BackgroundSemaglutide is a glucagon-like peptide-1 analog that is on the market to treat type 2 diabetes and weight loss (Ozempic, Wegovy). Two phase 3 clinical trials have been conducted, Evoke and Evoke+, testing the drug in patients with Alzheimer's disease. The trial management presented results of the intermediate readout at week 104 of the CDR-SB scores, which were negative. On the basis of that, the management decided to declare the trials a failure. However, data from week 130 and 156 had not been statistically analyzed.ObjectiveWhen evaluating time points 130 and 156, several results show a separation between drug group and placebo group with semaglutide showing better results.MethodsUsing the means, converting the SEMs to SDs and numbers of patients per group, I analyzed the results using the Welch T-test (two-tailed), which does not assume equal SD.ResultsThe ADCS-ADL-MCI test, Evoke trial, week 130, did show a significant difference, p = 0.0039. Other test such as the ADAS-cog-13 results show trends towards improvement by semaglutide at week 156. Cerebrospinal fluid biomarker analyses showed significant differences in some AD markers, too.ConclusionsThe results did show some limited drug effects at later time points of the trials. However, Semaglutide has been designed to stay in the blood for a long time and therefore does not cross the blood-brain barrier readily. Novel GLP-1 type drugs that can cross the blood-brain barrier easily may show superior protective effects in AD patients.

BackgroundAuricular transcutaneous vagus nerve stimulation (atVNS) has been proposed as a non-invasive neuromodulation approach for cognitive disorders, including Alzheimer's disease (AD). Sleep represents a physiological state characterized by enhanced vagal activity and memory consolidation, making it a potentially optimal window for stimulation.ObjectiveTo investigate the cognitive effects of nocturnal atVNS in individuals diagnosed with mild cognitive impairment (MCI) and AD.MethodsParticipants underwent nightly atVNS using a Vguard device, specifically designed for non-invasive stimulation during sleep. Cognitive performance was evaluated using four standardized neuropsychological instruments, including the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog).ResultsRepeated nocturnal atVNS over several months was associated with significant improvements in global cognitive function. Among the administered tests, the ADAS-Cog demonstrated the greatest sensitivity in detecting stimulation-related changes.ConclusionsNocturnal atVNS may constitute a promising therapeutic strategy for enhancing cognition in patients with MCI and AD. By leveraging sleep-related vagal activity, this approach could potentially delay or prevent the progression of MCI to AD and dementia.

BackgroundPerioperative neurocognitive disorders (PND) encompass delayed neurocognitive recovery (dNCR; ≤30 days) and postoperative neurocognitive disorder (NCD; >30 days). While the HMGB1-TLR4/NF-κB axis drives acute neuroinflammation, the temporal dynamics of this signaling beyond the acute phase and distinct contributions of HMGB1 versus TLR4 to dNCR-to-NCD transition remain elusive. This study investigated whether glycyrrhizin attenuates sevoflurane-surgery-induced recognition memory deficit via modulation of HMGB1-TLR4 signaling.MethodsEight-month-old male C57BL/6J mice underwent right common carotid artery dissection under prolonged sevoflurane anesthesia (3%, 2 h) with or without glycyrrhizin pretreatment (30 mg/kg, i.p., 1 h preoperatively; n = 15/group for Batch 1, n = 7/group for Batch 2). Cognitive function was assessed via open field, novel object recognition, Y-maze, and Morris water maze. Hippocampal neuroinflammation (cytokines, microglia/astrocyte activation), HMGB1-TLR4-NF-κB signaling, synaptic proteins (synaptophysin, PSD-95), and histological alterations (Nissl staining) were evaluated at postoperative day 7 and day 20.ResultsProlonged sevoflurane exposure combined with surgical trauma induced recognition memory impairment and reduced platform crossings in the Morris water maze, both attenuated by glycyrrhizin. While peripheral IL-6 normalized by day 7, hippocampal cytokines (IL-6, IL-1β, TNF-α) and glial activation persisted through day 20. At the molecular level, HMGB1 was elevated at day 7 but normalized by day 20, whereas TLR4/NF-κB remained elevated at both time points; glycyrrhizin suppressed this cascade. Synaptic proteins were reduced and CA3/dentate gyrus exhibited Nissl staining reductions at days 7 and 20, protected by glycyrrhizin, whereas CA1 Nissl staining showed no significant alterations at either time point.ConclusionsThese findings demonstrate a temporal dissociation between HMGB1 normalization and sustained TLR4/NF-κB activation following sevoflurane-surgery in middle-aged mice. Prophylactic glycyrrhizin attenuates recognition memory deficits and suppresses hippocampal neuroinflammation, though mechanistic inferences remain speculative and require rigorous validation.

