Growth factors, neuroinflammation, exercise, and brain integrity

描述(申请人提供)：老化的大脑遭受进行性脑组织丢失的痛苦，使我们中的数亿人面临记忆丧失和痴呆症的风险，目前尚无治愈方法。我们最近在与身体活动、生长因子和同型半胱氨酸相关的研究中，发现了几条关于什么可能促进大脑完整性的新线索。这些变量相互作用，与炎症、大脑结构和疾病风险以复杂而引人注目的方式相互作用。为了抵抗迫在眉睫的退行性疾病的流行，我们必须确定这些变量如何阻止大脑衰退。我们将以前所未有的敏感度绘制出这些可通过干预措施瞄准的重要过程与大脑结构的关系。我们还将大脑测量与机器学习相结合来预测谁会很快衰落。我们将三个人群的大脑和认知能力下降与(1)炎症标记物和相关的神经退化风险基因，(2)生长因子和同型半胱氨酸水平，以及(3)体育锻炼联系起来。我们将在我们的感兴趣区域(ROI)--海马体、前额叶皮质(PFC)和扣带回--发现这些变量是如何相互作用来促进或阻止大脑疾病的。这项工作对于对抗阿尔茨海默病(AD)和精神分裂症(SZ)等疾病至关重要，这些疾病都与这些变量有关，并以这些ROI的缺陷为标志。我们还将用新的脑图方法调查整个大脑。体育活动在一定程度上通过对生长因子的影响，促进了这些区域的人脑再生。它可以降低炎症和同型半胱氨酸水平，这两者都与海马体的完整性有关。我们的项目将通过确定有针对性的疾病驱动机制来提高临床试验的能力。在我们最新发现的基础上，我们使用(1)炎症相关基因的基因分型变体，(2)可控的“环境”变量(运动)，以及(3)与炎症、神经发生和同型半胱氨酸相关的外周测量，以评估海马体、PFC和扣带回的完整性及其进行性下降。我们检查了三个已经接受MRI扫描的人群：阿尔茨海默病神经成像倡议(ADNI)队列(566名AD、MCI和正常老年人受试者)，心血管健康研究(CHS；517名AD、MCI和对照受试者，其中85人有我们的靶向血清指标)，以及显性遗传性阿尔茨海默病网络，由来自常染色体显性AD突变家族的年轻人组成(DIAN；~400：~20%AD；~50%突变携带者)。我们将评估：3/4与AD和炎症相关的候选基因变异(见方法)如何与炎症的血清标记物(肿瘤坏死因子α；肿瘤坏死因子α)以及海马体体积相关。3/4血清生长因子和同型半胱氨酸水平与海马、PFC和扣带回体积的关系。3/4运动水平如何影响海马体体积；生长因子和肿瘤坏死因子α如何调节这种关系。3/4在两年的随访期内，基线血清生长因子、肿瘤坏死因子α和同型半胱氨酸水平、相关基因的多态和锻炼如何共同预测大脑和认知的变化。

DESCRIPTION (provided by applicant): The aging brain suffers from progressive brain tissue loss, putting hundreds of millions of us at risk for memory loss and dementia with no known cure. We recently discovered, in studies related to physical activity, growth factors, and homocysteine, several new leads about what may promote brain integrity. These variables interact with each other, with inflammation, and with brain structure and disease risk in complex and striking ways. To resist the looming epidemic of degenerative disease, we must determine how such variables deter brain decline. We will map, with unprecedented sensitivity, how these vital processes, which are targetable with interventions, relate to brain structure. We also combine brain measures to predict, with machine learning who will imminently decline. We relate brain and cognitive decline in 3 populations to (1) an inflammatory marker and related neurodegenerative risk genes, (2) growth factor and homocysteine levels, and (3) physical exercise. We will discover how these variables interact to promote or deter brain disease, in our regions of interest (ROIs) - the hippocampus, prefrontal cortex (PFC), and cingulate gyrus. This work is crucial to combat diseases such as Alzheimer's disease (AD) and schizophrenia (SZ), among others that are both related to these variables and marked by deficits in these ROIs. We will also survey the whole brain with novel brain mapping methods. Physical activity promotes human brain regeneration in these regions, in part through its effects on growth factors. It decreases inflammation and homocysteine levels, both of which relate to hippocampal integrity. Our project will boost power in clinical trials by identifying targetable disease-driving mechanisms. Building on our recent discoveries, we use (1) genotyped variants in inflammation-related genes, (2) a controllable "environmental" variable (exercise), and (3) peripheral measures related to inflammation, neurogenesis, and homocysteine to assess integrity of the hippocampus, PFC, and cingulate gyrus, and their progressive decline. We examine three populations already scanned with MRI: the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (566 AD, MCI, and normal elderly subjects), the Cardiovascular Health Study (CHS; 517 AD, MCI, and control subjects; of whom 85 have our targeted serum measures), and the Dominantly Inherited Alzheimer Network, composed of younger adults from families with autosomal dominant AD mutations (DIAN; ~400: ~20% with AD; ~50% mutation carriers). We will assess: 3/4 how candidate gene variants associated with AD and inflammation (see Approach) relate to a serum marker of inflammation (tumor necrosis factor alpha;TNFα), and to hippocampal volume. 3/4 how serum levels of growth factors and homocysteine relate to hippocampal, PFC, and cingulate volume. 3/4 how exercise levels affect hippocampal volume; how growth factors and TNFα modulate this relationship. 3/4 how baseline serum levels of growth factors, TNFα, and homocysteine, polymorphisms in related genes, and exercise together predict brain and cognitive changes over a 2-year follow-up period.