Central Nervous System Research Articles

Invasive pulmonary cryptococcosis mimicking metastatic lung cancer: A case report and review of literature

BACKGROUND Worldwide, there has been a steady increase in the number of cases of pulmonary cryptococcosis diagnosed in immunocompetent patients, where symptoms can range from mild to severe. Clinical and radiological distinction of disease may be made when compared with immunodeficient cases and in those presenting with primary lung carcinoma. In the latter case confusion can lead to initial misdiagnosis and delayed treatment. We report a case of disseminated cryptococcosis in an immunocompetent patient which mimicked a primary lung carcinoma with brain metastases. CASE SUMMARY A 51-year-old male farmer with a 30-year smoking history presented with a two-week history of productive cough, streaky hemoptysis, and low-grade fever. He had no history of immunosuppression, tuberculosis, or specific risk factors. Chest computed tomography revealed a posterior basal left lower lobe mass, but tumor markers and transbronchial tests were negative. Brain magnetic resonance imaging showed an enhancing left frontal lobe lesion, raising suspicion for metastatic lung cancer. However, computed tomography-guided biopsy confirmed fungal pneumonia with “titan” cells, and a positive serum cryptococcal antigen test confirmed Cryptococcus neoformans infection. Bronchoscopy and lavage detected fungal spores, while cerebrospinal fluid cytology and culture were negative. Fluconazole (0.4 mg/day) was initiated, but progressive central nervous system lesions required amphotericin B. A six-week combination of fluconazole (600 mg/day) and flucytosine led to resolution. At 24-month follow-up, he remained asymptomatic with no recurrence. CONCLUSION Cryptococcosis is increasing in immunocompetent individuals in China and should be considered in pneumonia and lung or brain lesions.

Glymphatic Transport as a Possible New Mechanism for the Long-Range Signaling of Extracellular Vesicles Through the CNS.

Extracellular vesicles (EVs) are secreted by all types of cells in the central nervous system (CNS) and participate in intercellular communication in physiological and pathological settings. However, an emerging view of multidirectional communications is getting incredibly complex, and, in most cases, it is unclear whether EVs secreted by specific cell populations have specific cellular targets. Here we propose to discriminate between short- (adjacent cells) and long- (different brain regions) range signaling of the EVs in the CNS. We also hypothesize that besides its primary function of brain clearance, the glymphatic system can also serve for the long-range transport and signaling of the EVs throughout the CNS. In the first part of the review, we will describe currently available experimental models used for labeling and tracking cell-type specific EVs in the CNS. Then we will briefly overview the glymphatic system and discuss current evidence showing the physiological and pathological significance of long-range EV signaling in the CNS. Finally, we will provide a hypothetical model describing the possible role of the glymphatic system in the transport and long-range signaling of the EVs.

Astrocytic RIPK3 exerts protective anti-inflammatory activity in mice with viral encephalitis by transcriptional induction of serpins

Flaviviruses pose a substantial threat to public health because of their ability to infect the central nervous system (CNS). Receptor-interacting protein kinase 3 (RIPK3) is a central coordinator that promotes neuroinflammation during viral infection of the CNS, a role that occurs independently of its canonical function in inducing necroptosis. Here, we used mouse genetic tools to induce astrocyte-specific deletion, overexpression, and chemogenetic activation of RIPK3 to demonstrate an anti-inflammatory function for astrocytic RIPK3. RIPK3 activation in astrocytes promoted host survival during flavivirus encephalitis by limiting immune cell recruitment to the CNS. Despite inducing a proinflammatory transcriptional program, astrocytic RIPK3 restrained neuroinflammation by increasing the abundance of the protease inhibitor SerpinA3N, which preserved blood-brain barrier integrity, reduced leukocyte infiltration, and improved survival outcomes during flavivirus encephalitis. These findings highlight a previously unappreciated role for astrocytic RIPK3 in suppressing pathologic neuroinflammation.

Genetic, neuroimaging, and clinical characteristics of a cohort of individuals with L-2-hydroxyglutaric aciduria from Türkiye.

