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TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72 -related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases., Competing Interests: Competing Interests. C.M.F. is currently employed at GlaxoSmithKline. J.D.R. has pending patents on 1) increasing/restoring expression of POM121 for mitigation of NPC injury and TDP-43 dysfunction in neurodegeneration, 2) CHMP7 therapy (ASO, protein degradation, siRNA) in ALS, dementia (AD/FTD), neurodegeneration, and other neurological disorders, and 3) other relevant pending patents regarding nuclear biology and neurodegeneration. Additional Declarations: No competing interests reported.

Alzheimer's disease and related dementias (AD/ADRDs) pose a significant global public health challenge, underscored by the intricate interplay of genetic and environmental factors that differ across ancestries. To effectively implement equitable, personalized therapeutic interventions on a global scale, it is essential to identify disease-causing mutations and genetic risk and resilience factors across diverse ancestral backgrounds. Exploring genetic-phenotypic correlations across the globe enhances the generalizability of research findings, contributing to a more inclusive and universal understanding of disease. This study leveraged biobank-scale data to conduct the largest multi-ancestry whole-genome sequencing characterization of AD/ADRDs. We aimed to build a valuable catalog of potential disease-causing, genetic risk and resilience variants impacting the etiology of these conditions. We thoroughly characterized genetic variants from key genes associated with AD/ADRDs across 11 genetic ancestries, utilizing data from All of Us, UK Biobank, 100,000 Genomes Project, Alzheimer's Disease Sequencing Project, and the Accelerating Medicines Partnership in Parkinson's Disease, including a total of 25,001 cases and 93,542 controls. We prioritized 116 variants possibly linked to disease, including 18 known pathogenic and 98 novel variants. We detected previously described disease-causing variants among controls, leading us to question their pathogenicity. Notably, we showed a higher frequency of APOE ε4/ε4 carriers among individuals of African and African Admixed ancestry compared to other ancestries, confirming ancestry-driven modulation of APOE -associated AD/ADRDs. A thorough assessment of APOE revealed a disease-modifying effect conferred by the TOMM40 :rs11556505, APOE :rs449647, 19q13.31 :rs10423769, NOCT :rs13116075, CASS4 :rs6024870, and LRRC37A :rs2732703 variants among APOE ε4 carriers across different ancestries. In summary, we compiled the most extensive catalog of established and novel genetic variants in known genes increasing risk or conferring resistance to AD/ADRDs across diverse ancestries, providing clinical insights into their genetic-phenotypic correlations. The findings from this investigation hold significant implications for potential clinical trials and therapeutic interventions on a global scale. Finally, we present an accessible and user-friendly platform for the AD/ADRDs research community to help inform and support basic, translational, and clinical research on these debilitating conditions (https://niacard.shinyapps.io/MAMBARD_browser/)., Competing Interests: Potential Conflicts of Interest FF, HL, MJK, MBM and MAN’s participation in this project was part of a competitive contract awarded to Data Tecnica LLC by the US National Institutes of Health (NIH). The other authors declare that they have no conflict of interest.

TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72 -related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.

The G 4 C 2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G 4 C 2 hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G 4 C 2 ) 66 mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G 4 C 2 ) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.

