Aberrant reactivation of embryonic patterning programs is a hallmark of cancer. We previously identified HOXD12 activation in aggressive oligodendrogliomas, but its broader significance across brain tumors remains unexamined. Here, we evaluated HOXD12 protein expression via immunohistochemistry in 162 primary CNS tumors and 84 brain metastases. HOXD12 expression was significantly enriched in primary CNS tumors over brain metastases (P < .0001). Among primary malignancies, medulloblastoma exhibited the highest HOXD12 expression compared to diffuse gliomas, ependymomas, and meningiomas (P < .0001). Conversely, HOXD12 levels did not vary by diffuse glioma subtype or metastatic site of origin. To resolve subgroup-specific patterns, we integrated whole-genome DNA methylation (n = 1338) and bulk RNA-sequencing (n = 876) datasets across medulloblastoma molecular subgroups. Multi-omic analysis revealed maximal HOXD12 gene body methylation and transcript expression specifically within the WNT-activated medulloblastoma subgroup (P < .0001). These findings demonstrate that HOXD12 reactivation is preferentially associated with primary CNS tumors and is highly pronounced in WNT-activated medulloblastomas. Our results position HOXD12 as a candidate immunohistochemical surrogate for the WNT-activated medulloblastoma subgroup.

Cardiovascular risk factors are implicated in Alzheimer disease (AD) progression and its neuropathological hallmarks but their specific contributions to regional brain pathology within AD remain understudied. In this cohort study (n = 276), we examined associations between diabetes, hypertension, and hypercholesterolemia (present vs absent), and neuropathologies in decedents with pathologically confirmed Intermediate/High AD from 3 Alzheimer's Disease Research Centers. Regional arteriolosclerosis, cerebral amyloid angiopathy (CAA), cored plaques (CPs), diffuse plaques (DPs), neurofibrillary tangles (NFTs), neuritic plaques (NPs), and neuropil threads (NTs) were semi-quantitatively assessed by adapting established scoring schemes. Differences in neuropathology by cardiovascular risk factor status were assessed using Wilcoxon rank-sum tests and ordinal logistic regression models adjusted for ethnicity, sex, age at death, and center. In adjusted analyses, diabetes was associated with higher frontal NTs (odds ratio, 3.2 [95% CI, 1.2-8.4]). Hypercholesterolemia was associated with higher CAA in the parietal lobe (odds ratio, 2.7 [95% CI, 1.3-5.8]) and posterior hippocampus (odds ratio, 2.8 [95% CI, 1.3-6.1]). None of these associations remained statistically significant following false discovery rate (FDR) correction. These findings suggest vascular risk factors do not substantially modify the burden of AD pathology once advanced disease is present and any independent effects on AD-related lesions are likely modest within this select cohort.

The presence of a CDKN2A homozygous deletion (HD) plays an important role in the diagnostic approach of neuropathologists to several central nervous system (CNS) tumors. CDKN2A is located on chromosome 9p21, next to CDKN2B and MTAP, and encodes for the protein p16. CDKN2A/B HD constitutes a frequent alteration in some circumscribed gliomas such as high-grade astrocytomas with piloid features (HGAP) and pleomorphic xanthoastrocytomas (PXA). The diagnosis of these tumor types remains complex and having a rapid and easy tool to suggest these diagnoses would be useful. Herein, we studied a cohort of 42 HGAP and PXA to analyze the concordance of CDKN2A/B and MTAP status between 3 different molecular techniques (FISH, DNA-methylation profiling providing copy number variation analysis, and SNP array), and compared the results to those of p16 and MTAP immunohistochemistry. HD was present in 11/12 HGAP and 28/30 PXA, however, with a wide variety of deletion size, including of CDKN2A, CDKN2B, and MTAP genes. There was excellent concordance between p16/MTAP immunoexpression and the genetic detection of HD, demonstrating 100% sensitivity and 100% specificity. In conclusion, combined p16/MTAP IHC presented a positive predictive value for detecting HD and may assist neuropathologists in their diagnostic approach to circumscribed glial/glioneuronal tumors.