L-2-hydroxyglutaric aciduria (L2HGA) is a hereditary metabolic disorder characterized by the accumulation of L-2-hydroxyglutaric acid in body fluids, particularly in cerebrospinal fluid, which disrupts neuron function in the central nervous system and triggers oxidative stress. It can cause seizures, developmental disorders, and behavioral abnormalities. The study retrospectively evaluated the demographic information, initial symptoms, clinical characteristics, cranial magnetic resonance imaging (MRI) findings, and post-treatment biochemical changes of 10 cases diagnosed with L2HGA. The study included five paediatric and five adult cases with a molecular diagnosis of L2HGA. The mean age at diagnosis was 10.1 years. Convulsion was identified as the primary presenting symptom in 70 % of cases. We identified intellectual disability in 80 % of our cases. In addition to the classic cranial MRI findings of subcortical white matter involvement, basal ganglia involvement was detected in 60 % of cases. We found that 2-hydroxyglutaric acid levels in urine organic acid analysis were significantly decreased riboflavin and carnitine post-treatment, with a mean decrease of 133.89±101.43 mmol/mol creatinine (p=0.017). The most common missense variant identified in the L2HGDH gene was c.905C>T (p.Pro302Leu), occurring at a frequency of 50 % (5/10). The cases did not report significant improvement in their symptoms with treatment. L2HGA is a rare metabolic disorder that is more common in communities where consanguineous marriages are prevalent. Early diagnosis enables early treatment and protection of the brain from oxidative stress. As more cases are reported publicly, studies on genotype-phenotype relationships will yield more significant findings.

CD8 T cell dynamics and immune cell trafficking in ZIKV infection: implications for neuroinflammation and therapy

Abstract The 2015–2016 Zika virus (ZIKV) epidemic underscored the severe consequences of congenital Zika syndrome (CZS) and the broader challenges posed by neurotropic flaviviruses. As key mediators of cytotoxic immunity, CD8 T cells play a crucial and multifaceted role in ZIKV pathogenesis. While essential for controlling viral replication, their infiltration into the central nervous system (CNS)—an immune-privileged site—raises potential concerns regarding immunopathology. This review explores the dual roles of CD8 T cells during ZIKV infection, emphasizing both their antiviral functions and their potential to drive neuroinflammation. We examine how ZIKV infection and chemokine-mediated signals facilitate immune cell trafficking across the blood–brain barrier, drawing parallels with other neurotropic flaviviruses. We also explore how therapeutic agents, such as the S1P receptor modulator FTY720, influence lymphocyte trafficking and CNS immune regulation. Finally, we review emerging interventions—including vaccines, antivirals, immunomodulators, and passive immunotherapies—that aim to achieve effective viral control while minimizing neural damage. A balanced understanding of immune cell responses in flavivirus infections is essential for guiding future therapeutic strategies against ZIKV and related neurotropic viruses.

Serological diagnosis of cysticercosis in humans and pigs: status, limitations, and prospects

Cysticercosis is a neglected zoonosis caused by Taenia solium, which involves pigs as intermediate hosts, leading to pig cysticercosis (PCC). Humans are the only definitive hosts, harbouring the mature tapeworm in the small intestines, but they can also act as intermediate hosts upon accidental ingestion of eggs, resulting in human cysticercosis (HCC), called neurocysticercosis (NCC) when the cysts lodge in the central nervous system. Diagnosis of HCC/NCC in humans is based on imaging technologies and serology. The gold standard method for PCC diagnosis is the full carcass dissection and recovery of cysts. However, tongue palpation and meat inspection are the most widely used methods in endemic countries. These methods are specific at the genus level but cannot distinguish mixed infection from other taeniids and are not sufficiently sensitive in pigs with low infection. Available serological tests for human and pig infection are based on parasite-specific immunoglobulin G (IgG). Still, most tests are either cross-reactive with other taeniids or not sensitive enough for single or inactive cysts, particularly for NCC patients. Here, we compare various serological techniques for PCC and NCC published since 2000 and discuss the benefit of IgE-based serodiagnosis as a potential alternative to traditional serology. Considering the diagnostic limitations described above and the need to identify endemic areas to prevent transmission between humans and pigs and monitor control efforts, the development of more sensitive and specific serological tests, followed by a field-applicable point-of-care (POC) test for cysticercosis, is of the utmost importance.

