Cognitive and Neural Consequence of Long Term Cortisol Exposure in Human Aging.

描述（由申请人提供）：本修订后的提案正在作为研究者发起的R01申请提交给国家老龄化研究所。动物研究中有相当多的证据表明，长期暴露于高水平的肾上腺皮质类固醇会导致海马体萎缩，并导致与年龄相关的记忆力下降。在人类中，有证据表明类似的副作用可能伴随着过量的皮质醇(C)暴露。本研究的长期目标是调查个体之间和个体内部内源性C浓度变化率对认知和神经结果的变异性可能产生的后果。我们建议的具体目的是评估长期皮质醇浓度对i)痴呆风险ii)认知能力下降风险iii)区域脑容量变化率iv)区域脑血流量变化率v)空间导航期间大脑激活的影响。我们的中心假设是，C水平与痴呆风险增加、认知能力下降风险增加、海马体和前额皮质神经功能障碍风险增加有关。我们计划通过分析巴尔的摩老龄化纵向研究（BLSA）的现有数据来评估内源性C测量对这些神经结果的影响。在这个数据集中，我们可以获得BLSA参与者长达30年的尿液样本。现有尿液样本的免疫酶分析将允许测定C水平以及C在个体内部和个体之间增加和/或减少的比率。皮质醇值将被用作我们的认知和神经结果的混合模型回归分析的主要预测因子。我们的主要结果测量包括痴呆的诊断和认知评估。此外，一部分BLSA参与者接受了脑MRI和PET扫描（N = 158），分别评估脑结构和功能。除了对现有数据的分析外，我们还提出了一项辅助研究。我们建议根据C暴露史选择两组受试者参与功能性MRI空间导航评估。这项研究的重要之处在于，它将使我们能够确定与年龄相关的认知和神经功能下降的假定风险因素，并最终导致可能的治疗策略，以改善或延缓认知和神经功能障碍。

DESCRIPTION (provided by applicant): This revised proposal is being submitted as an investigator-initiated R01 application to the National Institute on Aging. There is considerable evidence from animal research that chronic exposure to high levels of adrenal corticosteroids causes atrophy of the hippocampus and contributes to age-related declines in memory. In humans, evidence suggests that similar adverse effects may accompany excess cortisol (C) exposure. The long term goal of this research is to investigate the possible consequences of variability among and within individuals in rates of change in endogenous C concentrations on cognitive and neural outcomes. The specific aims of our proposal are to evaluate the impact of long term cortisol concentration on i) risk for dementia ii) risk for cognitive decline iii) rates of change in regional brain volumes iv) rates of change in regional cerebral blood flow v) brain activation during spatial navigation. Our central hypothesis is that levels of C will be associated with increased risk for dementia, increased risk for cognitive decline and increased risk for neural dysfunction in the hippocampus and pre-frontal cortex. We plan to evaluate the influence of endogenous C measures on these neural outcomes by analysis of existing data from the Baltimore Longitudinal Study of Aging (BLSA). In this dataset, we have access to urine samples from BLSA participants spanning a time interval of up to 30 years. Immunoenzymatic assay of existing urine samples will allow determination of C levels as well as rates of C increases and/or decreases within and between individuals. Cortisol values will be used as the primary predictor in mixed model regression analyses of our cognitive and neural outcomes. Our primary outcome measures include diagnoses of dementia as well as cognitive assessments. In addition, a subset of BLSA participants have received brain MRI and PET scans (N = 158) for assessment of brain structure and function, respectively. In addition to the analysis of existing data, we propose an ancillary study. We propose to select 2 groups of subjects based on their history of C exposure for participation in a functional MRI assessment of spatial navigation. The proposed research is significant in that it that it will allow us to identify a putative risk factor for age-related declines in both cognitive and neural function and ultimately lead to possible treatment strategies to ameliorate or delay cognitive and neural dysfunction.