Neurotrophic Factors: Genetic Variation and Serum Levels in Brain Aging

描述（由申请人提供）：阿尔茨海默病（AD）造成了巨大的社会负担。临床AD可能通过3个因素的相互作用产生：储备、AD和血管病理学。脑MRI和认知测试可以识别AD和血管病理学的储备和亚临床标志物（可遗传的内表型）的替代措施。神经营养因子（NTF）促进神经元的存活和功能，是储备的可能关键决定因素，这种能力使一些人能够忍受更大的脑病理而没有临床症状。NTF还影响AD和缺血相关的病理过程。实验和临床数据表明，健康的饮食和运动会增加循环NTF水平，并随着年龄的增长而下降。然而，没有先前的研究已经全面检查了临床和遗传相关的NTF在社区为基础的样本，或关联的NTF与脑老化和临床AD。我们假设NTF通路的遗传变异与血清NTF水平的变化有关，较低的循环NTF水平与较低的储备、MRI和认知测试中更多的脑老化横断面证据、这些指标的纵向下降以及临床痴呆和AD的风险较高有关。我们建议对NTF和NTF受体进行全面的基因分型，并在大型、中年至老年人、社区为基础的Frachial Heart Study（FHS）原始、后代和Omni队列中测量三种NTF的血清水平：脑源性神经营养因子（BDNF）、神经生长因子（NGF）和血管内皮生长因子（VEGF）。IGF 1的血清水平已由合作者测量。DNA、大脑MRI和认知测试措施已经可用。我们提供了以下，相互关联的具体目标：目标1：在所有3个FHS队列中检查NTF的临床和遗传相关性。目标二：将NTF血清水平和NTF通路基因的遗传变异与FHS后代和Omni队列的脑MRI和认知测试的横断面测量相关。目标3：前瞻性地将基线血清水平和NTF通路基因的遗传变异与FHS后代和Omni的MRI和认知测试的纵向变化相关。目标4：为了前瞻性地将NTF的基线血清浓度（在1992-94年储存的血清中测量）和NTF通路基因的遗传变异与长达16年的随访期内发生痴呆和AD的风险联系起来，拟议的研究应有助于我们更好地了解生活方式和临床痴呆之间的生物学联系以及NTF在亚临床脑老化和AD发展中的作用。公共卫生相关性：神经营养因子（NTF）在大脑发育，记忆形成以及成年和衰老神经元的生存和健康功能中非常重要;循环水平随着运动和节俭饮食而增加，因此NTF也可能是健康身心之间的生物联系。我们建议研究NTF通路基因和血清NTF水平的变化，在一个超过5000名中年和老年人的社区中进行随访（FractionalOriginal，Offspring和Omni队列），并将这些数据与脑MRI和认知表现的基线和5年随访测量结果相关联，以及在16年的随访期内发展为临床痴呆和阿尔茨海默病的风险。这项研究将提高我们对NTF通路在健康和异常衰老中所起作用的理解，也许会导致改善预防和治疗策略，以对抗认知衰老和阿尔茨海默病的发展。

DESCRIPTION (provided by applicant): Alzheimer disease (AD) imposes a substantial societal burden. Clinical AD likely results through the interaction of 3 factors: reserve, AD- and vascular pathology. Brain MRI and cognitive tests can identify proxy measures of reserve and subclinical markers (heritable endophenotypes) of AD- and vascular pathology. Neurotrophic factors (NTF) promote neuronal survival and function and are possible key determinants of reserve, the capacity that allows some persons to tolerate greater brain pathology without clinical symptoms. NTF also impact AD- and ischemia-related pathological processes. Experimental and clinical data suggest that circulating NTF levels are increased by a healthy diet and exercise, and decline with age. However, no prior study has comprehensively examined the clinical and genetic correlates of NTF in a community-based sample, or the association of NTF with brain aging and clinical AD. We hypothesize that genetic variation in the NTF pathway will be related to variation in serum NTF levels, and that lower circulating NTF levels will be associated with lower reserve, more cross-sectional evidence of brain aging on MRI and cognitive testing, greater longitudinal decline in these measures, and a higher risk of clinical dementia and AD. We propose to genotype a comprehensive panel of NTF and NTF receptors and measure serum levels of three NTF: brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) in the large, middle-aged to elderly, community-based, Framingham Heart Study (FHS) Original, Offspring and Omni cohorts. Serum levels of IGF1 have been measured by a collaborator. DNA, brain MRI and cognitive test measures are already available. We offer the following, interlinked specific aims: Aim 1: To examine the clinical and genetic correlates of NTF in all 3 FHS cohorts. Aim 2: To relate NTF serum levels and genetic variation in NTF pathway genes to cross-sectional measures on brain MRI and cognitive tests in the FHS Offspring and Omni cohorts. Aim 3: To prospectively relate baseline serum levels and genetic variation in NTF pathway genes to longitudinal changes in MRI and cognitive tests in the FHS Offspring and Omni. Aim 4: To prospectively relate baseline serum concentrations of NTF (measured in stored sera from 1992-94) and genetic variation in NTF pathway genes to risk of incident dementia and AD over a follow-up period of up to 16 years The proposed research should help us better understand the biological link between lifestyle and clinical dementia and the role of NTF in both subclinical brain aging and in the development of AD. PUBLIC HEALTH RELEVANCE: Neurotrophic factors (NTF) are important in brain development, in memory formation, and for the survival and healthy functioning of adult and aging neurons; circulating levels increase with exercise and a frugal diet, so NTF may also be the biological link between a healthy body and mind. We propose to study variation in NTF pathway genes and serum NTF levels in a longitudinally-followed community of over 5000 middle-aged and elderly adults (the Framingham Original, Offspring and Omni cohorts), and relate these data to baseline and 5-year follow-up measures of brain MRI and cognitive performance, as well as to the risk of developing clinical dementia and Alzheimer's disease over a 16 year follow-up period. This study will improve our understanding of the role the NTF pathway plays in healthy and abnormal aging, perhaps leading to improved prevention and treatment strategies to combat cognitive aging and the development of Alzheimer's disease.