Antibody engagement with amyloid-beta does not inhibit [11C]PiB binding for PET imaging.

The elimination of amyloid-beta (Aß) plaques in Alzheimer's disease patients after treatment with anti-Aß antibodies such as lecanemab and aducanumab is supported by a substantially decreased signal in amyloid positron emission tomography (PET) imaging. However, this decreased PET signal has not been matched by a similar substantial effect on cognitive function. There may be several reasons for this, including short treatment duration and advanced disease stages among the patients. However, one aspect that has not been investigated, and the subject of this study, is whether antibody engagement with amyloid plaques inhibits the binding of amyloid-PET ligands, leading to a false impression of Aß removal from the brain. In the present study, tg-ArcSwe mice received three injections of RmAb158, the murine version of lecanemab or phosphate-buffered saline (PBS) before the administration of the amyloid-PET radioligand [11C]PiB, followed by isolation of brain tissue. Autoradiography showed that RmAb158- and PBS-treated mice displayed similar [11C]PiB binding. Moreover, the total Aß1-40 levels, representing the major Aß species of plaques in the tg-ArcSwe model, as well as soluble triggering receptor on myeloid cells 2 (sTREM2) levels, were similar in both groups. Interestingly, the concentration of soluble Aß aggregates was decreased in the RmAb158-treated group, along with a small but significant decrease in the total Aß1-42 levels. In conclusion, this study indicates that the binding of [11C]PiB to Aß accurately mirrors the load of Aß plaques in the brain, aligning with how amyloid-PET is interpreted in clinical studies of anti-Aß antibodies. However, early treatment effects on soluble Aß aggregates and Aß1-42 levels were not detected.

Assessing volumetric brain differences in migraine and depression patients: a UK Biobank study.

BACKGROUND: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls. METHODS: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume. RESULTS: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm3, 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm3, 95% CI [-7, 100]) and gray matter (mean difference: 49 mm3, 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm3, 95% CI [-7, 40]). CONCLUSION: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.

Ketamine treatment for refractory anxiety: A systematic review.

There is a growing interest in the psychiatric properties of the dissociative anaesthetic ketamine, as single doses have been shown to have fast-acting mood-enhancing and anxiolytic effects, which persist for up to a week after the main psychoactive symptoms have diminished. Therefore, ketamine poses potential beneficial effects in patients with refractory anxiety disorders, where other conventional anxiolytics have been ineffective. Ketamine is a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor, which underlies its induction of pain relief and anaesthesia. However, the role of NMDA receptors in anxiety reduction is still relatively unknown. To fill this paucity in the literature, this systematic review assesses the evidence that ketamine significantly reduces refractory anxiety and discusses to what extent this may be mediated by NMDA receptor antagonism and other receptors. We highlight the temporary nature of the anxiolytic effects and discuss the high discrepancy among the study designs regarding many fundamental factors such as administration routes, complementary treatments and other treatments.

Phonological working memory is adversely affected in adults with anorexia nervosa: a systematic literature review.

PURPOSE: Cognitive restraint has potentiating and deleterious effects on working memory (WM) in anorexia nervosa (AN). Conflicting evidence may be due to heterogeneity of tasks examining different WM components (e.g., verbal/auditory versus visuospatial), and differences in adolescent versus adult AN. Additionally, differential cognitive profiles of restricting versus binge/purging subtypes, comorbid psychiatric disorders and psychotropic medication use may confound findings. METHODS: To address these conflicts, 25 studies, published between 2016 and 2021, investigating WM in children, adolescents and adults with AN were systematically reviewed using PRISMA guidelines. RESULTS: In 71% of WM tasks, no difference in performance between AN patients and age-matched controls was reported, while 29% of WM tasks showed worse performance. Adults with AN displayed deficits in 44% of the verbal/auditory tasks, while performance remained unaffected in 86% of visuospatial tasks. CONCLUSION: Examining age groups and WM subsystems separately revealed novel findings of differentially affected WM components in AN. Comorbidities and psychotropic medications were common among AN participants and should be regarded as critical confounding factors for WM measures. Future studies examining different components of WM, acknowledging these confounding factors, may reveal specific deficits in AN to aid treatment improvement strategies. LEVEL OF EVIDENCE: I, systematic review.

