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

概要：项目2-调节因素 最近针对b-淀粉样蛋白的试验结果令人失望，这强调了我们识别， 测量，并更好地了解典型阿尔茨海默病病理学之外的因素， 出现晚年认知能力下降。这种需求对于潜在可改变的风险因素尤其迫切， 可以单独或与针对b-淀粉样蛋白的治疗联合进行干预的靶向下降 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 （HABS），以评估体力活动、炎症和血管因素改变纵向 认知能力下降，基于MRI的神经退行性变指标，以及这些潜在的可改变的风险 因子与阿尔茨海默病病理级联反应相互作用，引起加速的神经变性， 认知能力下降目标1和2：基于横断面和纵向PET、MRI和认知数据 在HABS中，我们将增加客观的血管风险纵向评估，白色破坏， 推测的脑血管损伤，以及评估昼夜活动模式。主要分析 这些目标将评估血管和活动参数的个体差异是否预示着纵向 认知的变化（与项目4联合），海马体积的变化和tau蛋白的积累 通过PET测量的病理学（与项目1联合）。次要分析将评估以下方面的区域差异： 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 分析核心，我们将采用因果模型来研究血管和活动的方向性影响， 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 因果关系目的3：在这个探索性的目的中，我们将使用一组集中的血管生物流体标记物， 炎症和神经退行性过程，以阐明调节 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子可以与β-淀粉样蛋白相互作用以调节认知能力下降， 神经退行性变，并通过使用新的，高灵敏度的免疫测定来更深入地识别 这些潜在的可改变的风险因素的影响的生物学途径。

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.