This review discusses key publications in forensic neuropathology from the 2025 literature. In abusive head trauma (AHT), biomechanical models help clarify injury mechanisms, particularly the role of sagittal angular acceleration in younger infants. However, challenges remain, such as detecting subtle brainstem pathology with neuroimaging, stressing the need for prospective clinicopathological correlation. Meanwhile, understanding of chronic traumatic encephalopathy (CTE) is expanding beyond contact sports to include victims of intimate partner violence. Research on sudden unexpected death in epilepsy (SUDEP) indicates overlaps with sudden infant death syndrome (SIDS) and identifies key risk factors. At the same time, forensic neuropathology's primary role remains the exclusion of other causes of death. Artificial intelligence shows promise for analyzing radiological and histopathological data in traumatic brain injury (TBI) and epilepsy, though its adoption for routine purposes remains a distant goal. Further developments include a better understanding of the cerebellum's vulnerability to TBI, standardized postmortem MRI protocols, and the use of cerebrospinal fluid biomarkers, such as GFAP and S100B, to estimate time of death. Finally, research continues to probe the complex links between brain morphology and behavior, and recent studies of the neuropathology of alcohol use disorder have revealed microglial changes rather than overt neuronal loss.
Neuroinvasive free-living amoebae (FLA), particularly Naegleria fowleri and Acanthamoeba spp., are responsible for rare but devastating infections of the central nervous system (CNS). Approximately 480 cases of primary amoebic meningoencephalitis (PAM) and fewer than 200 well-documented cases of Acanthamoeba-associated granulomatous amoebic encephalitis (GAE) have been reported worldwide. Mortality rates frequently exceed 90%. PAM typically develops following exposure to warm freshwater contaminated with N. fowleri and progresses rapidly in otherwise healthy individuals. In contrast, GAE usually follows a more indolent course and occurs predominantly in immunocompromised hosts. Despite their distinct clinical courses, both infections are characterized by CNS invasion, amoeba-mediated tissue destruction, blood-brain barrier (BBB) disruption, and host inflammatory responses. These processes drive neuroinflammation, neuronal injury, and neurological deterioration. Early diagnosis remains challenging because clinical manifestations are nonspecific and disease progression can be either fulminant or initially subtle. Therapeutic management is hindered by poor CNS drug penetration, limited efficacy of currently available therapies, treatment-related toxicity, and the absence of standardized treatment protocols or controlled clinical trials. This narrative review critically synthesizes current evidence on CNS invasion, neuroinflammation, neuropathology, diagnostic challenges, and therapeutic strategies in neuroinvasive FLA infections. It also highlights key translational priorities, including earlier diagnosis, standardized treatment protocols, stronger clinical evidence, and improved CNS-targeted drug delivery.
Medulloblastoma in infants (iMB; aged < 5 years) presents the challenge of achieving cure while minimising deleterious cranio-spinal irradiation (CSI)-associated late-effects. Non-randomised phase 2 studies have examined upfront CSI omission and chemotherapy intensification for favourable-risk desmoplastic/nodular (DN) tumours associated with the sonic hedgehog (SHH) molecular group (iMBSHH). Comparison of these therapies in large molecularly defined iMBSHH cohorts, alongside investigations of prognostic biomarkers in therapy-specific context, is urgently required to define future therapeutic strategies. In this international retrospective cohort study, a multi-national cohort of molecularly and clinically annotated iMBSHH was assembled from patient datasets in nine countries. Inclusion criteria was a principal iMBSHH group classification using DNA methylation array-based classification. Patient cohorts were assigned into upfront treatment groups based on the receipt of radiotherapy (RTx) or chemotherapy (CTx)-only. Upfront RTx treatment groups were assigned as those receiving focal-RTx or CSI. Upfront CTx only regimens used were classified into three groups to reflect disease treatment conventions: standard-dose, high-dose (intensified regimens of sufficient dosage to require stem cell support) and those including intraventricular methotrexate (IVT-MTX). We investigated molecular pathology, upfront treatments, and relationships to outcome, in this real-world setting. Outcomes of interest were progression-free survival (PFS), overall survival (OS), and post-relapse survival (PRS). Between January 20, 2018 and October 6, 2021, patient data from 267 infants with SHH medulloblastoma were collected from Canada (n = 74), Germany/USA (n = 67), and the UK (n = 54), alongside national cohorts collected from France (n = 26), Italy (n = 4), Japan (n = 20), the Netherlands (n = 11), and Spain (n = 33). 