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AD相关的神经病理学变化开始于海马体和周围区域，已知这些大脑区域对记忆至关重要。最近对AD的概念化表明，这些变化早在临床症状变得明显之前开始，并且症状的发作及其进展可能受到增加这些区域神经元脆弱性的任何共病因素的影响。一个潜在的共病因素是慢性心理压力。许多研究表明，慢性压力导致糖皮质激素的释放，这些激素靶向大脑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的下降。这表明，共病，长期的压力会对内侧颞叶结构的完整性产生不利影响，因此，将加速发展的痴呆综合征的特点，AD的个人谁可能是在临床前阶段。其中一组，轻度认知障碍（MCI），已被确定为有记忆投诉，轻度记忆丧失的客观心理测试，和很少或没有损失的其他认知功能或技能的日常生活活动。本项目将比较老年人、正常对照组和MCI受试者的基线心理和生理（皮质醇）应激指标，并关注MCI受试者对潜在应激事件和困难（包括记忆丧失）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随时间持续的程度，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。如果记忆力下降和痴呆的发展在患有临床前AD的个体中因慢性应激而加剧，则改善应激的行为和/或精神药理学手段可以将AD临床症状的发作延迟数月甚至数年。

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.