Heritable natural variation of light/dark preference in an outbred zebrafish population.

Anxiety is a fear-like response to stimuli perceived to be threatening. Excessive or uncontrollable anxiety is a debilitating psychiatric disorder which affects many people throughout their lifetime. In unravelling the complex genetic and environmental regulations of anxiety-like phenotypes, models measuring the natural dark avoidance of larval zebrafish have shed light on the individual variation and heritability of this anxiety-related trait. Using the light/dark choice paradigm and selective breeding, this study aims to validate previous findings of the variable (VDA) and strong dark aversion (SDA) heritability in AB-WT larval zebrafish using the outbred zebrafish strain EK, which offers more genetic diversity to aid in future molecular mapping efforts. 190 larvae (6 days post fertilization [dpf] and 7 dpf) were tested across four trials and divided into variable (VDA), medium (MDA) and strong (SDA) dark aversion for further in-crosses. VDA and MDA larvae became more explorative with time, whereas SDA larvae rarely left the preferred light zone. The SDA and VDA in-crosses significantly increased the respective phenotypes in the second generation of larvae, whereas VDA × MDA inter-crosses did not. For the second-generation SDA cohort, dark aversion correlated with increased thigmotaxis, which reinforces SDA as an anxiety-like phenotype. Our finding that the dark aversion trait and SDA and VDA phenotypes are heritable in an outbred zebrafish population lays an important foundation for future studies of genetic underpinnings using whole-genome mapping methods. This conserved fear/anxiety-like response in a highly accessible model organism also allows for further pharmacological and behavioral studies to elucidate the etiology of anxiety and the search for novel therapeutics for anxiety disorders.

Job satisfaction has differential associations with delay discounting and risk-taking.

Low job satisfaction has been associated with both negative health and negative organizational outcomes. Knowledge on which factors influence job satisfaction remains limited. This study assesses the associations between job satisfaction and three personality traits related to cognitive- and inhibitory control: delay discounting, risk-taking and sensation seeking (DRS-traits). Delay discounting and sensation seeking were inferred using self-reported behavioral data and health measurements for 80,676 participants in the UK Biobank. Multiple linear regression analysis produced beta coefficients and confidence intervals for each DRS-trait and job satisfaction. Analyses were adjusted for age, socioeconomic status and sleep quality. A combination of the three DRS-traits (CDRS) was assessed as well. Delay discounting and risk-taking were associated with, respectively, lower and higher job satisfaction in both sexes. Sensation seeking had no significant association with job satisfaction for either sex. The combined score, CDRS, was only negatively associated with job satisfaction in females but not in males. We discuss that the negative association between delay discounting and job satisfaction may be due to career related delay discounting effects, but also highlight that low job satisfaction itself may also lead to increased delay discounting. Additionally, we discuss why increased risk-taking behavior may have a positive effect on job satisfaction.

The influence of personality on the risk of myocardial infarction in UK Biobank cohort.

Personality is a strong determinant for several health-related behaviours and has been linked to the development of cardiovascular diseases. However, the reports of personality's mediating role have been inconsistent with no data available from large population-based cohorts. The study aimed to create proxies for the Big Five personality traits, extraversion, agreeableness, conscientiousness, openness and neuroticism, to examine the longitudinal relationship between personality and myocardial infarction in the UK Biobank. The study sample comprised of 484,205 participants (55% female, 45% male, mean age 56.4 ± 8.1 years) from UK Biobank cohort with a mean follow-up of 7 years. The personality proxies sociability, warmth, diligence, curiosity and nervousness were created using self-reported data on psychological factors, mental health and social support, to match the facets of the Big Five traits. As neuroticism is the only Big Five personality trait available in the UK Biobank, it was included to validate the personality proxies. Myocardial infarction outcome information was collected from hospital records, death registries or was self-reported. Logistic regression and Cox proportional hazard regression were used to estimate odds ratio (OR) and hazard ratios (HR), respectively with 95% confidence intervals (CI) adjusted for demographics (age, sex, socioeconomic status, ethnicity), health-related factors (BMI, diabetes, systolic and diastolic blood pressure) and lifestyle factors (alcohol intake, smoking, and moderate-to-vigorous physical activity). Diligence was found to be significantly associated with lower prevalent myocardial infarction [OR: 0.87; (CI 0.84-0.89)] and lower incident myocardial infarction [HR: 0.88; (CI 0.85-0.92)]. Sociability was also protective against prevalent [OR: 0.89; (CI 0.87-0.92)] and incident [HR: 0.90; (CI 0.87-0.93)] myocardial infarction. Conversely, nervousness inferred a higher risk for both prevalent [OR: 1.10; (CI 1.08-1.12)] and incident [HR: 1.07; (CI 1.04-1.09)] myocardial infarction during follow-up. Sex-stratified analyses revealed that nervousness significantly increases the risk for incident myocardial infarction among women [HR: 1.13; (CI 1.08-1.19)] compared to men [HR: 1.05; (CI 1.02-1.08)]. By using our created proxies, we were able to investigate the impact of personality on the development of myocardial infarction. Persons with higher levels of diligence and sociability mimicking predominantly conscientiousness and extraversion personalities respectively are less likely to experience myocardial infarction, while personalities predominantly characterised by nervousness pose higher risk for developing myocardial infarction. These initial findings invite further validation of the use of the personality proxies in UK Biobank cohort.