226 patients with PFS and OS data comprised the iMB survival cohort and were split into upfront treatment groups based on the receipt of RTx (n = 74, 33%) or CTx-only (n = 132, 58%). Among iMBSHH patients treated upfront with CTx-only regimens, IVT-MTX therapy (5-year PFS, 72.6%; n = 72) or high-dose therapy (73.0%; n = 29) achieved PFS outcomes comparable to upfront CSI-based regimens (n = 49; 74.0%; p = 0.51); whereas lower-intensity, standard-dose, chemotherapy-only regimens (n = 31) were inferior (48.4% PFS; p = 0.006). Rescue was common post-relapse after IVT-MTX/high-dose protocols and translated into 5-year OS of 85.6% and 88.6%, respectively. However, information on pattern of relapse and treatments received at recurrence was only available for a small proportion of our cohort (n = 43). The 5-year PFS of patients receiving focal-RTx was (58.2%; n = 25). iMBSHH encompassed SHH-1 (38%), SHH-2 (47%) and SHH-3 (14%) WHO subgroups. In CSI-naïve iMBSHH, standard-dose chemotherapy was associated with worse PFS in SHH-1 (p = 0.001), but not SHH-2. Non-DN/MBEN histology (21.2% of iMBSHH) conferred worse PFS in the upfront CSI-treated and standard-dose (p < 0.001 and p = 0.003, respectively) groups. Metastatic disease only associated with prognosis with upfront IVT-MTX-only therapies (p = 0.013), while established high-risk features of non-infant MBSHH (TP53-mutation, LCA-histology, MYCN-amplification) only associated with poor prognosis in older SHH-3 (7/7 relapsed). Finally, CSI-naïve PFS findings were validated in a re-evaluation of smaller historical trials cohorts. Our findings show that iMBSHH outcomes and prognostic biomarkers are therapy dependent. In our retrospective patient group, non-metastatic iMBSHH treated with high-dose or IVT-MTX chemotherapy-only had equivalent favourable outcomes, independent of histology and subgroup. With outcomes established, clinical trials are now encouraged to focus on quality-of-life following different intensified approaches to identify the kindest curative strategies. Cancer Research UK, Children with Cancer UK, Children's Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero and Blue Skye Thinking.
Tissue-resident memory T cells (TRM) are a distinct subset of memory T cells that persist long-term within non-lymphoid tissues and provide rapid, localized immune protection. The central nervous system (CNS) was among the first sites in which these TRM were detected, but only recently has their importance in brain immune surveillance been fully appreciated. Despite their relative low abundance, brain TRM can protect against reinfection, contribute to neuropathology, and participate in neurologic diseases. This review provides an overview of what is currently known about TRM in the brain, with a focus on CD8+ T cells, identifies major knowledge gaps, and highlights implications for human brain TRM biology. Addressing these gaps will help contextualize brain TRM in health and disease and guide strategies to harness or modulate them for vaccination and neuroimmune therapies.
Infant medulloblastoma (age <3-5 years at diagnosis) is a major challenge in paediatric oncology. Clinical studies of molecularly defined non-WNT/non-SHH infant medulloblastoma (~60% of cases) have not been done, and this group is currently considered to have uniformly high risk. Understanding the potential for its biological subclassification and clinical stratification is an essential goal towards improved outcomes. This study therefore aimed to directly compare different therapeutic approaches in non-WNT/non-SHH infant medulloblastoma and assess the relationships between outcomes and clinicomolecular features. We assembled an international cohort of infants with non-WNT/non-SHH medulloblastoma identified from non-trial cohorts in nine countries. Inclusion criteria were age 0-5 years and a principal non-WNT/non-SHH medulloblastoma classification (group 3 [MBGroup3] or group 4 [MBGroup4]; confidence score >0·8) using DNA methylation array-based classification. Patient clinical and molecular data were collected from contributing institutions