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 最近单独针对 b-淀粉样蛋白的试验结果令人失望，这凸显出我们必须确定： 测量并更好地了解影响阿尔茨海默病典型病理学之外的因素 晚年认知能力下降的出现。对于潜在可改变的风险因素来说，这种需求尤其迫切 可以单独或与针对 b-淀粉样蛋白的疗法联合进行干预 或 tau 蛋白。在这种背景下，这个新项目将利用哈佛大脑衰老研究的几个核心优势 （HABS）评估体力活动、炎症和血管因素改变纵向的程度 认知能力下降、基于 MRI 的神经退行性疾病测量，以及这些潜在可改变的风险 因素与阿尔茨海默氏病病理级联相互作用，导致神经退行性加速， 认知能力下降。目标 1 和 2：建立在横截面和纵向 PET、MRI 和认知数据的基础上 HABS 中可用，我们将添加对血管风险、白质破坏的客观、纵向评估 假定的脑血管损伤，并评估白天和夜间的活动模式。初步分析 这些目标将评估血管和活动参数的个体差异是否预示着纵向 认知的变化（与项目 4 一起）、海马体积的变化以及 tau 蛋白积累的变化 通过 PET 测量的病理学（与项目 1 联合）。二次分析将评估区域差异 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）， 并确定可能受到这些调节因素不同影响的认知领域。连同 在分析核心，我们将采用因果模型来检查血管和活动影响的方向性 认知和神经退行性轨迹，并检查活动影响是否可以归因于逆转 因果关系。目标 3：在这个探索性目标中，我们将使用一组针对血管、 炎症和神经退行性过程，以阐明调节背后的机制 我们在这里研究的因素。总之，这些研究将使我们能够更广泛地了解如何 这些潜在可改变的因素可能与 b-淀粉样蛋白相互作用，调节认知能力下降和 神经退行性变，并通过使用新推出的高灵敏度免疫分析来更深入地识别 这些潜在可改变的危险因素影响的生物途径。