Subliminal Emotional Faces Elicit Predominantly Right-Lateralized Amygdala Activation: A Systematic Meta-Analysis of fMRI Studies.

Prior research suggests that conscious face processing occurs preferentially in right hemisphere occipito-parietal regions. However, less is known about brain regions associated with non-conscious processing of faces, and whether a right-hemispheric dominance persists in line with specific affective responses. We aim to review the neural responses systematically, quantitatively, and qualitatively underlying subliminal face processing. PubMed was searched for Functional Magnetic Resonance Imaging (fMRI) publications assessing subliminal emotional face stimuli up to March 2022. Activation Likelihood Estimation (ALE) meta-analyses and narrative reviews were conducted on all studies that met ALE requirements. Risk of bias was assessed using the AXIS tool. In a meta-analysis of all 22 eligible studies (merging clinical and non-clinical populations, whole brain and region of interest analyses), bilateral amygdala activation was reported in the left (x = -19.2, y = 1.5, z = -17.1) in 59% of studies, and in the right (x = 24.4, y = -1.7, z = -17.4) in 68% of studies. In a second meta-analysis of non-clinical participants only (n = 18), bilateral amygdala was again reported in the left (x = -18, y = 3.9, z = -18.4) and right (x = 22.8, y = -0.9, z = -17.4) in 56% of studies for both clusters. In a final meta-analysis of whole-brain studies only (n=14), bilateral amygdala was also reported in the left (x = -20.2, y = 2.9, z = -17.2) in 64% of studies, and right (x = 24.2, y = -0.7, z = -17.8) in 71% of studies. The findings suggest that non-consciously detected emotional faces may influence amygdala activation, especially right-lateralized (a higher percentage of convergence in studies), which are integral for pre-conscious affect and long-term memory processing.

Association of Diligence and Sociability with Stroke: A UK Biobank Study on Personality Proxies.

BACKGROUND: There is a growing interest in how personality may be related to the risk of developing disease. Associations between personality and stroke have so far only been studied in relation to stroke mortality. However, many stroke survivors suffer severe impairment of quality of life due to sequelae such as aphasia, hemiparesis, depression and anxiety. In this study we assess the association between personality and risk of stroke, regardless of mortality. METHODS: Using self-reported data on psychological factors, mental health and social support, proxies for the Big Five personality traits were developed for 482,535 participants in the UK Biobank. Logistic regression and Cox proportional hazard models, with 95% confidence intervals (CI), were used to estimate odds ratios (OR) and hazard ratios (HR) between each personality trait and stroke prevalence (N = 6793) and incidence (N = 3312), respectively. Models were adjusted for demographic, health-related, and lifestyle factors. RESULTS: Diligence and sociability were associated with a lower risk of stroke incidence in the fully adjusted model (respectively: [HR = 0.92; 95% CI = (0.88, 0.96)], [HR = 0.93; 95% CI = (0.89, 0.97)]). However, nervousness, curiosity and warmth were not significantly associated with a risk of stroke incidence. CONCLUSIONS: Individuals with higher levels of diligence and sociability may be at a reduced risk of developing stroke. With respect to the debated role of neuroticism in relation to cardiovascular disease, we did not find evidence of an association between nervousness and risk of developing stroke.

Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4).

Compounds that contain (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid substituted with bicyclic amino moiety (2-aza-bicyclo[2.2.1]heptane) were designed using molecular modelling methods, synthesised, and found to be potent DPP-4 (dipeptidyl peptidase-4) inhibitors. Compound 12a (IC50 = 16.8 ± 2.2 nM), named neogliptin, is a more potent DPP-4 inhibitor than vildagliptin and sitagliptin. Neogliptin interacts with key DPP-4 residues in the active site and has pharmacophore parameters similar to vildagliptin and sitagliptin. It was found to have a low cardiotoxic effect compared to sitagliptin, and it is superior to vildagliptin in terms of ADME properties. Moreover, compound 12a is stable in aqueous solutions due to its low intramolecular cyclisation potential. These findings suggest that compound 12a has unique properties and can act as a template for further type 2 diabetes mellitus drug development.

THC-induced behavioral stereotypy in zebrafish as a model of psychosis-like behavior.

High doses of the Cannabis constituent Δ9-tetrahydrocannabinol (THC) increase the risk of psychosis in humans. Highly accessible animal models are needed to address underlying mechanisms. Using zebrafish with a conserved endocannabinoid system, this study investigates the acute effects of THC on adult zebrafish behavior and the mechanisms involved. A concentration-dependent THC-induced behavioral stereotypy akin to THC's effect in rats and the psychotropics phencyclidine and ketamine in zebrafish was established. Distinctive circular swimming during THC-exposure was measured using a novel analytical method that we developed, which detected an elevated Repetition Index (RI) compared to vehicle controls. This was reduced upon co-administration of N-methyl-D-aspartate (NMDA) receptor agonist NMDA, suggesting that THC exerts its effects via biochemical or neurobiological mechanisms associated with NMDA receptor antagonism. Co-treatment of γ-aminobutyric acid receptor antagonist pentylenetetrazol also showed signs of reducing the RI. Since THC-induced repetitive behavior remained in co-administrations with cannabinoid receptor 1 inverse agonist AM251, the phenotype may be cannabinoid receptor 1-independent. Conversely, the inverse cannabinoid receptor 2 agonist AM630 significantly reduced THC-induced behavioral stereotypy, indicating cannabinoid receptor 2 as a possible mediator. A significant reduction of the THC-RI was also observed by the antipsychotic sulpiride. Together, these findings highlight this model's potential for elucidating the mechanistic relationship between Cannabis and psychosis.

Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales.

Type 2 diabetes mellitus (T2DM) continues to be a substantial medical problem due to its increasing global prevalence and because chronic hyperglycemic states are closely linked with obesity, liver disease and several cardiovascular diseases. Since the early discovery of insulin, numerous antihyperglycemic drug therapies to treat diabetes have been approved, and also discontinued, by the United States Food and Drug Administration (FDA). To provide an up-to-date account of the current trends of antidiabetic pharmaceuticals, this review offers a comprehensive analysis of the main classes of antihyperglycemic compounds and their mechanisms: insulin types, biguanides, sulfonylureas, meglitinides (glinides), alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZD), incretin-dependent therapies, sodium-glucose cotransporter type 2 (SGLT2) inhibitors and combinations thereof. The number of therapeutic alternatives to treat T2DM are increasing and now there are nearly 60 drugs approved by the FDA. Beyond this there are nearly 100 additional antidiabetic agents being evaluated in clinical trials. In addition to the standard treatments of insulin therapy and metformin, there are new drug combinations, e.g., containing metformin, SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors, that have gained substantial use during the last decade. Furthermore, there are several interesting alternatives, such as lobeglitazone, efpeglenatide and tirzepatide, in ongoing clinical trials. Modern drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, DPP4 inhibitors and SGLT2 inhibitors have gained popularity on the pharmaceutical market, while less expensive over the counter alternatives are increasing in developing economies. The large heterogeneity of T2DM is also creating a push towards more personalized and accessible treatments. We describe several interesting alternatives in ongoing clinical trials, which may help to achieve this in the near future.