and centrally reviewed using standardised annotation protocols. A survival cohort was defined by the availability of complete progression-free and overall survival data, and grouped by whether principal upfront therapy included craniospinal irradiation or consisted of chemotherapy only. Chemotherapy was subclassified into high-dose, intraventricular methotrexate-based, and standard-dose regimens. We assessed the relationships between tumour molecular pathology, treatments received, and outcomes (progression-free and overall survival) using Kaplan-Meier plots, univariable log-rank tests, and Cox regression. The total collected cohort (n=375) comprised 262 males and 110 females (three patients had missing sex data), with a median age of 3·0 years (IQR 2·5-4·0). MBGroup3 tumours predominated (246 [66%] of 375 patients), among which molecular subgroups 4 (98 [40%]), 2 (75 [30%]), and 3 (46 [19%]) were most common. The remaining 129 (34%) of 375 patients had MBGroup4 tumours. 313 patients were included in the survival cohort. Upfront craniospinal irradiation was associated with significantly better 5-year progression-free survival (62% [95% CI 55-70]) than non-craniospinal irradiation approaches (including focal radiotherapy or chemotherapy-only strategies; 33% [23-44]; p<0·0001). When upfront chemotherapy-only approaches were used, high-dose chemotherapy produced better survival rates (5-year overall survival 60% [95% CI 42-87]) than standard-dose chemotherapy (27% [13-57]). Patients with MBGroup3 subgroup 4 represented a novel chemosensitive group, with 5-year progression-free survival of 64% (95% CI 44-95) when treated upfront with high-dose chemotherapy only (n=14). Patients with MBGroup3 subgroup 2 or 3 with MYC amplification (n=10) had 5-year progression-free and overall survival rates of 0% when treated with chemotherapy only. Patients with MBGroup3 subgroup 2 or 3 without MYC amplification who were treated upfront with chemotherapy only (n=10) had 5-year progression-free survival of 30% (12-77) and 5-year overall survival of 58% (34-100). Non-WNT/non-SHH infant medulloblastoma outcomes are associated with specific biomarkers and type of therapy received. This real-world experience identifies a favourable-risk group (MBGroup3 subgroup 4) with good prognosis and a very-high-risk group (MBGroup3 subgroup 2 or 3 with MYC amplification) with poor prognosis, providing a foundation for biomarker-driven MBGroup3 clinical trials. Cancer Research UK, Children with Cancer UK, Children's Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero, and Blue Skye Thinking.
Balancing seizure outcomes and cognitive deficits is always a challenge in both mesial and neocortical temporal lobe epilepsy cohorts. The present study evaluated the long-term seizure outcomes and perceived quality of life (QOL) in both of these groups, along with factors predictive of these outcomes. A retrospective analysis of patients undergoing temporal lobe epilepsy (TLE) surgery from 2015 to 2023, with at least 1 year of follow-up (N = 175), is presented. Patients were grouped as MTLE (mesial temporal sclerosis only) and NTLE (neocortical) based on neuroimaging. Surgical approaches included standard anterior temporal lobectomy with amygdalohippocampectomy (ATL + AH) and hippocampal-sparing resections. Seizure outcomes were classified using Engel's scale; QOL was assessed telephonically using a questionnaire adopted from QOLIE-10-P. Predictors for seizure freedom and perceived QOL outcomes were studied in both groups. At a mean follow-up of 55 months, 83.5% of patients achieved seizure freedom, MTLE (85%), and NTLE (81%) patients. Of the entire TLE cohort, 38% were free from drugs at the last follow-up. In MTLE, the presence of red flags significantly lowers the chances of complete seizure freedom (59% vs. 93%.) (OR 0.11, 95% CI 0.03-0.37; p < 0.001). Preserving the hippocampus in NTLE is associated with a lower the seizure freedom rate (68% vs. 86%) (OR 0.34, 95% CI 0.10-1.08). In NTLE, the odds of perceived memory decline were marginally higher in the standard ATL + AH group (OR 1.48, 95% CI 0.37-5.87) compared to hippocampus-preserving resection (p = 0.7). Approx. 75% patients reported improvement in all QOL parameters in the entire TLE cohort. No mortality or permanent neurological deficits recorded. TLE surgery provides robust seizure control and significant perceived QOL improvements for most patients in the long term. Hippocampal sparing surgery in NTLE did not seem to affect perceived memory difficulties but was more likely to be associated with suboptimal seizure outcomes.