Intravascular Lymphoma: A Unique Pattern Underlying a Protean Disease

Intravascular lymphoma (IVL) is a rare, aggressive subtype of non-Hodgkin lymphoma (NHL) characterized by the selective proliferation of neoplastic lymphoid cells within small and medium-sized blood vessels, most frequently of B-cell origin (IVLBCL). Its protean clinical presentation, lack of pathognomonic findings, and absence of tumor masses or lymphadenopathies often lead to diagnostic delays and poor outcomes. IVLBCL can manifest in classic, hemophagocytic syndrome-associated (HPS), or cutaneous variants, with extremely variable organ involvement including the central nervous system (CNS), skin, lungs, and endocrine system. Diagnosis requires histopathologic identification of neoplastic intravascular lymphoid cells via targeted or random tissue biopsies. Tumor cells are highly atypical and display a non-GCB B-cell phenotype, often expressing CD20, MUM1, BCL2, and MYC; molecularly, they frequently harbor mutations in MYD88 and CD79B, defining a molecular profile shared with ABC-type DLBCL of immune-privileged sites. Therapeutic approaches are based on rituximab-containing chemotherapy regimens (R-CHOP), often supplemented with CNS-directed therapy due to the disease’s marked neurotropism. Emerging strategies include autologous stem cell transplantation (ASCT) and novel immunotherapeutic approaches, potentially exploiting the frequent expression of PD-L1 by tumor cells. A distinct but related entity, intravascular NK/T-cell lymphoma (IVNKTCL), is an exceedingly rare EBV-associated lymphoma, showing unique own histologic, immunophenotypic, and molecular features and an even poorer outcome. This review provides a comprehensive overview of the current understandings about clinicopathological, molecular, and therapeutic landscape of IVL, emphasizing the need for increased clinical awareness, standardized diagnostic protocols, and individualized treatment strategies for this aggressive yet intriguing malignancy.

3D-Printing of Electroconductive MXene-Based Micro-Meshes in a Biomimetic Hyaluronic Acid-Based Scaffold Directs and Enhances Electrical Stimulation for Neural Repair Applications.

No effective treatments are currently available for central nervous system neurotrauma although recent advances in electrical stimulation suggest some promise in neural tissue repair. It is hypothesized that structured integration of an electroconductive biomaterial into a tissue engineering scaffold can enhance electroactive signaling for neural regeneration. Electroconductive 2D Ti3C2Tx MXene nanosheets are synthesized from MAX-phase powder, demonstrating excellent biocompatibility with neurons, astrocytes and microglia. To achieve spatially-controlled distribution of these MXenes, melt-electrowriting is used to 3D-print highly-organized PCL micro-meshes with varying fiber spacings (low-, medium-, and high-density), which are functionalized with MXenes to provide highly-tunable electroconductive properties (0.081±0.053-18.87±2.94 S/m). Embedding these electroconductive micro-meshes within a neurotrophic, immunomodulatory hyaluronic acid-based extracellular matrix (ECM) produced a soft, growth-supportive MXene-ECM composite scaffold. Electrical stimulation of neurons seeded on these scaffolds promoted neurite outgrowth, influenced by fiber spacing in the micro-mesh. In a multicellular model of cell behavior, neurospheres stimulated for 7 days on high-density MXene-ECM scaffolds exhibited significantly increased axonal extension and neuronal differentiation, compared to low-density scaffolds and MXene-free controls. The results demonstrate that spatial-organization of electroconductive materials in a neurotrophic scaffold can enhance repair-critical responses to electrical stimulation and that these biomimetic MXene-ECM scaffolds offer a promising new approach to neurotrauma repair.

Environmental risk factors for multiple sclerosis: a comprehensive systematic review and meta-analysis

