Brain Pathology最新文献

The fifth edition of the WHO classification of CNS Tumors (WHO CNS5) has revised the diagnostic and grading criteria for Adult-type Diffuse Gliomas (ADGs) by integrating molecular parameters with histologic features. Conducting molecular testing for most ADGs is now crucial in fulfilling the WHO CNS5 diagnostic criteria. However, due to additional costs and technical barriers, implementing molecular diagnostics is often not feasible in Low-Income Countries (LICs) and Lower Middle-Income Countries (LMICs). Therefore, practical approaches are needed for diagnosis in resource-restrained settings. Hence, the Asian Oceanian Society of Neuropathology (AOSNP), through the ‘ADAPTR’ (Adapting Diagnostic Approaches for Practical Taxonomy in Resource-Restrained Regions) initiative, aimed to provide resource-stratified recommendations for diagnosing ADGs based on available resources while adhering to the WHO guidelines as much as possible. ADAPTR identified different resource levels (RLs) of diagnostic pathology services, ranging from RL I to RL V, with RL I to RL IV being applicable to the LMICs, and provides recommendations for a ‘Histology-oriented integrated diagnosis format’ for each tumor type at different RLs. In addition, diagnostic flow charts for ADGs have been generated to suit these RLs. The emphasis is mainly on using histopathological approaches with immunohistochemistry, while molecular testing recommendation is categorized as ‘can be considered’, ‘highly recommended’ or ‘obligatory’, to reach the next level diagnosis. In each RL, either a WHO CNS5 diagnosis with an accompanying CNS WHO grade or an ADAPTR descriptive diagnosis with an associated ADAPTR histologic grade is provided, depending on the context. ADAPTR recommendations are therefore a practical adaptation of the WHO CNS5 guidelines that will suit routine diagnostic practices in resource-restrained regions.

Astrocytes contribute in critical ways to the pathophysiology of epilepsy not only through trophic support but also through the regulation of neuronal excitability by modulating glutamate, γ-aminobutyric acid (GABA), adenosine triphosphate (ATP), and adenosine levels. Calponin-3 is an actin-binding protein that is enriched in the brain. We have previously reported that increased calponin-3 expression is correlated with epileptic seizures. In the present study, we revealed that in the hippocampus of epileptic mice models, increased calponin-3 protein expression was correlated with the expression of the astrocytic marker glial fibrillary acidic protein (GFAP). Calponin-3 overexpression in the hippocampus significantly increased susceptibility to epileptic seizures, whereas calponin-3 downregulation was associated with reduced spontaneous recurrent seizures in mice. Furthermore, changes in calponin-3 levels corresponded to astrocyte activation in both mice and cultured human astrocytes and were associated with changes in the protein levels of adenosine kinase (ADK) and equilibrative nucleoside transporter 1 (ENT1), which are two key regulators of adenosine metabolism that have been shown to play critical roles in epileptogenesis. Collectively, our findings suggest that calponin-3 may regulate astrocyte-mediated adenosine metabolism and could represent a potential therapeutic target for epilepsy.

This study leverages x-ray phase-contrast tomography (XPCT) for detailed analysis of neurodegenerative diseases, focusing on the three-dimensional (3D) visualization and quantification of neuropathological features within fixed human postmortem tissue. XPCT with synchrotron radiation offers micrometer and even sub-micron resolution, enabling us to examine intra- and extraneuronal aggregates and inclusions such as Lewy bodies (LBs), granulovacuolar degeneration (GvD), Hirano bodies (HBs), neurofibrillary tangles (NFTs), β-amyloid plaques, and vascular amyloid deposits in three dimensions. In the reconstructions, we identified the highest electron densities in Hirano and LBs, while NFTs exhibited no significant increase in XPCT contrast. Using cutting-edge high-resolution x-ray synchrotron beamlines, we were now able to detect even detect subcellular differences in electron densities found in GvD. Small-scale inhomogeneities of the electron density were also detected in LBs, potentially relating to inclusions of organelles. Additionally, we reveal here a peculiar 3D geometry of HBs and demonstrate the co-occurrence with GvD in the same neuron. These findings underscore the potential of XPCT as a powerful, label-free tool for spatially resolved neuropathological investigations, opening new avenues for the systematic 3D characterization of inclusions and aggregates in neurodegeneration.