Consolidation therapy for primary CNS lymphoma (PCNSL) includes high-dose chemotherapy with autologous stem-cell transplantation (HCT-ASCT), yet its efficacy compared with non-myeloablative chemoimmunotherapy remains uncertain. This study aimed to provide randomised comparative evidence on the efficacy and safety of thiotepa-based HCT-ASCT versus non-myeloablative R-DeVIC consolidation after uniform MATRix induction in newly diagnosed PCNSL. This open-label, randomised, phase 3 trial was conducted across 56 university and academic non-university hospitals with established transplantation facilities in five European countries. Eligible for inclusion were untreated, immunocompetent patients with B-cell PCNSL, aged 18-65 years regardless of Eastern Cooperative Oncology Group (ECOG) performance status, or 66-70 years with ECOG performance status 0-2. Pretreatment corticosteroids were permitted. Exclusion criteria included lymphoma manifestation outside the CNS, and congenital or acquired immunodeficiency. Patients received four cycles of MATRix induction (comprising rituximab, high-dose cytarabine, and thiotepa, in addition to high-dose methotrexate). Patients reaching at least partial response were randomly assigned (1:1) to two cycles of R-DeVIC (rituximab plus dexamethasone, etoposide, ifosfamide, and carboplatin) or HCT-ASCT with carmustine and thiotepa. The primary endpoint was progression-free survival, assessed in the full analysis set (excluding patients with major violations of entry criteria). The safety analysis set contained all randomised patients who initiated therapy. This study is registered with ClinicalTrials.gov (NCT02531841) and the EU Clinical Trials Register (EudraCT number 2012-000620-17). The study is completed. Between July 16, 2014, and Aug 31, 2019, 368 patients were enrolled. 346 (94%) patients started induction treatment, and 230 were randomly assigned; 229 patients were analysed (R-DeVIC group, n=115; HCT-ASCT group, n=114). After a median follow-up of 45·3 months, 3-year progression-free survival was significantly superior in the HCT-ASCT group (hazard ratio 0·43 [95% CI 0·27-0·68]; p=0·0003). The 3-year progression-free survival was 78% (95% CI 69-85) in the HCT-ASCT group compared with 51% (41-60) in the R-DeVIC group. The mean number of adverse events per patient was 9·3 (SD 4·4) in the R-DeVIC group and 14·6 (5·8) in the HCT-ASCT group. Fatal serious adverse events following consolidation treatment occurred in two patients in the R-DeVIC group (both acute myeloid leukaemia) and in five patients in the HCT-ASCT group (infections and infestations [n=4], pulmonary embolism [n=1]); all of these events apart from the pulmonary embolism were judged to be possibly related to treatment. In the largest randomised trial in untreated PCNSL to date, HCT-ASCT significantly improved progression-free and overall survival compared with non-myeloablative consolidation in patients who had completed induction treatment, establishing it as the preferred consolidation strategy in fit patients. German Federal Ministry of Research, Technology and Space; Swiss Cancer Research Foundation; and Riemser Pharma.
The relationship between inflammation and tumorigenesis has been widely investigated, with tumor-promoting inflammation proposed as an "enabling characteristic." However, little is known about the prognostic value of surgery-related inflammation. This study evaluates whether postoperative inflammation affects prognosis in patients operated for colorectal cancer (CRC). Consecutive patients undergoing elective minimally invasive curative surgery for stage I-III CRC between 2014 and 2022 were included. Patients were divided into two groups based on the highest C-reactive protein (CRP) value measured within 30 days from surgery. Receiver operating characteristics curve analysis identified an optimal cutoff of 151.5 mg/L (area under the curve = 0.599), defining low-CRP (L-CRP) and high-CRP (H-CRP) groups. The primary endpoint was recurrence-free survival; secondary endpoints included overall survival (OS), cancer-specific survival (CSS), and recurrence pattern. A total of 436 patients were analysed. Recurrence-free survival (p = 0.005) was significantly worse in the H-CRP group, as were OS (p < 0.001) and CSS (p = 0.001). Subgroup analysis confirmed results only in stage III. Regarding pT, no differences were found in early pT patients, while significance was maintained for pT3 and pT4. The H-CRP group showed a higher proportion of locoregional and peritoneal metastases (p = 0.018). On multivariate analysis, H-CRP was an independent risk factor for recurrence (p = 0.02), alongside rectal location (p = 0.001), lymphovascular invasion (p = 0.014), and stage III (p = 0.001). This study highlights the potential role of postoperative CRP as a negative prognostic factor for recurrence-free survival following curative resection for CRC.
