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.
Traumatic axonal injury is a common endophenotype of traumatic brain injury (TBI) in which injury to axons is a dominant component. In previous investigations, we identified a significant reduction of white matter (WM) volume from 3 to 12 months post-injury, an increased rate of atrophy during this period associated with a longer duration of post-traumatic amnesia (PTA), widespread reductions in white-matter fractional anisotropy (FA), and elevated free-water (FW) content in a cohort of moderate-to-severe TBI patients. To provide a more comprehensive characterization of the spatiotemporal trajectory of TBI-induced WM degeneration, we have estimated the spatial distribution of WM atrophy related to the duration of PTA in the first year following moderate-to-severe TBI (msTBI) (N = 33) and examined the degree to which baseline diffusion measures of WM integrity, FW and FW-corrected fractional anisotropy (F-FA), were each associated with subsequent WM atrophy. WM atrophy was observed diffusely across the brain, with the greatest effects in the splenium of the corpus callosum, corona radiata, and brainstem. Increased atrophy in the central WM was correlated with greater duration of PTA. Finally, elevated FW volume fraction at 3 months post-injury predicted greater subsequent WM atrophy, while F-FA did not show a significant relationship. These findings suggest that early FW elevation may serve as a biomarker of progressive WM neurodegeneration following TBI, and neuroinflammatory processes may underlie this relationship. Future research should directly investigate the underlying mechanisms of FW-related neuropathology and its role in progressive neurodegeneration following msTBI.
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.
Spinal tumor surgery requires rapid tissue diagnosis to guide surgical decisions and further treatment strategies, yet current intraoperative methods are time-intensive and require specialized expertise. No AI systems exist for real-time spinal tumor classification during surgery. We developed SpineXtract, the first AI-powered system for rapid intraoperative spinal tumor diagnosis using stimulated Raman histology (SRH) - a label-free Raman spectromics imaging technique without tissue processing available during surgery. We created a transformer-based classifier optimized for spinal tissue characteristics to identify common tumor types: meningioma, schwannoma, ependymoma, and metastasis. The system was tested in an international, multicenter, simulated, single-arm study using existing SRH datasets (44 patients, 142 slide-images) from three international institutions, with final pathological diagnosis as reference standard. SpineXtract achieved a 92.9% macro-average balanced accuracy (95% CI: 85.5-98.2) within 5 minutes (tumor-specific accuracy range, 84.2-98.6%), while providing quantitative microscopic feedback for granular tissue analysis. Performance remained consistent across institutions (macro balanced accuracy 91.4-92.0%) and outperformed existing brain tumor classifiers by 15.6%. Our results demonstrate clinical applicability, enabling rapid intraoperative diagnosis with performance exceeding current methods, potentially transforming intraoperative diagnostic workflows in spinal tumor surgery.
Low grade glioma (LGG) is a disease associated with survival >10 years in most cases. Some patients, however, do not respond well to treatment and exhibit early progression as well as low overall survival. It is a challenge to identify these at-risk patients. Here, we used resting-state functional MRI (rsfMRI) to identify patients with LGG at risk for poor clinical outcome. Twenty-five patients with suspected LGG were prospectively enrolled. All patients underwent rsfMRI before any invasive procedure. Patient data was compared to a reference cohort of 1000 healthy controls to determine abnormality of functional connectivity on an individual level, resulting in a relative numerical measure called the dysconnectivity index (DCI). A median split was performed in order to divide the cohort into 2 groups with low and high DCI, respectively. Progression-free survival (PFS) as a primary outcome measure was calculated in both groups. Twelve patients were diagnosed with astrocytoma, IDH-mutated, CNS WHO grade 2, and 13 patients were diagnosed with oligodendroglioma, IDH-mutated, 1p/19q-codeleted, CNS WHO grade 2. Eight patients had tumor progression, and 2 patients died during the observation period. 1/12 patients in the low DCI group and 7/13 patients in the high DCI group had tumor progression, resulting in significantly shorter PFS for patients with high DCI (P  = 0.028). No patient in the low DCI group died while 2 patients in the high DCI group died. Malignant transformation occurred in 4 patients with high DCI and in 0 patients with low DCI. There was no statistically significant difference in age, sex, diagnosis, and RANO resect class between the 2 groups. Greater disturbance of functional connectivity at the time of diagnosis as determined by rsfMRI was associated with shorter PFS in our cohort of patients with LGG. This suggests that rsfMRI might be used to identify LGG patients who are at risk of poor clinical outcome.
