Vascular factors, physical activity, and inflammation as modulators of neurodegenerative and cognitive trajectories (Project 2)

血管因素、体力活动和炎症作为神经退行性和认知轨迹的调节剂（项目 2）

• 批准号: 10541811
• 负责人: JASMEER P CHHATWAL
• 金额: $ 26.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541811
• 关键词: Acceleration; Acute; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amino Acids; Amyloid; Biological; Biological Markers; Blood Vessels; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Data; Development; Elderly; Episodic memory; Etiology; Funding; Hippocampus; Home; Image; Immunoassay; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Injury; Interferon Type II; Interleukin-4; Intervention; Light; Literature; Magnetic Resonance Imaging; Measurement; Measures; Medical History; Modeling; N-terminal; Nerve Degeneration; Participant; Pathologic; Pathology; Pathway interactions; Pattern; Physical activity; Physical assessment; Plasma; Positron-Emission Tomography; Process; Risk; Risk Factors; Role; Variant; Vascular Diseases; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; actigraphy; aging brain; biomarker panel; causal model; cerebral atrophy; cerebrovascular; cognitive performance; executive function; follow-up; imaging biomarker; immune activation; individual variation; inflammatory marker; lifestyle factors; modifiable risk; molecular pathology; neurofilament; novel; pedometer; prospective; regional atrophy; secondary analysis; systemic inflammatory response; tau Proteins; tau aggregation; vascular factor; vascular injury; wearable device; white matter; β-amyloid burden

SUMMARY: PROJECT 2- MODULATING FACTORS Disappointing results from recent trials targeting b-amyloid alone underscore it is critical that we identify, measure, and better understand factors outside of canonical Alzheimer’s pathology that influence the emergence of late-life cognitive decline. This need is particularly acute for potentially-modifiable risk factors for decline that can be targeted for intervention, either alone or in combination with therapies directed at b-amyloid or tau. In this context, this new project will leverage several core strengths of the Harvard Aging Brain Study (HABS) to assess the extent to which physical activity, inflammatory, and vascular factors modify longitudinal cognitive decline, MRI-based measures of neurodegeneration, and whether these potentially-modifiable risk factors interact with Alzheimer’s disease pathological cascades to cause accelerated neurodegeneration and cognitive decline. Aims 1 and 2: Building on cross-sectional and longitudinal PET, MRI, and cognitive data available in HABS, we will add objective, longitudinal assessments of vascular risk, white matter disruption due to putative cerebrovascular injury, and assessment of day and night activity patterns. Primary analyses for these aims will assess whether individual variations in vascular and activity parameters presage longitudinal changes in cognition (jointly with Project 4), changes in hippocampal volume, and in the accumulation of tau pathology as measured by PET (jointly with Project 1). Secondary analyses will assess regional variations in brain atrophy, examine the interplay of activity patterns with functional network integrity (jointly with Project 3), and identify cognitive domains which may be differentially impacted by these modulating factors. Together with the Analytic Core, we will employ causal models to examine the directionality of vascular and activity effects on cognitive and neurodegenerative trajectories and examine whether activity effects can be ascribed to reverse causation. Aim 3: In this exploratory aim, we will use a focused set of biofluid markers of vascular, inflammatory, and neurodegenerative processes to elucidate the mechanisms underlying the modulating factors we examine here. Together, these studies will allow us to develop a broader understanding of how these potentially-modifiable factors may interact with b-amyloid to modulate cognitive decline and neurodegeneration, and to go deeper by using newly-available, high-sensitivity immunoassays to identify biologic pathways underlying the effects of these potentially-modifiable risk factors.

摘要：项目2-调节因素 仅针对B-淀粉样蛋白的最近试验的令人失望的结果强调了我们确定，至关重要的是，至关重要的是 衡量，更好地理解法典阿尔茨海默氏症病理之外的因素，该病理影响 后期认知能力下降的出现。对于潜在可修改的风险因素的可能性尤其急切 可以单独或与针对B-淀粉样蛋白的疗法结合的衰落可以针对干预措施 或tau。在这种情况下，这个新项目将利用哈佛衰老大脑研究的几个核心优势 （HAB）评估体育锻炼，炎症和血管因素的程度可修改纵向 认知能力下降，基于MRI的神经退行性措施，以及这些潜在可修改的风险是否 因素与阿尔茨海默氏病的病理级联相互作用，引起加速的神经变性和 认知能力下降。目标1和2：建立在横截面和纵向宠物，MRI和认知数据上 我们将在HABS中提供，我们将增加客观的，纵向评估血管风险，白质中断 进行假定的脑血管损伤，并评估白天和夜间活动模式。主要分析 这些目标将评估血管和活动参数的个体变化是否存在纵向 认知的变化（与项目4联合），海马体积的变化以及tau的积累 通过PET测量的病理（与项目1共同测量）。次要分析将评估区域变化 脑萎缩，检查活动模式与功能网络完整性的相互作用（与项目3联合）， 并确定可能受这些调节因素影响不同的认知领域。一起 分析核心，我们将采用因果模型来检查血管和活动对 认知和神经退行性轨迹和检查是否可以分配活动效应 因果关系。目标3：在这个探索性目的中，我们将使用一组重点的血管生物流体标记， 炎症和神经退行性过程，以阐明调制的机制 我们在这里检查的因素。这些研究一起将使我们能够对 这些潜在可调节的因素可能与B-淀粉样蛋白相互作用，以调节认知能力下降和 神经变性，并通过使用新的高敏化免疫测定法来深入研究 这些潜在可修改的危险因素的影响的生物途径。