Penn PET Addiction Center of Excellence (PACE)

摘要/总结 阿片类药物使用障碍（OUD）是由于阿片类药物过量（OD）相关的公共卫生紧急事件 死亡率和非致命性发病率。OD导致严重的呼吸抑制和缺氧缺血， 可能损害对氧合减少敏感的脑区域（例如，海马体），从而损害 神经认知功能有充分的证据表明阿尔茨海默病样病理学，即， 高磷酸化的tau蛋白和淀粉样前体蛋白，在患有 OUD。OUD和/或非致命性OD后的神经认知障碍可能反映了早期痴呆- 导致不良结局，包括OUD治疗抵抗。或者，OUD和/或非致命性OD可能 是阿尔茨海默病的独立危险因素。到目前为止，还没有研究评估非致命性 OD或慢性阿片样物质暴露对人体内tau蛋白沉积的影响因此，本建议的中心目标是 研究非致命性OD和慢性阿片类药物暴露对阿尔茨海默病样病理学的影响：脑 视觉情景记忆编码过程中tau蛋白沉积、脑形态和脑反应 任务使用PET/CT和MRI成像。将招募三组5名个体（总共N=15）：一组具有 OUD将至少有一个 的 过去一年的OD（OUD/OD+），一组OUD将没有历史 OD（OUD/OD-），并且一组将包括非依赖性健康对照个体（HC）。所有组 用[18F]PI-2620进行tau PET/CT脑扫描、脑结构MRI扫描和视觉情景记忆 基于任务的功能性MRI扫描，其性能已被证明在OUD和 老年痴呆症在目标1中，我们将检验OUD/OD+组具有更大的脑tau蛋白的假设。 沉积比OUD/OD-和HC组，表明缺氧缺血性损伤的病理作用 在OD之后。在目标2中，我们将检验OUD/OD+个体海马灰质较小的假设 体积比OUD/OD-和HC组。在目标3中，我们将检验OUD/OD+个体具有以下假设： 与对照组相比，视觉情景记忆任务的行为表现和海马激活受损 OUD/OD-和HC组，海马/内嗅皮质[18 F]PI-2620结合将与 海马激活这项研究的成功完成将使我们能够估计以下因素的效应量和功效： 设计一项确定性研究，以确定非致命性OD和/或慢性阿片类药物使用史是否相关 类似阿尔茨海默病的病理学拟议的一系列研究将有助于阐明 OUD患者认知障碍的基础，并提高我们对 慢性阿片类药物使用和OD对认知能力的影响。研究结果可以帮助选择新的治疗方法 旨在OUD的脑恢复和复发预防的方法，并提供一种监测变化的方法 随着时间的推移与阿尔茨海默病风险相关的病理影响。

ABSTRACT/SUMMARY Opioid use disorder (OUD) is a public health emergency due to the increasing opioid overdose (OD)-related deaths and non-fatal morbidity rate. OD results in severe respiratory depression and hypoxic ischemia, which can damage brain areas sensitive to reduced oxygenation (e.g., the hippocampus) and thereby impair neurocognitive functioning. There is ample evidence of Alzheimer's disease-like pathology, i.e., hyperphosphorylated tau and amyloid precursor protein, in the post-mortem brain tissues of individuals with OUD. The neurocognitive impairments in OUD and/or after non-fatal OD may reflect incipient dementia – contributing to poor outcomes, including OUD treatment resistance. Alternatively, OUD and/or non-fatal OD may be independent risk factors for Alzheimer's disease. To date, no studies have evaluated the effects of non-fatal ODs or chronic opioid exposure on tau deposition in humans in vivo. Thus, the central aim of this proposal is to investigate the effects of non-fatal OD and chronic opioid exposure on Alzheimer's disease-like pathology: brain tau deposition, brain morphology, and brain responses during memory encoding on a visual episodic memory task using PET/CT and MRI imaging. Three groups of 5 individuals (total N=15) will be recruited: one group with OUD will have a history of at least one of OD in the past year (OUD/OD+), one group with OUD will have no history OD (OUD/OD-), and one group will comprise non-dependent healthy control individuals (HC). All groups will undergo a tau PET/CT brain scan with [18F]PI-2620, a brain structural MRI scan, and a visual episodic memory task-based functional MRI scan, for which performance has been shown to be impaired in both OUD and Alzheimer's disease. In Aim 1, we will test the hypothesis that the OUD/OD+ group has greater brain tau deposition than the OUD/OD- and HC groups, indicative of the pathological effects of hypoxic-ischemic injury after OD. In Aim 2, we will test the hypothesis that OUD/OD+ individuals have smaller hippocampal gray matter volume than the OUD/OD- and HC groups. In Aim 3, we will test the hypotheses that OUD/OD+ individuals have impaired behavioral performance and hippocampal activation on a visual episodic memory task compared to the OUD/OD- and HC groups, and that hippocampal/entorhinal cortical [18F]PI-2620 binding will covary with hippocampal activation. Successful completion of this study will enable us to estimate effect sizes and power for the design of a definitive study of whether a history of non-fatal OD and/or chronic opioid use are associated with Alzheimer's disease-like pathology. The proposed set of studies will help to elucidate the pathophysiological basis for cognitive impairments in individuals with OUD and improve our understanding of the contribution of chronic opioid use and OD on cognitive performance. Study findings could aid in the selection of novel treatment approaches aimed at brain recovery and relapse prevention in OUD and provide a method to monitor changes in pathologic effects over time associated with Alzheimer's disease risk.