Gliomas, particularly glioblastoma, are characterized by profound molecular and cellular heterogeneity that drives tumor progression, therapeutic resistance, and poor clinical outcomes. Increasing evidence indicates that epigenetic deregulation, extending beyond genetic alterations, plays a central role in glioma initiation, evolution, and treatment response. This review summarizes current advances in the epigenetic landscape of adult gliomas with particular emphasis on the interplay between DNA methylation, histone modifications, chromatin remodeling and their contributions to molecular heterogeneity and precision neuro-oncology. We discuss key epigenetic mechanisms, including global DNA hypomethylation, promoter CpG island hypermethylation, histone acetylation and methylation and their effects on genome stability, transcriptional regulation, stemness, immune modulation, metabolic reprogramming, and therapeutic resistance. Clinically relevant biomarkers, including O6-methylguanine-DNA methyltransferase promoter methylation and the glioma CpG island methylator phenotype, are highlighted alongside emerging therapeutic targets such as histone deacetylases, Enhancer of Zeste Homologue 2, G9a, and protein arginine methyltransferase 5. We further examine the impact of spatial and temporal epigenetic heterogeneity on biomarker interpretation and treatment selection, as well as recent advances in methylation-based tumor classification. Collectively, this review highlights epigenetic deregulation as both a fundamental driver of adult glioma biology and a promising foundation for precision oncology.

Primary genetic mitochondrial diseases (GMDs) are clinically and genetically diverse diseases. Leigh syndrome (LS), the most common pediatric presentation of GMD is a severe progressive multi-system disorder with diverse manifestations. No effective treatments currently exist. Recent data from the Ndufs4(-/-) LS mouse model show that peripheral macrophages contribute to brain lesions, that disease is driven by innate immune populations and that depletion of innate immune cells prevents disease. However, the mechanisms underlying the immune activation in LS remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and DNA are detected by toll-like receptors (TLRs) at the endosome and may mediate innate immune activation in LS. To assess TLR signaling in an LS mouse model, we generated TLR signaling-deficient Ndufs4(-/-)/MyD88(-/-) animals. Prophylactic antibiotic treatment with enrofloxacin enabled production of MyD88(-/-) animals from Ndufs4(+/-)/MyD88(+/-) breeder pairs. Loss of MyD88 in Ndufs4(-/-) animals increased survival and delayed the onset but disease courses were not altered. We conclude that Myd88-mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of MyD88(-/-) animals modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in mitochondrial diseases warrants further investigation.

Tumor maturation is a property of neuroblastomas but can also be observed in unique cases of primary brain malignancies. We hypothesized that the mechanisms of peripheral and central neurogenic tumor maturation could be similar. This study encompassed 19 cases of neuroblastoma and solitary cases of CNS tumors having undergone a morphologically verified maturation. The tumors were analyzed by sequencing and gene expression profiling. We revealed potential similarity of different tumor types upon maturation, associated with stimulated MAPK, PI3K-AKT-mTOR, and TrkA signaling and suppressed regulation of cell cycle and DNA replication and repair. Tumors completing maturation similarly showed enhanced immunogenicity. The levels of NTRK2 expression increased during maturation. Expression of NTRK1 and positive epigenetic regulators (SWI/SNF subunits) increased prior to maturation and decreased upon the differentiation completion. Expression of negative epigenetic regulators EZH2, HDAC10, HDAC2, and DNMT3A decreased in maturing tumors. These data suggest that central and peripheral neurogenic tumors are likely to have common maturation mechanisms. Molecular scenarios associated with neuroblastoma maturation could be: (1) TrkA signaling (seen in cases presenting in < 18-month-olds), or (2) altered expression of epigenetic regulators and transcription factors (seen in cases presenting in >18-month-olds); treatment-induced maturation of CNS malignancies could involve both scenarios.

Alzheimer disease (AD) pathology affects the transentorhinal/entorhinal region early but whether entorhinal cortex (EC) astrocytes are causal drivers or therapeutic targets remains unresolved. This narrative review evaluates EC astrocytes through an explicit evidence hierarchy. We distinguish: (1) human EC-specific neuropathology, imaging, and transcriptomic findings, (2) human AD astrocyte data lacking EC-cell resolution, (3) mechanistic evidence from animal and cellular models, and (4) translational hypotheses. Human data support early EC vulnerability and region- and stage-dependent astrocyte remodeling, whereas the most direct functional evidence comes from rodent medial EC layer II and should be interpreted as circuit plausibility rather than anatomical equivalence to the human EC. We therefore prioritize candidate astrocyte modules according to astrocyte specificity, relevance to EC or medial temporal pathology, mechanistic links to circuit dysfunction, and the availability of measurable target-engagement readouts. These modules include inflammatory-complement signaling, EAAT2/GLT-1-mediated glutamate clearance, MAO-B/GABA metabolism, AQP4-related gliovascular regulation, astrocytic calcium signaling, and APOE-related lipid handling. Cell transplantation, glial reprogramming, and engineered extracellular vesicles remain experimental platforms. EC astrocytes should therefore be viewed as candidate circuit-glial vulnerability nodes requiring human validation, not as established clinical targets.

