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Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients. [ABSTRACT FROM AUTHOR]

AbstractIschaemic stroke is a central nervous system disease with high morbidity, recurrence and mortality rates. Thrombolytic and neuroprotective therapies are the main therapeutic strategies for ischaemic stroke, however, the poor delivery efficiency of thrombolytic and neuroprotective drugs to the brain limits their clinical application. So far, the development of nanomedicine has brought opportunities for the above challenges, which can not only realise the effective accumulation of drugs in the target site, but also improve the pharmacokinetic behaviour of the drugs. Among the most rapidly developing nanoparticles, micelles gradually emerging as an effective strategy for ischaemic stroke treatment due to their own unique advantages. This review provided an overview of targeted and response-release micelles based on the physicochemical properties of the ischaemic stroke microenvironment, summarised the targeting strategies for delivering micellar formulations to the thrombus, blood-brain barrier, and brain parenchyma, and finally described the potentials and challenges of polymeric micelles in the treatment of ischaemic stroke. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex degenerative disease of the central nervous system, and elucidating its pathogenesis remains challenging. In this study, we used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization (MR) analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of the IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease, Medical laboratory science, Imaging, Anthropometric, Treatment, Molecular trait, Gut microbiota, Past history, Family history, and Lifestyle trait. More importantly, a freely accessed online platform called MRAD (https://gwasmrad.com/mrad/) has been developed using the Shiny package with MR analysis results. Additionally, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. The findings of our research advance our understanding of the etiology of AD. [ABSTRACT FROM AUTHOR]

As most traditional drugs used to treat central nervous system (CNS) diseases have a single therapeutic target, many of them cannot treat complex diseases or diseases whose mechanism is unknown and cannot effectively reverse the root changes underlying CNS diseases. This raises the question of whether multiple functional components are involved in the complex pathological processes of CNS diseases. Organelles are the core functional units of cells, and the replacement of damaged organelles with healthy organelles allows the multitargeted and integrated modulation of cellular functions. The development of therapies that target independent functional units in the cell, specifically, organelle-based therapies, is rapidly progressing. This article comprehensively discusses the pathogenesis of mitochondrial homeostasis disorders, which involve mitochondria, one of the most important organelles in CNS diseases, and the machanisms of mitochondrion-based therapies, as well as current preclinical and clinical studies on the efficacy of therapies targeting mitochondrial to treat CNS diseases, to provide evidence for use of organelle-based treatment strategies in the future. [ABSTRACT FROM AUTHOR]

Background: Progressive multifocal leukoencephalopathy (PML) is an often fatal disease of the central nervous system caused by opportunistic infection of John Cunningham Polyomavirus (JCV). There's still no antiviral therapeutic strategy which was generally recognized as effective. The prognosis may differ in patients with different pathological mechanisms and treatments. We aim to report the effectiveness of combined treatment of low-dose, long-term immunoglobulin and mirtazapine in a pathologically proved PML case. Case presentation: A patient presented with progressive acalculia, right-left confusion and visual neglection was recorded. She received 10-year immunosuppressive therapy for dermatomyositis. White matter lesions located in bilateral parietal lobe and callosum area symmetrically in MR scanning. JC virus analysis and brain biopsy in left parietal lobe were performed. The number of JCV copies was 2595 in CSF and 282,809 in brain specimen. Abundant foamy macrophages and the lymphatic cells were obvious in immunohistochemistry staining. Few SV-40 positive JC infected cell and more CD4 + and CD68 + cells were predominant. Immunosuppressive drugs were terminated after being diagnosed as PML for positive JCV and pathological characteristics. In addition, immunoglobulin (5 g/day) and mirtazapine (45 mg/day) were used. JC virus in CSF decreased to 0 after treatment for 4 months and was still negative in June 2023. The clinical symptoms improved, and white matter lesions recovered significantly. Conclusions: We demonstrated that the combination treatment of IVIG and mirtazapine was effective in PML. Low-dose, long-term immunoglobulin might regulate the immune status in our case with controlled inflammatory reaction instead of destructive virus spreading. The therapy may be a prospective option for PML. [ABSTRACT FROM AUTHOR]

The incidence of central nervous system (CNS) disease has persistently increased over the last several years. There is an urgent need for effective methods to improve the cure rates of CNS disease. However, the precise molecular basis underlying the development and progression of major CNS diseases remains elusive. A complete molecular map will contribute to research on CNS disease treatment strategies. Emerging technologies such as single-cell RNA sequencing (scRNA-seq) and Spatial Transcriptomics (ST) are potent tools for exploring the molecular complexity, cell heterogeneity, and functional specificity of CNS disease. scRNA-seq and ST can provide insights into the disease at cellular and spatial transcription levels. This review presents a survey of scRNA-seq and ST studies on CNS diseases, such as chronic neurodegenerative diseases, acute CNS injuries, and others. These studies offer novel perspectives in treating and diagnosing CNS diseases by discovering new cell types or subtypes associated with the disease, proposing new pathophysiological mechanisms, uncovering novel therapeutic targets, and identifying putative biomarkers. Implications of scRNA-seq and ST for CNS diseases. A comprehensive understanding of cellular information and spatial context using scRNA-seq and ST, helping to elucidate the biological functions, the intricate connection between crucial regulatory pathways, and cell communication after CNS diseases. [ABSTRACT FROM AUTHOR]

Valproic acid (VA) is a widely used drug for the treatment of diseases affecting the central nervous system. Due to its epigenetic modulatory potential, it has been studied for possible therapeutic application in anticancer therapies. However, the VA exhibits different side effects in its application. Thus, synthetic coordination complexes with valproate can generate promising candidates for new active drugs with reduced toxicity. In this sense, we investigated the genotoxic and mutagenic potential of the sodium valproate and of the mixed ternary mononuclear Mg complex based on VA with 1,10‐phenanthroline (Phen) ligand ‐ [Mg (Valp)2Phen], in Saccharomyces cerevisiae and V79 cells. The MTT and clonal survival assays in V79 cells indicated that the Mg complex has higher cytotoxicity than sodium valproate. A similar cytotoxicity profile is observed in yeast. This fact is possibly due to the intercalation capacity of [Mg(Valp)2Phen], inducing DNA strand breaks, as observed in the comet assay and micronucleus test. In this sense, members of the NER, HR, NHEJ and TLS repair pathways are required for the repair of DNA lesions induced by [Mg(Valp)2Phen]. Interestingly, BER proteins apparently increase the cytotoxic potential of the drug. Furthermore, the [Mg(Valp)2Phen] showed higher cytotoxicity in V79 cells and yeast when compared to sodium valproate indicating applicability as a cytotoxic agent. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNA) are endogenously produced small, non-coded, single-stranded RNAs. Due to their involvement in various cellular processes and cross-communication with extracellular components, miRNAs are often coined the "grand managers" of the cell. miRNAs are frequently involved in upregulation as well as downregulation of specific gene expression and thus, are often found to play a vital role in the pathogenesis of multiple diseases. Central nervous system (CNS) diseases prove fatal due to the intricate nature of both their development and the methods used for treatment. A considerable amount of ongoing research aims to delineate the complex relationships between miRNAs and different diseases, including each of the neurological disorders discussed in the present review. Ongoing research suggests that specific miRNAs can play either a pathologic or restorative and/or protective role in various CNS diseases. Understanding how these miRNAs are involved in various regulatory processes of CNS such as neuroinflammation, neurovasculature, immune response, blood-brain barrier (BBB) integrity and angiogenesis is of empirical importance for developing effective therapies. Here in this review, we summarized the current state of knowledge of miRNAs and their roles in CNS diseases along with a focus on their association with neuroinflammation, innate immunity, neurovascular function and BBB. [ABSTRACT FROM AUTHOR]

