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IntroductionAlzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play a significant role in disease risk and resilience. However, the role of genetic diversity in preclinical AD studies has received limited attention.MethodsWe crossed five Collaborative Cross strains with 5xFAD C57BL/6J female mice to generate F1 mice with and without the 5xFAD transgene. Amyloid plaque pathology, microglial and astrocytic responses, neurofilament light chain levels, and gene expression were assessed at various ages.ResultsGenetic diversity significantly impacts AD-related pathology. Hybrid strains showed resistance to amyloid plaque formation and neuronal damage. Transcriptome diversity was maintained across ages and sexes, with observable strain-specific variations in AD-related phenotypes. Comparative gene expression analysis indicated correlations between mouse strains and human AD.DiscussionIncreasing genetic diversity promotes resilience to AD-related pathogenesis, relative to an inbred C57BL/6J background, reinforcing the importance of genetic diversity in uncovering resilience in the development of AD.HighlightsGenetic diversity's impact on AD in mice was explored. Diverse F1 mouse strains were used for AD study, via the Collaborative Cross. Strain-specific variations in AD pathology, glia, and transcription were found. Strains resilient to plaque formation and plasma neurofilament light chain (NfL) increases were identified. Correlations with human AD transcriptomics were observed.

Hospital-treated intentional self-poisoning is common. The possibility of changed (increased) suicidal behaviors during the COVID-19 pandemic has been raised. To compare frequencies in self-poisoning events (SPEs) and the proportions with in-hospital mortality, in the year prior to and following the official onset of the COVID-19 pandemic, in a population of hospital-treated self-poisoning patients in Iran. All self-poisoned patients admitted to Loghman-Hakim Hospital, a clinical toxicology specialty hospital in Tehran, were included. The frequency of SPEs was compared between the one-year periods immediately before and after the onset of COVID-19 pandemic using Poisson regression. Differences in proportions of in-hospital mortality were also compared using logistic regression. A total of 14,478 patients with 15,391 SPEs (8,863 [61.2%] females) were evaluated in the study. There was no difference in the overall frequency of SPEs (relative risk [RR] of 0.99 [CI95% 0.96-1.03]), but a small increase in males (RR 1.07; 1.02-1.13) and a minor decrease in females (RR 0.95; 0.91-0.99). In total, 330 patients died (2.3% of all SPEs). There was no difference in overall in-hospital mortality odds ratio (OR: 0.98 [0.79-1.22]), in females (OR = 1.14 [0.80-1.60]) or males (OR = 0.92 [0.69-1.23]). There was no change in the frequency of SPEs and no difference in the in-hospital mortality proportions, suggesting that the COVID-19 pandemic had little or no effect on these aspects of suicidal behavior in Iran., Author(s): Seyed Kaveh Hadeiy [sup.1] , Narges Gholami [sup.2] , Rebecca McDonald [sup.3] , Omidvar Rezaei [sup.4] , Ali-Asghar Kolahi [sup.5] , Nasim Zamani [sup.5] [sup.6] , Alireza Shamsi-Lahijani [sup.1] [...]

ObjectivesHigher prevalence of suicidality has been reported in individuals with ASD. This study aimed to (1) Estimate the prevalence of suicidal ideation (SI) in epidemiologically-ascertained, population-based, samples of children with ASD or Autism Spectrum Screening Questionnaire (ASSQ) Screen Positivity (ASP); (2) Determine whether ASD/ASP is an independent risk factor for SI, controlling for known SI risk factors; and, (3) Develop an explanatory model for SI in children with ASD/ASP.MethodsParticipants came from three epidemiologically-ascertained samples of school-aged Korean children (n = 14,423; 3,702; 4,837). ASSQ ≥ 14 was the cutoff for ASP. A subsample (n = 86) was confirmed to have ASD. SI was based on parents' endorsement of items on the Behavioral Assessment System for Children-2-Parent Report Scale-Children. Logistic regressions were used to assess associations between SI and ASD/ASP, controlling for demographics, peer victimization, behavior problems, and depression. To develop an explanatory model for SI within ASD/ASP, the associations between SI and child characteristics (comorbid conditions, ASD symptoms, IQ, adaptive function) were tested.ResultsSI was higher in children with ASD (14%) and ASP (16.6-27.4%) than ASSQ Screen Negative (ASN) peers (3.4-6.9%). ASD/ASP was strongly predictive of SI (ORs: 2.87-5.67), after controlling for known SI risk factors compared to ASN. Within the ASD and ASP groups, anxiety was the strongest predictor of SI.ConclusionsSI prevalence was higher in non-clinical samples of children with ASD and ASP, relative to ASN peers. These results underscore the need for routine screening for SI in children with ASD and social difficulties, particularly those with high anxiety. HighlightsPopulation-based, epidemiologically-ascertained, school-aged childrenASD and ASP are independent risk factors for SI in school-aged childrenAnxiety is an independent risk factor for SI in children with ASD or ASP.

