Acta Neuropathologica Communications最新文献

Introduction: Dedifferentiated (DC) and poorly differentiated chordomas (PDC) are rare, aggressive chordomas with a significantly worse prognosis than conventional chordomas (CC). The molecular mechanisms driving them remain poorly understood.

Methods: Matched primary CC and recurrent DC cryopreserved samples from one patient were analyzed with whole-exome sequencing (WES). Samples from three additional DCs and one PDC underwent targeted sequencing of cancer-related genes. Furthermore, 102 CC cases - 32 novel and 70 from literature, were analyzed. Functional and survival analysis was performed.

Results: WES revealed striking genomic changes during progression from CC to DC, with the number of somatic mutations increasing from 211 in primary to 430 in the recurrent DC; recurrence acquired TP53 and BRCA1 deleterious mutations, along with copy-number alterations, including loss of 6q containing the TBXT locus. Targeted sequencing identified TP53 mutations in 4/5 DC&PDC cases compared to 1/102 cases in combined CC cohorts (p = 2.7×10^-5, OR=162.9). In 3 recurrent DC samples with TP53 variant, presence of the mutation was assessed in primary CC sample and in neither, this variant was found. Literature review revealed TP53 mutations in 9/23 (39%) DC&PDC cases versus 5/445 (1.24%) CC cases. Survival analysis demonstrated that TP53 mutations confer a significantly worse prognosis in DC patients (p = 0.03).

Conclusion: TP53 mutations are acquired during chordoma progression and are associated with an aggressive phenotype; TP53 sequencing could serve as a prognostic and potentially predictive biomarker in aggressive chordomas.

Vincristine is an essential chemotherapy agent administered for various pediatric cancers including acute lymphoblastic leukemia (ALL). While multi-agent chemotherapy for pediatric ALL is highly curative, with survival approaching 95%, it carries the risk of irreversible neurocognitive late effects. Vincristine is known to cause peripheral neuropathy, but its relationship to brain toxicity remains understudied. We investigated vincristine-mediated brain toxicity in young mice lacking Sarm1, a gene whose deletion protects against vincristine-induced peripheral neuropathy. Littermate wildtype and knockout mice were randomly assigned to saline or vincristine groups. In vivo MRI was performed from childhood to early adulthood to measure brain structure volumes, followed by ex vivo diffusion tensor imaging (DTI) to assess microstructural changes. In a separate cohort, electron microscopy (EM) quantified axon morphology in the sciatic nerve and corpus callosum. Vincristine induced significant volume reduction across the brain, while Sarm1 knockout reduced loss in both grey and white matter. Several regions, including the amygdala and dentate gyrus, showed near-complete recovery in knockouts. DTI revealed limited changes with no genotype differences. EM demonstrated vincristine-induced axon morphology alterations in wildtype mice in both the sciatic nerve and corpus callosum. Sarm1 knockout rescued sciatic nerve morphology but not corpus callosum axons. These findings suggest that SARM1-mediated peripheral axon damage may contribute to vincristine-induced brain volume deficits, whereas brain axons may be affected through distinct, SARM1-independent mechanisms. These results suggest a link between vincristine-induced peripheral axon damage and alterations in brain development, with implications for neurocognitive deficits experienced by ALL survivors. Our results suggest that mitigating vincristine-induced peripheral neuropathy may also help reduce neurocognitive deficits in pediatric patients undergoing vincristine treatment.

The nervous system evolved a variety of connections and neuron types to sustain diverse functions. While challenging, unlocking the universal mechanisms that support neuron integrity can be addressed in giant axonal neuropathy (GAN), a rare and fatal disease with broad deterioration of the nervous system. Here, we describe a new mouse strain that recapitulates key aspects of the GAN pathology following the introduction of a disease-causing mutation in GAN. Unlike previous GAN knock-out mice which show no overt phenotype, GAN^A49E/A49E mice exhibit early sensory-motor deficits and ataxia, giant axons and demyelination which, together with increased abundance, dramatic compaction and disorganization of neurofilaments across the nervous system, mimics the human disease. Using this model, we uncover novel alterations within neuromuscular junctions and muscles that might contribute to GAN pathogenesis. Interestingly, we pinpoint a sex bias whereby females show more severe histopathological damage and disease severity. Altogether, the GAN^A49E strain provides the first robust rodent model for GAN, recapitulating the symptoms and histological hallmarks of the human pathology. This model will be invaluable when investigating the cellular and molecular mechanisms that uphold neuron integrity along with effective therapies for GAN.

