Acta Neuropathologica最新文献

We examined whether total joint arthroplasty (TJA) is associated with increased metal accumulation in the brain and histopathologic changes of Alzheimer’s disease. We measured ultra-trace metal concentrations (aluminum, chromium, cobalt, manganese, molybdenum, nickel, titanium, and vanadium) on postmortem frozen tissues of the occipital lobe of 177 subjects (89 non-TJA and 88 TJA) using a triple-quadrupole inductively coupled plasma mass spectrometry and correlated elemental concentrations to the degree of Alzheimer’s disease neuropathic change (ADNC). To effectively assess the relationship between TJA and brain metal concentrations, subjects with and without TJA were matched for baseline clinical characteristics and showed no difference in postmortem Alzheimer’s disease neuropathic change. TJA subjects had increased concentrations of cobalt and titanium and both metals were associated with increased amyloid plaques. In both the TJA and non-TJA subjects, increased concentrations of cobalt, titanium, manganese, and molybdenum were associated with increased odds of neuritic and diffuse plaques. Lastly, the brain’s inter-metal correlations were altered in the presence of increased neuritic plaques and/or implantable artificial joints. These findings suggest that metal concentrations and homeostasis vary in presence of TJA.

In Alzheimer’s disease (AD), microglia form distinct cellular aggregates that play critical roles in disease progression, including Aβ plaque-associated microglia (PaM) and the newly identified coffin-like microglia (CoM). PaM are closely associated with amyloid-β (Aβ) plaques, while CoM are enriched in the pyramidal layer of the CA2/CA1 hippocampal subfields, where they frequently engulf neurons and associate with tau-positive tangles and phosphorylated α-synuclein. To elucidate the role of these microglial subtypes, we employed high-content neuropathology, integrating Deep Spatial Profiling (DSP), multiplex chromogenic immunohistochemistry and confocal microscopy, to comprehensively map and characterise their morphological and molecular signatures, as well as their neuropathological and astrocytic microenvironments, in AD and control post-mortem samples. PaM and PaM-associated astrocytes exhibited signatures related to complement system pathways, ErbB signalling, and metabolic and neurodegenerative processes. In contrast, CoM displayed markers associated with protein degradation and immune signalling pathways, including STING, TGF-β, and NF-κB. While no direct association between CD8 + T cells and either microglial type was observed, CD163 + perivascular macrophages were frequently incorporated into PaM. These findings provide novel insights into the heterogeneity of microglial responses, in particular their distinct interactions with astrocytes and infiltrating immune cells, and shed light on specific neurodegenerative hotspots and their implications for hippocampal deterioration in AD.

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.