Background/Objectives: Bladder outlet obstruction (BOO) resulting from benign prostate enlargement (BPE) is a common cause of lower urinary tract symptoms (LUTS) in men. Patients with central nervous system (CNS) diseases, such as spinal cord injury (SCI), Parkinson's disease (PD), cerebrovascular accident (CVA) and multiple systemic atrophy (MSA), commonly experience lower urinary tract dysfunction. Men who suffer from CNS diseases may also experience symptoms related to BPE and BOO, which pose an additional burden to their overall clinical status and result in the need for catheter use and a deterioration in quality of life. The aim of this study was to identify if prostate surgery will benefit men with CNS diseases who have been diagnosed with BPE-related BOO. Methods: The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. EMBASE, MEDLINE, Cochrane systematic reviews, Cochrane Central Register of Controlled Trials, Google Scholar, and ClinicalTrials.gov were searched from 1946 up to July 2023 for peer-reviewed publications addressing the primary outcome (success rate) and the secondary outcomes (postoperative changes in incontinence episodes, urodynamic parameters, questionnaire scores, and quality of life). In addition, the perioperative outcomes (adverse events and the need for further medical or surgical therapy) were reported. Results: A total of 1572 abstracts were screened, and 13 studies involving 1144 patients were eligible for inclusion. Six studies assessed the effect of prostate surgery for BPE-related BOO in SCI, four studies in CVA, two studies in PD, and one study in the MSA population. All studies were considered to have a high risk of bias. Transurethral resection of the prostate (TURP) was the most common de-obstruction procedure, followed by prostatic artery embolism and open prostatectomy. The overall pooled success rate was calculated as 81.4% (65–100%) in SCI, 27.1% (9–70%) in PD, and 66.7% (50–79%) in CVA populations. The risk of de novo incontinence was 24.7–50% in SCI, 20% in PD, 21–50% in CVA, and 60% in MSA population. In patients with SCI with BPE-related BOO, prostate surgery improved mean bladder compliance and detrusor filling pressure and resolved detrusor overactivity in up to 50% of patients. Improvement of free flow rate, voided volume, and post-void residual was observed in all patients. Patients with CVA had an increased risk of perioperative mortality compared to non-CVA patients, and the risk of postoperative complications was inversely proportional to the timing of the CVA insult since surgery. Conclusions: This systematic review provides an overview of the available evidence on the outcome of prostate surgery in patients with neurologic diseases and BPE-related BOO. Identifying the optimal practice was challenging due to the limited availability of high-quality studies and the high variability of the reported outcomes. Properly selected patients with neurological diseases may benefit from prostate surgery, provided that preoperative investigations indicate BPE-related BOO. [ABSTRACT FROM AUTHOR]

The nasal route of administration can bypass the blood–brain barrier in order to obtain a higher concentration in the brain, thus offering a feasible alternative route of administration for diseases associated with the central nervous system. The advantages of the intranasal administration and the potential favorable therapeutic effects of intranasally administered insulin led to the formulation of carboxymethyl chitosan (CMC) and sodium hyaluronate (NaHA) hydrocolloidal systems with insulin for nasal administration, targeting nose-to-brain delivery and the initial assessment of these systems. The influence of the formulation variables on the response parameters defined as surface properties, rheology, and in vitro release of insulin were analyzed using experimental design and statistical programs (Modde and Minitab software). The systems recorded good wetting and adhesion capacity, allowing the spread of the hydrocolloidal systems on the nasal mucosa. The samples had a pseudoplastic flow and the rapid release of the insulin was according to our objective. According to the physico-chemical characterization and preliminary assessment, these formulations are appropriate for administration on the nasal mucosa, but further studies are necessary to demonstrate the beneficial therapeutic actions and the safety of using intranasal insulin. [ABSTRACT FROM AUTHOR]

Cellular senescence is cell type and inducer specific. Therefore, senescent cells are not easily recognizable, and multiple markers should be used for their identification. Tauopathies are characterized by an increased presence of senescent cells, including microglia, astrocytes, oligodendrocytes, and neurons. Senescence is detected not only in culture and animal models but also in human postmortem tauopathy brains. Multiple phenotypes characterizing senescent cells, such as cell cycle arrest markers, DNA damage, and the release of a senescence-associated secretory profile (SASP), are present in tauopathies. The release of a SASP by senescent cells contributes to the inflammatory phenotype seen in tauopathies and may involve the activation of the NLRP3 inflammasome. Several neurodegenerative disorders, including the most common dementia in humans, Alzheimer's disease, as well as other dementias and movement disorders, show abnormal intracellular accumulation of the microtubule-associated protein tau (MAPT). Most of these diseases are of the elderly. With aging, accumulation of senescent cells can be observed in the central nervous system (CNS). Recent evidence suggests a putative involvement of these senescent cells in the pathology of tauopathies. Thus, elucidating the mechanisms by which senescent cells might contribute to driving tauopathies constitutes an important area of investigation. During mammalian aging, senescent cells accumulate in the body. Recent evidence suggests that senescent cells potentially contribute to age-related neurodegenerative diseases in the central nervous system (CNS), including tauopathies such as Alzheimer's disease (AD). Senescent cells undergo irreversible cell cycle arrest and release an inflammatory 'senescence-associated secretory profile' (SASP), which can exert devastating effects on surrounding cells. Senescent markers and SASP factors have been detected in multiple brain cells in tauopathies, including microglia, astrocytes, and perhaps even post-mitotic neurons, possibly contributing to the initiation as well as progression of these diseases. Here, we discuss the implications of presenting a senescent phenotype in tauopathies and highlight a potential role for the NOD-like receptor protein 3 (NLRP3) inflammasome as a newfound mechanism implicated in senescence and SASP formation. [ABSTRACT FROM AUTHOR]

Cognitive deficits are a common comorbidity with neurological disorders and normal aging. Inflammation is associated with multiple diseases including classical neurodegenerative dementias such as Alzheimer's disease (AD) and autoimmune disorders such as multiple sclerosis (MS), in which over half of all patients experience some form of cognitive deficits. Other degenerative diseases of the central nervous system (CNS) including frontotemporal lobe dementia (FTLD), and Parkinson's disease (PD) as well as traumatic brain injury (TBI) and psychological disorders like major depressive disorder (MDD), and even normal aging all have cytokine‐associated reductions in cognitive function. Thus, there is likely commonality between these secondary cognitive deficits and inflammation. Neurological disorders are increasingly associated with substantial neuroinflammation, in which CNS‐resident cells secrete cytokines and chemokines such as tumor necrosis factor (TNF)α and interleukins (ILs) including IL‐1β and IL‐6. CNS‐resident cells also respond to a wide variety of cytokines and chemokines, which can have both direct effects on neurons by changing the expression of ion channels and perturbing electrical properties, as well as indirect effects through glia–glia and immune‐glia cross‐talk. There is significant overlap in these cytokine and chemokine expression profiles across diseases, with TNFα and IL‐6 strongly associated with cognitive deficits in multiple disorders. Here, we review the involvement of various cytokines and chemokines in AD, MS, FTLD, PD, TBI, MDD, and normal aging in the absence of dementia. We propose that the neuropsychiatric phenotypes observed in these disorders may be at least partially attributable to a dysregulation of immunity resulting in pathological cytokine and chemokine expression from both CNS‐resident and non‐resident cells. [ABSTRACT FROM AUTHOR]

