Brain Pathology最新文献

Dysregulation of the complement system plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). In post-mortem AD brains, complement is deposited in and around amyloid plaques, and peri-plaque complement activation drives synapse loss in AD mouse models. Studies to date have focused on amyloid pathology; however, aggregated tau is also involved in neuronal loss in AD. Primary tauopathies are characterised by tau pathology in the absence of amyloid. The role of complement in human tauopathies remains largely unexplored. Here, we address this knowledge gap by assessing complement activation in human tauopathy brains using immunohistochemistry and well-characterised detection tools. Post-mortem pre-frontal cortex was obtained from three tauopathy subtypes, Pick's disease (PiD), globular glial tauopathy (GGT) and corticobasal degeneration (CBD) (3–5 cases each). C1q and the complement activation markers iC3b and terminal complement complex (TCC) were assessed by immunohistochemistry and were elevated in all tauopathy cases compared to controls, with C1q and C3b/iC3b deposition particularly prominent on neurons, demonstrating complement activation on these cells. TCC deposits were present on and adjacent neurons in all tauopathy brains examined and were significantly increased compared to controls in CBD and GGT. Uniquely in GGT, abundant deposition of C3b/iC3b on myelin was also observed, implicating complement in GGT-associated demyelination. To validate these findings, complement proteins (C1q, C3, factor B), regulators (factor I, clusterin) and activation products (Ba, C3b/iC3b, and TCC) were measured in brain homogenates by ELISA, revealing significant elevation in C3b/iC3b, Ba, and FI in CBD and GGT cases compared to controls. Together, our data demonstrate complement activation on and adjacent neurons in post-mortem brains from all tauopathy subtypes.

Patients with late-onset (LO) multiple system atrophy (MSA), whose initial symptoms appear at age 75 years or older, are more common than previously assumed, but their clinicopathological characteristics remain unclear. We aimed to clarify the clinicopathological features of LO-MSA. Of 102 patients with autopsy-confirmed MSA, 5 were identified as having LO-MSA and 24 as having usual-age-onset MSA (UO-MSA) with a similar disease duration. On the basis of previous reports, we defined UO-MSA as the appearance of initial symptoms between the ages of 55 and 65 years. We compared the clinical pictures of the two groups and assessed their histopathological features using quantitative and semi-quantitative methods. The investigated features included the severity of degeneration in the striatonigral (StrN) and olivopontocerebellar (OPC) systems, the numbers of neurons in the brainstem autonomic and spinal intermediolateral nuclei, and the density of α-synuclein-immunopositive inclusions in the putamen, inferior olivary nucleus, and ventrolateral medulla (VLM). Most patients with both LO-MSA and UO-MSA exhibited the MSA-olivopontocerebellar atrophy (OPCA) subtype (3/5 and 18/24, respectively). The median disease duration for LO-MSA patients was 5.5 years, which was comparable to that for patients in our cohort who had developed symptoms below 75 years of age. Pathologically, degeneration of the StrN and OPC systems in LO-MSA was less severe than that observed in UO-MSA. Quantitative analysis revealed better preservation of neuron numbers in the brainstem autonomic nuclei in LO-MSA than in UO-MSA, with a significantly higher number of serotonergic neurons in the VLM (p = 0.013). The density of α-synuclein-positive inclusions in the putamen was significantly lower in LO-MSA than in UO-MSA (p < 0.001). Neuronal degeneration in LO-MSA may progress more slowly than in UO-MSA. Accordingly, the prognosis of LO-MSA may not necessarily be less favorable than that of MSA generally, especially with appropriate care.

Thank you very much for presenting this instructive case, which demonstrates classical features of anti-synthetase syndrome (ASS) through its clinical triad (arthritis, myositis, and interstitial lung disease) and characteristic muscle pathology (perifascicular necrosis with MHC-II overexpression). We would like to provide the following insights based on our experience:

In our previous studies, when anti-Ha antibodies were identified via immunoblotting, we further validated results using cell-based assays (CBA) and immunoprecipitation (IP). However, significant discrepancies were observed across these methods. For instance, some samples showed strong positivity in IP but weak reactivity in CBA, while others exhibited faint IP signals despite prominent immunoblot bands. We hypothesize that these inconsistencies may arise from: (1) variations in the conformational structure of the Ha-antigen complex across different platforms; (2) technical differences in antigen presentation and assay conditions. While IP remains the current gold standard, our findings highlight the need for harmonized protocols to improve cross-method reproducibility.