Plasma phosphorylated tau217 (p-tau217) is a promising biomarker for Alzheimer's disease (AD) risk detection. Its relationship with brain microstructure and cognitive impairment remains unclear. Multi-component T2-relaxometry is an MRI technique sensitive to myelin content, axonal degeneration, and neuroinflammation. A total of 229 participants classified by p-tau217 levels into p-tau217- (n = 176), p-tau217+ (n = 26), and intermediate (n = 27) underwent neuropsychological testing and MRI. Voxel-wise general linear models controlling for age, sex, education, apolipoprotein E (APOE, and white matter lesions were performed for total water content (TWC), myelin water fraction (MWF), intra-/extracellular water fraction (IEWF), geometric mean of intra-/extracellular water (T2IE), and free/quasi-free water fraction (FQFWF). The p-tau217+ participants showed poorer cognition, increases in FQFWF and TWC, and reductions in IEWF and T2IE across cortical and subcortical regions and white matter tracts. High p-tau217 level associates with brain microstructure alterations and poorer cognition, supporting it as a biomarker of AD-related neuropathology and the utility of T2-relaxometry for detecting tissue integrity.
Prognosis in low-grade gliomas (LGGs) remains highly variable, and treatment-related late toxicity is a concern. This trial was comparing single-modality therapies in patients who often survive for years or decades and investigating differential responses according to molecular markers. Four hundred seventy-eight patients with clinical high-risk LGG (WHO grade 2) were randomly assigned to standard radiotherapy (RT; 28 × 1.8 Gy) or dose-dense temozolomide (TMZ; 75 mg/m2 once daily × 21/28 days, up to 12 cycles). There was no significant difference in progression-free survival or overall survival (OS) between study arms. Analyzable tumor tissue in 73% (351/478) of patients allowed for post hoc reclassification according to the 2021 WHO pathologic criteria. In astrocytoma, IDHmt/1p/19q noncodeleted (n = 178), median OS was similar, 6.6-6.7 years irrespective of arm (0.67-1.44, P = .93). In oligodendroglioma, IDHmt/1p/19q codeleted (n = 109), median OS was 12.9 years (9.4-not reached) with RT and 14.9 years (10.1-number of events not reached) with TMZ (hazard ratio [HR], 0.88 [0.52-1.49], P = .63). In 64 tumors without isocitrate dehydrogenase (IDH) mutations, survival favored the TMZ arm: OS 2.5 (1.8-3.3) versus 4.7 (2.2-7.2) years (HR, 0.47 [0.27-0.82], P = .0068). Patients age 40 years and older fared better than patients younger than 40 years, challenging the current notion of age alone as a negative prognostic factor. The assigned initial treatment modality did not affect progression-free survival or OS, regardless of the molecular subtype. Combined-modality therapy was not tested in this trial but has since become a standard of care for IDH-mutant astrocytoma. With emerging novel therapeutic options, rational treatment strategies tailored at the individual clinical and pathologic recurrence risk profiles will be needed. The validity of an age cutoff as prognostic factor is challenged when tumors are molecularly classified.
Synucleinopathies, including Parkinson's disease and multiple system atrophy (MSA), are neurodegenerative disorders characterized by aggregation of α-synuclein (ASN). Nanomaterials capable of modulating protein misfolding represent a potential intervention strategy. Here, we synthesized graphene quantum dots (GQDs) and systematically evaluated their physicochemical properties and biological activity against ASN aggregation. The GQDs were characterized using spectroscopic, electron microscopy, and colloidal techniques to determine surface chemistry, charge, optical properties, and crystalline structure. Biological evaluation demonstrated cytocompatibility in human dermal fibroblasts (IC5 0 = 90 µg mL-1 at 24 h) with assessments of DNA damage and inflammatory responses. Functionally, GQDs destabilized preformed ASN fibrils in a cell-free assay, as evidenced by reduced Thioflavin-T fluorescence. In primary murine dopaminergic neurons, GQDs decrease pS129-ASN inclusion formation without compromising neuronal viability. Most importantly, intranasal administration of GQDs in an MSA mouse model reduced ASN immunoreactivity in the brain. Collectively, our data indicate that the synthetized GQDs are bioactive and can modulate ASN aggregation across cell-free, neuronal, and in vivo models. Importantly, physicochemical properties govern nano - bio interactions, providing a rationale for further refinement of GQDs as a biomaterial platform for synucleinopathy-related applications. Graphene quantum dots developed in this study destabilize α-synuclein fibrils in vitro and attenuate α-synuclein pathology in a mouse model of multiple system atrophy, suggesting a promising direction for synucleinopathy research.
