Journal of Neuropathology and Experimental Neurology最新文献

This review discusses terminology recently proposed for the classification of dementia and, more specifically, nosology related to aging-associated TDP-43 pathology: limbic-predominant age-related TDP-43 encephalopathy (LATE), and limbic-predominant amnestic neurodegenerative syndrome (LANS). While the "gold standard" for these clinical conditions is still LATE neuropathologic changes (LATE-NC), clinical criteria and biomarkers are evolving. The newly proposed clinical rubrics are discussed with emphasis on the need for terminology that acknowledges the distinctions between clinical syndrome-, molecular biomarker-, and pathologically defined disease concepts. As further progress is made on research into the specific biomarker-based detection and prediction of TDP-43 proteinopathy in the clinical setting, the definitions of "Probable" and "Possible" LATE are likely to become more useful clinically. For people interested in the pathological diagnoses or basic research related to LATE-NC, the relevant terminology remains unchanged by the newly proposed clinical criteria.

The prevalence of focal granule cell bilamination (FGCB) in the hippocampal dentate gyrus varies from 0% to 44%, depending on age and study population. FGCB is commonly thought to be a specific feature of temporal lobe epilepsy (TLE) but its prevalence in cases without TLE is unclear. Using formalin-fixed, paraffin-embedded hippocampal sections, this retrospective postmortem study evaluated the prevalence of FGCB and other granule cell pathologies in infants (1-12 months of age, n = 16), children (4-10 years, n = 6), and adults (28-91 years, n = 15) with no known history of epilepsy or seizures. We found FGCB in 6% of infants, 17% of children, and 27% of adults. We then compared our findings with those in published reports of sudden unexpected deaths in infancy (SUDI), childhood (SUDC), and epilepsy (SUDEP), and in surgical specimens from patients with TLE. The reported prevalence of FGCB in those studies was 6%-19% in infants, 0%-17% in children, and 0%-2% in adults in non-seizure-related cases and 9% in children and 3%-25% in adults with TLE. Our findings highlight the presence of FGCB in individuals with no known epilepsy/seizure-related histories in proportions similar to those reported in individuals with clinical epilepsy.

Glioblastoma (GBM) is a lethal brain tumor without effective treatment options. This study aimed to characterize longitudinal tumor changes in order to find potentially actionable targets to prevent GBM relapse. We extracted RNA and proteins from fresh frozen tumor samples from patient-matched IDHwt WHO grade 4 primary (pGBM) and recurrent (rGBM) tumors for transcriptomics and proteomics analysis. A tissue microarray containing paired tumor samples was processed for spatial transcriptomics analysis. Differentially expressed genes and proteins between pGBM and rGBM were involved in synapse development and myelination. By categorizing patients into short (STTR) and long (LTTR) time-to-lapse, we identified genes/proteins whose expression levels positively or negatively correlated with TTR. In rGBM, expressions of Fcγ receptors (FCGRs) and complement system genes were negatively correlated with TTR, whereas expression of genes involved in DNA methylation was positively correlated with TTR. Spatial transcriptomics of the tumor cells showed enrichment of oligodendrocytes in rGBM. Besides, we observed changes in the myeloid compartment such as a switch from quiescent to activated microglia and an enrichment in B and T cells in rGBM with STTR. Our results uncover a role for activated microglia/macrophages in GBM recurrence and suggest that interfering with these cells may hinder GBM relapse.

Rubinstein-Taybi syndrome (RTS) is a congenital disorder with characteristic clinical manifestations. In the vast majority of cases, it is caused by mutations of the gene encoding the transcriptional co-activator cAMP-response element binding protein (CBP)-binding protein (CREBBP). It has been thought to be a tumor predisposition syndrome as RTS patients have an increased risk of developing tumors including meningiomas. However, RTS-associated meningiomas are rarely reported. We report a unique RTS-associated meningioma in which an oncogenic CREBBP mutation is identified. We also comprehensively review the reported RTS-associated meningiomas, from epidemiology and pathogenesis to clinicopathological characteristics and treatment. All RTS patients with meningiomas are female and have the exclusive mutations of CREBBP. In population-based studies RTS-associated meningiomas seem to develop at younger ages. Their pathogenesis may be driven by the CREBBP/CBP alterations resulting in aberrant signal transduction in the CBP-mediated signaling pathways. Meningiomas in RTS patients have common clinicopathological characteristics including comorbidity with other tumors, radiologically intra-osseous growth, and uncommon histopathology such as ossifying and secretory features. Given the genetic nature and rarity of RTS-associated meningiomas, further investigation of their characteristics may define molecular targets for improved therapeutic options for RTS patients.