Although the classic ASS triad and perifascicular necrosis are well recognized, our cohort of anti-Ha-positive patients rarely presented with such prototypical features as described in this report by Marie-Thérèse Holzer et al. Potential explanations for this divergence include: (1) Selection bias: there might be some differences in patient referral patterns between neuromuscular centers (focused on myopathy subtypes) and rheumatology centers (prioritizing systemic manifestations); (2) Genetic predispositions: Population-specific HLA haplotypes or modifier genes may influence phenotypic expression.

We aim to publish our previous findings to raise awareness of anti-Ha-associated ASS heterogeneity and encourage multicenter collaborative efforts to validate these observations across diverse populations. Enhanced recognition of anti-Ha antibody cases through interdisciplinary collaboration will ultimately refine the clinicopathological profile of this rare ASS subtype and optimize therapeutic strategies.

Bing Zhao: Writing—Original draft preparation. Lining Zhang, Tingjun Dai: Writing—Reviewing and Editing.

Comparative pathology boards bring together anatomic pathologists with expertise in canine and human histology to identify shared features, including immune or TME components, tumor subtypes, or prognostic tissue biomarkers. This article summarizes feedback to improve future initiatives and enhance the translational relevance of comparative oncology for human patients.

A 39-year-old woman, with no significant medical history, presented progressively worsening behavioral problems. Brain MRI revealed a nodular lesion in the pineal region, with a necrotic center, heterogeneous peripheral enhancement, and an ependymal spread to the floor of the third ventricle and posterior part of the bulb (Figure 1). Germ cell markers (HCG, AFP) in CSF were negative. Because of the development of obstructive hydrocephalus, a ventriculocisternostomy with endoscopic ventricular biopsy (three biopsies from 1 to 5 mm) was performed, followed by a resection 1 month later. The surgical specimen was composed of fragments with a total weight of 3 g (Box 1).

Histologically, the lesion had a predominantly piloid morphology with some radial perivascular arrangements on an abundant myxoid background. Most cells showed an eosinophilic cytoplasm and bi- or multipolar extensions as well as round to angular nuclei with homogeneous chromatin. Floret-like multinucleated cells were present. In certain places, the glial cells were arranged in cords, giving the tumor a chordoid morphology. Cytonuclear atypia ranged from mild to pronounced. Mitotic index was 4 mitoses per 10 fields. Endothelial vascular proliferation and necrotic areas were present. No Rosenthal fibers or granular bodies were found. Tumor cells were immunopositive for GFAP and OLIG2 as well as focally for synaptophysin, but were negative for CD34, TTF1, EMA, NeuN, and Chromogranin A. ATRX, H3K27me3, INI1, and BRG1 expression was retained (Figure 2).

No mutation or gene rearrangement was detected by next-generation sequencing (NGS), RNA sequencing, or droplet digital PCR (FGFR1) in panel genes, including MAPK pathway genes (BRAF, KRAS, HRAS, and FGFR1-3). The DNA methylation array data, obtained using EPICv2 Beadchips, was analyzed using the DKFZ brain classifier v12.8 (https://www.molecularneuropathology.org/) and the resulting methylation profiles matched (calibrated score 0.99) with the methylation class of high-grade astrocytoma with piloid features (HGAP). The profiles were then clustered within the HGAP class using Uniform Manifold Approximation and Projection (UMAP). Copy number analysis showed homozygous deletion of the CDKN2A/CDKN2B loci (Figure 2).

High-grade astrocytoma with piloid features (HGAP).

Gliomas account for about 14%–22% of all pineal region tumors. They are mainly circumscribed low-grade astrocytomas, especially in children, and diffuse high-grade gliomas. The 2021 WHO classification has expanded the scope of circumscribed gliomas to include HGAP. This novel and rare glioma, mainly occurring in the adult cerebellum, has not been previously reported in the pineal region. This particular tumor, with a distinctive DNA methylation profile essential to the diagnosis, without specific histological or molecular hallmarks, may mimic other malignant or benign gliomas developing in the pineal region [1].