Importance: B-cell-targeting monoclonal antibodies have demonstrated safety and efficacy in multiple sclerosis or anti-aquaporin-4 IgG positive neuromyelitis optica spectrum disorder. However, these therapies do not facilitate drug-free remission, which may become possible with cell-based therapies, including chimeric antigen receptor (CAR) T cells. CAR T-cell therapy holds promise for addressing other antibody-mediated CNS disorders, e.g., MOG-associated disease or autoimmune encephalitis. Objective: To provide an overview of the current clinical knowledge on CAR T-cell therapy in central nervous system autoimmunity. Evidence review: We searched PubMed, Embase, Google Scholar, PsycINFO, and clinicaltrials.gov using the terms 'CAR T cell' and 'multiple sclerosis/MS' or 'neuromyelitis optica/spectrum diseases/NMOSD' or 'MOG-associated disease/MOGAD 'or' autoimmune encephalitis' or 'neuroimmunology'. Findings: An ongoing phase I clinical trial has indicated the safety and benefits of anti-BCMA CAR T cells in 12 patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder. Case reports involving two individuals with progressive multiple sclerosis and one patient with stiff-person syndrome demonstrated a manageable safety profile following treatment with anti-CD19 CAR T cells. Recruitment has commenced for two larger studies in MS, and a phase I open-label basket study is underway to evaluate BCMA-directed CAR T cells in various antibody-associated inflammatory diseases, including MOG-associated disease. Preclinical research on NMDA receptor antibody autoimmune encephalitis treated with chimeric autoantibody receptor T cells generated promising data. Conclusions and relevance: There is minimal evidence of the benefits of CAR T-cell therapy in individuals with central nervous system-directed autoimmunity. Nevertheless, multicenter controlled clinical trials with a manageable safety profile appear feasible and are warranted due to very promising case experiences. [ABSTRACT FROM AUTHOR]

Rosai‐Dorfman disease (RDD) is characterized by clonal proliferation of S‐100 positive histiocytes and variable emperipolesis. It commonly affects cervical lymph nodes. Central nervous system (CNS) involvement is extremely rare. We attempted to evaluate the Cyclin D1 expression and frequency of KRAS and BRAF mutations in the RDD involving the CNS. All patients with histopathologically diagnosed RDD involving CNS were recruited from 2011 to 2022. All cases were subjected to immunohistochemistry for CD68, CD163, S100, CD1a, GFAP, CD207, EMA, ALK, BRAFV600E, IgG4, IgG, and CyclinD1. The real‐time polymerase chain reaction (RT‐PCR) for hotspot mutation analysis of KRAS (exons 2, 3, and 4) and BRAF (V600E) was conducted on formalin‐fixed paraffin‐embedded tissue using a commercial kit (EntroGen). A total of seven cases were included. The median age was 31 years, with six men and one woman. It showed spinal cord (n = 4) and intracranial (n = 3) involvement. Histologically, all cases showed histiocyte‐rich inflammation with evidence of emperipolesis. These histiocytes were positive for S100, CD68, CD163, and Cyclin D1, whereas negative for CD1a, CD207, and EMA. BRAF V600E was expressed in a single case. None of the control cases (demyelination and infarction) with histiocytic infiltrate showed Cyclin D1 expression. Four RDD cases showed increased IgG4‐positive plasma cells (>10/HPF) and IgG4/IgG ratio (>40%). BRAF V600E mutation was detected in one case (14.28%), while none showed KRAS mutation. RDD involving CNS is extremely rare and diagnostically challenging. Nuclear Cyclin D1 expression along with S‐100 positivity in the tumor cells is a strong diagnostic clue. BRAF and KRAS mutations are rare in CNS RDD. [ABSTRACT FROM AUTHOR]

Cinnamaldehyde (CA) is an active ingredient extracted from cinnamon and is widely used in the food industry as a natural additive. CA has a variety of biological functions, such as antibacterial, antioxidant, antiviral, and anticancer, as well as its role in regulating gut microbiota, have been well-established. Additionally, CA has shown positive effects on degenerative central nervous system diseases, cognitive impairment, arthritis, and ischemic reperfusion injury, and is widely used in the food industry and clinical medicine. However, its poor water solubility and easy oxidation have largely limited its broad application. To enhance the efficacy of CA delivery, innovative delivery systems have been developed. This review aims to compile the most recent literature on CA extraction methods, biological functions, delivery systems, and toxicology, highlighting the compound’s significance. By providing a comprehensive overview of CA, this review intends to serve as a valuable resource for the development and application of CA in both food and medical contexts. [ABSTRACT FROM AUTHOR]

Introduction: Multiple sclerosis (MS) is an immune-mediated, neurodegenerative disease of the central nervous system. Fatigue represents one of the most prevalent and limiting symptoms of MS, and is associated with vascular dysfunction, notably increased arterial stiffness. Objective: This study examined the relationship between arterial stiffness and perceived fatigue in persons with MS. Methods: The sample of 52 persons with MS (71.2% Female; Age: 46.7 ± 12.3 yrs.) completed arterial stiffness and fatigue assessments as baseline for an exercise training intervention. Applanation tonometry measured arterial stiffness, pulsatility and waveform characteristics, and yielded the following outcomes: carotid-femoral pulse wave velocity (cfPWV), carotid pulse-pressure (cPP), and aortic augmentation pressure (AP). Perceived fatigue was measured using the Fatigue Severity Scale (FSS). Results: The mean (SD) scores for cfPWV, cPP, and AP were 7.0 ± 1.8 m/s, 35.7 ± 8.8 mmHg, 8.2 ± 6.2 mmHg, respectively. The mean (SD) FSS score was 4.6 ± 1.4 and indicated elevated fatigue. There were statistically significant (p <.05) inverse correlations between cfPWV (r = –.32), cPP (r = –.37) and AP (r = –.32) with FSS scores, and the correlations remained significant even after controlling for disability, body mass index, age, and sex. Conclusion: Our results indicate a consistent pattern of inverse relationships between arterial stiffness, pulsatility, and waveforms with fatigue independent of disability, body mass index, age, and sex in MS. This could be explained by lower sympathetic activation linking higher arterial stiffness, pulsatility and augmentation pressure with lower fatigue in persons with MS. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a 38-year-old female patient with refractory leukemia who received CAR-T cell therapy. The patient experienced complications, including immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome and neurologic manifestations. The article explores the clinical manifestations of major complications, such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). The patient ultimately developed a sudden coma and was found to have a cerebellar hemorrhage. The article emphasizes the need for early involvement of neurointensivists in the evaluation and management of patients receiving CAR-T cell therapy. [Extracted from the article]

