Acta Neuropathologica Communications最新文献

Previous studies have revealed four distinct epigenetic consensus pineoblastoma (PB) subtypes. The aim of this study was to confirm and further extend their respective genetic underpinnings. Cytogenetics of 83 PB were analyzed by high-resolution genome-wide molecular inversion probe analysis and methylation profiling. Seventy-nine cases were screened for mutations by next-generation DNA panel sequencing and for 25 samples mRNA expression was analyzed using NanoString. Additionally, 24 further pineal parenchymal tumors were analyzed. Clinical data of 63 patients was available. Our cohort consisted of 48 PB-miRNA1, 19 PB-miRNA2, 8 PB-MYC/FOXR2, and 8 PB-RB1 cases. PB-miRNA subtype tumors had characteristic alterations in microRNA-processing genes; DICER1 mutations (n = 19/64) and homozygous deletions of the DROSHA locus (n = 18/67) were most abundant, followed by DROSHA mutations (n = 12/64). Most frequent cytogenetic aberrations in PB-miRNA cases were chromosome 7 gains (n = 31/67) and chromosome 14 losses (n = 26/67, including 5 cases with copy-neutral LOH). The latter were significantly associated with DICER1 mutations (p < 0.001). OTX2 gain represented the most frequent alteration that occurred in 37/83 PB of all subtypes. In the PB-miRNA subtypes we identified cases with polyploid cytogenetics (n = 16/67). In contrast to previous publications, we did not find a difference in survival for the PB-miRNA subtypes, whereas PB-MYC/FOXR2 and PB-RB1 in infants showed a worse outcome. Epigenetically defined PB subtypes are characterized by distinct genetic events. Frequent gains of the oncogene OTX2 indicate a role in the pathogenesis of PB independent of its subtype.

Human chorionic gonadotropin (hCG) is a hormone that may be abnormally secreted in several tumour types, including intracranial germ cell tumours. In pineal region tumors, hCG is a key tumor marker. In fact, mild elevation typically suggests a germinoma with syncytiotrophoblastic cells, whereas a markedly elevated level indicates a choriocarcinoma or a mixed germ cell tumor with trophoblastic differentiation. While histopathological confirmation remains the diagnostic gold standard, the anatomical situation of the pineal gland makes biopsy very challenging. In certain situations, diagnosis may therefore rely on a constellation of clinical, radiological, and biochemical findings, including cerebrospinal fluid (CSF) β-hCG levels. However, the differential diagnosis of pineal region tumours includes other primary neoplasms of the pineal parenchyma, which differ markedly in both prognosis and therapeutic management. Here, we report two cases of pineoblastoma with unexpectedly elevated CSF β-hCG levels, which might have led to a misdiagnosis of intracranial germinoma. These cases highlight the need for the development of novel, non-invasive biomarkers to improve the diagnostic accuracy of intracranial tumours.

The presence of amyloid and tau pathologies is the pathological hallmark of Alzheimer's disease (AD). However, the presence of non-demented individuals with sufficient AD pathology indicates that AD-linked pathology does not always lead to dementia. The current view is that a non-demented (ND) individual with sufficient AD pathology represents an individual resilient to AD pathology. To gain insight about resilience to AD pathology, we examined the neuropathology in the brainstem monoaminergic (MAergic) neurons in the Nun Study participants with equally high Braak AD stage (V-VI) with dementia and without clinical dementia. Because MAergic pathology is thought to occur in response to cortical AD pathology, any differences in MAergic pathology between the AD and ND groups with similarly advanced AD pathology could reflect the resilience of MAergic neurons to cortical AD pathology. Examination of Locus Coeruleus (LC) and/or Raphe for the presence of tau pathology showed that, despite the similar forebrain pathology, relative levels of perikaryal and neuritic tau pathology were significantly lower in ND than in AD subjects. The ND subjects exhibit greater pathology than control subjects without AD pathology, indicating that cortical AD pathology does impact subcortical neurons in both AD and ND cases. Significantly, the extent of neurodegenerative pathology in LC and Raphe neurons correlated with cognitive performance in AD cases, while no such correlation was seen in ND cases. Our results show that while cortical AD pathology is associated with increased MAergic neuropathology, quantitative differences in the extent of MAergic pathology in the brainstem may reflect underlying resistance to AD pathology.