Abstract Background and Objectives Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. Its etiology may involve both genetic and environmental factors, including vitamin D levels, body mass index, infections, and smoking. This is the first comprehensive systematic review with meta-analysis that synthesizes and explore the role of many environmental risk factors in the etiology of MS. Methods A systematic search of MEDLINE, SciVerse ScienceDirect and Web of Science were conducted for any original peer-reviewed article that included adult subjects diagnosed with and without MS that were exposed to any environmental risk factor. We did not set any time restrictions. Data were extracted and the quality assessment was performed with the Critical Appraisal Checklist for Case Control Studies. All the information was synthesized qualitatively and quantitatively (meta-analysis). We used the random-effects model based on the binomial distribution to calculate the pooled effects sizes (ES) regarding the risk of developing MS according to each potential risk factor. Results One-hundred thirty-two publications met all the eligibility criteria and were included in the review. Overall, 109,626 people with MS and 16,724,390 controls from 38 countries were included in the review. A total of 42 environmental risk factors were investigated as potential risk factors for MS. Among the various statistically significant associations, the pooled ES revealed a direct association between serological evidence of contact with EBV (ES = 1.96, 95% CI = 1.53–2.51), herpes virus type 6 (HHV-6) (ES = 2.84, 95% CI = 2.08–3.89) and varicella-zoster virus (ES = 1.33, 95% CI = 1.08–1.63) and the occurrence of MS. Similarly, smoking was associated with a greater likelihood of having MS (ES = 1.43, 95% CI = 1.27–1.61). Vitamin D levels at any time were negatively associated with the proportion of cases of MS and had a moderate pooled ES (g = – 0.48, 95% CI = – 0.88–0.09). Adult BMI was not associated with MS. Discussion This review furnishes a broad and detailed overview of the potential environmental risk factors associated with MS. Our findings hold notable implications for public health policies, clinical practices, and the focus of future research.

The Diagnostic Yield of Cerebrospinal Fluid Analysis for the Diagnosis of Primary Central Nervous System Lymphoma: A Systematic Review

Background: The gold standard for diagnosing primary central nervous system lymphoma (PCNSL) is brain biopsy, an invasive procedure with significant risks. The role of cerebrospinal fluid (CSF) examination, limited to cytology and flow cytometry in current practice, is acknowledged as a less invasive diagnostic method. We aimed to summarize available data concerning the efficacy and actual use of current standard CSF diagnostics in the diagnosis of PCNSL. Methods: A systematic review and meta-analysis of 144 studies (n = 9493 patients) was conducted, assessing detection rates of cytology and flow cytometry and the proportion of diagnoses based on CSF analysis. The QUADAS-2 tool was used to evaluate study quality and bias. Results: Meta-analysis showed an 18% pooled detection rate for positive CSF results, with 17% for cytology and 20% for flow cytometry. Only 8% of diagnoses were made using CSF analysis. Most studies had a high risk of bias. Conclusions: Despite its established role in guidelines, CSF analysis remains underutilized for diagnosing PCNSL, with room to improve its clinical impact. Novel techniques, such as chemokines and circulating tumor DNA (cfDNA) analysis, hold promise to unlock the untapped potential of CSF diagnostics, offering significant advancements in non-invasive PCNSL diagnosis.

Integrative Single-Cell Analysis Decodes Gene Expression and Chromatin Accessibility in the Developing Human Fetal Brain.

The brain is the core of the central nervous system, responsible for regulating and integrating various physiological and psychological functions. Abnormal disruptions in genes during brain development can lead to a range of neurodevelopmental disorders. In this study, we performed a systematic investigation of human fetal brain tissue from miscarriages between 8 and 17weeks of gestation using integrated single-cell RNA sequencing (scRNA-seq) and single-cell transposase-accessible chromatin sequencing (scATAC-seq). We constructed single-cell transcriptomic and epigenomic maps of neurodevelopment, revealing key signaling pathways involved in neural cell proliferation, differentiation, and functional maturation. Through pseudotime analysis, we reconstructed the developmental trajectory of neuronal differentiation and its dynamic regulatory mechanisms. Additionally, we identified cell type-specific chromatin accessibility regions during neurogenesis and, through integrated analysis, predicted potential regulatory elements involved in the process. Overall, the single-cell multi-omics integration map constructed in this study provides valuable resources for a deeper understanding of fetal brain development, cellular heterogeneity, lineage relationships, and transcriptional regulatory networks during neurogenesis.