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.
Bridging clinical and basic research is increasingly recognized as a priority in the epilepsy field, yet opportunities for integration remain limited by the time, space, and financial constraints of scientific meetings. To address this gap, the Research Task Force of the Young Epilepsy Section of the International League Against Epilepsy (ILAE-YES) organized a free global webinar series designed to promote translational dialogue and provide accessible research education for early-career clinicians, researchers, and physician-scientists. Based on a preliminary ILAE-YES community survey, eight topics of high interest were selected: (1) epigenetics, (2) EEG biomarkers, (3) ictogenesis, (4) thalamo-cortical network, (5) sudden unexpected death in epilepsy, (6) neurodegeneration and seizures, (7) seizure-related brain damage, and (8) neuromodulation therapy. From March to June 2025, eight live Zoom webinars were held, each featuring expert speakers representing both basic science and clinical perspectives, with recordings made available as unlisted YouTube videos to ensure on-demand access. A total of 1199 individuals from 116 countries registered, 63.2% from low- and middle-income countries. Live attendance averaged 50 participants per session, and the mean session duration was 71.6 min, including an average of 16 min of discussion. Post-session feedback was obtained from 285 respondents; overall satisfaction was high, with 93.3% rating their experience as 4 or 5 on a 5-point Likert scale. Speaker satisfaction was similarly high (95.4%), and 80.0% reported gaining new research ideas. Although access to YouTube and Google Forms may have limited participation in some regions, the series provided an inclusive and globally accessible platform. These findings demonstrated that free, discussion-focused online webinars represent a scalable, low-cost, and reproducible educational model that can effectively promote international engagement and integration between clinical and basic epilepsy research, aligning with the ILAE's global educational mission and complementing WHO IGAP priorities on capacity building and equitable access to knowledge. PLAIN LANGUAGE SUMMARY: Bringing together basic science and clinical research is important for improving epilepsy care, but many researchers have limited opportunities to learn across these fields. We organized a free global webinar series that helped early-career clinicians and researchers learn about epilepsy research by combining scientific talks with clinical perspectives and open discussion. More than 1100 participants from over 100 countries joined, and most reported high satisfaction and gaining new research ideas. These results show that free, discussion-based online webinars can provide an accessible way to support research education and international learning in epilepsy.
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.
Psychiatric disturbances are common in epilepsy and are associated with increased risk of premature mortality, lower quality of life, and poor response to antiseizure medications (ASMs). To evaluate the role of psychiatric disturbances at the time of epilepsy diagnosis in predicting risk of future treatment resistance in focal epilepsy. The Human Epilepsy Project (HEP) is a prospective, observational, international, and multicenter cohort study with follow-up for up to 6 years. Participants with newly diagnosed focal epilepsy, enrolled within 4 months of initiating ASM treatment, between the ages 18 and 60 years, and without significant other comorbidities were recruited during the open period of 2012 to 2020. Data analysis was performed from January to September 2025. Presence of a psychiatric diagnosis. Presence of psychiatric diagnosis (mood/anxiety disorders) measured by Mini International Neuropsychiatric Interview (MINI) and/or