The condensed form of the neural extracellular matrix (ECM), known as perineuronal nets (PNNs), is predominantly associated with parvalbumin-expressing (PV+) interneurons in the cortex and hippocampus. PNNs are enriched in lecticans, including neurocan (Ncan). Genetic variation in the human Ncan gene has been linked to alterations in hippocampus-dependent memory, structural differences in the prefrontal cortex (PFC), and increased risk for schizophrenia and bipolar disorder. However, the specific contribution of Ncan to PFC-dependent cognitive functions and synaptic organization remains incompletely understood. Here, we investigated the consequences of region-specific reduction of Ncan in the infralimbic cortex of mice, a region considered homologous to the dorsomedial part of the human medial PFC. Using intracortical adeno-associated virus delivery of shRNA targeting Ncan, we examined PNN-associated markers, synaptic organization, and PFC-dependent behaviors. Ncan knockdown was associated with reduced Wisteria floribunda agglutinin (WFA) labeling of PNNs surrounding PV+ interneurons, suggesting alterations in PNN composition. Behaviorally, mice with reduced Ncan expression exhibited mild but consistent impairments in medial PFC-dependent temporal order recognition memory and in aspects of reversal spatial learning in a labyrinth task. At the cellular level, immunohistochemical analyses revealed a reduction in markers associated with perisomatic GABAergic innervation of PV+ interneurons, together with an increase in the density of vGLUT1-immunopositive puncta in the surrounding neuropil. These structural changes were not observed in constitutive Ncan knockout mice, suggesting the presence of compensatory mechanisms in this model. Together, our findings highlight a functional role of Ncan in supporting perisomatic GABAergic innervation, temporal order recognition memory and cognitive flexibility, important cognitive resources impaired in neuropsychiatric disorders.

In mammals, slow-wave sleep is characterized by synchronized neuronal activity that alternates between on and off periods. Slow-wave activity (SWA) and synchrony reflect sleep need, are correlated with synaptic strength in cortical circuits and promote synaptic downselection and memory consolidation. Here we assessed whether these core benefits of sleep can be obtained during waking. We locally induced alternating on/off periods during wakefulness using optogenetics in mice. This led to a local ipsilateral reduction in SWA and synchrony during subsequent sleep, and to reduced markers of synaptic strength. Moreover, bilateral induction of off periods over sensorimotor cortex during sleep deprivation restored memory consolidation. Thus, inducing on/off activity during wakefulness is sufficient to reduce local sleep need and fulfill core functions of sleep.

We employ the Hamiltonian Monte Carlo (HMC) algorithm to estimate model parameters and quantify their uncertainties in a fractional-order lumped-element model of the human ear in a Bayesian inference framework. The model, originally developed by Naghibolhosseini and Long (2018), incorporates fractional-order elements to capture viscoelastic memory effects in ear tissues that otherwise cannot adequately be represented via conventional integer-order models. Using previously optimized model parameters to construct informative priors, we perform Bayesian parameter estimation via the No-U-Turn Sampler (NUTS) implementation. From the inferred posterior distributions, we compute the model's outer-middle ear gain (OMEG) and validate predictions against experimental OMEG derived from DPOAE measurements. Additionally, we compare stapes velocity transfer functions and ear canal pressure gain with established experimental and computational literature. HMC sampling yields well-convergent posterior distributions for all parameters, centered near original optimized values with uncertainty quantified through credible intervals. The posterior predictive OMEG frequency response closely matches the experimental OMEG measurements. Interestingly, the Bayesian-derived parameter sets correctly exhibit stapes velocity resonances near 1 kHz and ear canal pressure gain peaks between 2.5 and 4 kHz, with amplification ranging from 4 to 12 dB, consistent with cadaveric experimental measurements and existing computational models. The model demonstrates a minimal intersubject variability while capturing realistic biological variations within experimentally reported ranges. The present Bayesian HMC simulation approach then provides a robust uncertainty quantification for fractional-order ear model parameter inference, maintaining physiologically consistent predictions across multiple validation datasets. Hence, the proposed framework enhances the model's credibility by establishing a firm foundation for further developing probabilistic diagnostic tools for hearing assessment in the future.

Depression and mood dysregulation are among the most prevalent and clinically consequential neuropsychiatric symptoms (NCD-NPS) across the spectrum of neurocognitive disorders (NCD). These symptoms impair quality of life, increase carer burden, and are associated with accelerated functional and cognitive decline. At the same time, major depressive disorder across the lifespan represents a potentially modifiable risk factor for later-life dementia, while late-onset depressive symptoms may signal prodromal neurodegeneration. This dual role positions depression at a critical intersection between symptom management and dementia prevention. This International Psychogeriatric Association (IPA) white paper was developed through expert consensus meetings held in Buenos Aires (2024) and Kanazawa (2025) to identify key knowledge gaps and define global priorities in nomenclature, biomarkers, treatment, and prevention. Current diagnostic frameworks inadequately capture dementia-specific depressive phenotypes and the marked heterogeneity of depression in NCD, including variation by disease stage, dementia subtype, symptom profile, apathy overlap, sleep and circadian disruption, exposomic risk, caregiver context, and treatment response. Although advances in neuroimaging, inflammatory markers, molecular biomarkers, digital phenotyping, and life-course risk assessment offer promise, none are yet validated for routine diagnostic stratification or treatment selection. Pharmacologic therapies demonstrate modest and inconsistent efficacy, and no agent is specifically approved for depression comorbid with dementia. Psychosocial, behavioral, caregiver-inclusive, sleep-focused, and multimodal interventions remain essential but require greater scalability and integration into care systems. The IPA Depression Workgroup proposes a next-decade roadmap emphasizing NCD-specific diagnostic criteria, biomarker-informed and exposome-aware subtyping, development of targeted and scalable interventions, routine attention to sleep health and caregiver context, and integration of depression prevention into brain health and NCD care frameworks to advance precision psychiatry and dementia risk reduction.