Multiple sclerosis (MS) is a chronic CNS disease characterized by demyelinated lesions. Gray matter lesions (GMLs) are associated with neurodegeneration and clinical disability, and normal appearing gray matter (NAGM) also shows neuropathology. The extracellular matrix (ECM) supports neuronal health, with perineuronal nets (PNNs) regulating synaptic stability. Microglia remodel the ECM by secreting matrix metalloproteinases, while ECM composition affects microglia behavior. We examined ECM composition in decellularized human control gray matter, NAGM and GML slices and investigated its effects on microglia. Label-free quantitative mass spectrometry of decellularized control gray matter and NAGM revealed differential abundances in PNN ECM components and condition-specific synaptic and basement membrane ECM components. ECM composition was similar between decellularized GMLs and perilesional gray matter. Microglia introduced to decellularized NAGM and GML slices lost IBA1 expression in half the cells, while some remaining IBA1+ microglia acquired proinflammatory marker inducible nitric oxide synthase (iNOS). These findings suggest ECM alterations in NAGM influencing microglial characteristics potentially contributing to MS pathology.
Myelin enables rapid action potential conduction and axonal support, and its disruption underlies diverse neurological disorders. Its assessment is essential for studying development, plasticity, and repair of the nervous system (NS), and for diagnosing demyelinating diseases and evaluating remyelination therapies. Multiple histological methods detect myelin, each with trade-offs in sensitivity, cost, and reproducibility. Among them, Eriochrome Cyanine R (EC-R) is a simple, affordable myelin stain widely used in thin sections, but remains poorly standardized, and underexplored in thick vibratome sections. Here we describe and validate a simple, inexpensive, solvent-free EC-R protocol for central and peripheral nervous system tissue across seven vertebrate species and multiple demyelinating conditions. The method replaces subjective microscopic differentiation with fixed, time-controlled incubations scaled to section thickness, improving reproducibility. Using perfusion and immersion-fixed samples, we show that the protocol yields homogeneous myelin labeling with sharp white/gray matter contrast in whole brains, cortical slabs, spinal cord, and peripheral nerves. Thick sections stained with EC-R preserve 3-dimensional tissue architecture, resolve single myelinated axons and intracortical bands, and can be combined with Nissl-like counterstains and immunohistochemistry. Developmental series in neonatal rats reveal expected PNS-CNS myelination gradients, while experimental demyelination models and naturally occurring diseases (canine distemper and human multiple sclerosis) illustrate the method's ability to delineate lesion cores, perilesional gradients, and associated glial and immune activation. This standardized EC-R approach provides a robust and versatile tool for comparative neuroanatomy, experimental neuropathology, and translational studies of myelination, demyelination, and remyelination, as well as for the clinical diagnosis of myelin-related disorders.
Alzheimer's disease (AD) disproportionately affects women, yet the biological basis of this sex bias remains unclear. Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomic profiling of postmortem AD tissue and APP/PS1 mice revealed preferential enrichment of interferon-responsive gene programs in females. In APP/PS1 mice, heightened interferon responses were associated with increased neurodegenerative features, and single-cell transcriptomic analyses identified microglia as a major cellular compartment engaging interferon responses. To test causality, we manipulated interferon signaling in vivo. Acute systemic interferon activation promoted AD-like neuropathological alterations. Genetic amplification of interferon signaling in microglia exacerbated neuroinflammatory and neurodegenerative features in APP/PS1 mice, whereas pharmacological inhibition through cGAS-STING blockade suppressed interferon responses, reduced neuropathology, and preserved cognitive performance in female APP/PS1 mice. Together, these findings identify microglial interferon signaling as a modifiable contributor to AD-associated neuropathology and suggest a neuroimmune mechanism underlying the increased vulnerability of females to the disease.
