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、认知障碍和酒精使用障碍之间存在着长期存在的关系。 痴呆症的发展。研究表明，中年人大量饮酒 即使没有被诊断患有痴呆症的患者也会损害认知功能（Giovanni Piumatti， 2018；凯瑟琳·斯塔夫罗，2012）。传统上，酗酒者神经认知障碍的研究 重点关注硫胺素缺乏导致韦尼克脑病或韦尼克-科尔萨科夫病 综合症。最近，证据开始将酒精使用障碍与其他类型联系起来 包括阿尔茨海默病在内的痴呆症。最近的流行病学数据表明，该危害 患有酒精使用障碍的人患阿尔茨海默病的比例是其两倍 与一般人群相比（Michael Schwarsinger，2018）。这种关系尤其 当酗酒被视为女性患痴呆症的一个危险因素时，这一点就很强烈 中年成年人。这些流行病学数据表明，患痴呆症的“危险期” 患有酒精使用障碍的人会转移到中年。与这个观念一致 与对照组相比，饮酒的啮齿动物显示出几种蛋白质表达的增加 （如b-淀粉样蛋白前体蛋白、C-末端片段-b、酶b-分泌酶1、未成熟的 尼卡斯特林等）参与β-淀粉样斑块（Ab）的合成。然而，唯一的 对人类这个问题进行的尸检研究发现， 与对照组相比，酗酒者中抗体、过度磷酸化 𝜏 或 𝛼-突触核蛋白的聚集（Leena 阿霍，2009）。鉴于尸检研究的回顾性以及它不能排除共同的事实 病态的医学、精神和药物滥用疾病，很难解释这些数据。有一个 非常需要体内研究来进一步研究酒精使用障碍、Ab、 和阿尔茨海默病。正电子发射断层扫描 (PET) 放射性示踪剂 [11C]PiB 匹兹堡大学发现的是最广泛使用和经过充分验证的抗体之一 显像剂（Klunk 等，2004）。在这里，我们建议使用[11C]PiB和PET来对比速率 40-65 岁酗酒者和对照者中抗体阳性 (+) 的 (%)。我们假设 Ab+ 增加 酗酒者与对照组相比。这样的发现表明 Ab+ 的风险增加，并且通过 延伸解释了最近报道的酗酒者阿尔茨海默氏痴呆症发病率的增加 流行病学研究。