Visuo-spatial learning and memory deficits in C57BL/6 mice following postnatal ethanol exposure

ABSTRACT Background: Postnatal alcohol exposure impairs the development of the central nervous system, including the visual system. The behavioral consequences of such exposure on visual function remain poorly understood. Objectives: In this study, we investigated the effects of postnatal ethanol exposure on visuospatial learning and memory in C57BL/6 mice. Methods: Ethanol (3.0 g/kg) was administered via intubation on postnatal days 3–20. Controls received intubation only or no intervention. Pups were assigned to alcohol-treated (A, n = 11), intubation control (IC, n = 11), or non-intubated control (C, n = 9) groups. At three months, mice underwent the Novel Object Recognition (NOR) test and a visual water task. The NOR test measured recognition memory and exploratory behavior. The visual water task assessed visual acuity using sinusoidal gratings presented on monitors. Mice were trained over 17 days to associate a grating with a hidden platform, and visual acuity thresholds were determined based on performance at varying spatial frequencies. Results: Alcohol-exposed mice showed significant deficits in recognition memory and visual acuity. No group differences in body weight were observed. However, alcohol-treated mice displayed reduced exploration of novel objects (p = .0085, R2 = 0.29) and lower visual acuity thresholds at higher spatial frequencies (p = .048, R2 = 0.24). Conclusion: These findings demonstrate that early postnatal alcohol exposure can lead to lasting impairments in visual-cognitive functions. Given their similarity to deficits seen in children with Fetal Alcohol Spectrum Disorders (FASD), our results suggest the importance of early behavioral and visual assessments in children with suspected prenatal or early postnatal alcohol exposure.

Fermented Soybean Pulp Alleviates Disease Progression of 5×FAD Model Mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder of the central nervous system, characterized by memory loss and cognitive decline. The two main hypotheses regarding AD involve the accumulation of amyloid-β (Aβ) forming plaques and the intracellular hyperphosphorylation of tau protein, leading to the formation of neurofibrillary tangles (NFT). These processes are accompanied by neuroinflammation and oxidative stress, and eventual neuronal death. While soy foods are widely recognized for their nutritional benefits, soybean pulp (okara), the residue left over from making tofu or soybean milk, is mostly discarded as kitchen waste, despite being rich in nutrients such as dietary fiber, protein, and isoflavones. This underutilized byproduct may serve as a valuable resource for functional food development and sustainable resource use. In this study, fermented soybean pulp (FS) demonstrated neuroprotective effects. In vitro, FS at concentrations of 0.001µg/mL and 0.01µg/mL significantly improved cell viability in Aβ-induced HT-22 cells and reduced lipid peroxidation. Further, in vivo oral administration of FS attenuated the cognitive deficits of 5 × FAD mice, enhancing both short and long-term memory and reducing anxiety-like behaviors. Immunohistochemical analysis revealed that the FS-treated 5 × FAD mice group significantly reduced hippocampal amyloid plaque accumulation and gliosis. FS also upregulated the expression levels of brain-derived neurotrophic factor (BDNF), PSD95, and synaptophysin, while preventing hippocampal neuronal loss. Mechanistically, FS may activate the Nrf2 antioxidant pathway and NF-κB-mediated inflammation through the modulation of the Akt/GSK3β signaling axis in the hippocampus. These molecular actions likely contribute to increased antioxidant enzymes and suppressed neuroinflammatory responses. Overall, this study suggests that FS has therapeutic potential for alleviating cognitive and behavioral impairments in AD. Moreover, the repurposing of soybean pulp, which would otherwise be discarded, enhances its utilization value and supports sustainable green recycling.

Case Reports: Three cases of autoimmune glial fibrillary acidic protein astrocytosis in disguise

Autoimmune glial fibrillary acidic protein astrocytosis (GFAP-A), a novel inflammatory autoimmune disorder of the central nervous system, manifests with insidious onset and demonstrates protean clinical manifestations, which frequently leads to diagnostic ambiguity in early disease stages. We describe three typical GFAP-A cases exhibiting multisystem neurological involvement. Our observations show that GFAP-A frequently clinically mimics tuberculous meningitis (TBM), autoimmune encephalitis (AE), neuromyelitis optica spectrum disorder (NMOSD), Parkinson’s disease (PD), and other neurological diseases. Notably, isolated ataxia is a rare presentation in GFAP-A, which allows us usually to consider spinocerebellar ataxia (SCA). Currently, no established diagnostic criteria or standard treatment protocols exist for GFAP-A. Patients with GFAP-A respond well to corticosteroid therapy. We found detecting GFAP-IgG in cerebrospinal fluid or serum is essential for differentiation.