Background: Patients with schizophrenia (SZ) or bipolar disorder (BD) may have increased risk of complications from prescribed opioids, including opioid-induced respiratory depression. We compared prescription opioid pain medication dispensing for patients with SZ or BD versus controls over 5 years to assess dispensing trends., Methods: This retrospective, observational study analysed US claims data from the IBM® MarketScan® Commercial and Multi-State Medicaid databases for individuals aged 18-64 years with prevalent SZ or BD for years 2015-2019 compared with age- and sex-matched controls. Baseline characteristics, comorbidities, and medication use were assessed. Proportions of individuals dispensed prescription opioids chronically (ie, ≥70 days over a 90-day period or ≥ 6 prescriptions annually) or nonchronically (≥1 prescription, chronic definition not met) were assessed., Results: In 2019, the Commercial and Medicaid databases contained records for 4773 and 30,179 patients with SZ and 52,780 and 63,455 patients with BD, respectively. Patients with SZ or BD had a higher prevalence of comorbidities, including pain, versus controls in each analysis year. From 2015 to 2019, among commercially insured patients with SZ, chronic opioid-dispensing proportions decreased from 6.1% (controls: 2.7%) to 2.3% (controls: 1.2%) and, for patients with BD, from 11.4% (controls: 2.7%) to 6.4% (controls: 1.6%). Chronic opioid dispensing declined in Medicaid-covered patients with SZ from 15.0% (controls: 14.7%) to 6.7% (controls: 6.0%) and, for patients with BD, from 27.4% (controls: 12.0%) to 12.4% (controls: 4.7%). Among commercially insured patients with SZ, nonchronic opioid dispensing decreased from 15.5% (controls: 16.4%) to 10.7% (controls: 11.0%) and, for patients with BD, from 26.1% (controls: 17.5%) to 20.0% (controls: 12.2%). In Medicaid-covered patients with SZ, nonchronic opioid dispensing declined from 22.5% (controls: 24.4%) to 15.1% (controls: 12.7%) and, for patients with BD, from 32.3% (controls: 25.9%) to 24.6% (controls: 13.6%)., Conclusions: The proportions of individuals dispensed chronic or nonchronic opioid medications each year were similar between commercially and Medicaid-insured patients with SZ versus controls and were higher for patients with BD versus controls. From 2015 to 2019, the proportions of individuals who were dispensed prescription opioids chronically or nonchronically decreased for patients with SZ or BD and controls., (© 2024. The Author(s).)

The beta‑site amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its "amyloidogenic" activity which contributes to the production of amyloid-beta (Aβ) peptides. However, BACE1 also possesses an "amyloidolytic" activity, whereby it degrades longer Aβ peptides into a non‑toxic Aβ34 intermediate. Here, we examine conditions that shift the equilibrium between BACE1 amyloidogenic and amyloidolytic activities by altering BACE1/APP ratios. In Alzheimer disease brain tissue, we found an association between elevated levels of BACE1 and Aβ34. In mice, the deletion of one BACE1 gene copy reduced BACE1 amyloidolytic activity by ~ 50%. In cells, a stepwise increase of BACE1 but not APP expression promoted amyloidolytic cleavage resulting in dose-dependently increased Aβ34 levels. At the cellular level, a mislocalization of surplus BACE1 caused a reduction in Aβ34 levels. To align the role of γ-secretase in this pathway, we silenced Presenilin (PS) expression and identified PS2-γ-secretase as the main γ-secretase that generates Aβ40 and Aβ42 peptides serving as substrates for BACE1's amyloidolytic cleavage to generate Aβ34., (© 2023. The Author(s).)