suicidality measured by Columbia-Suicide Severity Rating Scale (C-SSRS) at enrollment. Treatment response included the following outcomes: treatment resistant (TR), defined as failure of first 2 adequate ASM trials (ongoing seizures at/above therapeutic doses); treatment sensitive (TS), defined by a minimum period of seizure freedom on first 2 adequate ASM trials (12 months/3-fold greatest pretreatment seizure-free interval, whichever is longer); and indeterminate (neither TR/TS). Of 376 enrolled adults, 347 (median [IQR] age at seizure onset, 33 [23-44] years; 209 female [60.2%]) completed the MINI and C-SSRS at enrollment. Of these individuals, 191 (55%) were TS, 83 (24%) TR, and 73 (21%) indeterminate. The rate of psychiatric disturbance (mood/anxiety disorder; suicidality) at epilepsy diagnosis was 38% (n = 133). Fifty-seven (16%) had mood/anxiety disorder(s) without suicidality, and 75 (22%) expressed suicidality with or without a psychiatric disorder. Suicidality at epilepsy diagnosis was associated with greater than 2-fold risk of developing TR (relative risk [RR], 2.02; 95% CI, 1.32-3.09; P = .001). There were no significant overall associations between mood/anxiety disorders and TR. Suicidality alone significantly increased TR probability from 16.3% (95% CI, 11.3%-21.3%) in those with no psychiatric disturbance to 47.1% (RR, 2.89; 95% CI, 1.65-5.05; P < .001). Anxiety disorder alone increased TR probability to 32.9% (RR, 2.02; 95% CI, 1.10-3.71; P = .02), although this was not statistically significant after correcting for multiple comparisons. There was no significant change in TR probability when mood disorder alone was present; however, presence of mood disorder with suicidality increased TR probability to 39.6% (RR, 2.43; 95% CI, 1.26-4.68; P = .008). Results of this cohort study reveal that suicidality at the time of focal epilepsy diagnosis was associated with future drug resistance and may be a marker of more severe neuropathology. Psychiatric screening at time of diagnosis may facilitate early identification of patients at risk for treatment refractory epilepsy syndromes.
Cerebrospinal fluid (CSF) is a valuable source of biomarkers for neurological diseases, but detection of low-abundance proteins is often masked by highly abundant proteins. Enrichment strategies can enhance proteomic coverage and improve biomarker discovery, yet comparative evaluations of such methods in equine CSF are limited. This study compared the ProteoMiner Small-Capacity Enrichment Kit and the PreOmics Enrich-iST Kit for their ability to deplete high-abundance proteins and enhance detection of low-abundance proteins relevant to neuropathology. Equine CSF samples were processed with either a native in-solution trypsin digestion without further enrichment, ProteoMiner Small-Capacity Enrichment Kit, or PreOmics enrichment. Samples were analysed by label-free liquid chromatography-tandem mass spectrometry. Proteins were identified and quantified using emPAI scores, and gene ontology pathway analyses were performed to evaluate enrichment efficiency and biological relevance. The PreOmics Enrich-iST Kit identified the highest number of proteins overall, including neurobiology-relevant low-abundance proteins not detected by other methods, and achieved superior depletion of high-abundance proteins. Gene ontology pathway analysis revealed broader enrichment of neuropathology-relevant pathways. The PreOmics Enrich-iST Kit outperformed the ProteoMiner Small-Capacity Enrichment Kit and native digestion in equine CSF proteomics, providing greater depletion of high-abundance proteins and enhanced detection of neurobiology-relevant low-abundance proteins. This method offers a robust tool for comprehensive proteomic profiling and may facilitate the discovery of novel biomarkers for equine neurological disorders.
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.