Repetitive mild traumatic brain injury (r-mTBI) is strongly associated with the increased risk of developing neurodegenerative diseases. Previously, we have revealed the histopathological, biochemical, and transcriptional changes following exposure to chronic r-mTBI in wild-type (WT) mice. Herein, we performed a complementary electron microscopy analysis in a young adult (3-month-old) WT cohort to reveal the ultrastructural changes observed 3 months following chronic r-mTBI. Additionally, because age at injury has been associated with an increased risk for poorer outcomes after TBI, an older WT cohort (12-month-old, middle-aged) was included to determine this relationship. While the cortical grey-matter exhibited minimal ultrastructural abnormalities after r-mTBI, we observed prominent TBI-related changes in the corpus callosum, including increased axonal g-ratios and higher density of degenerating axons in both cohorts. However, no age-dependent injury differences were observed across measured parameters, except for a notable TBI-dependent increase in phagolysosome-bearing perivascular cells within the corpus callosum of injured aged mice compared to younger TBI counterparts. Collectively, these findings suggest that chronic r-mTBI in young adulthood and middle age produces similar white matter ultrastructural changes 3 months after r-mTBI. Future studies are warranted to determine whether ultrastructural differences emerge with injuries administered earlier in life or at advanced age.

Encephalitic alphaviruses such as Western equine encephalitis virus (WEEV) result in significant morbidity through acute viremia and postencephalitic neurologic dysfunction. Viral neurotropism is linked to chronic glial-mediated neuroinflammation and increased risk for neurodegenerative disorders including Alzheimer disease and Parkinson disease. We previously showed that sublethal WEEV infection induces nigrostriatal gliosis, neuronal loss, and Parkinsonian-like motor deficits in mice. However, the temporal progression of glial activation and neurodegeneration in brain regions relevant to dementia remains unclear. To address this, we performed a longitudinal assessment of hippocampal pathology following intranasal infection with McMillan WEEV. Brain tissue was collected at 1, 2, and 4 weeks postinfection and analyzed using high-content fluorescence imaging, deep learning-based image analysis, and population-level cellular phenotyping. We observed a marked increase in gliosis peaking at 1-week postinfection, coinciding with fibrotic, immune cell-dense lesions that inversely correlated with eosinophilic neuronal density. Automated skeletonization analysis revealed increased astrocyte reactivity and a predominantly bushy microglial morphology at this time point. Heat map densitometry further demonstrated progressive amyloid-β accumulation across all time points. Together, these findings define a dynamic sequence of glial activation, lesion formation, and protein aggregation underlying WEEV-induced hippocampal neurotoxicity.

Quantitative digital image analysis has emerged as a powerful tool for assessing neuropathological burden. Although previous studies have compared quantitative digital and semiquantitative pathology measures, their respective relationships with regionally corresponding in vivo tau PET measures remain poorly characterized. We compared quantitative digital pathology quantification and semiquantitative regional gradings of phosphorylated tau (ptau) immunohistochemical staining and assessed their correlations with regional in vivo [18F]flortaucipir standardized uptake value ratios (SUVRs) in 52 cases from the AVID A16 end-of-life study. Digital pathology quantification and semiquantitative gradings of ptau were strongly correlated across all 19 cortical and mesial temporal regions examined (Spearman's rho range: 0.6-0.9; all P < .0001). Both approaches showed similarly robust associations with regionally corresponding tau PET SUVRs. Direct comparison of matched correlation coefficients revealed stronger PET-pathology associations for the digital quantification in the left amygdala and the inferior parietal lobule. Overall, digital pathology quantification and semiquantitative assessments of ptau pathology yielded highly comparable results, both in the quantification of regional pathology burden and in their relationships with tau PET measures. These findings support the use of digital pathology quantification methods and suggest that semiquantitative pathology gradings remain a valid and informative approach for clinicopathological correlation studies.