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

描述(申请人提供)：背景和目标：在美国，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之一。有证据表明，阿片类药物可能损害大脑功能：研究发现，吸食毒品的年轻吸毒者的大脑出现类似阿尔茨海默病的变化，阿片类药物会导致小胶质细胞(大脑免疫细胞)和神经元的程序性细胞死亡。但之前的流行病学研究还没有研究过老年大脑结果与处方阿片类药物使用的关系。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的使用与包括痴呆症和阿尔茨海默病在内的结果的相关性。方法：我们将使用成人思维变化(ACT)前瞻性队列研究的数据，该研究自1994年以来已经招募了近4500名居住在社区的老年人。在两年一次的研究访问中筛查出可能患有痴呆症的参与者进行彻底的临床评估，多学科共识委员会使用标准化研究标准确定痴呆症状态。经过29,000人年的跟踪，841名参与者患上了痴呆症，414人接受了尸检。ACT是在一个集成的医疗保健系统中设置的，其计算机化的药房数据可以追溯到1977年，这使得研究与使用许多处方药有关的大脑结果成为可能。我们之前研究了与使用非类固醇抗炎药物相关的痴呆症和神经病理变化，非类固醇抗炎药物是阿片类药物的主要治疗替代品。现在，我们建议使用ACT数据来解决以下目标：目标1：确定长期累积使用阿片类药物是否与a)全因痴呆症或阿尔茨海默病风险更高有关；b)全球认知功能更快下降；以及c)阿尔茨海默病神经病理负担更高(例如神经炎斑块、神经原纤维缠结)。目标2：确定当前或最近使用阿片类药物与远距离使用阿片类药物之间的关系 导致痴呆症或阿尔茨海默氏症；b)全球认知功能。影响：这项研究将提供有关处方阿片类药物使用与老年大脑结果(包括痴呆症和阿尔茨海默病)之间的关系的新信息。我们的发现对患者和他们的提供者来说很重要，他们正在决定长期使用阿片类药物治疗慢性疼痛。

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.