Journal of Neuropathology and Experimental Neurology最新文献

Patients with incomplete spinal cord injuries can experience partial recovery of motor function, a phenomenon believed to be linked to neural plasticity, as evidenced by numerous studies in rodent models. However, postinjury synaptic plasticity in non-human primates, which better mirror human neuroanatomy, is less well understood. This study investigated the effects of T10 thoracic spinal cord hemisection or over-hemisection (transection beyond the posterior median sulcus) injuries in 7 rhesus monkeys. Analysis of lumbar motor neurons (MNs) innervating gluteal and crural muscles showed increased inhibitory projections and a shift in the excitatory-inhibitory balance. In the hemisection group, spontaneous recovery of motor function occurred, with lumbar MNs on the injured side receiving increased proprioceptive afferent inputs compared to the intact side, a phenomenon absent in the over-hemisection group. Additionally, the injured side of hemisected monkeys retained more descending monoaminergic fibers, possibly due to sprouting from contralateral intact fibers. These changes, including enhanced proprioceptive inputs and monoaminergic fiber sprouting, may contribute to spontaneous recovery after hemisection and represent potential targets for therapeutic strategies to improve recovery following spinal cord injury.

Glioblastomas (GBMs) are common malignant brain tumors that currently lack effective therapies. Therefore, exploring potential molecular regulatory mechanisms is crucial for developing new treatment strategies. Centromeric protein I (CENPI) is a member of the centromere protein family that affects the development of various cancers. Using the TCGA, we found that CENPI was significantly overexpressed in GBMs. CENPI knockdown repressed the proliferation, migration, and invasion ability of GBM cells in vitro. Gene enrichment analysis (GSEA) demonstrated that CENPI was enriched in arginine (Arg) and proline (Pro) metabolic pathways; CENPI knockdown inhibited the metabolism of these two amino acids in GBM cells. Through JASPAR prediction, dual luciferase and ChIP detection, FOXM1 was confirmed as a key transcriptional activator of CENPI. FOXM1 knockdown also depressed Arg and Pro metabolism in GBM cells thereby reducing their malignant phenotype whereas CENPI overexpression or exogenous addition of L-Arg and L-Pro restored the pro-cancer trend induced by FOXM1. Additional experiments demonstrated that the FOXM1/CENPI axis regulated the metabolism of Pro and Arg to promote GBM malignant progression modelled in vitro. In summary, our research indicated that FOXM1/CENPI signaling enhances the proliferation, migration, and invasion of GBM cells by promoting the metabolism of Arg and Pro.

Impaired proteasome function is associated with various neurodegenerative disorders that are hallmarked by neuroinflammation and neurodegeneration, including Alzheimer disease (AD); however, the relationships between these phenomena remain unclear. By utilizing a neuron-specific Psmc1 conditional knockout (cKO) mouse model in which one of the 19S proteasome is disrupted, we studied the effect of impaired proteasome function on neuroinflammation and neuronal death in the brain. We discovered that disrupting the 19S proteasome led to increased release of mitochondrial double-stranded DNA into the cytosol, upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon gene (STING), phosphorylated TBK1, and IRF3, and the downstream pro-inflammatory mediators, including STAT1, NF-κB, IL-1β, IL-6, and TNFα in the cKO mouse brains as compared to control brains. Importantly, we also observed reduced brain weight and elevation in levels of factors involved in necroptosis, ie the mixed lineage kinase domain-like (MLKL) protein, phosphorylated MLKL, and receptor-interacting protein kinases (RIPK) 1 and 3 in the cKO mouse brains. Together, our data suggest that proteasome dysfunction activates the cGAS-STING pathway and induces neuroinflammation and necroptotic neuronal death.

Marchiafava-Bignami disease (MBD) is a rare disorder, characterized by demyelination and cystic necrosis of the corpus callosum; it is typically seen in the setting of chronic alcoholism but may also occur with severe malnutrition. Clinical features include altered mental status, loss of consciousness, dysarthria, spasticity, ataxia, and seizures. To our knowledge, only 1 case of MBD with antemortem histology has been reported in the literature. Herein, we describe the clinical, radiologic, and histopathologic features of 2 new cases with corpus callosum demyelination consistent with MBD that were identified on antemortem biopsy; 1 was related to chronic alcoholism and the other was in the setting of severe malnutrition. Imaging studies showed that the initial lesions involved the full thickness of the corpus callosum with later evolution into the characteristic linear zone of necrosis in the mid-third of the corpus callosum. There was additional evidence of extracallosal involvement in both patients. Biopsies in both patients demonstrated numerous macrophages with myelin debris in their cytoplasm and relative axonal preservation, although there was some axonal loss in areas with the densest collection of macrophages. These findings highlight the clinical and radiographic progression in 2 cases of biopsy-proven MBD.

