Opioids and the Aging Brain: Dementia, Cognitive Decline and Neuropathology

背景和目标：美国许多老年人长期使用处方阿片类药物治疗慢性疼痛。我们对阿片类药物安全性的认识存在重大差距，包括对认知的长期影响。痴呆症和认知能力下降是与衰老相关的最可怕的疾病。有证据表明，阿片类药物可能损害大脑功能：研究发现，使用麻醉品的年轻药物滥用者的大脑会发生类似阿尔茨海默病的变化，阿片类药物会导致小胶质细胞（脑免疫细胞）和神经元的程序性细胞死亡。但之前没有流行病学研究调查过处方阿片类药物使用与晚年大脑结果的关系。我们的目标是利用现有的流行病学数据来研究阿片类药物使用与痴呆和阿尔茨海默病等结果的关系。方法：我们将使用来自成人思想变化（ACT）前瞻性队列研究的数据，该研究自1994年以来招募了近4500名社区居住的老年人。在两年一次的研究访问中对可能的痴呆筛查呈阳性的参与者进行全面的临床评估，多学科共识委员会使用标准化的研究标准确定痴呆状态。在超过29000人年的随访中，841名参与者患上了痴呆症，414名参与者接受了尸检。ACT是在一个综合医疗保健系统中设置的，该系统拥有可追溯到1977年的计算机化药房数据，这使得研究与使用许多处方药相关的大脑结果成为可能。我们之前研究了与使用非甾体抗炎药相关的痴呆和神经病理变化，非甾体抗炎药是阿片类药物的主要治疗选择。现在我们建议使用ACT数据来解决以下目标：目标1：确定较高的累积长期阿片类药物使用是否与a)全因痴呆或阿尔茨海默病的高风险相关；B)整体认知功能下降更快；c)阿尔茨海默病神经病理学负担加重（如神经性斑块、神经原纤维缠结）。目的2：确定当前或近期与远期阿片类药物使用与a)所有风险的关系

DESCRIPTION (provided by applicant): Background and goals: Many older adults in the US use prescription opioid medications long-term for chronic pain. There are major gaps in our knowledge about opioid safety, including long-term effects on cognition. Dementia and cognitive decline are among the most feared conditions associated with aging. There is evidence that opioids may harm brain function: studies have found Alzheimer's Disease-like changes in the brains of young drug abusers who use narcotics, and opioids cause programmed cell death in microglia (brain immune cells) and neurons. But no prior epidemiologic study has examined late-life brain outcomes in relation to prescription opioid use. Our goal is to leverage existing epidemiologic data to study the associations of opioid use with outcomes including dementia and Alzheimer's Disease. Methods: We will use data from the Adult Changes in Thought (ACT) prospective cohort study, which since 1994 has enrolled nearly 4500 community-dwelling older adults. Participants who screen positive for possible dementia at biennial study visits undergo thorough clinical evaluation, and a multidisciplinary consensus committee determines dementia status using standardized research criteria. Over 29,000 person-years of follow-up, 841 participants have developed dementia and 414 have undergone autopsy. ACT is set within an integrated health care system with computerized pharmacy data going back to 1977, which makes it possible to study brain outcomes in relation to use of many prescription medications. We previously studied dementia and neuropathologic changes associated with use of nonsteroidal anti-inflammatory drugs, the major therapeutic alternative to opioids. Now we propose to use ACT data to address the following aims: Aim 1: Determine whether higher cumulative, long-term opioid use is associated with a) higher risk of all-cause dementia or Alzheimer's Disease; b) more rapid decline in global cognitive functioning; and c) higher burden of Alzheimer's Disease neuropathology (e.g. neuritic plaques, neurofibrillary tangles). Aim 2: Determine the relationships of current or recent vs. distant opioid use with a) risk of all cause dementia or Alzheimer's Disease and b) global cognitive functioning. Impact: This research will provide new information about the association of prescription opioid use with late- life brain outcomes including dementia and Alzheimer's Disease. Our findings will be important to patients and their providers who are making decisions about long-term opioid use for chronic pain.