Background: Extended-release injectable naltrexone (XR-naltrexone) is effective for treatment of patients with opioid use disorder (OUD), but initiation remains a barrier due to the challenge of tolerating opioid withdrawal prior to administration. Understanding factors associated with successful initiation of XR-naltrexone could facilitate its implementation through patient-treatment matching., Methods: We combined data from five consecutive studies that sought to initiate patients with active opioid use onto XR-naltrexone using a rapid procedure consisting of minimal buprenorphine, non-opioid medications for treating opioid withdrawal, and ascending low doses of oral naltrexone. Associations between patient characteristics and initiating naltrexone were estimated with logistic regression models. To evaluate whether associations differed between inpatient and outpatient settings, patient characteristic-by-setting interactions were also estimated., Results: 409 patients were included in the analyses and 228 (56%) received the first injection. A significantly greater percent of inpatients (62%) vs outpatients (48%) initiated XR-naltrexone. Initiation success was significantly more likely on an inpatient basis for heroin (60.9% inpatient vs 36.2% outpatient), intravenous (56.3% inpatient vs 22.5% outpatient), and speedball users (68.1% inpatient vs 32.3% outpatient). Prescription opioid users showed similar, higher initiation rates across settings (68.9% inpatient; 73.7% outpatient)., Conclusions: An inpatient setting may be the preferred strategy for rapid initiation of XR-naltrexone for opioid users with greater severity, including heroin or speedball injection users or those who use opioids intravenously. Initiation on an outpatient basis may be more likely to succeed for prescription opioid users., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Treatment for individuals receiving medication for opioid use disorder (MOUD) should follow an informed patient-centered approach. To better support patient autonomy in the decision-making process, clinicians should be aware of patient preferences and be prepared to educate and assist patients in transitioning from one MOUD to another, when clinically indicated. This posthoc analysis describes the characteristics of clinical trial participants (NCT02696434) with a history of opioid use disorder (OUD) seeking to transition from buprenorphine (BUP) to extended-release naltrexone (XR-NTX)., Methods: The posthoc analysis included adults with OUD currently receiving BUP (≤8 mg/day) and seeking transition to XR-NTX (N = 101) in a residential setting. Baseline participant characteristics and OUD treatment history were reviewed. All patients completed a screening questionnaire that asked about their reasons for seeking transition to XR-NTX and for choosing BUP., Results: The most common reasons for initiating a transition to XR-NTX were "Seeking to be opioid-free" (63.4%) and "Tired of daily pill taking" (25.7%). Positive predictors of transition included a more extensive BUP treatment history and a history of prescription opioid abuse. Most participants stated they were not aware of XR-NTX as a treatment option when initiating BUP (78.2%)., Discussions and Conclusions: Patients' reasons for seeking XR-NTX transition, more extensive BUP treatment history, and a history of prescription opioid abuse, may positively predict outcomes., Scientific Significance: These findings may assist clinicians in optimizing outcomes of the BUP to XR-NTX transition and supporting patients to make better informed MOUD decisions., (© 2022 Alkermes, Inc. The American Journal on Addictions published by Wiley Periodicals LLC on behalf of The American Academy of Addiction Psychiatry (AAAP).)

Background: Pharmacologic treatment is recommended for many individuals with opioid use disorder (OUD). For patients who select opioid antagonist treatment, effective management of opioid withdrawal symptoms during transition to antagonist treatment requires consideration of the patient experience., Objectives: To compare patterns of opioid withdrawal between those withdrawing from untreated opioid use and those withdrawing from buprenorphine., Methods: We performed a post hoc, cross-study comparison of the temporal pattern of opioid withdrawal during 1-week induction onto extended-release naltrexone by similar protocols enrolling two participant populations: participants with OUD entering a study with untreated opioid use (N = 378, NCT02537574) or on stable buprenorphine (BUP) treatment (N = 101, NCT02696434)., Results: The temporal pattern of withdrawal from induction day 1 through day 7 differed between the two participant populations for Clinical Opiate Withdrawal Score (COWS) and Subjective Opiate Withdrawal Score (SOWS): participants with untreated OUD prior to study entry were more likely to experience an earlier relative peak in opioid withdrawal followed by a gradual decline, whereas participants on stable BUP treatment prior to study entry were more likely to experience a relatively later, though still mild, peak opioid withdrawal. The peak COWS was reached at a mean (standard deviation) of 1.9 (1.5) days for participants with untreated OUD and 5.0 (1.5) days for participants on stable BUP. Daily peak cravings were generally higher for participants with untreated OUD than participants on stable BUP., Conclusion: Awareness of population-specific variations in the patient experience of opioid withdrawal may help clinicians anticipate the expected course of withdrawal.