Intracranial mesenchymal tumors (IMTs) with FET::CREB fusion are newly recognized molecular entities, provisionally classified into subgroups A and B. Although Group B has been partially characterized, the clinicopathological and molecular heterogeneity of Group A remains poorly defined. This study aimed to conduct an integrated analysis of 6 newly diagnosed and 20 previously reported IMTs with FET::CREB fusion. Notably, Group A was further stratified into two distinct entities A1 and A2 based on unsupervised methylation profiling. Compared to Group A1, Group A2 demonstrated significantly shorter progression-free survival (PFS), a higher proportion of male patients, and less frequent occurrence of myxoid-rich stroma. Amplification of 10p15.3 was frequently observed in Group A2. Furthermore, GLUT-1 could serve as a potential diagnostic indicator in IMTs with FET::CREB fusion. Overall, we identified a new subgroup of IMTs with FET::CREB fusion with poor PFS and distinct clinicopathological and molecular features, offering actionable insights to refine therapeutic strategies and improve risk stratification in this emerging diagnostic category.

Focal cortical dysplasia (FCD) is a neurodevelopmental malformation that often manifests as medically refractory epilepsy. A key histological hallmark of FCD type II is the presence of cytomegalic dysmorphic neurons (CDNs), which are considered to be major contributors to cortical network hyperexcitability. However, the relatively low frequency of CDNs within resected lesions has challenged their unbiased molecular characterization. Here, we leverage deep learning approaches to objectively map key anatomical compartments of FCD IIb and guide regional spatial transcriptomic profiling. Using this approach, we generate an anatomical transcriptional catalog of type IIb FCD, and uncover non-canonical markers of signaling and neurotransmitter pathways in CDNs that may serve as new therapeutic targets for this debilitating disorder.

Glycosylation is the most common form of post-translational modification in the brain and becomes significantly altered in the context of neurodegeneration. One notable alteration is an enrichment of terminal sialic acid (SA) modifications. Previous studies provide evidence of increased sialylation on microglia, the innate immune cell of the brain, in Alzheimer's disease (AD), particularly near amyloid beta plaques. Yet, there is little understanding of the relationship between SA and other amyloid beta-related diseases like Cerebral Amyloid Angiopathy (CAA). Nearly half of all AD cases have CAA; thus, it is critical to understand the relationship between amyloid pathology and SA modifications. The present study aimed to overcome this gap in knowledge by investigating sialylation patterns in AD cases with CAA compared with CAA-negative AD cases and amyloid-negative control cases. The localization of SA modifications was investigated in the frontal cortex of 30 post-mortem cases with or without diagnoses of AD and/or CAA. Quantitative digital pathology analyses were used to determine regional SA differences in parenchymal and leptomeningeal blood vessels. First, we found no difference in intravascular amyloid-beta levels between the parenchymal and leptomeningeal vessels of AD with CAA cases, suggesting no regional differences in this amyloid aggregation. Next, there was a visual increase in microglia sialylation surrounding parenchymal blood vessels in the CAA cases. Notably, there were significant differences in intravascular SA levels across the three comparison groups. AD cases with CAA had significantly greater sialylation levels in both the parenchymal and leptomeningeal vessels compared with the AD-only and control groups. This is a novel finding that supports the consideration of glycosylation changes that contribute to worse pathological outcomes in AD with CAA.

