Stress and the Development of Alzheimer's Disease

描述(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障碍的潜伏性发作和逐渐发展。与阿尔茨海默病相关的神经病理变化始于海马体及其周围区域，这是已知的对记忆至关重要的大脑区域。最近对AD的概念化研究表明，这些变化早在临床症状显现之前就开始了，症状的开始和发展可能受到任何增加这些区域神经元脆弱性的共病因素的影响。一个潜在的共病因素是慢性心理压力。大量研究表明，慢性应激会导致糖皮质激素的释放，糖皮质激素以大脑为靶点，主要作用于海马体，从而导致神经元和突触的丧失以及记忆力的下降。这表明，共同的，长期的应激将对近侧颞叶结构的完整性产生不利影响，因此，将加速痴呆综合征的发展，这是可能处于临床前阶段的AD患者的特征。其中一组人，轻度认知障碍(MCI)，已被确定为有记忆主诉，在客观心理测试中轻度记忆丧失，以及在日常生活活动中很少或根本没有其他认知功能或技能的损失。本项目将比较老年、正常对照组和MCI受试者在基线心理和生理(皮质醇)压力方面的测量，并关注MCI受试者对潜在应激事件和困难的反应，包括记忆力丧失。考虑到AD的其他风险因素(例如，年龄、APOE状态)，该项目将确定随着时间的推移，心理和生理压力所承受的程度，增加认知能力下降的易感性，特别是记忆丧失，并转变为临床上明显的AD。如果临床前阿尔茨海默病患者的记忆力下降和痴呆的发展因慢性应激而加剧，缓解应激的行为和/或精神药理手段可能会将阿尔茨海默病的临床症状推迟数月甚至数年。

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.