCI和AD的存在区分开。我们的具体目的是：AIM 1。在1874年的老年人参与者中表征血浆蛋白质组第十届考试（2019-2021），并将蛋白质组横截面与危险因素，生活方式和药物联系起来；身体系统和合并症的功能；和AD的结构/认知内表型。目标2。评估血浆蛋白的纵向变化在25年的随访期内衰老（第五和第10个介于第10期之间考试；使用以前的现有蛋白质数据），并将蛋白质的变化与纵向轨迹相关联神经认知和大脑成像措施。 AIM 3。在考试10中关联血浆蛋白质组在考试之间），前瞻性认知能力下降，中风和AD的发生率。目标4。关联顶部目标1-3中的蛋白质组学发现在子集中对PET扫描的脑淀粉样蛋白和TAU。我们将验证我们的发现使用质谱法，并在独立的队列中复制它们。我们的多学科团队将确定 AD和ADRD的新型纵向蛋白质组学特征；构建与在临床试验中可能针对预防中年及以后的认知能力下降和AD的AD。