Introduction: After treatment with naltrexone extended-release injectable suspension (XR-NTX), a µ-opioid receptor antagonist, opioid tolerance is reduced from pretreatment baseline. Patients may be vulnerable to opioid overdose if they attempt to override the blockade during treatment, at the end of a dosing interval, after missing a dose, or after discontinuing treatment., Objective: We analyzed postmarketing data to characterize reporting rates of opioid overdose during treatment with and after discontinuation of XR-NTX., Methods: Postmarketing adverse event reports within the XR-NTX safety database, received 2006-2018, for patients treated with XR-NTX for any indication were reviewed for opioid overdose cases. Assessable cases were categorized by timing of the event from the last dose of XR-NTX (latency): ≤28 days (on treatment), 29-56 days, and >56 days from last dose of XR-NTX. Within each latency group, cases were further classified as serious and, of those, cases that had a fatal outcome., Results: During the 12-year period, an estimated 495,602 patients received XR-NTX. Opioid overdose was reported in 161 cases; of these, 66 contained sufficient information to determine latency. Reporting rates of opioid overdose per 10,000 patients treated were similar among latency groups: 0.54 for ≤28 days (0.24 fatal), 0.34 for 29-56 days (0.16 fatal), and 0.44 for >56 days (0.40 fatal) from the last dose of XR-NTX., Conclusions: Over the 12-year period, the reporting rates of opioid overdose were similar during treatment with or after discontinuation of XR-NTX and <10/10,000 patients exposed. Our findings are limited by the nature of spontaneously reported safety data.

Background: Opioid use disorder (OUD) is associated with cognitive dysfunction. Understanding how pharmacotherapy may affect cognition is an important treatment consideration., Methods: This was a hybrid residential-outpatient, randomized trial assessing transition regimens (naltrexone/buprenorphine [NTX/BUP] vs placebo-NTX/buprenorphine [PBO-N]/BUP) to extended-release naltrexone (XR-NTX) in patients with OUD seeking BUP discontinuation. Cognition was assessed at baseline, Day 22 (XR-NTX Day 14), and Day 36 (XR-NTX Day 28) using a range of measures (Brief Assessment of Cognition Symbol Coding test, Controlled Oral Word Association Task, Wechsler Memory Scale-III Spatial Span test, Continuous Performance Test, and Test of Attentional Performance). Pre-specified exploratory analyses compared treatment groups. Post hoc analyses were treatment-arm-independent analyses overall and by baseline BUP dose (<8 mg/day [low-dose] or 8 mg/day [higher-dose])., Results: Baseline cognitive measures were similar between NTX/BUP and PBO-N/BUP groups and between BUP low-dose and higher-dose groups. There were improvements in several cognitive outcomes at Day 22 and Day 36 relative to baseline for the overall population, but no differences between NTX/BUP and PBO-N/BUP treatment groups were observed. Participants entering the study on low-dose BUP showed improvements at Day 36 relative to baseline in 5 of 7 cognitive outcomes; participants entering the study on higher-dose BUP generally did not show improvements in cognitive outcomes., Conclusions: Improvements in most cognitive domains were associated with the transition from BUP to XR-NTX, particularly in participants entering the study on low-dose (<8 mg/day) BUP. These improvements may be due to the discontinuation of BUP, the treatment with XR-NTX, or both., Competing Interests: Declaration of competing interest Abigail Zavod, Sarah C. Akerman, and Maria A. Sullivan are employees and shareholders of Alkermes, Inc. Maria A. Sullivan previously received study medication from Alkermes for a NIDA-funded investigation. Narinder Nangia and Maria Lopez-Bresnahan are former employees of Alkermes, Inc. Thomas Kosten is a consultant and investigator for Alkermes, Inc. He is also supported by Indivior, Astellas, BioXcel, Embera, Opiant, Novartis, Otsuka, and US World Medsand. Efrat Aharonovich is a consultant for Alkermes, Inc., (Copyright © 2020 Alkermes, Inc. Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: When patients seek to discontinue buprenorphine (BUP) treatment, monthly injectable extended-release naltrexone (XR-NTX) may help them avoid relapse. The efficacy of low ascending doses of oral NTX vs placebo for patients transitioning from BUP to XR-NTX is evaluated in this study., Methods: In a phase 3, hybrid residential/outpatient study, clinically stable participants with opioid use disorder (N = 101), receiving BUP for more than or equal to 3 months and seeking antagonist treatment, were randomized (1:1) to 7 residential days of descending doses of BUP and low ascending doses of oral NTX (NTX/BUP, n = 50) or placebo (PBO-N/BUP, n = 51). Both groups received standing ancillary medications and psychoeducational counseling. Following negative naloxone challenge, participants received XR-NTX (day 8). The primary endpoint was the proportion of participants who received and tolerated XR-NTX., Results: There was no statistical difference between groups for participants receiving a first dose of XR-NTX: 68.6% (NTX/BUP) vs 76.0% (PBO-N/BUP; P = .407). The mean number of days with peak Clinical Opiate Withdrawal Scale (COWS) score less than or equal to 12 during the treatment period (days 1-7) was similar for NTX/BUP and PBO-N/BUP groups (5.8 vs 6.3; P = .511). Opioid withdrawal symptoms during XR-NTX induction and post-XR-NTX observation period (days 8-11) were mild and similar between groups (mean peak COWS score: NTX/BUP, 5.1 vs PBO-N/BUP, 5.4; P = .464). Adverse events were mostly mild/moderate., Conclusions and Scientific Significance: Low ascending doses of oral NTX did not increase induction rates onto XR-NTX compared with placebo. The overall rate of successful induction across treatment groups supports a brief BUP taper with standing ancillary medications as a well-tolerated approach for patients seeking transition from BUP to XR-NTX. (Am J Addict 2020;00:00-00)., (© 2020 The Authors. The American Journal on Addictions published by Wiley Periodicals LLC on behalf of The American Academy of Addiction Psychiatry (AAAP).)

