Penn PET Addiction Center of Excellence (PACE)

宾夕法尼亚州 PET 成瘾卓越中心 (PACE)

• 批准号: 10713668
• 负责人: HENRY RICHARD KRANZLER
• 金额: $ 40.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10713668
• 关键词: Adverse effects; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein Precursor; Area; Autopsy; Binding; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain Pathology; Brain scan; Cessation of life; Chronic; Dementia; Deposition; Development; Episodic memory; Hippocampus; Human; Image; Impaired cognition; Impairment; Individual; Intervention; Knowledge; MRI Scans; Magnetic Resonance Imaging; Methods; Monitor; Morbidity - disease rate; Nerve Degeneration; Neurocognition; Neurocognitive Deficit; Outcome; Overdose; PET/CT scan; Pathologic; Performance; Positron-Emission Tomography; Recording of previous events; Recovery; Research; Tauopathies; Testing; Time; Ventilatory Depression; Visual; Work; addiction; behavioral impairment; brain morphology; brain tissue; cognitive performance; dementia risk; design; entorhinal cortex; functional MRI scan; gray matter; hyperphosphorylated tau; hypoxic ischemic injury; improved; in vivo; insight; memory encoding; neuropathology; novel; opioid exposure; opioid overdose; opioid use; opioid use disorder; public health emergency; recruit; relapse prevention; respiratory hypoxia; response; tau Proteins; therapy resistant

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.

摘要/总结 阿片类药物使用障碍 (OUD) 是一种公共卫生紧急事件，因为与阿片类药物过量 (OD) 相关的事件不断增加 死亡和非致命性发病率导致严重的呼吸抑制和缺氧缺血。 会损害对氧合减少敏感的大脑区域（例如海马体），从而损害 有充分的证据表明存在类似阿尔茨海默病的病理学，即 高度磷酸化的 tau 蛋白和淀粉样前体蛋白，存在于患有以下疾病的个体死后脑组织中 OUD 中和/或非致命性 OD 后的神经认知障碍可能反映了早期痴呆症 – OUD 和/或非致命性 OD 可能会导致不良结果，包括 OUD 治疗耐药。 迄今为止，尚无研究评估非致命性的影响。 OD 或慢性阿片类药物暴露对人体内 tau 沉积的影响因此，该提案的中心目标是 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：大脑 视觉情景记忆的记忆编码过程中的 tau 沉积、大脑形态和大脑反应 将招募三组，每组 5 人（总共 N = 15）：一组使用 PET/CT 和 MRI 成像。 OUD 至少有一个历史 的 过去一年的OD（OUD/OD+），有OUD的一组将没有历史记录 OD (OUD/OD-)，一组将包含非依赖性健康对照个体 (HC)。 使用 [18F]PI-2620 进行 tau PET/CT 脑部扫描、脑部结构 MRI 扫描和视觉情景记忆 基于任务的功能性 MRI 扫描，其 OUD 和 在目标 1 中，我们将检验 OUD/OD+ 组脑 tau 含量更高的假设。 沉积量高于 OUD/OD- 和 HC 组，是缺氧缺血性损伤病理效应的指标 在目标 2 中，我们将检验 OUD/OD+ 个体的海马灰质较小的假设。 在目标 3 中，我们将检验 OUD/OD+ 个体的假设。 与视觉情景记忆任务相比，行为表现和海马激活受损 OUD/OD- 和 HC 组，海马/内嗅皮质 [18F]PI-2620 结合将覆盖 成功完成这项研究将使我们能够估计效应大小和功效。 设计一项确定性研究，以确定非致命性 OD 史和/或长期阿片类药物使用是否相关 拟议的一系列研究将有助于阐明阿尔茨海默病的病理生理学。 为 OUD 个体认知障碍奠定基础，并提高我们对 OUD 贡献的理解 慢性阿片类药物使用和 OD 对认知能力的影响研究结果可能有助于选择新的治疗方法。 旨在 OUD 的大脑恢复和复发预防的方法，并提供监测变化的方法 随着时间的推移，病理影响与阿尔茨海默病风险相关。

项目成果

Changes in synaptic markers after administration of ketamine or psychedelics: a systematic scoping review.

服用氯胺酮或致幻剂后突触标记物的变化：系统范围审查。

• 发表时间: 2023
• 作者: Zhornitsky, Simon;Oliva, Henrique N P;Jayne, Laura A;Allsop, Aza S A;Kaye, Alfred P;Potenza, Marc N;Angarita, Gustavo A
• 通讯作者: Angarita, Gustavo A

Integrating human brain proteomic data with genome-wide association study findings identifies novel brain proteins in substance use traits.

将人脑蛋白质组数据与全基因组关联研究结果相结合，识别出物质使用特征中的新型大脑蛋白质。

• 发表时间: 2022-12
• 作者: Toikumo, Sylvanus;Xu, Heng;Gelernter, Joel;Kember, Rachel L;Kranzler, Henry R
• 通讯作者: Kranzler, Henry R

A Delta-Opioid Receptor Gene Polymorphism Moderates the Therapeutic Response to Extended-Release Buprenorphine in Opioid Use Disorder.

Delta-阿片受体基因多态性调节阿片类药物使用障碍中缓释丁丙诺啡的治疗反应。

• 发表时间: 2021-02-15
• 作者: Kranzler, Henry R;Lynch, Kevin G;Crist, Richard C;Hartwell, Emily;Le Moigne, Anne;Laffont, Celine M;Andorn, Anne C
• 通讯作者: Andorn, Anne C

Analysis of genetic and clinical factors associated with buprenorphine response.

与丁丙诺啡反应相关的遗传和临床因素分析。

• 发表时间: 2021
• 影响因子: 4.2
• 作者: Crist, Richard C;Vickers;Kember, Rachel L;Rentsch, Christopher T;Xu, Heng;Edelman, E Jennifer;Hartwell, Emily E;Kampman, Kyle M;Kranzler, Henry R
• 通讯作者: Kranzler, Henry R