Journal of Neuropathology and Experimental Neurology最新文献

Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment (TME) of human meningiomas. They exhibit different functional phenotypes that contribute either to an anti-inflammatory and anti-tumor response (M1 phenotype), or an immunosuppressive and pro-tumor response (M2 phenotype). In meningiomas of cats, the specific role of TAMs in determining prognosis and post-surgery outcome remains unclear. This study aimed to characterize the macrophage population in feline meningiomas, differentiate M1 from M2 phenotype, and investigate the relationship of the results to prognosis. Fifty-seven surgically removed feline meningiomas were studied. Immunolabeling was performed on formalin-fixed paraffin embedded samples with primary antibodies anti-MAC387 (M1 macrophage), CD163 and CD204 (M2 macrophage), Iba1 (pan-macrophage), and Ki67. The cells in all cases expressed Iba1 and CD163, while MAC387 and CD204-expression varied. Moreover, macrophages were more numerous in high-grade tumors across both M1 and M2 phenotypes. Although none of the markers were predictive of recurrence on Cox models (P > .05), based on the significant association between M2 CD163-positive macrophages and high-grade tumors, and their shorter post-surgery recurrence-free times, the results suggest that M2 macrophages might play a role in the behavior and prognosis of feline meningiomas.

We sought to validate previously proposed immunohistochemistry (IHC) markers that classify meningiomas into 4 molecular groups (MG) with superior predictive ability of progression compared to World Health Organization (WHO) grade. IHC for target proteins S100B, SCGN, ACADL, and MCM2 corresponding to molecular groups 1-4, respectively, was performed on 85 surgically resected primary meningiomas across WHO grades 1-3. Additional IHC for FOXM1 was included as a potential predictor of aggressiveness. All slides were digitally analyzed for percent of cells staining positive. The primary outcome measure was time to progression. In addition, 9% cell positivity was identified as the optimal cutoff although 31% of tumors could not be classified and only 53% (n = 45) were positive for a single, unique molecular group. Within these uniquely categorized tumors, there was no significant difference in time to progression between MG1-2 versus MG3-4 (P = .7). In a separate analysis, high staining of MCM2 (MG4) was associated with shorter time to progression (P = .02). Although the previously proposed IHC targets to identify molecular groups were not meaningfully reproducible in our analysis, MCM2 staining alone correlated with shorter time to progression across all grades and may be a simple, cost-effective IHC marker to identify clinically aggressive meningiomas.

Biallelic variants in sorbitol dehydrogenase (SORD) have been reported to be a major cause of autosomal recessive distal hereditary motor neuropathy (dHMN). In this study, the clinical and pathological features of 10 patients with SORD gene-related dHMN are reported. Homozygous c.757delG variant was detected in 6 patients while c.757delG, c.786 + 1G>A, c.218C>T, and a novel c.104T>A compound heterozygous variants were observed in the others. Serum sorbitol, xylitol, and D-arabinitol were measured by gas chromatography-mass spectrometry; increased sorbitol and xylitol, and decreased D-arabinitol were identified. Sural nerve biopsies showed mild loss of large, myelinated fibers, and a few thin myelinated fibers. Skeletal muscle biopsies exhibited a neurogenic pattern with vacuoles, tubular aggregates, and abnormal mitochondria. Proteomic analyses of muscle tissue were performed to explore potential mechanisms. Complex I deficiency was dominant in the proteomic analysis and the malic acid/oxaloacetic acid ratio was significantly higher in the patients than in controls. In summary, SORD gene-related dHMN is a systemic disorder of carbohydrate metabolism with subclinical myopathologic changes, including tubular aggregates and vacuoles. Mitochondrial complex I deficiency, may be a key mechanism in SORD gene-related dHMN.

Current therapies for multiple sclerosis (MS) exert immunomodulatory effects but do not directly repair central nervous system (CNS) damage. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy for MS, as they have been shown to promote myelin repair. Genetic modifications of MSCs have been reported to enhance their therapeutic efficiency in neurodegenerative diseases. This study aimed to investigate the therapeutic potential of MSCs engineered with secreted klotho (s-KL) in enhancing remyelination by mature oligodendrocytes in an experimental autoimmune encephalomyelitis (EAE) model in mice. The results showed that MSCs carrying s-KL alleviated clinical signs and reduced inflammation and demyelination in the CNS more significantly than MSCs. Compared to MSCs, s-KL MSCs also exhibited an enhanced capacity for differentiation and maturation of oligodendrocytes, as demonstrated by increased mRNA and protein expression of Olig2 and Nogo-A in the CNS of mice with EAE. These findings indicate that overexpression of s-KL enhances the therapeutic potential of MSCs to induce remyelination and may represent a novel approach to improve the efficacy of stem cell-based therapy in MS.

Digital histology offers a more objective, continuous definition of neuropathological severity than traditional staging systems, but its reliability remains underexplored. We calculated regional percentage areas occupied by phosphorylated tau (p-Tau, AT8), amyloid-β (Aβ, NAB228), and phosphorylated α-synuclein (p-αSyn, 81A) pathology in 24 autopsied cases with varying degrees of Alzheimer disease neuropathological change and Lewy body disease (LBD) using manual and automated immunostaining methods to investigate variability across protocols. We then compared natural log-transformed percent area occupied values (ln%AO) to blinded ordinal severity scores, Braak stages, Thal phases, and McKeith LBD stages. p-Tau ln%AO from methodologically similar runs had the highest correlations (R2 = 0.91-0.95, β  =  0.95-0.97 for manual and automated methods, respectively); p-αSyn ln%AO from disparate immunostaining methods had the lowest (R2 = 0.16-0.34 β  =  0.40-0.59). p-Tau and Aβ ln%AO increased regionally with higher Braak and Thal stages (p-Tau: z = 2.06 P = .04. Aβ: z = 3.70 P < .001). Regional p-αSyn ln%AO increased from limbic to neocortical stages (z = 5.86 P < .001); amygdala-predominant type LBD cases peaked in the amygdala and dropped in other limbic regions. These findings show the potential to quantify differences in p-Tau, Aβ, and p-αSyn pathologies using digital histological methods in single-center studies.