Background and Aims: Extended-release formulations of naltrexone have emerged as effective treatment options for opioid use disorder. This post-hoc analysis examined the temporal relationship between episodes of opioid use and subsequent dropout in a placebo-controlled trial of extended-release injection naltrexone (XR-NTX) to draw inferences about the mechanism by which extended blockade of opioid receptors translates into clinical effectiveness., Design: This was a 24-week multiple-site, double-blind, randomized trial of monthly XR-NTX versus placebo injections. We analyzed time to dropout from treatment using survival analysis with an extended Cox model as a function of treatment (XR-NTX versus placebo) and with weekly urine drug test (UDT) results for opioids at each week as a time-dependent covariate., Setting: Thirteen addiction treatment programs in Russia, 2008-09., Participants: A total of 250 adults with opioid use disorder who had completed in-patient detoxification., Intervention: XR-NTX injection or placebo injection every 4 weeks with weekly clinic visits and biweekly counseling., Measurements: Urine toxicology for opioids measured weekly and week of dropout from treatment., Findings: The Cox model yielded a significant interaction of time-dependent urine toxicology by treatment (P = 0.024). Among patients receiving placebo, a positive UDT in a given week increased the risk for dropout from treatment in the subsequent week [hazard ratio (HR) = 6.25; 95% confidence interval (CI) = 3.6-10.0], whereas among patients receiving XR-NTX, a positive UDT result showed no significant effect on risk for dropout (HR = 1.67; 95% CI = 0.6-4.5). The proportion of patients who completed all 24 weeks without any positive UDT result was 31% on XR-NTX compared with 20% on placebo (P = 0.051)., Conclusions: Extended-release injection naltrexone was effective at reducing the risk of dropout from opioid use disorder treatment after an episode of opioid use. Just under a third of patients (31%) on XR-NTX had no opioid-positive urine tests across the trial, but the hypothesis that this would differ from placebo (20%) was not confirmed., (© 2019 Society for the Study of Addiction.)