Anemia has been associated with increased dementia risk, but its relationship with Alzheimer disease (AD) blood biomarkers remains unclear. To investigate whether there is a cross-sectional association between hemoglobin and AD blood biomarker levels and a longitudinal association of hemoglobin and AD biomarkers with incident dementia. This cohort study used data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study. Randomly selected adults aged 60 years or older were enrolled at baseline (March 21, 2001, to August 30, 2004) and followed up every 3 or 6 years according to age through December 31, 2019. Data analysis was conducted between September 1, 2024, and January 7, 2026. Hemoglobin level measured at baseline. Anemia was defined according to World Health Organization criteria. Incident dementia, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and serum concentrations of phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), measured using Simoa assays. Cox proportional hazards regression and quantile regression models were used to examine the association of hemoglobin with dementia risk and AD blood biomarkers. The joint association of hemoglobin and AD blood biomarkers with dementia development using Cox proportional hazards regression was also explored. A total of 3363 adults were enrolled in SNAC-K (73.3% participation rate). After excluding those with dementia or missing AD biomarkers or hemoglobin measures, 2282 dementia-free participants were included in the current study (median age, 72.2 [IQR, 60.8-81.1] years; 1406 [61.6%] female). During a mean (SD) follow-up of 9.3 (4.3) years, 362 participants (15.9%) developed dementia. Compared with individuals with a normal hemoglobin level, those with anemia had higher baseline levels of p-tau217 (β, 0.22; 95% CI, 0.15-0.30), NfL (β, 0.25; 95% CI, 0.19-0.31), and GFAP (β, 0.08; 95% CI, 0.03-0.12) and showed a higher risk of developing dementia (hazard ratio [HR], 1.66; 95% CI, 1.21-2.28) during follow-up. Participants with both anemia and high p-tau217, NfL, or GFAP had the highest hazard of dementia (eg, adjusted HR of 3.64 [95% CI, 2.39-5.56] among those with anemia and high NfL). In this cohort study of dementia-free older adults, anemia was associated cross-sectionally with higher levels of AD blood biomarkers and longitudinally with increased dementia risk. The highest dementia risk occurred when low hemoglobin and elevated AD biomarkers coexisted, suggesting a potential interplay between anemia and neuropathology in dementia development.
Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). We performed spatial expression analyses, providing a rationale for dual inhibition of two non-redundant, spatially distinct acting factors, CXCL12 and VEGF. Subsequently, we expanded a multicentric phase 1/2 trial (NCT04121455), which initially combined RT and the CXCL12-neutralizing L-RNA-aptamer olaptesed pegol (NOX-A12) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT promoter methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose, recommended phase 2 dose, NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life, median progression-free survival (PFS), 6-months PFS and overall survival (OS). For the expansion arm, six patients were included that additionally received the VEGF-targeting antibody bevacizumab (BEV) to RT and NOX-A12. Combinatory treatment was well-tolerated and safe with no treatment-related deaths, resulting in abrogated tumor perfusion (rCBV, FTBhigh) and delayed tumor regrowth as per mRANO. Median progression-free (PFS) and overall survival (OS) after RT + BEV + NOX-A12 were 9.1 and 19.9 months, respectively, significantly outperforming RT + NOX-A12 (p = 0.009; p = 0.021) in a post-hoc comparative analysis, with two patients exceeding 2-year OS. These findings establish proof-of-principle for dual inhibition of CXCL12 and VEGF in patients with newly-diagnosed GBM following RT.
