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

摘要：项目2--调节因素 最近仅针对b-淀粉样蛋白的试验结果令人失望，这突显了我们识别 测量并更好地了解影响阿尔茨海默氏症典型病理的因素 晚年认知功能衰退的出现。对于潜在的可修改的风险因素，这种需求尤其迫切 可单独或与针对b-淀粉样蛋白的治疗相结合的靶向干预的下降 或者是陶。在这种背景下，这个新项目将利用哈佛大学老龄化大脑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 认知衰退，基于核磁共振的神经变性测量，以及这些潜在的可修改的风险 与阿尔茨海默病病理级联反应的因素相互作用，导致加速的神经变性和 认知能力下降。目标1和2：建立在横断面和纵向PET、MRI和认知数据的基础上 在HABS中，我们将添加对血管风险、白质干扰的客观、纵向评估 推测为脑血管损伤，并评估昼夜活动模式。对以下项目的初步分析 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合作)、海马体体积的变化以及tau的积累 正电子发射计算机断层扫描(与项目1联合)测量的病理学。二次分析将评估区域差异 脑萎缩，研究活动模式与功能网络完整性的相互作用(与项目3联合)， 并找出可能受到这些调节因素不同影响的认知域。与.一起 在分析核心中，我们将使用因果模型来检查血管和活动对 认知和神经退化的轨迹，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，我们将使用一组有针对性的血管生物流体标记物， 炎症和神经退行性变化过程，以阐明调节的潜在机制 我们在这里考察的因素。总之，这些研究将使我们能够更广泛地了解 这些潜在的可改变的因素可能与b-淀粉样蛋白相互作用，以调节认知能力下降和 神经退行性变，并通过使用新可用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的影响背后的生物途径。

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.