In most cases, routine neuropathological analysis can clearly distinguish between methylated and unmethylated MGMT promoters in glioblastoma (GBM). However, some GBMs display weak MGMT promoter methylation. This study aimed to evaluate its impact on disease progression and survival compared with fully methylated and unmethylated cases. A quantitative analysis of MGMT promoter methylation was performed on 140 of 190 samples from a cohort of adult patients with newly diagnosed GBM. The MGMT promoter was stratified into three subgroups based on methylation status: unmethylated, weakly methylated (9-28%), and methylated (29-100%). These cut-off values were selected based on previously published data demonstrating significant differences in progression-free survival (PFS) and overall survival (OS) among patients with these categories. Clinical characteristics, treatment regimens, and survival outcomes were analyzed and compared. Cox proportional hazards regression was used to evaluate the impact of MGMT methylation status on progression-free interval (PFI) and overall survival (OS). The MGMT promoter was unmethylated in 57 (40.7%) samples, methylated in 66 (47.1%) samples, and weakly methylated in 17 (12.1%) samples. Compared to patients with methylated and unmethylated MGMT promoters, the PFI of patients with weak MGMT methylation was comparable (P=0.53) and the OS was slightly longer (P=0.08). After stratification following chemoradiotherapy consisting of TMZ, patients with weakly methylated MGMT have a longer PFI. The Cox proportional hazards regression model revealed that a weakly methylated MGMT promoter was a significant risk factor for longer OS (P=0.02), while older age remained an unfavorable prognostic factor for survival (P<0.001). Weak MGMT promoter methylation may offer clinical benefits comparable to full methylation, including longer PFI and improved OS compared to unmethylated cases. This positive effect on PFI appears more pronounced in patients receiving concurrent chemoradiotherapy with TMZ. Advanced age continues to be associated with a less favorable prognosis.
Self-supervised learning (SSL) leverages vast unannotated medical datasets, yet steep technical barriers limit adoption by clinical researchers. We introduce Vision Foundry, a code-free, HIPAA-compliant platform that democratizes pre-training, adaptation, and deployment of foundational vision models. The system integrates the DINO-MX framework, abstracting distributed infrastructure complexities while implementing specialized strategies like Magnification-Aware Distillation (MAD) and Parameter-Efficient Fine-Tuning (PEFT). We validate the platform across domains, including neuropathology segmentation, lung cellularity estimation, and coronary calcium scoring. Our experiments demonstrate that models trained via Vision Foundry significantly outperform generic baselines in segmentation fidelity and regression accuracy, while exhibiting robust zero-shot generalization across imaging protocols. By bridging the gap between advanced representation learning and practical application, Vision Foundry enables domain experts to develop state-of-the-art clinical AI tools with minimal annotation overhead, shifting focus from engineering optimization to clinical discovery.
Alcoholic dementia (AlD) is a severe neurological disorder with no effective treatment. Development of pan-phosphodiesterase-4 (PDE4) inhibitors for clinical treatment of neurological conditions has been hampered by emetic side effects primarily mediated by PDE4D, one of the four subtypes of PDE4. Although PDE4A was shown to be upregulated by chronic alcohol exposure, its therapeutic relevance to AlD remains unclear. A stable mouse model of AlD was established in 3-month-old 3xTg-AD mice using a free-choice two-bottle protocol (25% alcohol) for 19 weeks. Mice received either rolipram injections for 3 weeks or PDE4A knockdown for 6 weeks. Cognitive function was assessed using the Morris water maze, novel object recognition, and Y-maze tests. Hippocampal neuropathology-including Aβ deposition, synaptic integrity, Tau phosphorylation (at Ser214/Ser404), and neuronal apoptosis-was evaluated by immunofluorescence or immunohistochemistry. Changes in key proteins of the cAMP/PKA/CREB signaling pathway were analyzed by Western blotting. This study demonstrated that selectively targeting PDE4A rescued cognitive and neuropathological deficits in a validated mouse model of AlD. Behavioral tests showed that PDE4A knockdown significantly improved spatial memory and cognition in the Morris water maze, novel object recognition, and the Y maze in the AlD mice. Pathological analysis revealed that PDE4A knockdown reduced amyloid-beta (Aβ) deposition and phosphorylated Tau levels. Furthermore, it restored synaptic integrity, as evidenced by the upregulation of PSD95 and Synaptophysin, enhanced dendritic complexity, and increased spine density, while also exerting neuroprotective effects by suppressing neuronal apoptosis in AlD mice. Mechanistically, the therapeutic benefits of PDE4A knockdown were mediated through the reactivation of the critically impaired cAMP/PKA/CREB signaling pathway, leading to elevated cAMP levels, increased PKA activity, and enhanced phosphorylation of CREB. Our findings established PDE4A as one of the key AlD pathological drivers and identified its selective inhibition as a novel and promising therapeutic strategy for AlD, offering a viable approach to circumvent the adverse effects associated with broad-spectrum PDE4 inhibition.
