Imaging beta-amyloid in middle age alcoholics as a mechanism that increases their risk for Alzheimer’s disease

中年酗酒者中的β-淀粉样蛋白是一种增加其患阿尔茨海默病风险的机制

• 批准号: 9718353
• 负责人: RAJESH NARENDRAN
• 金额: $ 33.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9718353
• 关键词: Abeta synthesis; Adult; Age-Years; Alcohol abuse; Alcohol consumption; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autopsy; C-terminal; Data; Dementia; Development; Disease; Drug abuse; Enzymes; General Population; Heavy Drinking; Human; Image; Impaired cognition; Individual; Link; Medical; Nature; Neurocognitive Deficit; Patients; Positron-Emission Tomography; Proteins; Reporting; Risk; Risk Factors; Rodent; Senile Plaques; Thiamine Deficiency; Universities; Wernicke Encephalopathy; Wernicke-Korsakoff Syndrome; Woman; alcohol use disorder; beta secretase; cognitive function; epidemiologic data; epidemiology study; hazard; human old age (65+); imaging agent; in vivo; middle age; nicastrin protein; problem drinker; radiotracer; synuclein

There is a long-established relationship between alcohol use disorders, cognitive impairments, and the development of dementia. Studies have shown that heavy alcohol use in middle aged individuals impairs cognitive function even in patients who are not diagnosed with dementia (Giovanni Piumatti, 2018; Katherine Stavro, 2012). Traditionally, the study of neurocognitive impairments in alcoholics have focused on thiamine deficiency resulting in Wernicke encephalopathy or Wernicke-Korsakoff syndrome. More recently, evidence has begun to arise linking alcohol use disorders with other types of dementia including Alzheimer’s disease. Recent epidemiological data suggests that the hazard ratio to develop Alzheimer’s disease is 2-fold greater amongst individuals with alcohol use disorders compared to the general population (Michael Schwarsinger, 2018). This relationship is especially strong when alcohol abuse is examined as a risk factor for the onset of dementia in women and middle-aged adults. These epidemiological data suggest that the ‘at risk’ period to develop dementia is shifted to the middle-age years in individuals with alcohol use disorder. Consistent with this notion alcohol consuming rodents relative to controls show an increase in the expression of several proteins (such as b-amyloid precursor protein, C-terminal fragment-b, enzyme b-secretase 1, immature nicastrin, etc.,) that are involved in the synthesis of beta-amyloid plaques (Ab). However, the only post-mortem study that examined this issue in humans found no significant increase in the aggregation of Ab, hyperphosphorylated 𝜏, or 𝛼-synuclein in alcoholics compared to controls (Leena Aho, 2009). Given the retrospective nature of postmortem studies and the fact it cannot exclude co- morbid medical, psychiatric, and drug abuse disorders, it is difficult to interpret these data. There is a great need for in vivo studies to further investigate the relationship between alcohol use disorders, Ab, and Alzheimer’s disease. The positron emission tomography (PET) radiotracer [11C]PiB, which was discovered at the University of Pittsburgh is one of the most widely used and well validated Ab imaging agents (Klunk et al., 2004). Here, we propose to use [11C]PiB and PET to contrast the rate (%) of Ab positivity (+) in 40-65 year old alcoholics and controls. We hypothesize increased Ab+ in alcoholics compared to controls. Such a finding would suggest an increased risk of Ab+, and by extension explain the increased rates of Alzheimer’s dementia in alcoholics reported in recent epidemiological studies.

酒精使用障碍，认知障碍和 痴呆症的发展。研究表明，中年个体中的大量酒精使用 即使在未被诊断患有痴呆的患者中，也会损害认知功能 2018;凯瑟琳·斯塔夫罗（Katherine Stavro），2012年）。传统上，酗酒者神经认知障碍的研究 专注于硫胺素缺乏，导致Wernicke脑病或Wernicke-Korsakaff 综合征。最近，已经有证据表明将酒精使用障碍与其他类型联系起来 包括阿尔茨海默氏病在内的痴呆症。最近的流行病学数据表明危害 患有酒精使用障碍的个体中，发展阿尔茨海默氏病的比率高2倍 与普通人群相比（Michael Schwarsinger，2018年）。这种关系尤其是 当将酗酒作为女性痴呆发作的危险因素和 中年成年人。这些流行病学数据表明，发展痴呆的“处于危险”时期 在患有饮酒障碍的人群中，已转移到中年。与这个概念一致 相对于对照组的饮酒啮齿动物的表达增加了几种蛋白质的表达 （例如B-淀粉样蛋白前体蛋白，C末端片段B，酶B-分泌酶1，未成熟 与β-淀粉样木斑合成（AB）合成的尼古斯林等）。但是，唯一的 在人类中检查了这一问题的验尸研究发现 与对照组相比 Aho，2009年）。鉴于验尸研究的回顾性，事实并不能排除共同 病态的医学，精神病和药物滥用障碍，很难解释这些数据。有一个 对体内研究的巨大需求，以进一步研究酒精使用障碍之间的关系，AB， 和阿尔茨海默氏病。极性发射断层扫描（PET）radiotracer [11C] PIB，它是 在匹兹堡大学发现的是最常用且经过良好验证的AB之一 成像剂（Klunk等，2004）。在这里，我们建议使用[11C] PIB和PET与速率进行对比 40-65岁的酗酒者和对照中的AB阳性（+）的（％）。我们假设增加的AB+在 与对照组相比，酗酒。这样的发现表明AB+的风险增加，并且 扩展解释了最近报道的阿尔茨海默氏症痴呆症的发生率提高 流行病学研究。