Postherpetic neuralgia (PHN) is a chronic, treatment-resistant pain condition following herpes zoster. Neuroinflammation plays a key role in its pathogenesis but the mechanisms are unclear. Cerebellin-1 (CBLN1), a synaptic protein of the C1q/TNF family, may modulate pain via interaction with GluD1. However, its role in PHN progression is also unclear. Herein, we investigated the role of CBLN1 in resiniferatoxin (RTX)-induced PHN in mice and uncover the mechanism. We found that CBLN1 was downregulated in the spinal dorsal horn of PHN model mice. Recombinant CBLN1 administration alleviated RTX-induced mechanical and thermal hypersensitivity, reduced proinflammatory cytokine levels, and decreased neuronal apoptosis. It also increased GluD1 expression. These effects were abolished by GluD1 inhibition, suggesting that CBLN1 exerts its protective role via the GluD1 pathway. Therefore, CBLN1 inhibits the inflammatory response by targeting GluD1 thereby alleviating RTX-induced postherpetic neuralgia in mice.

Astrocyte morphological changes and GFAP upregulation are hallmarks of traumatic brain injury (TBI) and quantifying these alterations in tissues is essential for assessing TBI severity and progression. However, conventional segmentation methods such as manual labeling or thresholding are labor-intensive and prone to artifacts. We systematically evaluated six deep learning segmentation architectures (U-Net, U-Net++, FPN, MANet, LinkNet, and PSPNet) paired with seven common backbones (ResNet50/101/152, MobileNetV2, VGG16/19, and EfficientNet-b4) for automated astrocyte segmentation. The performance was compared to segmentation tools such as Ilastik, Cellpose, and GESUnet. A dataset of 220 manually labeled GFAP-stained ferret brain images (631×486 pixels) was used, including 182 training images from a single TBI case and 38 test images from 18 ferrets under sham and TBI conditions. Models were trained with a learning rate of 0.0001 over 200 epochs and evaluated using metrics including Dice coefficient (DC or F1 Score), intersection over union (IoU), precision, accuracy, specificity, and sensitivity (or recall). Performance evaluation was conducted in two steps: 5-fold cross-validation and testing on a separate dataset. UNet++/VGG19 achieved the best results (IoU: 50.01%, DC: 65.48%), outperforming other configurations and existing tools (IoU: 28.00-39.86%, DC: 42.94-54.40%). This model demonstrated robust segmentation of complex astrocytic morphologies and enabled accurate quantification of astrocyte reactivity across experimental conditions, supporting the use of deep learning for automated pathology assessment in TBI.

MGMT promoter methylation is an important predictor of response to chemotherapy in adult-type diffuse gliomas. Currently, MGMT promoter methylation assessment requires formalin-fixed, paraffin-embedded (FFPE) tissue. We developed a droplet digital PCR (ddPCR) MGMT assay performed on bisulfite converted DNA utilizing primers targeting CpG positions with known clinical utility, which we validated against DNA methylation array (98.7% concordance). Smear preparations are routine for intraoperative neurosurgical consultation; thus, we sought to validate ddPCR using smear preparations. Thirty-six smears were collected during intraoperative consultation. For the first 28 samples, DNA from smears was extracted and bisulfite converted, and MGMT promoter methylation was quantified by ddPCR. These results were compared to DNA methylation array. For the final 8 samples, slides were H&E-stained and cover slipped for cellularity assessment prior to DNA extraction and directly compared with corresponding FFPE specimens. The smear ddPCR method showed concordance in 81.6% of cases, with a sensitivity of 85%, specificity of 100%, positive predictive value of 100% and negative predictive value of 81.3%. This novel approach will reduce turnaround time (approximately 2 days) over conventional MGMT analysis with FFPE and could provide clinically pertinent information for treatment planning and clinical trial enrollment options prior to discharge of the patient.