Human angiostrongyliasis, caused by consuming the larva stage of Angiostrongylus cantonensis, is an infectious disease involving the central nervous system (CNS) and ophthalmic system. Current treatment of angiostrongyliasis involves albendazole accompanied by analgesics and corticosteroids. However, long-term use of corticosteroids may lead to significant adverse effects. In the current study, we screened through different potentially effective flavonoid compounds and identified quercetin as an effective anti-inflammatory agent in an angiostrongyliasis mouse model. Our results identified that quercetin may reverse the neurological defects in mice with angiostrongyliasis. The brain pathology and inflammatory status were also improved by albendazole-quercetin co-therapy. Further analysis showed that albendazole-quercetin co-therapy had a better therapeutic effect than albendazole or quercetin monotherapy. This therapeutic effect was achieved by inhibiting the brain inflammasome activation and apoptosis. Albendazole-quercetin co-therapy also leads to the inhibition of brain IL-5, possibly leading to improved pathology. Our results here proved that quercetin may serve as a potential adjuvant drug in treating human angiostrongyliasis. Author summary: Human infection following accidental consumption of Angiostrongylus cantonensis can cause eosinophilic meningoencephalitis. Albendazole is the drug of choice for treatment, followed by continuous use of analgesics and corticosteroids, which may have safety concerns. On the other hand, flavonoids are derived from natural plants and have been shown to improve cognitive function by inhibiting the central nervous system (CNS) inflammation. However, the effect of flavonoids combined with albendazole in treating angiostrongyliasis is still unclear. In the current study, we aimed to investigate the therapeutic potential of flavonoids in combination with albendazole for A. cantonensis infection. Our results found that quercetin exhibited the most significant therapeutic effect with albendazole, by which the combined regimen improved the brain histopathology and recovered the mice's neurological functions. This combined therapy also reduces inflammasome activation, pyroptosis, apoptosis, and immune imbalance in the infected mouse brains. Our current study indicated that quercetin possessed the potential as an anti-inflammatory drug and may be helpful in the treatment of A. cantonensis-induced meningoencephalitis. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a disabling disease of the central nervous system. People living with MS often have co-existing sleep disorders and cognitive dysfunction. The objective of this study was to scrutinize the relationship between cognitive outcomes and sleep conditions in MS. Methods: This study followed the Joanna Briggs Institute's (JBI) and PRISMA guidelines. PubMed, Scopus, Embase, and Web of Science databases were searched and original studies delineating the relationship between sleep status and cognitive findings in MS patients‌ were included. The risk of bias was assessed using the JBI critical appraisal tools. Results: In the final review, out of 1635 screened records, 35 studies with 5321 participants were included. Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and polysomnography were the most common assessment tools for evaluation of sleep condition, and cognitive evaluations were conducted using the tests including Paced Auditory Serial Addition Test (PASAT), California Verbal Learning Test (CVLT), Symbol Digit Modalities Test (SDMT) and Brief Visuospatial Memory Test (BVMT). Assessing the quality of studies showed no significant bias in most of the included articles. A link between sleep condition and cognitive abilities was suggested in the literature, especially with objective measurement of sleep condition; however, current evidence did not support a substantial association between self-reported sleep quality and processing speed and working memory in patients with MS. Discussion: Evidence proposes sleep is an independent factor associated with cognitive outcomes in MS. Given the limitations of the evidence such as the lack of well-designed prospective studies, these findings need to be interpreted with caution. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionsAutoimmune encephalitis (AE) is a group of autoimmune diseases targeting the central nervous system, characterized by severe clinical symptoms and substantial consumption of medical resources. Neuroinflammation plays a crucial role in disease progression, and detecting inflammatory responses can provide insights into disease status and disease severity. The systemic immune-inflammation index (SII), a novel marker of inflammatory status, has been rarely studied in AE.Retrospective analysis of data from AE patients admitted to the First Affiliated Hospital of Zhengzhou University between January 2019 and September 2023 was conducted. Univariate analysis and logistic regression were used to assess the association between SII and patient severity. Nomograms for predicting AE severity were established, and receiver operating characteristic (ROC) curves, concordance index (C-index), calibration curves, and decision curve analysis were employed to evaluate predictive accuracy. Additionally, the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score was used to assess patient severity.This study enrolled 157 patients, of whom 57 were classified as severe according to the CASE score. SII, cerebrospinal fluid (CSF) cell counts, disturbance of consciousness, and behavioural abnormalities independently associated with the occurrence of severe cases. The C-index of the nomograms was 0.87, indicating strong association with disease severity, as supported by the calibration. Additionally, SII levels were highest within seven days of onset and decreased after one month. In subgroup analyses of different antibodies, SII also associations with severe cases in NMDAR encephalitis.Higher SII levels are associated with an increased likelihood of developing severe AE, peaking within 7 days of disease onset and decreasing thereafter, potentially offering a prognostic marker to assess disease progression early in its course. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, leading to significant disability through neurodegeneration. Despite advances in the understanding of MS pathophysiology, effective treatments remain limited. Mesenchymal stem cells (MSCs) have gained attention as a potential therapeutic option due to their immunomodulatory and regenerative properties. This review examines MS pathogenesis, emphasizing the role of immune cells, particularly T cells, in disease progression, and explores MSCs' therapeutic potential. Although preclinical studies in animal models show MSC efficacy, challenges such as donor variability, culture conditions, migratory capacity, and immunological compatibility hinder widespread clinical adoption. Strategies like genetic modification, optimized delivery methods, and advanced manufacturing are critical to overcoming these obstacles. Further research is needed to validate MSCs' clinical application in MS therapy. [ABSTRACT FROM AUTHOR]

Japanese encephalitis is an acute infectious disease of the central nervous system caused by neurotropic Japanese encephalitis virus (JEV). As a member of TAM (Tyro3, Axl and Mertk) family, Mertk has involved in multiple biological processes by engaging with its bridging ligands Gas6 and Protein S, including invasion of pathogens, phagocytosis of apoptotic cells, inflammatory response regulation, and the maintenance of blood brain barrier (BBB) integrity. However, its role in encephalitis caused by JEV infection has not been studied in detail. Here, we found that Mertk−/− mice exhibited higher mortality and more rapid disease progression than wild-type mice after JEV challenge. There were no significant differences in viral load and cytokines expression level in peripheral tissues between Wild type and Mertk−/− mice. Furthermore, the absence of Mertk had little effect on the inflammatory response and immunopathological damage while it can cause an increased viral load in the brain. For the in vitro model of BBB, Mertk was shown to maintain the integrity of the BBB. In vivo, Mertk−/− mice exhibited higher BBB permeability and lower BBB integrity. Taken together, our findings demonstrate that Mertk acts as a protective factor in the development of encephalitis induced by JEV infection, which is mainly associated with its beneficial effect on BBB integrity, rather than its regulation of inflammatory response. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) comprises a diverse range of brain cell types with distinct functions and gene expression profiles. Although single-cell RNA sequencing (scRNA-seq) provides new insights into the brain cell atlases, integrating large-scale CNS scRNA-seq data still encounters challenges due to the complexity and heterogeneity among CNS cell types/subtypes. In this study, we introduce a self-supervised contrastive learning method, called scCM, for integrating large-scale CNS scRNA-seq data. scCM brings functionally related cells close together while simultaneously pushing apart dissimilar cells by comparing the variations of gene expression, effectively revealing the heterogeneous relationships within the CNS cell types/subtypes. The effectiveness of scCM is evaluated on 20 CNS datasets covering 4 species and 10 CNS diseases. Leveraging these strengths, we successfully integrate the collected human CNS datasets into a large-scale reference to annotate cell types and subtypes in neural tissues. Results demonstrate that scCM provides an accurate annotation, along with rich spatial information of cell state. In summary, scCM is a robust and promising method for integrating large-scale CNS scRNA-seq data, enabling researchers to gain insights into the cellular and molecular mechanisms underlying CNS functions and diseases. scCM, a self-supervised contrastive learning method, effectively integrates large-scale CNS scRNA-seq data by clustering functionally related cells and separating dissimilar ones. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) comprises a diverse range of brain cell types with distinct functions and gene expression profiles. Although single-cell RNA sequencing (scRNA-seq) provides new insights into the brain cell atlases, integrating large-scale CNS scRNA-seq data still encounters challenges due to the complexity and heterogeneity among CNS cell types/subtypes. In this study, we introduce a self-supervised contrastive learning method, called scCM, for integrating large-scale CNS scRNA-seq data. scCM brings functionally related cells close together while simultaneously pushing apart dissimilar cells by comparing the variations of gene expression, effectively revealing the heterogeneous relationships within the CNS cell types/subtypes. The effectiveness of scCM is evaluated on 20 CNS datasets covering 4 species and 10 CNS diseases. Leveraging these strengths, we successfully integrate the collected human CNS datasets into a large-scale reference to annotate cell types and subtypes in neural tissues. Results demonstrate that scCM provides an accurate annotation, along with rich spatial information of cell state. In summary, scCM is a robust and promising method for integrating large-scale CNS scRNA-seq data, enabling researchers to gain insights into the cellular and molecular mechanisms underlying CNS functions and diseases. scCM, a self-supervised contrastive learning method, effectively integrates large-scale CNS scRNA-seq data by clustering functionally related cells and separating dissimilar ones. [ABSTRACT FROM AUTHOR]

