Acta Neuropathologica最新文献

Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head injuries, is characterised by perivascular hyperphosphorylated tau (p-tau) accumulations within the depths of cortical sulci. Although the majority of CTE literature focuses on p-tau pathology, other pathological features such as glial reactivity, vascular damage, and axonal damage are relatively unexplored. In this study, we aimed to characterise these other pathological features, specifically in CTE p-tau lesion areas, to better understand the microenvironment surrounding the lesion. We utilised multiplex immunohistochemistry to investigate the distribution of 32 different markers of cytoarchitecture and pathology that are relevant to both traumatic brain injury and neurodegeneration. We qualitatively assessed the multiplex images and measured the percentage area of labelling for each marker in the lesion and non-lesion areas of CTE cases. We identified perivascular glial reactivity as a prominent feature of CTE p-tau lesions, largely driven by increases in astrocyte reactivity compared to non-lesion areas. Furthermore, we identified astrocytes labelled for both NAD(P)H quinone dehydrogenase 1 (NQO1) and L-ferritin, indicating that lesion-associated glial reactivity may be a compensatory response to iron-induced oxidative stress. Our findings demonstrate that perivascular inflammation is a consistent feature of the CTE pathognomonic lesion and may contribute to the pathogenesis of brain injury-related neurodegeneration.

IDH-mutant astrocytomas are diffuse gliomas that are defined by characteristic mutations in IDH1 or IDH2 and do not have complete 1p/19q co-deletion. The established grading criteria include histological features of brisk mitotic activity (grade 3) and necrosis and/or microvascular proliferation (grade 4). In addition, homozygous deletion of the CDKN2A/B locus has recently been implemented as a molecular marker for grade 4 IDH-mutant astrocytomas. Here, we describe a subgroup of high-grade IDH-mutant astrocytomas characterised by a primitive neuronal component based on histology and a distinct DNA methylation profile (n = 51, ASTRO PNC). Misinterpretation as carcinoma metastasis was common, since GFAP expression was absent in the primitive neuronal component, whereas TTF-1 expression was detected in 15/19 cases (79%) based on immunohistochemistry. Apart from mutations in IDH1, TP53, and ATRX, we observed enrichment for alterations in RB1 (n = 19/51, 37%) and MYCN (n = 14/51, 27%). Homozygous CDKN2A/B deletion (n = 1/51, 2%) and CDK4 amplification (n = 3/51, 6%) were relatively rare events. Clinical (n = 31 patients) and survival data (n = 23 patients) indicate a clinical behaviour similar to other CNS WHO grade 4 IDH-mutant astrocytomas, however with an increased risk for leptomeningeal (n = 7) and extra-axial (n = 2) spread. Taken together, ASTRO PNC is defined by a distinct molecular and histological appearance that can mimic metastatic disease and typically follows an aggressive clinical course.

Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a new histopathological entity identified in the surgically resected brain tissue of patients with drug-resistant epilepsy. Somatic variants in SLC35A2 have been increasingly identified in MOGHE brain resections. SLC35A2 protein transports uridine 5’-diphosphogalactose (UDP-Gal) into the Golgi lumen, playing a crucial role in the process of N-glycosylation. Currently, research on the pathogenic mechanism of SLC35A2 variants in MOGHE is limited. Here we conducted genetic testing on brain samples and paired blood samples from 28 pediatric patients pathologically diagnosed with MOGHE. We performed an in-depth functional analysis of somatic variants identified in SLC35A2, integrating glycan labeling and intact glycopeptide profiling to assess N-glycosylation defects. With whole-exome sequencing and validation with ultra-deep amplicon sequencing, we identified 101 potentially pathogenic somatic variants (PPSVs) across 87 genes. Nine PPSVs in SLC35A2 were found in 10 samples. The 9 identified variants of SLC35A2, characterized by various mutation types (4 frameshift, 3 missense and 2 nonsense variants), were all confirmed to be loss-of-function via altered glycan chains. Intact glycopeptide analysis at the cellular level indicated an increase in truncated N-glycan glycoforms. Analysis of brain tissue revealed N-glycosylated proteins and glycosites modified with agalactosylated glycoforms, and glycoproteins bearing agalactosylated N-glycans were significantly enriched in cell adhesion and axon guidance-related pathways. Additionally, chemoenzymatic glycan labeling in lesions demonstrated N-glycan damage of heterotopic neurons, suggesting a potential diagnostic approach for MOGHE. Our findings provide a comprehensive somatic landscape of MOGHE and a rich resource of somatic SLC35A2 variant-related glycoform and glycoprotein abnormalities, thereby unveiling valuable insights into compromised N-glycosylation and MOGHE formation.

Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2. The aim of this study was to establish a generalized screening for Lynch syndrome and constitutional MMR deficiency (CMMRD) in pedHGG patients, as the detection of MMR deficiencies (MMRD) may enable the upfront therapeutic use of checkpoint inhibitors and identification of variant carriers in the patients’ families. We prospectively enrolled 155 centrally reviewed primary pedHGG patients for MMR-immunohistochemistry (IHC) as part of the HIT-HGG-2013 trial protocol. MMR-IHC results were subsequently compared to independently collected germline sequencing data (whole exome sequencing or pan-cancer DNA panel next-generation sequencing) available in the HIT-HGG-2013, INFORM, and MNP2.0 trials. MMR-IHC could be successfully performed in 127/155 tumor tissues. The screening identified all present cases with Lynch syndrome or CMMRD (5.5%). In addition, MMR-IHC also detected cases with exclusive somatic MMR gene alterations (2.3%), including MSH2 hypermethylation as an alternative epigenetic silencing mechanism. Most of the identified pedHGG MMRD patients had no family history of MMRD, and thus, they represented index patients in their families. Cases with regular protein expression in MMR-IHC never showed evidence for MMRD in DNA sequencing. In conclusion, MMR-IHC presents a cost-effective, relatively widely available, and fast screening method for germline MMRD in pedHGG with high sensitivity (100%) and specificity (96%). Given the relatively high prevalence of previously undetected MMRD cases among pedHGG patients, we strongly recommend incorporating MMR-IHC into routine diagnostics.

Traumatic brain injury (TBI) often leads to impaired regulation of cerebral blood flow, which may be caused by pathological changes of the vascular smooth muscle cells (VSMCs) in the arterial wall. Moreover, these cerebrovascular changes may contribute to the development of various neurodegenerative disorders such as Alzheimer’s-like pathologies that include amyloid beta aggregation. Despite its importance, the pathophysiological mechanisms responsible for VSMC dysfunction after TBI have rarely been evaluated. Here, we show that acute human TBI resulted in early pathological changes in leptomeningeal arteries, closely associated with a decrease in VSMC markers such as NOTCH3 and alpha smooth muscle actin (α-SMA).These changes coincided with increased aggregation of variable-length amyloid peptides including Aβ_1-40/42, Aβ_1-16, and β-secretase-derived fragment (βCTF) (C99) caused by altered processing of amyloid precursor protein (APP) in VSMCs. The aggregation of Aβ_1-40/42 peptides were also observed in the leptomeningeal arteries of young TBI patients. These pathological changes also included higher β-secretase (BACE1) when compared to α-secretase A Disintegrin And Metalloprotease 10 (ADAM10) expression in the leptomeningeal arteries, plausibly caused by hypoxia and oxidative stress as shown using human VSMCs in vitro. Importantly, BACE1 inhibition not only restored NOTCH3 signalling but also normalized ADAM10 levels in vitro. Furthermore, we found reduced ADAM10 activity and decreased NOTCH3, along with increased βCTF (C99) levels in mice subjected to an experimental model of TBI. This study provides evidence of early post-injury changes in VSMCs of leptomeningeal arteries that can contribute to vascular dysfunction and exacerbate secondary injury mechanisms following TBI.

Down syndrome (DS) is strongly associated with Alzheimer’s disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R² = .77), DS and LOAD (R² = .73), and EOAD and LOAD (R² = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 × 10⁻⁵) for DS, immune system regulation (p = 4.33 × 10⁻⁵) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R² = .59) and LOAD (R² = .33) compared to the correlation between EOAD and LOAD (R² = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein–DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.

The foremost feature of glioblastoma (GBM), the most frequent malignant brain tumours in adults, is a remarkable degree of intra- and inter-tumour heterogeneity reflecting the coexistence within the tumour bulk of different cell populations displaying distinctive genetic and transcriptomic profiles. GBM with primitive neuronal component (PNC), recently identified by DNA methylation-based classification as a peculiar GBM subtype (GBM-PNC), is a poorly recognized and aggressive GBM variant characterised by nodules containing cells with primitive neuronal differentiation along with conventional GBM areas. In addition, the presence of a PNC component has been also reported in IDH-mutant high-grade gliomas (HGGs), and to a lesser extent to other HGGs, suggesting that regardless from being IDH-mutant or IDH-wildtype, peculiar genetic and/or epigenetic events may contribute to the phenotypic skewing with the emergence of the PNC phenotype. However, a clear hypothesis on the mechanisms responsible for this phenotypic skewing is still lacking. We assumed that the biphasic nature of these entities represents a unique model to investigate the relationships between genetic alterations and their phenotypic manifestations. In this study we show that in HGGs with PNC features both components are highly enriched in genetic alterations directly causing cell cycle deregulation (RB inactivation or CDK4 amplification) and p53 pathway inactivation (TP53 mutations or MDM2/4 amplification). However, the PNC component displays further upregulation of transcriptional pathways associated with proliferative activity, including overexpression of MYC target genes. Notably, the PNC phenotype relies on the expression of EBF3, an early neurogenic transcription factor, which is directly controlled by MYC transcription factors in accessible chromatin sites. Overall our findings indicate that the concomitant presence of genetic alterations, impinging on both cell cycle and p53 pathway control, strongly predisposes GBM to develop a concomitant poorly differentiated primitive phenotype depending on MYC-driven EBF3 transcription in a subset of glioma stem-like progenitor cells.