Stress, Glucocorticoids and Alzheimer Disease

压力、糖皮质激素和阿尔茨海默病

• 批准号: 7676085
• 负责人: JOHN G CSERNANSKY
• 金额: $ 29.22万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676085
• 关键词: AP40; Adrenalectomy; Age-Months; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Animals; Behavioral; Blood; Boxing; Brain Mapping; Cerebrovascular Disorders; Chronic; Clinical; Clinical dementia rating scale; Cognitive; Corticosterone; Data Analyses; Dementia; Deposition; Disease; Disease Progression; Dose; Elderly; Elements; Enzyme-Linked Immunosorbent Assay; Glucocorticoids; Half-Life; Hippocampus (Brain); Hormones; Housing; Human; Hydrocortisone; Image; Intercellular Fluid; Investigation; Magnetic Resonance; Magnetic Resonance Imaging; Mammals; Measures; Mediating; Medical; Memory; Memory impairment; Microdialysis; Modeling; Mus; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurotic Disorders; Patients; Performance; Personality inventories; Physiological; Plasma; Procedures; Process; Protons; Psychological Stress; Psychosocial Stress; Randomized; Reporting; Resolution; Salivary; Sampling; Scanning; Senile Plaques; Serum; Severities; Shapes; Staging; Stress; Structure; Study Subject; Sum; Testing; Tg2576; Time; Tissues; Transgenic Mice; Transgenic Organisms; Treatment/Psychosocial Effects; Weaning; Weight; Work; brain volume; comparison group; density; drinking water; hypothalamic-pituitary-adrenal axis; inhibitor/antagonist; mouse model; neuropsychological; primary outcome; psychosocial; research study; secondary outcome; secretase; stressor; white matter

DESCRIPTION (provided by applicant): Alzheimer disease (AD) is a progressive neurodegenerative disease and the most common cause for dementia in the elderly. Among patients with AD, the rate of disease progression varies considerably, related in some degree to stage of illness and comorbid medical conditions. Psychological stress is well known to increase activity of the hypothalamic-pituitary-adrenal (HP A) axis by promoting release of glucocorticoid (GC) hormones in a variety of mammalian species, and chronically increased levels of GC hormones have been associated with decreases in hippocampal volume and memory deficits. Associations between stress, increased GC activity and hippocampal degeneration may have special relevance for understanding the neurobiology of AD, since hippocampal degeneration is also a marker of early AD. However, there have been few investigations of the relationship between stress, GC hormones and the progression of AD. The overall aim of this project is to investigate the general hypothesis that stress, by increasing GC levels, accelerates the rate of progression of AD. In preliminary work, we have made two key findings that support this general hypothesis. First, in a study of patients with very mild-to-mild dementia of the Alzheimer type (DAT), we found a correlation between SAM serum cortisol concentrations and the rate of change of clinical and neuropsychological measures of dementia. Second, in Tg2576 mice that overproduce the human form of amyloid precursor protein (APP), chronic isolation stress increased serum levels of corticosterone, the severity of deficits in contextual memory, and the rate of deposition of a-amyloid plaques in the hippocampus and cortex. We now propose to further investigate the general hypothesis that stress can accelerate the rate of progression of AD via increases in GC activity. First, we propose to assess correlations between blood and salivary cortisol levels and the rate of disease progression in DAT subjects measured using neuroanatomical as well as clinical and neuropsychological measures. Second, we propose to investigate the mechanism(s) by which isolation stress increases the rate of beta-amyloid plaque deposition in APP-transgenic mice, and in specific, to determine the degree to which GC hormones are an element of this mechanism.

描述（由申请人提供）：阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，是老年人痴呆的最常见原因。在AD患者中，疾病进展率有很大差异，在某种程度上与疾病和合并症阶段有关。众所周知，通过促进多种哺乳动物物种中糖皮质激素（GC）激素的释放，心理压力会增加下丘脑 - 垂体 - 肾上腺（HP A）轴的活性，而GC激素的慢性水平与海马体积和记忆力下降的降低有关。压力，增加的GC活性和海马变性之间的关联对于理解AD的神经生物学可能具有特殊意义，因为海马变性也是早期AD的标志。但是，对压力，GC激素与AD进展之间的关系的研究很少。 该项目的总体目的是调查一个总体假设，即通过提高GC水平，压力可以加速AD的进展速度。在初步工作中，我们提出了两个关键发现，以支持这一普遍假设。首先，在对阿尔茨海默氏症类型（DAT）非常轻度痴呆症患者的研究中，我们发现SAM血清皮质醇浓度与痴呆症的临床和神经心理学测量的变化率之间存在相关性。其次，在TG2576小鼠中，淀粉样蛋白前体蛋白（APP）过量产生的小鼠，慢性隔离应激增加了皮质酮的血清水平，情境记忆中缺陷的严重程度以及海马和皮特克斯中A-淀粉样蛋白斑的沉积率。 现在，我们建议进一步研究一个普遍的假设，即应力可以通过增加GC活性来加速AD的进展速度。首先，我们建议评估血液与唾液皮质醇水平之间的相关性以及使用神经解剖学以及临床和神经心理学指标测量的DAT受试者的疾病进展率。其次，我们建议研究隔离应力在APP-转基因小鼠中增加β-淀粉样蛋白斑块沉积速率的机制，并在具体上确定GC激素是该机制的元素的程度。

项目成果

Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia.

• DOI: 10.1176/ajp.2006.163.12.2164
• 发表时间: 2006-12
• 期刊: The American journal of psychiatry
• 作者: J. Csernansky;Hongxin Dong;A. Fagan;Lei E. Wang;C. Xiong;D. Holtzman;J. Morris

Neuroanatomic and behavioral traits for autistic disorders in age-specific restricted index selection mice.

• DOI: 10.1016/j.neuroscience.2011.05.017
• 发表时间: 2011-08-25
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: Meng, L.;Lu, L.;Murphy, K. M.;Yuede, C. M.;Cheverud, J. M.;Csernansky, J. G.;Dong, H.
• 通讯作者: Dong, H.