Background: Increasing evidences suggest that nonalcoholic fatty liver disease (NAFLD) is associated with neuropsychiatric disorders. Nevertheless, whether there were causal associations between them remained vague. A causal association between neuropsychiatric disorders and NAFLD was investigated in this study. Methods: We assessed the published genome-wide association study summary statistics for NAFLD, seven mental disorder-related diseases and six central nervous system dysfunction-related diseases. The causal relationships were first assessed using two-sample and multivariable Mendelian randomization (MR). Then, sensitivity analyses were performed, followed by a reverse MR analysis to determine whether reverse causality is possible. Finally, we performed replication analyses and combined the findings from the above studies. Results: Our meta-analysis results showed NAFLD significantly increased the risk of anxiety disorders (OR = 1.016, 95% CI = 1.010–1.021, P value < 0.0001). In addition, major depressive disorder was the potential risk factor for NAFLD (OR = 1.233, 95% CI = 1.063–1.430, P value = 0.006). Multivariable MR analysis showed that the causal effect of major depressive disorder on NAFLD remained significant after considering body mass index, but the association disappeared after adjusting for the effect of waist circumference. Furthermore, other neuropsychiatric disorders and NAFLD were not found to be causally related. Conclusions: These results implied causal relationships of NAFLD with anxiety disorders and Major Depressive Disorder. This study highlighted the need to recognize and understand the connection between neuropsychiatric disorders and NAFLD to prevent the development of related diseases. [ABSTRACT FROM AUTHOR]

RGS (Regulator of G protein signaling) proteins have long captured the fascination of researchers due to their intricate involvement across a wide array of signaling pathways within cellular systems. Their diverse and nuanced functions have positioned them as continual subjects of scientific inquiry, especially given the implications of certain family members in various cancer types. Of particular note in this context is RGS20, whose clinical relevance and molecular significance in hepatocellular carcinoma we have recently investigated. These investigations have prompted questions into the prevalence of pathogenic mutations within the RGS20 gene and the intricate network of interacting proteins that could contribute to the complex landscape of cancer biology. In our study, we aim to unravel the mutations within the RGS20 gene and the multifaceted interplay between RGS20 and other proteins within the context of cancer. Expanding on this line of inquiry, our research is dedicated to uncovering the intricate mechanisms of RGS20 in various cancers. In particular, we have redirected our attention to examining the role of RGS20 within hematological malignancies, with a specific focus on multiple myeloma and follicular lymphoma. These hematological cancers hold significant promise for further investigation, as understanding the involvement of RGS20 in their pathogenesis could unveil novel therapeutic strategies and treatment avenues. Furthermore, our exploration has extended to encompass the latest discoveries concerning the potential involvement of RGS20 in diseases affecting the central nervous system, thereby broadening the scope of its implications beyond oncology to encompass neurobiology and related fields. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Neuromyelitis optica spectrum disorder (NMOSD) is an anti‐aquaporin 4 (anti‐AQP4) autoantibodies‐mediated idiopathic inflammatory demyelinating disease of the central nervous system. While intravenous pulse methylprednisolone (IVMP) is the recommended initial treatment option for acute onset NMOSD, its therapeutic mechanism remains unclear. We hypothesized that IVMP would reduce the expression of pro‐inflammatory factors and increase the resolution of inflammation in patients with NMOSD.Mendelian randomization (MR) analysis was used to screen meaningful inflammatory and resolution factors for inclusion. Three MR methods with inverse variance weighting (IVW) were primarily used to identify positive results. Interleukin (IL)‐10, IL‐1β, IL‐6, C‐X‐C motif chemokine ligand 12 (CXCL12), and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) were screened from 41 inflammatory factors, and resolvin D1 (RvD1), maresin 1 (MaR1), and lipoxin A4 (LXA4) were screened from 6 resolution markers for inclusion. Subsequently, 12 patients with NMOSD were enrolled and treated with IVMP. Serum levels of the aforementioned inflammatory and resolution markers were measured by enzyme‐linked immunosorbent assay before and after IVMP treatment.High levels of TRAIL, CXCL12, and IL‐1β were associated with an increased risk of NMOSD (TRAIL: odds ratio [OR], 1.582; 95% confidence interval [CI], 1.003–2.495; CXCL12: OR, 3.610; 95% CI, 1.011–12.889; IL‐1β: OR, 4.500; 95% CI, 1.129–17.927). High levels of RvD1, MaR1, and LXA4 were associated with a reduced risk of NMOSD (RvD1: OR, 0.725; 95% CI, 0.538–0.976; MaR1: OR, 0.985; 95% CI, 0.970–0.999; LXA4: OR, 0.849; 95% CI, 0.727–0.993). Among patients with NMOSD, serum levels of IL‐6, CXCL12, and TRAIL significantly decreased following IVMP treatment, compared with pretreatment levels, while levels of IL‐1β, LXA4, and MaR1 significantly increased after IVMP treatment (p < 0.05). A significant positive correlation was observed between CXCL12 levels and Expanded Disability Status Scale (EDSS) scores (r = 0.451, p < 0.05).Several systemic inflammatory regulators associated with the pathogenesis of NMOSD were identified. The protective roles of LXA4 and MaR1 may be indispensable components of glucocorticoid treatment. Therefore, the use of resolution markers may be a potential strategy for improving central nervous system injury in individuals with NMOSD. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system affecting predominantly adults. It is a complex disease associated with both environmental and genetic risk factors. Although over 230 risk single‐nucleotide polymorphisms have been associated with MS, all are common human variants. The mechanisms by which they increase the risk of MS, however, remain elusive. We hypothesized that a complex genetic phenotype such as MS could be driven by coordinated expression of genes controlled by transcriptional regulatory networks. We, therefore, constructed a gene coexpression network from microarray expression analyses of five purified peripheral blood leukocyte subsets of 76 patients with relapsing remitting MS and 104 healthy controls. These analyses identified a major network (or module) of expressed genes associated with MS that play key roles in cell‐mediated cytotoxicity which was downregulated in monocytes of patients with MS. Manipulation of the module gene expression was achieved in vitro through small interfering RNA gene knockdown of identified drivers. In a mouse model, network gene knockdown modulated the autoimmune inflammatory MS model disease—experimental autoimmune encephalomyelitis. This research implicates a cytotoxicity‐associated gene network in myeloid cells in the pathogenesis of MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a strong neuroinflammatory component. Current treatments principally target the immune system but fail to preserve long‐term myelin health and do not prevent neurological decline. Studies over the past two decades have shown that the structurally related neuropeptides VIP and PACAP (vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide, respectively) exhibit pronounced anti‐inflammatory activities and reduce clinical symptoms in MS disease models, largely via actions on their bivalent VIP receptor type 1 and 2. Here, using the cuprizone demyelination model, we demonstrate that PACAP and VIP, and strikingly the PACAP‐selective receptor PAC1 agonist maxadilan, prevented locomotor deficits in the horizontal ladder and open field tests. Moreover, only PACAP and maxadilan were able to prevent myelin deterioration, as assessed by a reduction in the expression of the myelin markers proteolipid protein 1, oligodendrocyte transcription factor 2, quaking‐7 (APC) and Luxol Fast Blue staining. Furthermore, PACAP and maxadilan (but not VIP), prevented striatal synaptic loss and diminished astrocyte and microglial activation in the corpus callosum of cuprizone‐fed mice. In vitro, PACAP or maxadilan prevented lipopolysaccharide (LPS)‐induced polarisation of primary astrocytes at 12–24 h, an effect that was not seen with maxadilan in LPS‐stimulated microglia. Taken together, our data demonstrates for the first time that PAC1 agonists provide distinctive protective effects against white matter deterioration, neuroinflammation and consequent locomotor dysfunctions in the cuprizone model. The results indicate that targeting the PAC1 receptor may provide a path to treat myelin‐related diseases in humans. [ABSTRACT FROM AUTHOR]

