Targeted Proteomics of Resilient Cognition in Aging

衰老过程中弹性认知的靶向蛋白质组学

• 批准号: 8449147
• 负责人: STEVEN E ARNOLD
• 金额: $ 42.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449147
• 关键词: Accounting; Age; Aging; Alzheimer' s Disease; Antibodies; Apoptosis; Apoptotic; Brain; Calcium; Case Study; Categories; Cerebrovascular Disorders; Cognition; Cognitive; Cohort Studies; Comorbidity; Complement; Correlation Studies; Data; Dementia; Disease; Education; Elderly; Environmental Risk Factor; Epidemiologic Studies; Family; Genotype; Health; Immunoassay; Impaired cognition; Impairment; Individual; Infarction; Inflammatory; Lead; Learning; Lesion; Machine Learning; Measures; Metabolic; Natural regeneration; Neurobiology; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Plasticity; Oxidative Stress; Participant; Pathologic Processes; Pathology; Pathway interactions; Persons; Prefrontal Cortex; Process; Protein Microchips; Proteins; Proteomics; Psychosocial Factor; Relative (related person); Religion and Spirituality; Risk Factors; Sampling; Sex Education; Signal Transduction Pathway; Stratification; Synapses; Synaptic plasticity; Testing; Tissues; Validation; abstracting; aging brain; base; brain tissue; cognitive function; cohort; density; epigenomics; innovation; interest; neuron loss; neuropathology; neurotransmission; novel; pro-apoptotic protein; public health relevance; regenerative; relational database; resilience; response; synaptogenesis; transcriptomics

DESCRIPTION (provided by applicant): Targeted Proteomics of Resilient Cognition in Aging Abstract Cognition in later life deteriorates when age-associated degenerative and other pathological processes overwhelm the brain's capacity to withstand, counteract or compensate for those processes through neuroplastic, reparative responses. Thus, while clinicopathological correlation studies show significant associations of plaques, tangles, infarctions and other lesions with cognitive impairment, the relationships are imperfect, and it is increasingly recognized that some elderly persons may have abundant pathology and yet still are unimpaired. We propose an innovative clinicopathological approach in the richly characterized Religious Orders Study (ROS) cohort to identify candidate proteins and pathways that best confer cognitive resilience despite the presence of neurodegenerative disease pathologies. To accomplish this we apply non-biased stratification in the ROS cohort to identify three distinct test groups of 60 each: 1) AD-Dementia (dementia with abundant plaque and tangle pathology), 2) AD-Resilient (normal cognition despite abundant AD plaque. tangle and other pathology), and 3) Healthy (normal cognition and minimal AD or other pathology). We will measure the expression of >500 proteins that span functional families of apoptosis, synaptic neurotransmission and neuroplasticity, metabolic, inflammatory, cytoskeletal, signal transduction pathways and others. We will test two hypotheses that pro-apoptotic proteins and synaptic plasticity proteins differentiate the clinicopathological category groups and we will conduct machine learning approaches to further identify these and novel analytes that best predict categories. Based on these analyses, we will generate a targeted multi-analyte immunoassay panel. This will be used to validate the association of candidate proteins with cognitive resilience in another set of 480 ROS cases. Our focus on the neurobiology of resilient brain aging will be an important counterpoint and complement to historical and current efforts focused on the neurobiology of disease pathology.

当年龄相关的退行性和其他病理过程压倒了大脑通过神经可塑性、修复性反应来承受、抵消或补偿这些过程的能力时，晚年的认知能力就会恶化。因此，尽管临床病理相关研究显示斑块、缠结、梗死等病变与认知功能障碍有显著关联，但这种关系并不完美，而且人们越来越认识到，一些老年人可能有丰富的病理，但仍未受到损害。我们在特征丰富的宗教秩序研究（ROS）队列中提出了一种创新的临床病理学方法，以确定尽管存在神经退行性疾病病理，但仍能最好地赋予认知弹性的候选蛋白质和途径。为了实现这一目标，我们在ROS队列中应用无偏见分层，确定了三个不同的测试组，每组60人：1)AD-痴呆（具有丰富斑块和纠缠病理的痴呆），2)AD-弹性（尽管有丰富的AD斑块，但认知正常）。3)健康（认知正常，AD或其他病理极少）。我们将测量跨越凋亡、突触神经传递和神经可塑性、代谢、炎症、细胞骨架、信号转导途径等功能家族的bbb500蛋白的表达。我们将测试促凋亡蛋白和突触可塑性蛋白区分临床病理类别组的两个假设，我们将进行机器学习方法来进一步识别这些和新的分析，以最好地预测类别。基于这些分析，我们将生成一个靶向的多分析物免疫分析面板。这将用于在另一组480例ROS病例中验证候选蛋白与认知弹性的关联。我们对弹性脑衰老的神经生物学的关注将是对疾病病理学神经生物学的历史和当前努力的重要对照和补充。