Publications

Abstract

Abstract

Abstract

Abstract

Abstract

Introduction: This study examined whether selective serotonin reuptake inhibitors (SSRIs) treatment influenced cognitive trajectory and progression to Alzheimer’s disease (AD) dementia in amnestic mild cognitive impairment (MCI) patients, stratified by AD pathology.

Methods: Four hundred fifty-seven amnestic MCI participants in the ADNI database were analyzed. AD pathology was determined by baseline amyloid beta (Aβ) and tau positron emission tomography. Kaplan-Meier survival analysis and Cox proportional hazards models evaluated MCI-to-AD progression. Linear mixed models analyzed longitudinal cognitive trajectories, amyloid accumulation, and cortical thickness.

Results: SSRI treatment showed no significant effect on AD dementia progression (hazard ratio = 1.64, 95% confidence interval: 0.61 to 4.38) or cognitive trajectories, regardless of AD pathology. No significant differences in Aβ accumulation or cortical thickness were observed between SSRI users and non-users. External validation confirmed no significant SSRI effect on AD progression or cognitive decline.

Discussion: SSRI treatment was not associated with long-term cognitive effects in amnestic MCI, irrespective of underlying AD pathology.

Highlights: SSRI treatment was not associated with long-term AD dementia risk in MCI. SSRI treatment had no impact on long-term cognitive performance changes in MCI. SSRI treatment did not affect Aβ accumulation or cortical thickness in MCI. SSRIs had no effect on MCI progression, regardless of underlying AD pathology.

Full Article: https://pubmed.ncbi.nlm.nih.gov/41292493/

Abstract

Global warming is expanding mosquito habitats and increasing mosquito-borne diseases. In tropical and sub-tropical regions, chikungunya virus (CHIKV) transmitted by Aedes mosquitoes has become a major concern due to the debilitating chronic joint disease it causes. Mosquito saliva contains bioactive factors that enhance viral infection, with sialokinin identified as a key contributor to vascular leakage and viral spread in mice. Here, we demonstrate that sialokinin binds to neurokinin receptors and restricts the activation of human myeloid cells. Mechanistically, sialokinin facilitates early viral dissemination, as evidenced by increased viral load in the contralateral footpad at 1 day post-infection, and significantly reduces circulating CD169+ monocytes while suppressing IFN-γ-producing T-cell-driven inflammation, as reflected by reduced joint footpad swelling in female CHIKV-infected mice. Clinically, patients with severe CHIKV disease exhibited higher levels of IgG antibodies against sialokinin, which correlated with higher viral loads and systemic inflammatory markers. Our findings highlight the multifaceted role of sialokinin in facilitating early viral dissemination and modulating host immunity during CHIKV infection. Given the growing threat of mosquito-borne diseases in a warming, disease-burdened world, targeting mosquito salivary factors like sialokinin could offer a novel therapeutic strategy to mitigate viral-induced inflammation and improve clinical outcomes.

Full Article: https://www.nature.com/articles/s41467-025-64468-x

Abstract

Cortical cerebral microinfarcts are associated with brain atrophy in cross-sectional studies, with further investigation using longitudinal datasets being warranted. Moreover, little is known about their combined impact on cognition. This study aimed to establish the association between cortical cerebral microinfarcts and brain volume loss over time and explore whether they synergistically contribute to cognitive decline.

A total of 475 patients, aged 72.7 ± 7.9 years, were enrolled from a memory clinic cohort, who underwent neuroimaging and neuropsychological assessments at least twice over 5 years. Cortical cerebral microinfarcts and other cerebrovascular disease were assessed using 3-T MRI. Brain volumes were calculated semi-automatically using FreeSurfer. Cognitive function was assessed using a neuropsychological test battery including six domains. Linear mixed-effect models were utilized to examine the association between cortical cerebral microinfarcts and brain volume loss and their interaction on cognitive decline. Estimated marginal means were derived to plot global cognitive trajectories.

Cortical cerebral microinfarcts were associated with a greater decrease over 2 years in total brain volume [β = −1.94 (−3.07, −0.82) at Year 2, P-interaction with time < 0.001], grey matter volume [β = −1.00 (−1.69, −0.30) at Year 2, P-interaction = 0.002] and white matter volume [β = −0.95 (−1.54, −0.35) at Year 2, P-interaction < 0.001]. Brain volume loss was more pronounced in patients with multiple microinfarcts. Patients with high brain volume loss and cortical cerebral microinfarcts, particularly multiple microinfarcts, exhibited significantly lower global cognitive scores [single microinfarct: β = −1.83 (−2.68, −0.97) at Year 5, P-interaction with time < 0.001; multiple microinfarcts: β = −3.13 (−4.21, −2.05) at Year 5, P-interaction < 0.001]. The synergistic effects were more significant in the domains of executive function, memory, language and visuospatial function. Global cognitive trajectories revealed greater cognitive decline in patients with high brain volume loss and single or multiple microinfarcts, with the latter showing the steepest slope.

