Journal of Neuropathology and Experimental Neurology最新文献

Adult-onset neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease that is pathologically characterized by eosinophilic hyaline intranuclear inclusions, mainly in astrocytes, and cerebral white matter degeneration. However, the pathogenesis underlying these neuropathological findings remains unclear. We previously reported an autopsy case of adult-onset NIID with characteristic perivascular findings. In that case, the perivascular areas were preserved despite cerebral white matter damage but dense glial fibrillary acidic protein-immunoreactive astrocytic processes were observed around the blood vessels. The present study examined 2 additional cases and confirmed that the above findings were common in patients with adult-onset NIID. To investigate the underlying pathophysiology behind these findings, immunohistochemistry was performed for proteins located in the astrocytic end-feet. In the cerebral white matter of all NIID cases, there was an altered distribution of aquaporin 4 (AQP4) with increased AQP4-immunopositive areas compared to control cases. These results suggest that the interaction between astrocytes and blood vessels, particularly involving water homeostasis, may be impaired in the cerebral white matter of patients with NIID.

Oncometabolite production plays a key role in the development and progression of isocitrate dehydrogenase-mutant gliomas. The aberrant gain-of-function activity of the mutant isocitrate dehydrogenase protein results in the production of the oncometabolite D-2-hydroxyglutarate, which in turn promotes DNA hypermethylation and gliomagenesis through several mechanisms. Rare gliomas in patients with fumarate hydratase deficiency syndrome share many morphologic and molecular features with isocitrate dehydrogenase-mutant gliomas, with the oncometabolites succinate and 2-succinocysteine similarly thought to promote global DNA hypermethylation. Like isocitrate dehydrogenase and fumarate hydratase, succinate dehydrogenase is also a member of the citric acid cycle that additionally participates in oxidative phosphorylation. While succinate dehydrogenase deficiency has been implicated in familial tumor syndromes, it has not yet been associated with glial neoplasms. Here we report 3 cases of diffuse glioma with succinate dehydrogenase deficiency that show many similarities with isocitrate dehydrogenase-mutant gliomas. We propose that succinate dehydrogenase deficiency with accumulation of the oncometabolite succinate can promote gliomagenesis in a similar manner as seen in isocitrate dehydrogenase-mutant and fumarate hydratase-deficient gliomas, and we discuss the proposed mechanisms that may lead to tumor formation.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease linked to repetitive traumatic brain injury, but its prevalence and risk factors in the general population remain poorly defined. We investigated CTE neuropathological changes (CTE-NC) in an admixed, population-based clinicopathological cohort. Neuropathological evaluation was conducted on brain samples from 1151 individuals in the University of São Paulo Biobank for Aging Studies collected from 2004 to 2022. CTE-NC and aging-related tau astrogliopathy (ARTAG) were assessed across 14 963 histological slides using p-tau immunostaining. Clinical, cognitive, and neuropsychiatric data were obtained via informant interviews; information on sports exposure and traumatic brain injury history was limited. Seven cases (0.6%) met criteria for CTE-NC, mean age at death 73.4 ± 12.5 years; 1 was female. Dementia was present in 43% of CTE-NC cases; 57% exhibited neuropsychiatric symptoms. Most common co-pathologies were Alzheimer disease-type changes, ARTAG, and argyrophilic grain disease. Comprehensive exposure histories were unavailable for most cases; 2 had documented soccer involvement. These findings indicate that CTE-NC is rare in this population-based Brazilian cohort and predominantly affects males with frequent coexisting neuropathologies. Findings align with reports from high-income countries and support prioritizing primary prevention by reducing exposure to repetitive head impacts in sport and other settings.