A Scoping Review of Sarcoglycan Expression in Non-Muscle Organs: Beyond Muscles

This scoping review explores the expression patterns and molecular features of sarcoglycans (SGs) in non-muscle organs, challenging the long-standing assumption that their function is confined to skeletal and cardiac muscle. By analyzing evidence from both animal models and human studies, the review highlights the widespread presence of SG subunits in organs, including the nervous system, glands, adipose tissue, oral mucosa, retina, and other structures, with distinct regional and cell-type-specific patterns. Studies on the central nervous system demonstrate a widespread “spot-like” distribution of SG subunits in neurons and glial cells, implicating their involvement in synaptic organization and neurotransmission. Similarly, SGs maintain cellular integrity and homeostasis in glands and adipose tissue. At the same time, the altered expression of SGs is associated with pathological conditions in the gingival epithelium of the oral mucosa. These findings underscore the multifaceted roles of SGs beyond muscle, suggesting that they may contribute to cellular signaling, membrane stability, and neurovascular coupling. However, significant gaps remain regarding SG post-translational modifications and functional implications in non-muscle organs. Future research integrating molecular, cellular, and functional approaches in animal models and human tissues is essential to fully elucidate these roles and explore their potential as therapeutic targets in various diseases.

Quercetin Ameliorates Learning and Memory in OVX/D-gal-Induced Alzheimer’s Disease in Rats by Inhibiting Neuroinflammation via cGAS-STING Signal Pathway

Alzheimer’s disease (AD) is an age-related degenerative disorder of the central nervous system. Neuroinflammation is considered a key factor in its etiology and progression. AD is more prevalent in women than men and may be related to postmenopausal hormone deficiency. This study constructed an AD rat model by bilateral ovariectomy (OVX) and intraperitoneal injection of D-galactose (D-gal) and an in vitro AD cell model was induced in PC12 cells using lipopolysaccharide (LPS). The Morris water maze test was employed to assess the impact of quercetin (Que) on learning and memory in OVX/D-gal rats. Immunohistochemistry was utilized to assess the impact of Que on the expression of Aβ protein, p-tau protein, GFAP, and Iba1 in the hippocampus of OVX/D-gal rats. Nissl staining was performed to examine hippocampal pathological damage. ELISA was conducted to measure serum estrogen levels and the release of inflammatory cytokines, specifically TNF-α and IL-1β, in the hippocampus of OVX/D-gal rats. HE staining was utilized to evaluate uterine pathological alterations in OVX/D-gal rats. Cell viability was assessed using the CCK-8 assay to determine the protective effect of quercetin on LPS-induced PC12 cells. Western Blot analysis was conducted to evaluate the expression levels of estrogen receptors and the proteins associated with the cGAS-STING pathway in both in vitro and in vivo models. Protein–protein docking studies were performed to investigate the binding affinity between the estrogen receptor and proteins involved in the cGAS-STING signaling pathway. Results demonstrated that Que enhanced learning and memory capabilities in OVX/D-gal rats, alleviated hippocampal pathological damage, reduced the expression of Aβ, p-tau, GFAP, and Iba1, and inhibited the release of inflammatory factors. Additionally, Que activated estrogen receptor expression and increased serum estrogen levels without exacerbating uterine lesions. Furthermore, Que activated the estrogen receptor in LPS-induced PC12 cells, which inhibited the release of IL-6 and exerted neuroprotective effects. Que also suppressed the expression of proteins associated with the cGAS-STING pathway both in vitro and in vivo. Estrogen receptors exhibited strong binding affinity with cGAS-STING pathway proteins. In conclusion, Que can inhibit neuroinflammation in vitro and in vivo, enhance learning and memory in OVX/D-gal rats, and exert neuroprotective effects. The underlying mechanism may involve the inhibition of the cGAS-STING signaling pathway, and the estrogen receptor potentially influences this pathway directly or indirectly.

