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。临床阿尔茨海默病可能是储备、阿尔茨海默病和血管病理三种因素共同作用的结果。脑MRI和认知测试可以识别阿尔茨海默病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）促进神经元存活和功能，可能是储备的关键决定因素，这种能力使一些人能够忍受更大的脑部病理而没有临床症状。NTF也影响AD和缺血相关的病理过程。实验和临床数据表明，健康的饮食和锻炼会增加循环NTF水平，并随着年龄的增长而下降。然而，之前没有研究全面检查NTF在社区样本中的临床和遗传相关性，或NTF与脑衰老和临床AD的关联。我们假设NTF通路的遗传变异将与血清NTF水平的变化有关，并且较低的循环NTF水平将与较低的储备、MRI和认知测试中更多的脑老化的横断面证据、这些测量的更大的纵向下降以及临床痴呆和AD的更高风险相关。我们建议对NTF和NTF受体进行全面的基因分型，并测量三种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），这些NTF分别适用于大型、中老年、社区、Framingham心脏研究（FHS）原始、后代和Omni队列。一位合作者测量了血清中IGF1的水平。DNA、大脑核磁共振和认知测试方法已经可用。我们提供以下相互关联的具体目标：目的1：检查所有3个FHS队列中NTF的临床和遗传相关性。目的2：在FHS后代和Omni队列中，将NTF血清水平和NTF途径基因的遗传变异与脑MRI和认知测试的横断面测量相关联。目的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联系起来。目的4：在长达16年的随访期内，前瞻性地将NTF基线血清浓度（在1992- 1994年储存的血清中测量）和NTF途径基因的遗传变异与痴呆和AD发生风险联系起来。拟议的研究将帮助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在亚临床脑衰老和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、记忆形成以及成人和衰老神经元的存活和健康功能中很重要；运动和节俭饮食会增加循环水平，因此NTF也可能是健康身心之间的生物联系。我们建议在纵向随访的5000多名中老年人社区（Framingham Original、Offspring和Omni队列）中研究NTF通路基因和血清NTF水平的变化，并将这些数据与基线和5年随访的脑MRI和认知表现测量以及16年随访期间发生临床痴呆和阿尔茨海默病的风险相关联。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，可能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.