Introduction: Neurosarcoidosis (NS) is a systemic inflammatory granulomatous disease affecting of patients with sarcoidosis. Its diagnosis is difficult as there is no specific test for it. Because of its rarity, the management of NS has so far only been described in case series and short retrospective cohorts. The objective of this study is description of the clinical, paraclinical presentation and the therapeutic management of central nervous system (CNS) involvement in NS patients in France. Methods: This multicenter, retrospective, observational study involved patients hospitalized between 2010 and 2019 with a diagnosis of sarcoidosis and CNS involvement. Results: We included 118 patients (38 with isolated NS, 80 with NS associated with systemic sarcoidosis). NS was the initial presentation in 78% of patients, with cranial nerve involvement (36%), medullary symptoms (23%), and seizures (21%). Twenty‐one percent of the patients had already been diagnosed with systemic sarcoidosis. The most frequent biological abnormality was lymphopenia (62.5%), while angiotensin‐converting enzyme was increased in 21%. Meningitis was present in 45% and hyperproteinorachia in 69.5% of cases. MRI mainly revealed white matter abnormalities and leptomeningeal enhancement (34%). Corticosteroids were the most useful treatment, and immunosuppressive agents were used in steroid‐resistant patients and to limit side effects. Methotrexate, cyclophosphamide, and anti‐TNFα were also used, exhibiting good efficacy. Conclusions: This cohort contributes to a better understanding of the clinical phenotype and associated imaging and biological abnormalities. Sharing of clinical, biological, and imaging data, as well as the therapeutic responses, of patients with NS helps to better understand and manage this disease that affects a small number of patients per center. A database project could be implemented in the future to enable this. [ABSTRACT FROM AUTHOR]

We analyzed data on pediatric invasive fungal diseases of the central nervous system (CNS-IFDs) reported by five of a total of eight Pediatric Hematology-Oncology Departments in Greece for 16 years (2007–2022). A total of twelve patients (11 boys, median age: 9.5 years, range: 2–16) were reported suffering from CNS-IFDs. The underlying malignancy was acute lymphoblastic leukemia in 9/12 and acute myeloid leukemia, Ewing sarcoma, and rhabdomyosarcoma in one each. Eleven patients presented with CNS-related symptoms (i.e., seizures, headache, cerebral palsy, ataxia, hallucination, seizures, blurred vision, amaurosis). All patients had pathological MRI findings. Multifocal fungal disease was observed in 6/12 patients. Nine proven and three probable CNS-IFD cases were diagnosed. Causative pathogens in proven cases were Aspergillus spp. and Candida albicans (n = 2 each), Mucor spp., Rhizopus arrhizus, Absidia spp., Fusarium oxysporum and Cryptococcus neoformans (n = 1 each). Causative pathogens in probable cases were Aspergillus spp. (n = 2) and Candida spp. (n = 1). All patients received appropriate antifungal therapy (median duration: 69.5 days, range 19–364). Two patients underwent additional surgical treatment. Six patients were admitted to the Intensive Care Unit due to complications. Three patients (25%) died, two due to IFD and one due to an underlying disease. Early recognition and prompt intervention of CNS-IFDs may rescue the patients and improve overall survival. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system with unknown etiology, resulting in various impairments that necessitate continuous rehabilitation to enhance functionality, quality of life, and motor function, including through Virtual Reality (VR) therapy. Comparing tasks in virtual environments and their potential skill transfer to real-world settings could aid in optimizing treatment programs to improve motor performance in individuals with MS. This study aimed to determine whether practicing acquisition and retention phases using two distinct interfaces (concrete—Touch Screen or abstract—Kinect system) affects performance in a subsequent task using a different interface (transfer phase). A randomized clinical trial was conducted with 56 volunteers with MS and 41 controls. Participants engaged in a computer game where they burst as many bubbles as possible within 10 s per attempt. After the acquisition and retention phases, all participants switched interfaces (e.g., those using Kinect switched to Touchscreen and vice versa). Significant performance improvements were observed in both groups during the acquisition phase, which were maintained in the retention phase. Although the abstract interface was more challenging for both groups, only the MS group that practiced with the abstract interface successfully transferred their improvements to the concrete interface. Thus, despite the increased difficulty of the abstract task during practice, it led to better performance transfer when required to complete a subsequent concrete task, suggesting that abstract devices may be beneficial in clinical practice for improving motor function in people with MS. [ABSTRACT FROM AUTHOR]

Lactate, an important metabolic product, provides energy to neural cells during energy depletion or high demand and acts as a signaling molecule in the central nervous system. Recent studies revealed that lactate-mediated protein lactylation regulates gene transcription and influences cell fate, metabolic processes, inflammation, and immune responses. This review comprehensively examines the regulatory roles and mechanisms of lactylation in neurodevelopment, neuropsychiatric disorders, brain tumors, and cerebrovascular diseases. This analysis indicates that lactylation has multifaceted effects on central nervous system function and pathology, particularly in hypoxia-induced brain damage. Highlighting its potential as a novel therapeutic target, lactylation may play a significant role in treating neurological diseases. By summarizing current findings, this review aims to provide insights and guide future research and clinical strategies for central nervous system disorders. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis is a chronic immune-mediated disease of the central nervous system affecting nearly 3 million people worldwide. Although much progress has been made in the understanding and treatment of MS, cures remain elusive. Objectives: To accelerate the development of cures for MS by updating the Pathways to Cures Research Roadmap based on a contemporary understanding of disease. The refined Roadmap will help to promote research in scientific areas with great potential to reveal insights leading to cures and inspire greater coordination of global resources. Methods: Refinements to the Roadmap were achieved during a Global Summit that included close to 200 academic and industry scientists, health care providers, policy makers, funders, and people with MS from 15 countries. Results: The refined Roadmap describes three pathways that target opportunities for generating scientific insights leading to cures. Recommendations for accelerating research progress include, lowering barriers for global data sharing, enhancing collaboration and coordination among research supporters, committing to sustained funding, considering implications for implementation, engaging PwMS and committing to diversity, equity, and inclusion in the global MS movement. Conclusion: The refined roadmap provides a strategic framework for tackling the complexities of MS and advancing prevention strategies, effective treatments, and cures. [ABSTRACT FROM AUTHOR]