Prediction of apolipoprotein A-I and high-density lipoprotein cholesterol in the neurological impairment and relapse of neuromyelitis optica spectrum disorder

Background and purposeNeuromyelitis Optica Spectrum Disorder (NMOSD) is a rare inflammatory demyelinating disorder of the central nervous system, frequently resulting in irreversible neurological deficits such as blindness and paralysis. Emerging evidence suggests that dyslipidemia is associated with increased disability and poorer outcomes in autoimmune diseases. The purpose of the study is to investigate the associations between lipid profile with neurological impairment and relapse.MethodsThis study retrospectively collected data from 130 hospitalized patients with AQP4-IgG positive NMOSD. Based on the Expanded Disability Status Scale (EDSS) scores at admission, patients were categorized into a mild-to-moderate group (EDSS ≤ 5.5) and a severe group (EDSS ≥ 6). All included patients were followed for at least 1 year, and were further divided into relapse and non-relapse groups based on whether a relapse occurred during the follow-up period. Logistic regression analysis was used to identify independent risk factors associated with the severity of neurological impairment and relapse. Receiver operating characteristic (ROC) curve analysis was conducted to determine the cutoff value of apolipoprotein A-I (ApoA-I) in predicting severe neurological impairment. Spearman correlation analysis was performed to assess the relationships among ApoA-I, high-density lipoprotein cholesterol (HDL-C) and CRP.ResultsMultivariate binary logistic regression analysis revealed that ApoA-I (OR = 0.138, 95% CI: 0.021–0.902, p = 0.039) and the number of spinal cord lesion segments (OR = 1.368, 95% CI: 1.181–1.584, p < 0.001) were independent risk factors for the severity of neurological impairment. The area under the ROC curve (AUC) for ApoA-I in predicting the severity of neurological impairment was 0.647 (95% CI: 0.542–0.751), with a cutoff value of 1.165, a sensitivity of 59.4%, and a specificity of 67.6%. Multivariate logistic regression analysis identified HDL-C (OR = 0.082, 95% CI: 0.008–0.847, p = 0.036), clinical phenotype—specifically, compared to optic neuritis, myelitis (OR = 0.130, 95% CI: 0.037–0.458, p = 0.002), brainstem/cerebral syndrome (OR = 0.070, 95% CI: 0.007–0.731, p = 0.026), and mixed phenotypes (OR = 0.107, 95% CI: 0.018–0.642, p = 0.014) —as well as the use of subsequent monoclonal antibody therapy (OR = 0.190, 95% CI: 0.045–0.799, p = 0.023) as independent protective factors against relapse. Spearman correlation analysis showed that ApoA-I and HDL-C were significantly negatively correlated with CRP (r = −0.230, p = 0.008; r = −0.310, p < 0.001, respectively).ConclusionReduced levels of ApoA-I and HDL-C were associated with more severe neurological deficits and an increased risk of relapse.

Predicting the molecular subtypes of 2021 WHO grade 4 glioma by a multiparametric MRI-based machine learning model.

Accurately distinguishing the different molecular subtypes of 2021 World Health Organization (WHO) grade 4 Central Nervous System (CNS) gliomas is highly relevant for prognostic stratification and personalized treatment. To develop and validate a machine learning (ML) model using multiparametric MRI for the preoperative differentiation of astrocytoma, CNS WHO grade 4, and glioblastoma (GBM), isocitrate dehydrogenase-wild-type (IDH-wt) (WHO 2021) (Task 1:grade 4 vs. GBM); and to stratify astrocytoma, CNS WHO grade 4, by distinguish astrocytoma, IDH-mutant (IDH-mut), CNS WHO grade 4 from astrocytoma, IDH-wild-type (IDH-wt), CNS WHO grade 4 (Task 2:IDH-mut grade 4 vs. IDH-wt grade 4). Additionally, to evaluate the model's prognostic value. We retrospectively analyzed 320 glioma patients from three hospitals (training/testing, 7:3 ratio) and 99 patients from ‌The Cancer Genome Atlas (TCGA) database for external validation‌. Radiomic features were extracted from tumor and edema on contrast-enhanced T1-weighted imaging (CE-T1WI) and T2 fluid-attenuated inversion recovery (T2-FLAIR). Extreme gradient boosting (XGBoost) was utilized for constructing the ML, clinical, and combined models. Model performance was evaluated with receiver operating characteristic (ROC) curves, decision curves, and calibration curves. Stability was evaluated using six additional classifiers. Kaplan-Meier (KM) survival analysis and the log-rank test assessed the model's prognostic value. In Task 1 and Task 2, the combined model (AUC = 0.907, 0.852 and 0.830 for Task 1; AUC = 0.899, 0.895 and 0.792 for Task 2) and the optimal ML model (AUC = 0.902, 0.854 and 0.832 for Task 1; AUC = 0.904, 0.899 and 0.783 for Task 2) significantly outperformed the clinical model (AUC = 0.671, 0.656, and 0.543 for Task 1; AUC = 0.619, 0.605 and 0.400 for Task 2) in both the training, testing and validation sets. Survival analysis showed the combined model performed similarly to molecular subtype in both tasks (p = 0.964 and p = 0.746). The multiparametric MRI ML model effectively distinguished astrocytoma, CNS WHO grade 4 from GBM, IDH-wt (WHO 2021) and differentiated astrocytoma, IDH-mut from astrocytoma, IDH-wt, CNS WHO grade 4. Additionally, the model provided reliable survival stratification for glioma patients across different molecular subtypes.