Post-translational modifications (PTM) of tau are implicated in Alzheimer disease (AD) progression and are established biomarkers in cerebrospinal fluid and plasma; however, the labor-intensive nature of conventional proteomics limits their investigation in histology-specific contexts. We describe the findings of an artificial intelligence-guided laser capture microdissection (LCM) pipeline for harvesting neurofibrillary tangles (NFTs) by maturation level into pretangles (pre-NFTs), mature tangles (iNFTs), and ghost tangles (eNFTs) using 38 cases obtained from 2 independent biobanks. We evaluated the performance characteristics of proprietary machine learning algorithms for the subclassification of these NFT categories in anti-pTau217-stained whole slide images of entorhinal cortex, hippocampus, frontal, and parietal cortex sections. Overall precision/recall/F1 scores were highest for Classifier A (0.6/0.46/0.5). The best performing algorithm was used to guide LCM capture and inform NFT enrichment. Targeted proteomics on tau signature peptides (pTau181, pTau217, and TauMTBR) was performed on approximately 1250 NFT collections. The results demonstrated that their abundance increased from pretangles to mature tangles (∼2-11-fold increase), and that this was followed by a sharp reduction in ghost tangles (∼3-116-fold decrease), with pTau217 showing the most drastic change. Pathologist-trained NFT classifiers represent an objective albeit imperfect means to enrich specific morphologic forms permitting coupled LCM-MS (mass spectrometry) to investigate AD-associated PTM.

Primary cilia are non-motile sensory organelles that detect extracellular signals; disruptions in their functions are linked to neurodevelopmental disorders. Because cilia lengths can rapidly change in response to stressors, they are important for both plasticity and brain homeostasis. Accurate measurement of ciliary length is therefore essential but the absence of standardized methods and the variability introduced by different techniques can compromise measurement reliability and precision. To address this challenge, our study employed two distinct methods to estimate the length of primary cilia in hippocampal subregions in mice. We compared stereology-based 3D quantification, which is considered a methodological gold standard due to its unbiased sampling design and correction for tissue shrinkage, with 3D reconstruction to measure primary cilia length. 3D reconstruction imaging used a 100× oil-immersion objective. With neuronal cilia typically ∼2-10 µm long in hippocampus, a 1-µm z-step provided multiple optical sections per cilium thereby ensuring full structural visualization. Our findings show that both methods allow simple and equally precise measurements of neuronal primary cilia length in hippocampal subregions. Their strong agreement provides researchers with reliable tools for studying primary cilia on immunohistochemically stained sections and supports a consistent methodological framework for investigating cilia dynamics.

Ex vivo MRI allows for ultra-high resolution image acquisition and valuable validation when combined with histology. Postmortem brain samples may undergo long scan times without motion artifacts. Perfluoropolyethers such as Fomblin have become a popular choice of immersion liquid for their "proton free" appearance and their ability to eliminate susceptibility artifacts from the tissue-air interface but the effect of Fomblin on downstream histology experiments has not been previously studied. We exposed rat brain samples to Fomblin (n = 4) versus a control group (n = 4). Samples underwent histochemical (Nissl) and immunohistochemical staining for NeuN to assess neurons and background staining. The optical fractionator method was applied to assess total neuron counts and tissue thickness. Samples from the Fomblin group showed consistent NeuN and Nissl staining when compared to the control group. The staining color, evenness, and neuron visualization appeared unaffected with no background staining. The total neuron counts, and tissue thickness showed only slight differences in absolute numbers between groups with insufficient evidence to conclude the distribution of total neuron number or tissue thickness differed by group. These data suggest that Fomblin may not negatively impact histochemical staining, immunohistochemistry, or total neuron counts in the short term.

Cardiotrophin-like cytokine factor 1 (CLCF1) is an unfavorable factor for the prognosis of patients with glioblastoma multiforme (GBM). This research explored the functions of CLCF1 in GBM progression and the underlying regulatory mechanisms. Reverse transcription-quantitative PCR (RT-qPCR) and Western blot were used to detect the mRNA and protein levels of targeted molecules. The abilities of GBM cell lines to proliferate, migrate, and invade and undergo apoptosis and angiogenesis were analyzed by colony formation, transwell, TUNEL, and tube formation assays, respectively. Interaction between CLCF1 and SRY-box transcription factor 9 (SOX9) was verified by chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assays. The results showed that CLCF1 was upregulated in GBM. Silencing of CLCF1 suppressed the malignant phenotypes of GBM cells in vitro and the development of GBM in a xenograft tumor model. Silencing CLCF1 also reduced programmed cell death 1 ligand 1 (PD-L1) expression in GBM cells and prolonged the longevity of CD8-positive T cells in vitro. SRY-box transcription factor 9 was highly expressed in GBM and this activated CLCF1 expression as one of its transcription factors to further enhance GBM development. Thus, CLCF1 regulated by SOX9 can enhance the development and immune evasion of GBM.