Background: Noradrenergic signaling declines in Parkinson's disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that β-acting drugs slow PD progression. Objective: The primary objective was to compare the safety and effects of 3 β-adrenoceptor (β-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of β-AR acting drugs in HVs and PD-patients. Methods: In Part A, HVs received single doses of 32 mg salbutamol, 160μg clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20μg on Day 1, 40μg on Day 2, 80μg on Days 3–7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests. Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral β2-AR effects were observed with clenbuterol. Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of β2-ARs in the CNS. Plain Language Summary: Aims and Purpose of the Research: This research aimed to explore how three different drugs affect brain function. These drugs are salbutamol, clenbuterol, and pindolol and work in the brain by stimulating specific brain cells that can improve aspects like memory and coordination. The main question was to see how safe these drugs were and how they impact the brain function after one dose in healthy people, and after multiple doses in both healthy people and those with Parkinson's disease. Background of the Research: Parkinson's disease is a condition where brain cells start to die, which affects different areas of the brain, including movement function, as well as memory and attention. This research matters because finding drugs that affect the brain function could improve the lives of people with Parkinson's disease. Methods and Research Design: The study was conducted in three parts. In the first part, healthy volunteers took one dose of each of the three drugs— salbutamol, clenbuterol, and pindolol— as well as a placebo (a harmless pill that has no effect). The researchers tested the participants' brain functions using various tasks including memory tests and eye response measurements. In the second and third part, healthy people and people with Parkinson's disease took the drug that performed best in healthy volunteers for seven days. Results and Importance: In the first part, a single dose of clenbuterol was safe and improved memory and attentions tasks in healthy people, and therefore was chosen for further testing in the second and third part. In these parts, multiple doses of clenbuterol were safe and helped improve memory and attention tasks in healthy people, with similar positive trends seen in people with Parkinson's disease. The study suggests that clenbuterol might help improve brain function by activating specific receptors in the brain. These results are important because they suggest that clenbuterol could be a potential treatment to help improve brain function in people with Parkinson's disease. However, more research is needed to fully understand its effects and to confirm these findings. [ABSTRACT FROM AUTHOR]

Pomegranate is a notable source of nutrients, containing a considerable proportion of organic acids, polysaccharides, vitamins, fatty acids, and polyphenols such as flavonoids, phenolic acids, and tannins. It is also rich in nutritionally important minerals and chemical elements such as K, P, Na, Ca, Mg, and N. The presence of several bioactive compounds and metabolites in pomegranate has led to its incorporation into the functional food category, where it is used for its numerous therapeutic properties. Pomegranate's bioactive compounds have shown antioxidant, anti-inflammatory, and anticancer effects. Aging is a process characterized by the chronic accumulation of damages, progressively compromising cells, tissues, and organs over time. Inflammaging is a chronic, subclinical, low-grade inflammation that occurs during the aging process and is linked to many age-related diseases. This review aims to summarize and discuss the evidence of the benefits of pomegranate extract and its compounds to slow the aging processes by intervening in the mechanisms underlying inflammaging. These studies mainly concern neurodegenerative and skin diseases, while studies in other fields of application need to be more practical. Furthermore, no human studies have demonstrated the anti-inflammaging effects of pomegranate. In the future, supplementation with pomegranate extracts, polyphenols, or urolithins could represent a valuable low-risk complementary therapy for patients with difficult-to-manage diseases, as well as a valid therapeutic alternative for the topical or systemic treatment of skin pathologies. [ABSTRACT FROM AUTHOR]

Transdermal drug delivery (TDD) has gained clinical approval over several decades, with extensive research dedicated to novel drug and device development. Despite notable research progress, the market adoption of TDD devices has not met anticipated levels, with oral administration and injection remaining predominant delivery methods. To maximize the potential of TDD, we identify bottlenecks hindering its widespread clinical application and propose promising research avenues. We begin by analyzing stringent demands necessary to truly benefit patients, addressing significant challenges in biomechanics, nanomedicine, and flexible electronics. Subsequently, we delve into skin anatomy, enhancement strategies, nano-carriers, and their underlining mechanisms, highlighting the importance and framework of quantitative modeling. Based on these discussions, we highlight the core strength of TDD, such as automatic precise administration based on feedback and high delivery efficiencies, especially applicable to localized conditions (e.g., central nervous system diseases, tumors). Finally, we envision the future of intelligent TDD device and its operation scenario, aiming to steer research efforts toward faster translation of laboratory innovations into widely used products for sufferers. [ABSTRACT FROM AUTHOR]

Valbenazine is commonly used to treat tardive dyskinesia, and we conducted a pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate neurological safety signals associated with valbenazine. Data was collected in FAERS from the second quarter of 2017 to the fourth quarter of 2023 for data cleaning. Neurological adverse event (AE) signals of valbenazine were mined by calculating reporting odds ratios (ROR), information component (IC) and empirical Bayesian geometric mean (EBGM). The serious and non-serious cases and signals were prioritized using a rating scale. The number of neurological AE reports where the primary suspect (PS) drug was 8981 for valbenazine. Significant AE signals were identified by the preferred term (PT) analysis for valbenazine, including somnolence (ROR 19.69), tremor (ROR 15.17), and tardive dyskinesia (ROR 236.91), among which 18 AEs were identified as new signals. Patient age (p < 0.009) and sex (p = 0.197) might be associated with an increased risk of neurological AE severity. Notably, the association between valbenazine and neurological disorders remained when stratified by sex, age, and reporter type. AE timing analysis was performed for the drug and four moderate clinical priority signals [i.e., somnolence, balance disorder, parkinsonism, and akathisia (priorities 7)], showing the same early failure type profiles. The increase in neurological safety signals is identified in the post-marketing research of valbenazine. Clinicians need to pay attention to not only common AEs but also be alert to new neurological AE signals when using valbenazine. • This study provides the latest valbenazine-related neurological safety profiles, and eighteen AEs were identified as new signals. • Neurological AEs most commonly identified for valbenazine were somnolence, tremor, dizziness, drooling, dyskinesia, and balance disorder. • Our findings could potentially prompt improved awareness of valbenazine-related toxicities and help healthcare professionals mitigate the risk of neurological events. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a degenerative disease of the central nervous system. The pathogenesis is still not fully clear. One of the main histopathological manifestations is senile plaques formed by β-amyloid (Aβ) accumulation. Aβ is generated from the sequential proteolysis of amyloid precursor protein (APP) by β-secretase [i.e. β-site APP cleaving enzyme 1 (BACE1)] and γ-secretase, with a rate-limiting step controlled by BACE1 activity. Therefore, inhibiting BACE1 activity has become a potential therapeutic strategy for AD. The development of reliable detection methods for BACE1 activity plays an important role in early diagnosis of AD and evaluation of the therapeutic effect of new drugs for AD. This article has reviewed the recent advances in BACE1 activity detection techniques. The challenges of applying these analysis techniques to early clinical diagnosis of AD and development trends of the detection techniques have been prospected. [ABSTRACT FROM AUTHOR]

Low-/negative-pressure hydrocephalus (LPH/NePH) is uncommon in clinical practice, and doctors are unfamiliar with it. LPH/NePH is frequently caused by other central nervous system diseases, and patients are frequently misdiagnosed with other types of hydrocephalus, resulting in delayed treatment. LPH/NePH therapy evolved to therapeutic measures based on "external ventricular drainage below atmospheric pressure" as the number of patients with LPH/NePH described in the literature has increased. However, the mechanism of LPH/NePH formation is unknown. Thus, understanding the process of LPH/NePH development is the most important step in improving diagnosis and treatment capability. Based on case reports of LPH/NePH, we reviewed theories of transcortical pressure difference, excessive cerebral venous drainage, brain viscoelastic changes, and porous elastic sponges. [ABSTRACT FROM AUTHOR]