Down syndrome results from the triplication of human chromosome 21 and is the leading cause of intellectual disability. Down syndrome cell adhesion molecule (DSCAM) is located on human chromosome 21 and is overproduced in Down syndrome. DSCAM is a homophilic cell adhesion molecule, a receptor for netrin-1, and plays a critical role in neural wiring during brain development. Using a Dscam gain-of-function mouse model and human induced pluripotent stem cell-derived cortical neurons, in combination with cellular, molecular, and behavioral approaches, this study aims to understand how DSCAM triplication and its subsequent excessive production contribute to changes in neural development and intellectual disability in Down syndrome. Analysis of morphological parameters revealed impaired neuronal development and loss of netrin-1-mediated axon guidance in mouse hippocampal pyramidal neurons overexpressing DSCAM. DSCAM overexpression also reduces interhemispheric connectivity in vivo. Furthermore, we find that DSCAM overexpression leads to impaired hippocampal-dependent learning and reduced anxiety in adult mice. Down syndrome human induced pluripotent stem cell-derived excitatory pyramidal neurons exhibit a similar phenotype: impaired morphological development and loss of netrin-1-mediated axon guidance. Remarkably, normalization of DSCAM in Down syndrome human induced pluripotent stem cell-derived neurons rescues many of these neuronal phenotypes, including reduced axon length and deficits in axon guidance. This study presents the first comprehensive cellular, molecular, and behavioural evidence that DSCAM is a significant contributor to multiple Down syndrome phenotypes, providing insight into a pathway for treatment. In summary, these results suggest that DSCAM plays an essential role in the development of neurons and neuronal networks, and its overproduction contributes to intellectual disability in Down syndrome.

Resilience is a poem about the unraveling of memory in Alzheimer's disease. Using medical images alongside personal encounters, it explores how physicians, patients, and families perceive memory loss differently. The poem suggests that resilience is not defeating the disease but finding meaning in its slow erasure. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Diabetes is a metabolic condition characterized by increased blood glucose levels resulting from defects in insulin secretion, utilization, or both. Sleep deprivation (SD) can alter homeostasis, while the consequences of diabetes can disrupt sleep homeostasis. These findings support the hypothesis of a bidirectional interaction between sleep homeostasis, metabolic disorders, and neurological or behavioral disorders. The present study aims to investigate the bidirectional interaction between chronic REM-SD and metabolic disorders in rats by combining assessments of affective and cognitive behaviors (anxiety, depression, and memory function), metabolic (glucose homeostasis, glucose tolerance, insulin sensitivity), oxidative, cholinergic, cytotoxic, neuroinflammatory parameters, and histopathological change in hippocampus (HP), hypothalamus (HYP), and prefrontal cortex (PFC) in male Wistar rats. Eighteen male Wistar rats were divided into three groups (CON, WP, and CSD). The REM-SD was carried out for 18 h a day (from 4:00 p.m. to 10:00 a.m.) over a period of five weeks, using the modified multi-platform method (MMPM). Glucose (ipGTT) and insulin tolerance (ipITT), corticosterone and blood hs-CRP levels were evaluated, along with affective behaviors (anxiety- and depression-like) and cognitive functions, including spatial learning, recognition memory, working memory, and long-term memory. We also measured acetylcholinesterase (AchE) activity, neurotoxicity, and oxidative stress markers, as well as histopathological changes in the HP, HYP, and PFC of male Wistar rats. The results demonstrated that chronic REM-SD induced glucose intolerance and insulin resistance, leading to hyperglycemia, which was accompanied by low-grade inflammation and activation of the HPA axis. Regarding behavioral conditions, REM-SD induced anxiety, depression, and learning and memory impairments. Specifically, in relation to the brain region, REM-SD exhibited disruption in cholinergic neurotransmission, oxidative stress balance (increase in NO, MDA, and decrease in CAT and SOD activity), and neurotoxicity (increase in LDH levels). The r-Spearman correlation analysis showed that AchE activity and memory performance were strongly correlated in sleep-deprived rats. In addition, histological examination demonstrates that chronic REM-SD induced structural atrophy, neuronal degeneration, and a marked decrease in neuronal density in the PFC, HYP, and HP, specifically in the CA3 and DG. Briefly, this finding provides novel insight into the bidirectional interplay pathway between SD and metabolic disorders, and between the mechanisms linking sleep health, diabetes, and behavioral disorders. Consequently, our future studies aim to examine the effect of pharmacological treatments and sleep recovery on biochemical and neurobiochemical parameters, cholinergic neurotransmission, and brain architecture.