Before DN

During Parkinson's disease (PD), loss of brainstem-based pedunculopontine nucleus' (PPN) cholinergic neurons induces progressive postural-gait disability (PGD). PPN-deep brain stimulation inconsistently alleviates PGD, due to stereotactic targeting inaccuracies resulting from insufficiently detailed human PPN anatomical descriptions. Relatedly, rodent studies show rostro-caudal clustering of PPN-cholinergic neurons, reflecting functional sub-territories. We applied unbiased cerebro-bilateral 3-dimensional (3-D) stereology to post-mortem PPNs from PD versus neurological-control cases, to estimate total numbers of cholinergic neurons and describe their rostro-caudal distribution. Given ambiguous descriptions of the PPN's confines, we utilized two complimentary definitions of the PPN's anatomical boundaries. The first was based on the structure's gross anatomy, by considering the nucleus as a recognizable “channel” enclosed by distinct white matter fiber tracts (WMFT) encompassing the medial lemniscus, central tegmental tract and decussation of the superior cerebellar peduncle. Second, the PPN was recognized by its histological architecture, as a dense collection of cholinergic neurons (the “Ch5” group) that were immunoreactive for choline acetyltransferase (ChAT), the enzyme responsible for biosynthesis of the neurotransmitter acetylcholine. Many such ChAT-immunoreactive neurons were dispersed within the traversing tracks and hence the PPN's Ch5-based outlining method permitted their stereological capture while also allowing distinction between the PPN's two subnuclei, namely the pars compacta (PPNc) and pars dissipata (PPNd), based on subnuclei-specific cholinergic cytoarchitectural organization. We further reconstructed template data as 3-D renders, revealing gross morphological differences between control and PD-affected PPNs. PD brains revealed significant PPN cholinergic neuronal loss, particularly affecting the PPNd. Control cases showed bimodal clustering of cholinergic neurons, prominently affecting left-sided PPNs. Most PD cases revealed more severe cholinergic neuronal loss in right-sided PPNs, potentially driving symptom lateralization. Our study provides a comprehensive cholinergic cytoarchitectural atlas of the human PPN in health versus during PD.

Remyelination of cortical lesions in people with multiple sclerosis (pwMS) has been shown to be extensive. In this work, we aimed to assess whether postmortem quantitative MRI (qMRI) can help detect those areas. We imaged six fixed whole brains of deceased pwMS by 3T-MRI using magnetization transfer ratio (MTR, 570 μm isotropic), myelin water fraction (MWF, 1000 μm isotropic), quantitative T1 (qT1, 670 μm isotropic), quantitative susceptibility mapping (QSM, 330 μm isotropic) and radial diffusivity (RD, 1300 or 1400 μm isotropic) maps. Immunohistochemistry for myelin proteins was performed in 129 tissue blocks including the cortex and enabled the detection of cortical demyelination (DM), cortical remyelination (RM), and normal-appearing cortex (NAC). We identified 25 DM, 25 RM, and for each of these areas, a corresponding NAC near the lesion. Wilcoxon paired tests showed that: (a) qT1 and RD were higher and QSM lower in DM versus NAC (all p < 0.001), whereas RD was higher and QSM lower in RM versus NAC (p = 0.048 and p < 0.01 respectively); (b) mean qT1 in RM did not differ from mean qT1 in NAC (p = 0.074); (c) MWF and MTR were not different between DM and RM. We compared the delta between DM versus NAC (∆DM) and the delta between RM versus NAC (∆RM) using a Mann–Whitney test, in which RM showed a partial recovery of qT1 only (∆qT1 DM > ∆qT1 RM, p = 0.045). Mixed-effect models confirmed the findings obtained using univariate analyses. qT1 and QSM, but not RD, correlated with MBP intensity (r = −0.28, p < 0.01 and r = 0.29, p < 0.01 respectively). A Bonferroni correction was performed for multiple testing. Our data show that qT1 is altered in demyelinated but not in remyelinated cortical areas, while QSM and RD are affected by any cortical abnormalities. Accordingly, qT1 might be considered a potential imaging biomarker of cortical RM.