This study established a longitudinal association between cortical cerebral microinfarcts and brain atrophy progression, with higher microinfarct burden associated with more pronounced brain volume loss. Furthermore, cortical cerebral microinfarcts and brain atrophy showed synergistic effects on cognitive decline. These findings highlight the importance of investigating the role of mixed pathologies in the development of cognitive impairment and dementia in future research.

Full Article: https://academic.oup.com/brain/article/148/11/3924/8232732

Abstract

Increasing evidence implicates ceramides in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH). However, the therapeutic potential of liver-targeted ceramide lowering remains unclear. In this study, we demonstrate that elevated ceramide levels in MASH patients and mouse models are closely associated with the activation of hepatic de novo ceramide synthesis. The analysis of human hepatic single-nucleus RNA sequencing (snRNA-seq) data revealed predominant up-regulation of SPTLC2, which encodes a subunit of the rate-limiting enzyme in the de novo ceramide synthesis pathway, in hepatocytes. By targeted inhibition of SPTLC2 with lipid nanoparticle–mediated siRNA delivery to hepatocytes, we reduced both hepatic and circulating ceramide levels. This intervention suppressed hepatic lipid uptake and lipogenesis, thereby alleviating MASH progression. Therapeutic efficacy was demonstrated in an 8-week methionine-choline–deficient diet-induced MASH model and validated in a 1-year choline-deficient high-fat diet–induced MASH model. Our findings highlight hepatocyte Sptlc2 as a promising therapeutic target for MASH.

Full Article: https://www.science.org/doi/10.1126/sciadv.adx2681

Abstract

Pancreatic ductal adenocarcinoma (PDAC) often metastasizes to the peritoneum and is highly resistant to treatments due to its immunosuppressive microenvironment. In this study, we evaluate the safety and efficacy of a novel therapeutic strategy that combines KRAS-targeting antisense oligonucleotides (ASOs) with immunomodulatory RNA (immRNA), a RIG-I agonist, both delivered by extracellular vesicles (EVs), in preclinical models using PDAC patient-derived organoids and mice bearing PDAC peritoneal metastasis. Our data demonstrate that the combination of KRAS ASO and immRNA synergistically activates anti-tumor immune responses. EV-mediated co-delivery of both agents significantly inhibits tumor growth, reduces peritoneal metastasis, and markedly prolongs overall survival through the induction of immunologic cancer cell death. Importantly, this combination therapy is well-tolerated in non-human primates, with no observable changes in physical condition or behavior, blood parameters, or organ histology. These findings suggest that EV-delivered KRAS ASO and immRNA is a safe and potent therapeutic approach for treating PDAC and its peritoneal metastasis, positioning it as a promising strategy for future clinical advancement.

Full Article:https://www.sciencedirect.com/science/article/pii/S016836592500851X?via%3Dihub

ABSTRACT

N-methyl-D-aspartate (NMDA) receptors mediate a slow, Ca2+-permeable component of excitatory synaptic transmis­sion in the brain and participate in neuronal development and synaptic plasticity. Most NMDA receptors are tetra­meric assemblies of two GluN1 and two GluN2 subunits encoded by five genes (GRIN1 and GRIN2A–GRIN2D), which produce GluN1 and GluN2A–GluN2D subunits. NMDA receptors that contain the GluN2B subunit have unique pharmacological properties, being inhibited by multiple structurally distinct series of biaryl compounds with high po­tency and selectivity. These agents are of considerable therapeutic interest, given the numerous roles that GluN2B-containing NMDA receptors play in normal brain function and pathological situations.
Among GluN2B-selective negative allosteric modulators, radiprodil inhibits NMDA receptors that contain GluN2B with high potency and selectivity and appears to be safe in humans. Here, we evaluate the structural determinants of radiprodil binding to the heterodimeric GluN1–GluN2B amino terminal domain by X-ray crystallography and ex­plore the molecular mechanism of inhibition. A large number of de novo variants have been identified in the GRIN gene family in patients with various neurological and neuropsychiatric conditions, including autism, intellectual dis­ability, epilepsy, language disorders and movement disorders. We show that radiprodil is an effective antagonist at >80% of human disease-associated GRIN1 and GRIN2B missense variants tested in vitro (22/27, equally or more effect­ive as wild-type receptors), including variants in the pore-forming region, linker regions and elsewhere that uniform­ly increase NMDA receptor-mediated charge transfer. We show that radiprodil blocks synaptic GluN2B receptors in brain slices acutely isolated from a knock-in mouse line harbouring the gain-of-function variant GluN2B-Ser810Arg associated with early-onset epileptic encephalopathy and intractable seizures in patients. In addition, radiprodil de­lays the onset of seizures (458 ± 90 s, versus 207 ± 23 s in the vehicle group) in response to in vivo administration of the chemoconvulsant pentylenetetrazole.
These data support the potential utility of GluN2B-selective antagonists, such as radiprodil, for clinical treatments of neurological conditions where clinical aetiologies might involve increased current mediated by GluN2B-containing NMDA receptors.

Full Article: https://doi.org/10.1093/brain/awaf355