Brain Pathology最新文献

Diffuse hemispheric glioma, H3 G34-mutant (DHG-H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high-resolution copy number profiling of a series of 60 DHG-H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187-gene mutation and fusion targeted neuro-oncology next-generation sequencing panel (n = 60) and Oncoscan chromosomal microarray (n = 26) by a single laboratory (2018-2022). A subset of cases had immunohistochemical results for OLIG2 (n = 42), p53 (n = 48), and ATRX (n = 46), and methylation array data (n = 8). Median age at testing was 21 years (range, 12-50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3-3A G34 mutations included G34R (n = 56; 94%), G34V (n = 3), and a non-canonical G34E (n = 1). Concurrent mutations most often involved TP53 (n = 55; 92%), ATRX (n = 50; 83%), and PDGFRA (n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy-neutral loss of heterozygosity (cnLOH) encompassing TP53. This copy number profile was reminiscent of that seen in Grade 4 IDH-mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high-resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG-H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH-a copy number abnormality that has been largely unrecognized-for this new 2021 World Health Organization central nervous system tumor type.

Tropomyosin receptor kinase A (TrkA), a high-affinity receptor for nerve growth factor (NGF), is implicated in nociception and local angiogenesis. We investigated TrkA localization and abundance in skin biopsies from multiple myeloma patients who developed peripheral neuropathy during bortezomib treatment. We recruited 50 multiple myeloma patients with bortezomib-induced peripheral neuropathy (BIPN), including 31 without pain and 19 with pain, and 27 matched healthy controls at University Hospital Würzburg (2021-2024). Skin biopsies from the distal leg were analyzed to determine intraepidermal nerve fiber density (IENFD) and area, TrkA mean fluorescence intensity (MFI) and gene expression levels. Additionally, the area of blood vessels and proximity to nerves was measured. BIPN patients exhibited significant sensory abnormalities, decreased IENFD, and increased TrkA protein abundance in surviving epidermal nerve fibers, correlating with cycles of bortezomib treatment. No substantial difference in TrkA gene expression was observed between groups. All BIPN patients demonstrated increased dermal vascularization compared with control, and only those without pain showed increased nerve-vessel interactions. These results suggest a strong association between dysregulated TrkA signaling and altered neurovascular interactions with small fiber pathology in BIPN.

Optic nerve sheath meningioma (ONSM) is a rare tumor that arises from the meninges enveloping the optic nerve. Although the genetic landscape of meningiomas has been extensively studied, the molecular alterations underlying ONSM remain poorly understood. We retrospectively analyzed consecutive patients surgically treated for ONSM between 2000 and 2025 at our institution, with available histological specimens. Intracranial meningiomas secondarily extending into the optic canal were excluded. Fresh-frozen tumor samples were subjected to whole-exome sequencing, and transcriptomic analyses were conducted and compared with those of intracranial meningiomas from four public datasets. Six cases were included, five of whom were female, with a median age of 63.5 years. While most cases remained stable after surgery, one patient experienced multiple recurrences and ultimately succumbed. Primary tumors were characterized by the absence of NF2 alterations, occasional POLR2A mutations, and few copy number variations (CNVs). Transcriptomic profiling in primary tumors revealed a neurotrophic microenvironment reflective of the close association with the optic nerve. The recurrent case exhibited high-risk CNVs at diagnosis and developed into an aggressive disease as additional CNV burdens accumulated, including the homozygous deletion of CDKN2A/B. Its expression profile was in line with that of hypermitotic, proliferative intracranial meningiomas. ONSM represents a predominantly NF2-intact meningioma subtype defined by neural niche-associated transcriptional signatures. Although typically indolent, ONSM can, in rare instances, evolve into an aggressive disease through further accumulation of CNVs.

The study of prion biology has traditionally relied on transgenic mouse models, which, while valuable, require significant time and resources to develop. Here, we present a rapid and flexible alternative using adeno-associated virus (AAV) vectors to express modified prion proteins in PrP-knockout (PrP-KO) mice. Through systematic evaluation of multiple AAV constructs, we optimized vector design by comparing different CNS-specific promoters and regulatory elements to generate prion disease models capable of faithfully propagating the inoculated prion strain. We identified an optimized AAV construct incorporating the human synapsin promoter, MVM enhancer, and WPRE posttranscriptional regulatory element encapsidated in the AAV9P31 serotype to drive neuron-specific expression of modified mouse PrP (W144Y epitope) and bank vole I109 PrP (W145Y epitope). Following intravenous administration, we achieved brain-wide expression at levels comparable to or even exceeding endogenous PrP in some regions. When challenged with mouse-adapted RML prions or human Gerstmann-Sträussler-Scheinker (GSS-A117V) disease-causing prions, AAV-PrP mice developed characteristic signs of prion disease with accelerated kinetics (58-106 days post-inoculation for RML; 105-112 dpi for GSS-A117V), displaying features typical of each strain. Serial transmission of AAV-generated RML prions to wild-type mice confirmed preservation of strain-specific properties (165 ± 4 dpi), validating the authenticity of prion propagation in this system. This approach provides a versatile platform for rapidly generating and studying prion variants in an authentic brain environment. By reducing model generation time from months to weeks, this system enables accelerated investigation of prion structure-function relationships, strain properties, and therapeutic strategies, with potential applications extending to other protein misfolding diseases.

Pediatric ependymoma (EPN) is one of the most common central nervous system cancers in children often accompanied by a poor prognosis. The circular RNA, circRMST, is known to be upregulated in posterior fossa (PF) EPN, but its functional role in the disease has not been explored. We found that circRMST is abundantly expressed in the cytoplasm of cancer cells in PF EPN patients. Moreover, knockdown of circRMST in EPN cancer stem cell-like cells induced differentiation-related pathways while the expression of cell cycle-related pathways was reduced, suggesting that it acts as an oncogene. We further validated these findings using flow cytometry-based cell cycle analysis and an in vitro serum-induced differentiation assay. Furthermore, we found that high circRMST expression and low promoter methylation levels are associated with poor prognosis. In conclusion, this study identifies circRMST as a novel oncogene in PF EPN.

Perinatal hypoxia-ischemia is a leading cause of preterm white matter injury (PWMI), yet mechanisms underlying oligodendrocyte precursor cells (OPCs) dysfunction remain poorly understood. Here, we identify endothelial-derived Netrin-4 (Ntn4) as a critical regulator of OPCs proliferation and differentiation in PWMI. Developmental analysis revealed that Netrin-4, predominantly expressed in cerebrovascular endothelial cells (ECs), peaks during postnatal myelination and correlates with OPCs marker PDGFR-α. Conditional endothelial deletion of Ntn4 in mice impaired spatial memory, induced anxiety-like behavior, and reduced mature oligodendrocytes, accompanied by disrupted myelin ultrastructure. In a PWMI model, endothelial Ntn4 knockout exacerbated myelination deficits and suppressed OPCs proliferation, while inducible deletion at later stages enhanced OPCs differentiation. Mechanistically, Netrin-4-overexpressing ECs elevated ET-1 secretion, which promoted OPCs proliferation but inhibited differentiation via ET-1 receptor EDNRB. Our findings reveal that endothelial Netrin-4 is a dual regulator of OPCs dynamics in PWMI, driving proliferation via ET-1 while impairing differentiation. Targeting the Netrin-4/ET-1 axis restores OPCs maturation, offering a potential strategy to mitigate myelination deficits in PWMI.