Computational Design of Drugs for Epilepsy using a Novel Guided Evolutionary Algorithm for Enhanced Blood Brain Barrier Permeability.

Epilepsy is a common disorder of the Central Nervous System (CNS). The rational design of small-molecule drugs for disorders of the CNS is a difficult process because the majority of small molecules are unable to cross the Blood-Brain-Barrier. An efficient method for the design of inhibitors that have high permeability through the Blood-Brain-Barrier has the potential for application in drug design for CNS disorders such as Addiction, Alzheimer's disease, Bipolar disorder, Depression, Epilepsy, Gliomas, and Tuberculous meningitis. Supervised learning was used to model the Blood-Brain-Barrier permeability of drugs like small organic molecules. This information was utilized to guide an evolutionary algorithm for the design of inhibitors with increased affinity for the target as well as higher Blood-Brain-Barrier permeability. The ligands designed with guided evolution were predicted to have higher binding affinity for the target as well as higher permeability across the Blood-Brain-Barrier compared to an evolutionary algorithm without the guidance. The guided evolutionary method was applied to design a set of drug-like ligands that were predicted to bind to GABA-T with high affinity, to be BBB permeable, and to be chemically synthesizable. Despite the availability of several drugs that are approved for the treatment of epilepsy, there are many cases that do not respond to available drugs or experience adverse effects. The novel ligands designed as part of this work have the potential to address the limitations of available drugs. Guided evolution is an efficient computational approach for the design of CNS drugs. The de novo design of drugs by application of the guided evolution algorithm, developed as part of this work, has resulted in the generation of ligands that are potential drugs for the cure of epilepsy. However, the effectiveness of these drugs for the cure of epilepsy has to be validated experimentally.

CNS Tumor with BCOR/BCORL1 Fusion: A Rare Tumor Entity

Central nervous system (CNS) tumor with BCL6 corepressor gene BCOR/BCORL1 fusion is an extremely rare tumor entity, with fewer than 40 cases reported. These tumors are distinct from the WHO 2021-defined CNS tumor with BCOR internal tandem duplication. Even rarer are CNS tumors that match to the methylation class of CNS tumors with BCOR/BCORL1 fusion, but lack fusions and instead harbor truncating small nucleotide variants in BCOR. To our knowledge, only two other cases of this scenario have been previously reported. Due to their scarcity and morphological features that mimic oligodendrogliomas and ependymomas, the diagnosis of CNS tumor with BCOR/BCORL1 fusion can be challenging, and misdiagnoses are not uncommon. Histologic findings of Olig2 positivity with focal to absent GFAP warrant further evaluation for this tumor entity. Moreover, no standard of care therapy exists for these tumors, making treatment selection difficult. We present a case of a 37-year-old woman with a midline CNS tumor with BCOR/BCORL1 fusion, harboring a pathogenic BCOR c.626del (p.S209Cfs*7) (Exon 4) variant, who was successfully treated with definitive radiation therapy and adjuvant temozolomide. Notably, EMA showed focal strong dot-like perinuclear immunoreactivity, which has not been previously reported in these tumors. This case adds to the limited but growing body of evidence supporting the use of radiation and temozolomide in treating tumors matching the methylation class of CNS tumors with BCOR/BCORL1 fusion without a detectable fusion.