Renal cell carcinoma (RCC) is characterized by considerable heterogeneity and variable clinical outcomes. The identification of reliable biomarkers is crucial to improve prognostic assessment and therapeutic decision-making. CMTM6 (chemokine-like factor-like MARVEL transmembrane domain-containing protein 6) has emerged as a regulator of programmed death ligand-1 (PD-L1), a key immune checkpoint protein involved in tumor immune evasion. The main objective of the study was to investigate the expression and prognostic significance of CMTM6 and to establish an automated immunohistochemical analysis. This was a retrospective analysis conducted at a single center. Tumor samples from 111 patients who underwent partial nephrectomy for localized RCC between 2006 and 2019 were retrospectively analyzed. CMTM6 expression in tumor cells and tumor-infiltrating immune cells (ICs) was quantified using automated digital image analysis of immunohistochemically stained slides. Associations between CMTM6 expression, clinicopathological features, and patient outcomes were evaluated. CMTM6 expression was heterogeneous across RCC samples, with significantly higher levels observed in clear cell RCC compared to non-clear cell subtypes. Elevated CMTM6 expression in ICs correlated with reduced overall survival (p = 0.049) and shorter time to metastasis (p = 0.009). Conversely, in patients with metastatic RCC receiving systemic therapy, lower CMTM6 expression was associated with shorter progression-free survival (p = 0.047). However, lower CMTM6 scores were also significantly associated with more unfavorable outcome according to prognostic group defined by the Stage, Size, Grade, and Necrosis risk model for localized RCC. CMTM6 expression represents a promising prognostic biomarker in RCC, with differential associations depending on disease stage and treatment setting. Its correlation with established clinical risk classifications underscores its potential utility in prognostic refinement. Given its regulatory role in PD-L1 expression, CMTM6 may also represent a therapeutic target, with implications for optimizing immunotherapeutic strategies in RCC. Further validation in larger cohorts and prospective studies are warranted. How CMTM6 expression relates to prognosis in renal cell carcinoma Renal cell carcinoma (RCC) is the most common form of kidney cancer and remains a major clinical challenge due to its variable outcomes and limited predictive markers. To improve patient care, new biomarkers that may help predict prognosis and guide treatment decisions are under investigation. One such molecule is CMTM6 (CKLF-like MARVEL transmembrane domain-containing protein 6). CMTM6 is known to regulate PD-L1, a key immune checkpoint protein that allows cancer cells to evade the immune system. In this study, we analyzed tumour samples from 111 patients who underwent surgery for localized RCC. We applied automated digital image analysis to measure CMTM6 expression in both tumour cells and immune cells within the tumour microenvironment. Our results showed that CMTM6 expression was heterogeneous, with higher levels in clear cell RCC compared to non-clear cell RCC. Importantly, patients with elevated CMTM6 expression in immune cells had a shorter overall survival and developed metastases earlier. Interestingly, in patients with advanced disease receiving systemic therapy, lower levels of CMTM6 were linked to shorter progression-free survival as well as more unfavorable outcome according to prognostic group defined by the SSIGN risk model for localized RCC. These findings suggest that CMTM6 may represent a novel prognostic biomarker in RCC, offering additional insight beyond current clinical risk models. Since CMTM6 is directly linked to immune regulation through PD-L1, it may also represent a therapeutic target. Modulating CMTM6 could influence immune activity in the tumour microenvironment and potentially enhance the effectiveness of immunotherapy. In conclusion, this study highlights the clinical relevance of CMTM6 in RCC and the feasibility of CMTM6 immunohistochemistry in RCC tissue slides using digital image analysis software for automated slide evaluation.
The prognosis of intracranial ependymoma correlates to complete surgery followed by focal irradiation(RT).No standard therapies exist at relapse. We analyzed relapsed patients between 2009 and 2023 both diagnosed in our institution as well as referred. Patients were 33 (females 12), median age 3.3 years. All treated according to AIEOP1st -2nd or SIOP 2nd protocol, i.e., operated and focally irradiated; some had chemotherapy (VEC or VEC/cisplatin + VCR) either after surgery(#13 for residual disease) or after radiotherapy(#10)0.25 tumors originated in posterior fossa,29 were grade 3,23 were tumor-free at RT. Relapses appeared at median 31 months after diagnosis: local in 22 cases, disseminated/combined in 11.21 tumors classified as PFA,8 as RELA/ZFTA.19 patients were again completely operated,16 received hypofractionated reirradiation at 8–16 Gy in 2/4 fractions,6 standard re-RT at 18–54 Gy,10 36 Gy craniospinal irradiation for dissemination; one no treatment. We evaluated the first EFS, OS, and post-first relapse EFS/OS (EFS2/OS2). Median EFS, OS, EFS2 and OS2 were 31.1,66.4,13.6 and 31.5 months, respectively. EFS was positively associated to female sex, grade 3,complete resection at diagnosis/at relapse(also of single metastatic relapse). RELA/ZFTA molecular subgroup tumors affected positively on OS2. Supratentorial location and RELA/ZFTA showed an association that approached statistical significance on EFS2. Type of re-RT had no impact on analyses, with craniospinal radiotherapy adopted only for disseminated/combined relapse. In mutivariable analysis RELA/ZFTA subgroup and complete resection at relapse were associated with improved OS. 13/33 patients survived more than 7 years: 9 alive and 7 tumor-free. Complete resection is a therapeutic resource also after relapse, ideal re-RT has to be found; outcome differed by molecular subgroup in our cohort.