Repetitive traumatic brain injury (TBI) is the main risk factor for chronic traumatic encephalopathy (CTE), a neurodegenerative disease that is defined by pathological inclusions of phosphorylated tau protein located at the depths of the cortical sulci and surrounding blood vessels. The cellular mechanisms involved in tau phosphorylation are upregulated by TBI, leading to increased levels of misfolded tau, which can progress to form insoluble aggregates and drive the progression of CTE. Targeting tau phosphorylation is thus an appealing strategy for reducing tau aggregation and preventing CTE. The phosphorylation of tau at Thr231 is a crucial step that promotes aberrant tau misfolding and fibril formation that occurs following TBI and in CTE. Lithium, known for its neuroprotective effects, has previously been shown to reduce tau phosphorylation. However, its effect on Thr231 in the context of TBI is unknown. In this study, we investigated the therapeutic potential of lithium on tau phosphorylation in a rodent model of TBI. Female adult rats subjected to a single TBI were administered daily lithium and histologically assessed for tau pathology, neuroinflammation, and neurodegeneration. In TBI animals, pThr231 tau pathology progressively increased throughout the hippocampus over the first 10 days and was associated with a loss of Calbindin 1 and an increase in mitochondrial calcium uniporter (MCU) expression. Lithium treatment reduced hippocampal pThr231 tau pathology and microgliosis at day 10 post-TBI. In lithium-treated TBI animals, the loss of Calbindin 1 was prevented and the level of MCU was decreased in regions associated with reduced pThr231 tau pathology. In CTE, the level of Calbindin 1 was similarly decreased in the presence of pThr231-positive neurofibrillary tangles. These findings demonstrate that lithium is effective in reducing hippocampal pThr231 tau pathology and attenuating neuroinflammation in TBI, accompanied by maintaining physiological expression of Calbindin 1 and MCU.

Meningiomas are the most common primary brain tumors in adults and have the potential for recurrence. Although most recurrent meningiomas retain their initial World Health Organization grade, a subset undergoes malignant transformation (MT). The molecular mechanisms underlying this transformation remain poorly understood. We aimed to characterize distinct recurrence subtypes-MT and grade 1-retained recurrence (GR)-using sequential multi-omic analyses. In this study, we reviewed meningioma patients with paired histological evaluations. Among these, 10 patients experienced MT and 25 showed GR. Patients with MT exhibited significantly higher Ki-67 proliferation indices and shorter overall survival. Comprehensive molecular profiling, including matched sequential recurrences, was performed on samples from six patients each with MT and GR meningiomas. Compared to GR tumors, MT tumors demonstrated a marked increase in tumor mutation burden and copy number alterations, with deletion of cyclin-dependent kinase inhibitor 2A emerging as a key acquired event. MT cases also showed selective upregulation of cell cycle-related genes, including Forkhead box M1, a feature absent in GR tumors. Notably, even prior to recurrence, MT tumors displayed distinct global DNA methylation patterns, particularly in regions targeted by the polycomb repressive complex 2 and H3K27me3 marks. Our findings suggest that molecular signatures evolve during MT and that certain intermediate aggressive meningiomas may progress toward malignancy. This study underscores the importance of DNA methylation and transcriptomic profiling in understanding tumor progression and recurrence. While molecular profiling holds promise for prognostication, further research is needed to identify key drivers of MT and clarify their roles in meningioma pathogenesis.

Hereditary spastic paraplegias (HSPs) comprise a large, heterogeneous group of inherited disorders characterized by length-dependent axonal degeneration of corticospinal motor neurons, leading to lower extremity spasticity and gait impairment. Currently, there are no effective treatments for HSPs targeting axonal dysfunction. Our previous study showed that lipid defects in glial cells result in degeneration of iPSC-derived cortical projection neurons (PNs) in SPG3A, the most common early-onset form of HSP caused by autosomal dominant mutations in the ATL1 gene encoding atlastin-1. However, how cortical PNs degenerate and whether therapeutic compounds targeting lipid defects can effectively mitigate degeneration in human ATL1 neurons remain unclear. Here, by comparing SPG3A patient iPSC-derived neurons with control cells using RNA-sequencing, we identified synaptic dysfunction as a top-altered pathway in addition to lipid-related pathways. To examine the novel role of synaptic dysfunction in SPG3A, we generated patient-specific iPSCs from two SPG3A patients with distinct missense mutations and differentiated them into cortical PNs. We observed significant reductions of synaptic genes and proteins in cortical PNs from both SPG3A-P342S and SPG3A-M408T patient iPSCs, emphasizing synaptic dysfunction in SPG3A neurons. Calcium imaging revealed a significant reduction of activity in SPG3A cortical neurons compared to control neurons, further supporting functional deficits in SPG3A neurons. To further examine the role of these processes in HSP pathogenesis, we treated cells with LXR623, an orally bioavailable liver-X-receptor (LXR) agonist that can modulate lipid metabolism and transfer. LXR623 significantly mitigated the reduction in synaptic proteins and calcium activity and rescued axonal degeneration and apoptosis in SPG3A cortical PNs. Furthermore, analyses of lipid and synaptic genes and proteins revealed that LXR623 treatment effectively restored mRNA expression patterns for these pathways in SPG3A neurons. Taken together, our data demonstrate the role of synaptic dysfunction in degeneration of SPG3A neurons and highlight the therapeutic potential of an LXR agonist in mitigating human cortical neuron degeneration in HSP.