BACKGROUND: The United States is experiencing an opioid epidemic. Better approaches to encourage outpatient utilization of Food and Drug Administration-approved medications for the treatment of opioid use disorder, including extended-release naltrexone (XR-NTX), are needed. Withdrawal management before initiation of XR-NTX is challenging for clinicians and patients and represents a major barrier to treatment. AIMS: To review psychoeducational strategies that support patients during outpatient withdrawal management and transition to XR-NTX. METHOD: We reviewed the literature on psychoeducational strategies used during opioid withdrawal management and described the role that nurses can play in facilitating transition to XR-NTX in a Phase 3, placebo-controlled, outpatient trial comparing induction regimens. RESULTS: Supportive interventions include general psychoeducation on addiction, overcoming ambivalence, treatment adherence, anticipating XR-NTX induction, managing psychological and physiological aspects of opioid withdrawal, risks of opioid use, and sources of support during recovery. CONCLUSIONS: Psychoeducational strategies led by nurses can promote treatment adherence during withdrawal management and induction onto XR-NTX.

There is increasing evidence suggesting that amyloidogenic proteins might form deposits in non-neuronal tissues in neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. However, the detection of these aggregation-prone proteins within the human skin has been controversial. Using immunohistochemistry (IHC) and mass spectrometry tissue imaging (MALDI-MSI), fresh frozen human skin samples were analyzed for the expression and localization of neurodegenerative disease-related proteins. While α-synuclein was detected throughout the epidermal layer of the auricular samples (IHC and MALDI-MSI), tau and Aβ34 were also localized to the epidermal layer (IHC). In addition to Aβ peptides of varying length (e.g., Aβ40, Aβ42, Aβ34), we also were able to detect inflammatory markers within the same sample sets (e.g., thymosin β-4, psoriasin). While previous literature has described α-synuclein in the nucleus of neurons (e.g., Parkinson's disease), our current detection of α-synuclein in the nucleus of skin cells is novel. Imaging of α-synuclein or tau revealed that their presence was similar between the young and old samples in our present study. Future work may reveal differences relevant for diagnosis between these proteins at the molecular level (e.g., age-dependent post-translational modifications). Our novel detection of Aβ34 in human skin suggests that, just like in the brain, it may represent a stable intermediate of the Aβ40 and Aβ42 degradation pathway.