Vasculitic neuropathy remains challenging to diagnose and monitor because of its heterogeneous clinical and laboratory presentation. Blood-based biomarkers indicating nerve damage could serve as an additional diagnostic tool to ensure early diagnosis, precise therapeutic monitoring, and a more targeted anti-inflammatory treatment. A potential marker for this purpose is neurofilament light chain (NfL), a marker of neuroaxonal damage that is used as a biomarker in several diseases of the central and peripheral nervous system. NfL has also been suggested to reflect disease activity in patients with vasculitic neuropathy. However, its biodynamics and link to degeneration of peripheral nerve tissue remain unconfirmed. To investigate the usefulness of NfL as a marker of peripheral nerve damage in this context, we retrospectively assembled a cohort of 35 patients undergoing sural nerve biopsies (including patients with vasculitic neuropathy and other neuropathies). We then measured NfL in serum samples cryoarchived at the time of biopsy and correlated NfL levels with histological parameters. For our histological analysis, we quantified parameters of acute axonal degeneration and chronic axonal loss using a combination of manual, threshold-based, and supervised learning-based analyses. We found a significant positive correlation between parameters of acute axonal degeneration and serum-NfL levels that persisted after adjusting for age and concomitant central nervous system disease. We did not find a similar correlation with parameters of chronic axonal loss quantified in nerve biopsies. These findings support the value of NfL as a marker for acute axonal degeneration in patients with vasculitic neuropathy.

To bridge between detailed post-mortem neuropathological assessments and Magnetic Resonance Imaging (MRI), we have created and share a three-dimensional (3D) account of an entire human brain with an intermediate Alzheimer's disease neuropathologic change. We combined multimodal imaging, using cryosectioning, histology, immunocytochemistry, and quantitative ultra-high field 7 Tesla (T) magnetic resonance imaging (MRI) at submillimeter resolution. Amyloid-β and phosphorylated-tau immunoreactivity, cell soma, and nerve fibers were visualized, together with quantitative MR parameters. All data were coaligned with at 200 μm resolution and are openly shared. The use of whole-brain sections allows for a detailed assessment of neuropathological alterations, revealing clear differences between the left and right hemispheres in terms of pathological load of amyloid-β and phosphorylated-tau in a single brain showing Alzheimer's disease neuropathologic change. This resource opens the door for a combination of detailed correlations between neuroimaging and neuropathological microscopy observations, as well as for detailed MRI validation.

The Consortium to Inform Molecular and Practical Approaches to Central Nervous System Tumor Taxonomy (cIMPACT-NOW) updates provide guidelines for the diagnosis of central nervous system (CNS) tumors and suggestions for future World Health Organization (WHO) classification. Following publication of the fifth edition WHO Classification of CNS Tumors (WHO CNS5) in 2021, the cIMPACT-NOW working group “Clarification” reviewed WHO CNS5 and prioritized two topics for further elucidation: (a) distinction of Glioblastoma, IDH-wildtype from Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype and (b) clarification of subgroups of posterior fossa (PF) ependymal tumors. Recommendations regarding the IDH- and H3-wildtype diffuse high-grade gliomas include: (1) use caution assigning CNS WHO grade 4 (diagnosis of Glioblastoma, IDH-wildtype) to a “TERT promoter only”, histologically low-grade, IDH-wildtype tumor; (2) EGFR gene amplification and +7/−10 chromosome copy number alterations should not be used as solitary defining features for diagnosing high-grade gliomas as Glioblastoma, IDH-wildtype in patients <40 years of age; (3) Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype should be considered in the differential diagnosis in adults, especially those <40 years of age; (4) PDGFRA alteration, EGFR alteration, or MYCN amplification count as key molecular features of Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype only in patients <25 years. Guidelines for improved diagnosis of posterior fossa ependymal tumors include: (1) immunohistochemical demonstration of nuclear EZHIP supports classification as PF group A ependymoma; (2) a PF ependymoma with retained nuclear H3 K27me3 expression and no nuclear EZHIP overexpression for which DNA methylation profiling is not performed should be considered as PF ependymoma, “not otherwise specified”; (3) for emerging tumors not included in WHO CNS5, “not elsewhere classified” (NEC) can be added to the diagnosis. Of note, these recommendations are not formal changes to the WHO definitions and diagnostic criteria but are intended to provide diagnostic guidance in advance of WHO CNS6.