Dysfunction of the glymphatic system (GS), a brain-wide waste clearance pathway dependent on polarized aquaporin-4 (AQP4) water channels on astrocytic endfeet, is increasingly recognized as a critical mechanism in both neurodegenerative diseases and brain tumors. In Alzheimer's (AD) and Parkinson's (PD) diseases, impaired glymphatic function leads to the accumulation of neurotoxic proteins, including amyloid-β (Aβ), tau, and α-synuclein (α-syn). Contributing factors include loss of AQP4 polarization, reduced arterial pulsatility, genetic risks (e.g., APOE4, FAM171A2 mutations), and sleep disturbances. These functional impairments can be quantified using neuroimaging biomarkers such as the diffusion tensor imaging along the perivascular space (DTI-ALPS) index and choroid plexus volume (CPV), which correlate with pathological burden and clinical decline, though the direct physiological interpretation of these metrics requires further validation. Conversely, in glioblastoma and other brain tumors, mechanical compression and lactate-driven acidosis obstruct perivascular fluid transport, promoting an immunosuppressive tumor microenvironment that limits T-cell infiltration and confers therapeutic resistance. Here, too, glymphatic dysfunction is reflected by a reduced ALPS index, which correlates with tumor grade, peritumoral edema, and survival. Emerging therapeutic strategies aimed at restoring GS function include pharmacological interventions (e.g., circadian regulators, AQP4 modulators), non-invasive techniques (e.g., cervical lymphatic stimulation, gamma stimulation, exercise), and surgical approaches (e.g., lymphatic-venous anastomosis). Advances in multimodal MRI and artificial intelligence (AI)-enhanced analytics further support novel diagnostic capabilities. This review highlights the dual role of the GS across neurological disorders and underscores its potential as a therapeutic target for enhancing waste clearance and immune modulation. However, significant challenges remain, including the validation of human biomarkers, elucidating bidirectional tumor-glymphatic crosstalk, and translating preclinical discoveries into clinical practice.

Spinal hemangioblastomas (sHB) are rare vascular tumors, with distinct clinical courses between von Hippel-Lindau (VHL)-associated and sporadic cases. The MIB-1 labeling index has been proposed as a surrogate marker for tumor proliferation, but its prognostic value remains unclear in this context. In this subgroup analysis from a multicenter retrospective study, we analyzed 116 primary sHB patients with available MIB-1 indices. Patients were stratified by VHL status. Statistical comparisons included ROC analyses for local progression-free survival (PFS) prediction and Kaplan-Meier survival curves for local PFS, stratified by a MIB-1 index cut-off derived from Youden's index. The MIB-1 index was significantly lower in VHL-associated tumors compared to sporadic ones (mean 2.17% vs. 3.02%, p = 0.008). In VHL-associated sHB, a higher MIB-1 index (≥ 2%) correlated with an increased risk of local tumor progression (AUC 0.74, 95% CI 0.49-0.98), whereas this was not observed in sporadic cases (AUC 0.56, 95% CI 0.23-0.88). Kaplan-Meier analysis showed that VHL patients with MIB-1 ≥ 2% had significantly shorter PFS (p = 0.05), while no significant association was found in sporadic tumors (p = 0.87). Our findings suggest that while VHL-associated sHB exhibit lower proliferative indices overall, elevated MIB-1 labeling indices might serve as a prognostic marker of shorter local PFS in this subgroup. In contrast, MIB-1 index appears to have limited prognostic relevance in sporadic sHB. These results highlight the importance of further molecular stratification and proliferation assessment in sHB to better inform clinical decision-making.