Cytomegalovirus is the leading viral cause of congenital infection with neurological sequelae. Effective medical treatments are limited due to an inadequate understanding of the underlying pathogenesis. Here, we applied single-cell transcriptomics to analyze neonatal mouse brains with congenital cytomegalovirus infection (cCMV). We profiled cCMV in 22 cell types and identified neural progenitor cells (NPCs) and monocyte-derived macrophages (MDMs) as the most commonly infected cells. Infected NPCs exhibited dysregulated neurodevelopment-associated signaling pathways, correlating with viral transcript levels that indicate viral replication levels. Genes associated with phagocytosis and antigen presentation were downregulated exclusively in infected MDMs but remained largely unaffected in microglia and barrier-associated macrophages regardless of infection status. Analysis of intrinsic and induced interferon-stimulated gene expression revealed great heterogeneity across cell types but no direct correlation with cCMV susceptibility. Furthermore, our findings indicate that interferon type II is crucial for the control of cCMV and consequent cortical damage and calcification in the neonatal brain. This study advances our understanding of cCMV tropism and the molecular details of cCMV-induced neurodevelopmental impairment, cerebral immune response, and brain pathology.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare diseases associated with genetic mutations in several genes including C19orf12. To explore the underlying mechanism of NBIA pathogenesis, we investigated a mouse homolog of human C19orf12 gene knockout mouse model. In the brains of knockout mice, an age-dependent accumulation of abundant axonal spheroids, alongside brain iron accumulation, neuroinflammation, α-synuclein and ubiquitin pathology was observed. Axonal spheroids were associated with abnormal ER and damaged mitochondria in knockout mice. These abnormal spheroids consistently contained the tubular ER protein reticulon 3 (RTN3) even at younger ages which preceded the onset of motor symptoms. The abnormal localized expansion of axonal ER underlies swollen axon terminals of dopaminergic neurons. The accumulated neuroaxonal swellings likely impair functioning of the dopaminergic system in the substantia nigra, striatum, and other brain regions, which ultimately led to motor function deficits in knockout mice. Altogether, the absence of C19orf12 in mouse brains recapitulates cardinal features of neuropathology in human NBIA, suggesting that C19orf12 is essential to maintain the tubular ER homeostasis in neuronal axon.

Molecular classifications enhance prognostic accuracy in meningiomas; however, their predictive significance following stereotactic radiosurgery (SRS) remains unclear. This study aimed to assess whether molecular characteristics identified by whole-exome sequencing (WES), specifically driver mutations and copy number alterations (CNAs), are prognostic indicators of outcomes after SRS. This retrospective cohort study included 95 patients (median age 61; 66% female) with 97 surgically resected meningiomas treated with SRS between 1999 and 2023. Primary outcomes were progression-free survival (PFS) and disease-specific survival (DSS). Tumors were molecularly classified using WES into Group A (NF2-wildtype), Group B (NF2 mutation/22q loss without high-risk CNAs), and Group C (high-risk CNAs including 1p loss, 1q gain, 6p/6q loss, 10p/10q loss, 14q loss, 18p/18q loss, and CDKN2A/B homozygous deletion). Group C exhibited significantly inferior PFS at 5 years (49.7%) compared with Groups A (88.5%, p < 0.001) and B (100%, p = 0.002). DSS at 10 years was also significantly reduced in Group C (60.4%) relative to Groups A and B (100%, p < 0.001 and p = 0.016, respectively). Within Group C, 1q gain correlated strongly with poorer outcomes, with significantly lower 5-year PFS (15.9% vs. 64.3%, p < 0.001) and DSS (51.3% vs. 90.4%, p < 0.001). Furthermore, even WHO grade 1 tumors with 1q gain demonstrated significantly worse outcomes (5-year PFS: 33.3% vs. 76.5%, p = 0.023; DSS: 44.4% vs. 89.3%, p = 0.011). Molecular classification utilizing WES-derived CNAs substantially improves prognostic prediction after SRS for meningiomas. Chromosome 1q gain was a critical biomarker indicating elevated risk for tumor progression and mortality, even among WHO grade 1 tumors.