Background and Aims: Extended-release naltrexone (XR-NTX), a μ-opioid receptor antagonist for prevention of relapse to opioid dependence, has demonstrated efficacy compared with placebo and comparative effectiveness with buprenorphine-naloxone. We report outcomes for XR-NTX in Vivitrol's Cost and Treatment Outcomes Registry., Design: Observational, open-label, single-arm, multi-center registry assessing baseline characteristics and clinical and health-related quality-of-life outcomes associated with XR-NTX treatment in clinical practice., Setting: 32 US treatment centers from 2011 to 2013., Participants: Patients with opioid dependence who were prescribed XR-NTX treatment and then enrolled into the registry., Measurements: Monthly visits were evaluated for the full population and for patient ubgroups retrospectively, defined by injection number, focusing on the period between baseline and month 6 (1-, 2/3- or 6-XR-NTX)., Findings: Of 403 enrolled patients, 395 were analyzed. Most patients (n = 349) received out-patient care. On average, patients received five injections (median = 3; range = 1-25). The median number of injections administered within 6 months was higher in patients who at baseline were employed (three versus two unemployed, P = 0.02) or had private insurance (five versus two self-payment, P = 0.005; versus two state-funded, P < 0.001). The 1-, 2/3- and 6-XR-NTX groups had 132, 152 and 111 patients, respectively. At baseline, the 6-XR-NTX patients were more likely to meet normal/minimal mental illness criteria and attend school and less likely to report recent drug use. Within 6 months, the 6-XR-NTX group demonstrated improvements in employment, mental health and psychosocial functioning, and decreases in opioid craving, drug use and drug-related behavior., Conclusions: Among opioid-dependent people receiving XR-NTX treatment, better mental health, higher education and lower recent drug use at baseline are associated with greater treatment duration; in turn, longer treatment duration is associated with lower relapse rates and improved outcomes generally., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Injectable extended-release naltrexone (XR-NTX), approved to prevent relapse to opioid dependence, requires initial abstinence. This multisite outpatient clinical trial examined the efficacy and safety of low-dose oral naltrexone (NTX), combined with a brief buprenorphine (BUP) taper and standing ancillary medications, for detoxification and induction onto XR-NTX., Methods: Patients (N = 378) were randomized, stratified by primary short-acting opioid-of-use, to one of three regimens: NTX + BUP; NTX + placebo BUP (PBO-B); placebo NTX (PBO-N) + PBO-B. Patients received 7 days of ascending NTX or placebo, concurrent with a 3-day BUP or placebo taper, and ancillary medications in an outpatient setting. Daily psychoeducational counseling was provided. On Day 8, patients passing a naloxone challenge received XR-NTX., Results: Rates of transition to XR-NTX were comparable across groups: NTX/BUP (46.0%) vs. NTX/PBO-B (40.5%) vs. PBO-N/PBO-B (46.0%). Thus, the study did not meet its primary endpoint. Adverse events, reported by 32.5% of all patients, were mild to moderate in severity and consistent with opioid withdrawal. A first, second, and third XR-NTX injection was received by 44.4%, 29.9%, and 22.5% of patients, respectively. Compared with the PBO-N/PBO-B group, the NTX/BUP group demonstrated higher opioid abstinence during the transition and lower post-XR-NTX subjective opioid withdrawal scores., Conclusions: A 7-day detoxification protocol with NTX alone or NTX + BUP provided similar rates of induction to XR-NTX as placebo. For those inducted onto XR-NTX, management of opioid withdrawal symptoms prior to induction was achieved in a structured outpatient setting using a well-tolerated, fixed-dose ancillary medication regimen common to all three groups., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Animal research suggests that medications that produce a weak dopamine D2 receptor blockade and potentiate noradrenergic activity may decrease alcohol drinking. In an open-label pilot study of subjects with alcohol dependence, we tested whether the combination of quetiapine, a weak dopamine D2 receptor antagonist, whose primary metabolite, desalkylquetiapine, is a norepinephrine reuptake inhibitor, and mirtazapine, a potent α2 norepinephrine receptor antagonist, would decrease alcohol drinking and craving. Twenty very heavy drinkers with alcohol dependence entered a trial of 8 weeks of treatment with quetiapine followed by 8 weeks of treatment with a combination of quetiapine plus mirtazapine. Alcohol use was assessed weekly with a Timeline Follow-Back interview and craving with the Penn Alcohol Craving Scale. Among the 11 completers, subjects reported improved outcomes in the quetiapine plus mirtazapine period compared to the quetiapine alone period: fewer very heavy drinking days per week (1.3 [SD = 2.4] vs. 2.1 [SD = 2.8]; t = 2.3, df = 10, p = 0.04); fewer total number of drinks per week (39.7 [SD = 61.6] vs. 53.4 [SD = 65.0]; t = 2.8, df = 10, p = 0.02); and lower craving scores (2.5 [SD = 1.4] vs. 3.2 [SD = 1.2]; t = 2.4, df = 10, p = 0.04). All subjects reported at least one adverse event; 72.7% reported somnolence. In this open-label pilot study, treatment with quetiapine plus mirtazapine was associated with a decrease in alcohol drinking and craving. These findings are consistent with our previous work in animal models of alcohol use disorders and suggest that further study of medications or combinations of medications with this pharmacologic profile is warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Smoking is associated with adverse effects on pregnancy and fetal development, yet 88-95% of pregnant women in medication-assisted treatment for an opioid use disorder smoke cigarettes. This review summarizes existing knowledge about smoking cessation treatments for pregnant women on buprenorphine or methadone, the two forms of medication-assisted treatment for opioid use disorder indicated for prenatal use. We performed a systematic review of the literature using indexed terms and key words to capture the concepts of smoking, pregnancy, and opioid substitution and found that only three studies met search criteria. Contingency management, an incentive based treatment, was the most promising intervention: 31% of participants achieved abstinence within the 12-week study period, compared to 0% in a non-contingent behavior incentive group and a group receiving usual care. Two studies of brief behavioral interventions resulted in reductions in smoking but not cessation. Given the growing number of pregnant women in medication-assisted treatment for an opioid use disorder and the negative consequences of smoking on pregnancy, further research is needed to develop and test effective cessation strategies for this group., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Perinatal opioid use disorders negatively impact maternal and neonatal outcomes and are a public health problem of increasing severity. More than half of women with a substance use disorder have a history of posttraumatic stress disorder that, if not adequately addressed, can impede substance use disorder treatment. This case report describes complexities in the treatment of a pregnant woman with opioid use disorder and posttraumatic stress disorder and reviews the psychotherapeutic and pharmacologic approaches available to treat these co-occurring disorders in pregnancy. This case demonstrates the importance of early screening and intervention for co-occurring posttraumatic stress disorder in pregnant women who use substances in a closely coordinated, multidisciplinary approach to improve outcomes for women and their infants.

