Stress and the Development of Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，导致记忆和其他认知和功能能力缺陷的潜伏发作和逐渐进展。与阿尔茨海默病相关的神经病理变化始于海马体和周围区域，这些大脑区域对记忆至关重要。最近对阿尔茨海默病的概念表明，这些变化早在临床症状变得明显之前就开始了，症状的发生及其进展可能受到任何增加这些区域神经元易感性的合并症因素的影响。一个潜在的合并症因素是慢性心理压力。大量研究表明，慢性压力会导致以大脑为目标的糖皮质激素的释放，并主要在海马体上发挥作用，从而导致神经元和突触的丧失以及记忆力下降。这表明，合并症、长期的应激会对颞骨内侧结构的完整性产生不利影响，因此，会加速痴呆综合征的发展，这是阿尔茨海默病可能处于临床前阶段的个体的特征。其中一组，患有轻度认知障碍（MCI）的人，在客观心理测试中被确定为有记忆抱怨，轻度记忆丧失，在日常生活活动中很少或没有其他认知功能或技能的丧失。本项目将比较老年人、正常对照组和轻度认知障碍受试者的基线心理和生理（皮质醇）压力，并关注轻度认知障碍受试者对潜在压力事件和困难（包括记忆力丧失）的反应。考虑到AD的其他风险因素（例如，年龄，APOE状态），该项目将确定MCI受试者的心理和生理压力持续时间的程度，增加认知能力下降的易感性，特别是记忆丧失，以及转化为临床明显的AD。如果临床前阿尔茨海默病患者的慢性应激加剧了记忆衰退和痴呆的发展，那么行为和/或精神药理学方法的改善应激可以将阿尔茨海默病临床症状的发作推迟数月甚至数年。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder that results in the insidious onset and gradual progression of deficits in memory and other cognitive and functional abilities. The neuropathologic changes associated with AD begin in the hippocampus and surrounding areas, brain regions known to be crucial for memory. Recent conceptualizations of AD suggest that these changes begin well before clinical symptoms become apparent, and that the onset of symptoms and their progression may be influenced by any comorbid factor that increases neuronal vulnerability in these regions. One potential comorbid factor is chronic psychological stress. Numerous studies have shown that chronic stress results in the release of glucocorticoids that target the brain and exert their actions primarily on the hippocampus, with consequent loss of neurons and synapses and decline in memory. This suggests that comorbid, prolonged stress will adversely affect the integrity of mesial temporal structures and, as a result, will hasten the development of the dementia syndrome that characterizes AD in individuals who are likely to be in a preclinical phase. One such group, those with Mild Cognitive Impairment (MCI), have been identified as having memory complaints, mild memory loss on objective psychometric testing, and little or no loss of other cognitive functions or skills in activities of daily living. The present project will compare older, normal control and MCI subjects on measures of baseline psychological and physiological (cortisol) stress, with attention to the reactions of MCI subjects to potentially stressful events and difficulties, including loss of memory. Taking into account other risk factors for AD (e.g., age, APOE status), the project will determine the degree to which psychological and physiological stress sustained over time, increase susceptibility to cognitive decline, particularly memory loss, and conversion to clinically apparent AD, in subjects with MCI. If memory decline and the development of dementia are exacerbated by chronic stress in individuals with preclinical AD, behavioral and/or psychopharmacological means of ameliorating stress could delay the onset of clinical symptoms of AD by months or even years.