IntroductionAlzheimer's disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer's Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline.Methods5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F-florbetapir (AV-45/Amyvid) (18F-AV45) and 18-FDG (fluorodeoxyglucose)-PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aβ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data.ResultsProphylactic verubecestat treatment resulted in dose- and region-dependent attenuations of 18F-AV45 uptake in male and female 5XFAD mice. Plasma Aβ40 and Aβ42 were also dose-dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F-FDG uptake.DiscussionProphylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aβ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD.

Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of the basic biological mechanisms underlying AD, we do not know how to prevent it, nor do we have an approved disease-modifying intervention. Both are essential to slow or stop the growth in dementia prevalence. While our current animal models of AD have provided novel insights into AD disease mechanisms, thus far, they have not been successfully used to predict the effectiveness of therapies that have moved into AD clinical trials. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD; www.model-ad.org) Consortium was established to maximize human datasets to identify putative variants, genes, and biomarkers for AD; to generate, characterize, and validate the next generation of mouse models of AD; and to develop a preclinical testing pipeline. MODEL-AD is a collaboration among Indiana University (IU); The Jackson Laboratory (JAX); University of Pittsburgh School of Medicine (Pitt); Sage BioNetworks (Sage); and the University of California, Irvine (UCI) that will generate new AD modeling processes and pipelines, data resources, research results, standardized protocols, and models that will be shared through JAX's and Sage's proven dissemination pipelines with the National Institute on Aging-supported AD Centers, academic and medical research centers, research institutions, and the pharmaceutical industry worldwide.

A range of anxiety measures is used in oncology but their comparability is unknown. We examined variations in measurement across three commonly used instruments: Hospital Anxiety and Depression-Anxiety subscale (HADS-A); Depression, Anxiety, Stress Scale - Anxiety subscale (DASS-A); and Generalised Anxiety Disorder scale (GAD-7). Participants (n = 164) completed the self-report measures and the Generalised Anxiety Disorder module of the Structured Clinical Interview for DSM-IV (SCID). We performed Rasch analysis and calculated diagnostic accuracy statistics. Instruments measured similar constructs of anxiety, but had different ranges of measurement, with the HADS-A including lower severity symptoms than the other two measures. Anxiety severity was similar for GAD-7 'mild' and HADS-A 'possible' categories, but 'mild' anxiety on the DASS-A represented more severe symptoms. Conversely, DASS-A 'severe' anxiety represented less intense symptoms than GAD-7 'severe' anxiety. Co-calibration indicated a score of eight on the HADS-A was equivalent in anxiety severity to scores of three on the DASS-A and six on the GAD-7. Area under the curve (AUC) was just acceptable for HADS-A and GAD-7 but not DASS-A. The HADS-A, DASS-A and GAD-7 displayed important differences in how they measured anxiety. In particular, categorical classifications of anxiety severity (mild/moderate/severe) were not equivalent across instruments. Thus, prevalence estimates of anxiety symptoms will vary as a consequence of the instrument used. The GAD-7 and HADS-A obtained more similar results and better AUC than the DASS-A. Our co-calibration could be used in future studies and meta-analyses of individual participant data to set cut-off points that provide more consistent classification of anxiety severity., Author(s): Kerrie Clover [sup.1] [sup.2] , Sylvie D. Lambert [sup.3] , Christopher Oldmeadow [sup.4] , Benjamin Britton [sup.2] , Madeleine T. King [sup.5] , Alex J. Mitchell [sup.6] , Gregory [...]

Objectives: To explore hepatitis C risk, knowledge, and stigma among individuals who inject substances in South Central Indiana. Design: A cross‐sectional study design was employed using a community‐based participatory research approach. The community partner was a grassroots harm reduction organization. Sample: Participants in this study were at least 18 years of age, current residents of Indiana, and self‐identified as injection substance users (n = 179). Measurements: The survey measured hepatitis C risk, knowledge, and stigma, as well as differences in hepatitis C risk scores among key demographic characteristics. Results: Most participants identified as male (n = 106, 59%), White (n = 139, 78%), and straight (n = 143, 80%). People of color reported lower hepatitis C knowledge than White participants. Women had significantly lower hepatitis C knowledge compared with men. LGBTQ participants reported increased hepatitis C risk compared with straight participants. Increased frequency of substance use was associated with decreased stigma. Unhoused participants demonstrated significantly lower hepatitis C knowledge compared with housing‐secure participants. Conclusions: Our findings increase understanding that knowledge and risk around hepatitis C are associated with demographic characteristics. Results underscore the need for tailored public health interventions to increase hepatitis C knowledge, reduce stigma, and improve testing and treatment among vulnerable populations. [ABSTRACT FROM AUTHOR]

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment. [ABSTRACT FROM AUTHOR]