Substance use disorders, common in patients with schizophrenia, can lead to poor outcomes. Here we review the literature on the use of antipsychotics in patients with co-occurring schizophrenia and substance use disorder as well as evidence for the use of adjunctive pharmacological treatments targeting substance use in these patients. We also discuss a neurobiological formulation suggesting that the cooccurrence of these disorders may be related to a dysfunction in the dopamine mediated brain reward circuitry. Typical antipsychotics do not appear to decrease substance use in this population. Randomized, controlled trials provide some support for use of the atypical antipsychotic clozapine for co-occurring cannabis use disorder, naltrexone and disulfiram for alcohol use disorder, and also nicotine replacement therapy, sustained-release bupropion and varenicline for tobacco use disorder. Nonetheless, data regarding treatment in patients with these co-occurring disorders are still limited, and many studies reported to date have been either underpowered or did not include a control condition. Further research is needed to evaluate optimal pharmacotherapeutic strategies for this population.

In the past decade opioid pain reliever misuse among the U.S. population has increased to epidemic proportions. While the U.S. has only 4% of the world's population, Americans consume 86% of the world's opioids. In 2011, approximately 13 million people (5% of the U.S. population) reported nonmedical use of prescription opioids, which are now the second most commonly abused class of drug behind cannabis. There has been little in the way of formal study examining the association between mental illness and prescription opiate abuse, but preliminary evidence suggests a strong association. Neurobiological processes involved in psychosis and opiate abuse may partially explain this association. Despite compelling evidence of the growth in opiate misuse and the potential relationship with mental illness, patients with mental disorders and/or substance abuse are routinely excluded from randomized trials, making it impossible to better understand these phenomena. Treatment guidelines, especially regarding opioid agonists such as methadone and buprenorphine for people with mental illness, are woefully inadequate. We present the case of a young man with schizoaffective disorder who sustained an injury and developed chronic back pain. Opioids were prescribed and he quickly progressed to abusing increasing doses of opioids, which eventually led to daily heroin use. The young man struggled with repeated relapses, serious use-related consequences and suicide attempts. This case highlights the role of chronic pain and opioid prescribing, the segue from prescribed use to abuse and dependence, and the transition to heroin use. It demonstrates the difficulty patients may have in obtaining adequate treatment for co-occurring mental illness and substance abuse and how outcomes are improved when treatment is integrated to address both disorders. Comprehensive treatment must involve a combination of case management and medical management, including possible opioid replacement therapy.

Postsacrectomy hernias are uncommon and can present with different signs and symptoms, including constipation, fecal incontinence, bowel obstruction, pain, and posterior bulging. We report a 50-year-old man who underwent sacrectomy for malignant fibrosarcoma complicated with sacral hernia. He presented with obstructive symptoms resulting from a strictured segment of herniated sigmoid colon and underwent bowel resection along with repair of his hernia. We additionally present a review of the literature and treatment of this rare disease.