This study provides systematic synthesis of therapeutic effects of magnolol (MN) in preclinical Alzheimer's disease (AD) models and integrates network pharmacology with molecular dynamics (MD) simulations to predict its core targets and binding stability. Systematic literature search was conducted in PubMed, CNKI, Wanfang, and Google Scholar up to January 1, 2026 following PRISMA guidelines. Network pharmacology, molecular docking, and 100 ns MD simulations were used to identify common targets, evaluate binding affinities, and assess complex stability. Fourteen studies (seven in vivo, five in vitro, two combined) were included. MN consistently ameliorated cognitive deficits and neuropathology through antioxidant, anti-inflammatory, anti-apoptotic, and anti-acetylcholinesterase activities, while preserving mitochondrial and synaptic function. Network pharmacology identified 60 common targets; Protein-Protein Interaction (PPI) analysis revealed five hub genes: AKT1, MMP9, MMP2, ERBB2, and EGFR. Molecular docking showed binding energies below -4.0 kcal/mol for all five targets, and MD simulations confirmed stable binding, with the ERBB2-MN complex exhibiting the lowest root mean square deviation (RMSD) (1.2 Å) and favorable free energy landscape. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations further confirmed that magnolol exhibited binding affinities comparable to the reference co‑crystal ligands. Unlike prior reviews, this study uniquely combines systematic evidence synthesis with computational predictions, identifying ERBB2 as a novel stable target of MN. MN exerts anti-AD effects via multi-pathway and multi-target regulation, with computational predictions aligning with experimental evidence, supporting MN as promising lead compound for AD drug development.
Anxiety disorders are associated with disrupted amygdala connectivity; however, resting-state functional MRI studies have reported heterogeneous findings. To clarify these inconsistencies, we conducted a meta-analysis of amygdala-based connectivity studies. A systematic search of Embase, PubMed, and Web of Science was performed through December 26, 2025. Studies comparing amygdala-based whole-brain resting-state functional connectivity in patients with anxiety disorders versus healthy controls were included. Meta-analysis was conducted with the latest software - Seed-based d Mapping with Permutation of Subject Images (SDM-PSI), which employs voxel-wise tests and multiple corrections to minimize false positives. Subgroup analyses were performed to examine differences by age and hemisphere. Fifteen datasets (378 patients, 405 controls) were included. Compared to healthy controls, patients with anxiety disorders had decreased amygdala-anterior cingulate cortex (ACC, g = -0.54, 95% confidence interval [CI]: -0.73 to -0.35) connectivity and increased connectivity with the left superior temporal gyrus (g = 0.46, 95% CI: 0.27-0.65), middle temporal gyrus (g = 0.38, 95% CI: 0.19-0.57), and cuneus (g = 0.35, 95% CI: 0.17-0.53). After threshold-free cluster enhancement correction, only reduced amygdala-ACC connectivity remained significant (g = -0.54, 95% CI: -0.73 to -0.35). Subgroup analyses confirmed this effect was driven mainly by adult patients and the left amygdala. Reduced connectivity between the left amygdala and the ipsilateral ACC was the most robust neuroimaging marker of anxiety disorders, which suggests a lateralized vulnerability. By applying updated analytic methods, this study refines our understanding of the neuropathology of anxiety disorders and provides a potential primary target for biomarker development and novel interventions.
Limbic white matter (WM) abnormalities are prevalent in aging and Alzheimer's disease (AD), but genetic drivers are unclear. In 2614 older adults (mean age ± SD: 73.7 ± 9.8 years; 26% cognitively impaired) from seven harmonized cohorts enriched for cognitive impairment, we quantified free-water-corrected diffusion MRI (dMRI) metrics in seven limbic tracts. We estimated single nucleotide polymorphism (SNP) heritability, performed cohort genome-wide association studies (GWASs) with meta-analysis, evaluated shared genetic architecture and enriched pathways, and assessed AD relevance using brain RNA-seq data. Limbic WM is heritable (h2 = 0.26-0.60; pFDR < 0.05). Meta-GWAS identified six loci (p < 5 × 10- 8), including a signal implicating CDH19, an oligodendrocyte-enriched cell-adhesion gene. Additional loci were near the KC6, SENP5, RORA, FAM107B, and MIR548A1 genes. In brain tissue, RORA, FAM107B, and KC6 expression was associated with cognition and AD neuropathology. Results converged on insulin and immune biology and shared genetic architecture with lipid and cardiovascular traits. Limbic WM microstructure is genetically influenced and links oligodendrocyte and vascular-inflammatory biology to AD-relevant outcomes.