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.
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.
Aging is the strongest risk factor for Alzheimer's disease (AD), yet the role of age-associated DNA methylation (DNAm) changes in blood and their relevance to AD remains poorly understood. We performed a meta-analysis of blood DNAm samples from 475 dementia-free subjects aged over 65 years across two independent cohorts, the Framingham Heart Study (FHS) at Exam 9 and the Alzheimer's Disease Neuroimaging Initiative (ADNI). We adjusted for sex and immune cell-type proportions and corrected batch effects and genomic inflation. Integrative analyses included pathway enrichment, mQTL analysis, colocalization with Alzheimer's disease and related dementia (ADRD) GWAS summary statistics, brain-blood DNAm correlations, and comparison to independent AD methylation studies. We identified 3758 CpGs and 556 differentially methylated regions (DMRs) consistently associated with chronological age in both cohorts at a 5% false discovery rate. Our pathway enrichment analyses highlighted metabolic regulation and synaptic signaling, processes previously implicated in Alzheimer's disease. Colocalization with ADRD GWAS summary statistics identified 32 genomic regions consistent with shared genetic signals for DNAm and ADRD risk. Roughly one-third of aging-associated CpGs overlapped CpGs associated with AD or AD neuropathology in external studies. Finally, we prioritized nine promoter CpGs (including those located in PDE1B, ELOVL2, and PODXL2) showing strong positive blood-to-brain methylation concordance and external AD associations, nominating them as candidate blood-based biomarkers. Our study demonstrated that late-life aging signatures in blood DNAm converge on processes implicated in AD and intersect with dementia genetics. A small set of CpGs with blood-brain concordance and external AD support offers promising candidate blood-based biomarkers for future validation.
Low-grade epilepsy-associated brain tumors (LEATs) are a frequent cause of drug-resistant focal epilepsy in both children and adults. Epilepsy surgery is a well-recognized treatment option, with almost 80% of patients being seizure-free at 1 year, and 50% of children being seizure- and drug-free at 5 years. Despite these outcomes, standardized management guidelines remain lacking. The present study aimed to assess current practices in Europe. A comprehensive web-based survey was conducted by EpiCARE (European Reference Network for Rare and Complex Epilepsies). Responses were collected from 172 clinicians representing 75 institutions in 26 European region countries. The questionnaire addressed institutional protocols, individual practices, referral pathways, presurgical evaluation, histopathology, molecular diagnostics, and follow-up. Clinicians largely agreed that epileptic seizures are a major comorbidity in LEAT patients, and most reported that seizure frequency and duration influence their treatment approach. This reflects an understanding of LEATs not only as an oncological entity, but above all as an epileptogenic lesion with a strong impact on quality of life, systematically requiring a multidisciplinary approach. Significant inconsistencies were identified, particularly regarding referral pathways, presurgical assessment (66% referred systematically to an epilepsy team), and molecular diagnostics. Only 48% of respondents reported having institutional protocols in place. Although the majority supported early referral to an epilepsy surgery team after diagnosis (even in the absence of confirmed drug resistance), 13% still required failure of at least two antiseizure medications. Long-term postsurgical follow-up was recommended by 89% of clinicians beyond 1 year after surgery. Almost all clinicians acknowledged that histopathology influenced clinical decision-making for follow-up, and 87.2% were familiar with the World Health Organization 2021 central nervous system tumor classification and molecular diagnostics. This large European study shows growing alignment with international recommendations, but significant inconsistencies remain in clinical practice, particularly regarding referral pathways, presurgical assessment, and molecular diagnostics. These findings highlight the need for consensus-driven international guidelines for LEAT management.
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.