Penn PET Addiction Center of Excellence (PACE)

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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.