Objective: To describe the radiological features of patients with headache as a presenting symptom of neurosarcoidosis. Background: Neurologic complications occur in approximately 5%–10% of patients with sarcoidosis, and approximately 50% of these patients have neurologic deficits at the time sarcoidosis is first diagnosed. A wide spectrum of central and peripheral nervous system clinical manifestations may be observed, including cranial nerve palsies, sensory and/or motor deficits, and headache. Magnetic resonance imaging (MRI) results in patients with neurosarcoidosis may include abnormal contrast enhancement, structural masses, and demyelinating lesions. Methods: This single‐center retrospective cohort study assessed patients who were diagnosed with neurosarcoidosis in an urban tertiary care center between 1995 and 2016. We included patients who had MRI results at the time of diagnosis. Patients were divided into two groups based on the presence or absence of headache as a presenting symptom. The MRI result of meningeal contrast enhancement was reviewed. Results: Of the 110 patients analyzed, 30 (27.3%) had an initial presenting symptom of headache while 80 (72.7%) did not. Patients with headache had a higher proportion of meningeal contrast enhancement on MRI (66.7% [20/30] vs. 25.0% [20/80]; p < 0.001) and leptomeningeal involvement (53.3% [16/30] vs. 7.5% [6/80], p < 0.001) compared to patients with no headache. However, those with headache had a lower proportion of spinal cord localization (13.8% [4/29] vs. 34.2% [26/76], p = 0.038) and intraparenchymal central nervous system involvement (16.7% [5/30] vs. 51.3% [41/80], p = 0.001) compared to patients with no headache. Conclusion: Patients with neurosarcoidosis who presented with headache as an initial symptom had a higher proportion of meningeal contrast enhancement seen by MRI than patients who presented with other neurological symptoms. This suggests a clinico‐radiologic link between headache and meningeal disruption in patients with neurosarcoidosis. [ABSTRACT FROM AUTHOR]

Background: Analysing data on adverse drug reactions (ADRs) in health facilities is an essential step to help develop effective strategies to reduce their incidence. The objective was to analyse spontaneous ADR reports sent to the Ghanaian Food and Drugs Authority (FDA) by two reporting health facilities over 5 years. Methods: Data from duplicate spontaneous ADR reports sent to the FDA (Ghana) from 2014 to 2018 were extracted. The relationship between independent variables such as age, sex, and source of drugs and ADR outcomes was assessed with either chi‐square or a Cramer's V test for association where appropriate. Results: Type A reactions (65.2%) were the most prevalent of the ADRs, followed by Type B (34.1%), with the majority (80%) of patients affected recovering fully. The majority of Type A reactions (54.1%) occurred in the clinic, while the majority of Type B reactions (43.5%) occurred in the hospital. The skin and central nervous system (CNS) were the most affected (70.8%) organs. A higher incidence of CNS and skin‐related ADRs was recorded in patients older than 30 (RR = 1.28 (1.07–1.53)). Also, females were more likely to experience a CNS‐related ADR. The seriousness of the ADR was found to be significantly associated with the (1) type of prescriber, (2) whether the drug was prescribed, or (3) whether the drug regimen prescribed was appropriate. Even though, in 86% of cases, the offending drug was withdrawn within the first 5 days, it exceeded 20 days in about 6% of cases. The record of allergy status in a patient's folder and the source of the drug were significantly associated with the chance that the offending drug was withdrawn. However, recording ADRs did not influence whether the offending drug was stopped. Conclusion: Most of the ADRs experienced by patients could be avoided if the current systems are improved to prevent the rechallenge of offending drugs. Efforts to improve and update patient medication records and steps to ensure continuity of care are essential in preventing these adverse drug events. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that causes damage to the myelin and axons and is caused by genetic or environmental factors. Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive degeneration of the motor neurons resulting in the presence of upper and lower motor-neuron signs and symptoms. Case presentation: A 46-year-old female patient presented with symmetrical weakness of the lower limbs and numbness that developed over weeks. Magnetic resonance imaging (MRI) of the brain exhibited typical demyelination features, high signal abnormality involving the periventricular and subcortical white matter, and an oval-shaped lesion. The patient was diagnosed with MS based on the clinical presentation and radiological examination. However, there was rapid progression of the symptoms, involvement of bulbar dysfunction, and muscle atrophy. Furthermore, the patient did not respond to acute therapy and immunotherapy, which made the diagnosis of MS less likely or suggested that it could be associated with another diagnosis. Her neurophysiological test met the criteria of ALS, and she was started on riluzole. Literature review: We reviewed all articles from 1986 to 2023, and there were 32 reported cases describing the co-occurrence of ALS and MS in different populations. Our case is the 33rd, and to our knowledge, it is the only case reported in the Middle East and specifically in Saudi Arabia. The main proposed mechanism according to postmortem examinations is a combination of degenerative and inflammatory processes with a cascade of production of reactive oxygen species and nitric oxide, which lead to cell death and apoptosis during concomitant ALS with MS. Conclusion: The co-occurrence of ALS and MS is extremely rare, but it can be explained by pathogenesis related to neurodegeneration, inflammation, or genetic susceptibility. Rapid progressive motor and bulbar symptoms could be red-flag symptoms, extensive evaluation might be needed for these patients. [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusions Magnetic resonance imaging (MRI) is heavily relied upon for the diagnosis and monitoring of multiple sclerosis (MS), a chronic, demyelinating disease of the central nervous system. Serum biomarkers may serve as an accessible tool for increasing sensitivity, improving accessibility, corroborating symptoms, and providing additional data to guide clinical management. This scoping review investigates the current understanding of how the serum biomarker glial fibrillary acidic protein (sGFAP) relates to brain MRI metrics.We adhered to the Joanna Briggs Institute methodology for scoping reviews and the Preferred Reporting Items for Systematic reviews and Meta‐Analyses guidelines. The databases Medline (Ovid), Embase (Ovid), CINAHL (Ebsco), and Web of Science (University of British Columbia institutional access) were searched on August 24, 2023 using a combination of medical subject headings and keyword terms for the topic of serum biomarkers in MS.A total of 9880 articles were retrieved in total of which 6271 unique titles and abstracts were screened. Twelve of the 259 resultant papers contained sGFAP data and proceeded to extraction. It was found that lesion MRI metrics generally had a positive relationship with sGFAP, while gray matter and white matter metrics, including normal‐appearing white matter, were related negatively or not at all.These results highlight that while sGFAP may not be specific for MS, it may have utility for increasing sensitivity in postdiagnosis monitoring of MS progression. [ABSTRACT FROM AUTHOR]

AbstractIn recent times, the nasal region has emerged as a distinctive and dynamic environment where a myriad of microbial communities establish residence from infancy, persisting as both commensal and opportunistic pathogens throughout the lifespan. Understanding the coexistence of microorganisms in respiratory mucosal layers, their potential for infections, and the underlying molecular mechanisms shaping these interactions is crucial for developing efficient diagnostic and therapeutic interventions against respiratory and neurodegenerative diseases. Despite significant strides in understanding the olfactory system’s nexus with nasal microbiota, comprehensive correlations with neurological diseases still need to be discovered. The nasal microbiome, a sentinel in immune defense, orchestrates a delicate equilibrium that, when disrupted, can precipitate severe respiratory infections, including Chronic Rhinosinusitis, Chronic obstructive pulmonary disorder (COPD), and Asthma, and instigate a cascade effect on central nervous system diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Multiple sclerosis (MS). This review aims to redress this imbalance by meticulously exploring the anatomical and microbiological nuances of the nasal mucosal surface in health and disease. By delineating the molecular intricacies of these interactions, this review unravels the molecular mechanisms that govern the intricate nexus between nasal microbiota dysbiosis, olfactory dysfunction, and the progression of respiratory and neurological diseases. [ABSTRACT FROM AUTHOR]

Objective: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and previous observational epidemiological studies have suggested an association between MS and male infertility; male infertility due to sperm abnormalities may result from a number of aetiological factors, such as genetics, autoimmune factors, etc., and there are currently no studies to assess whether MS is associated with sperm abnormalities in men. Therefore, we performed a Mendelian randomization (MR) analysis to assess the causal relationship between MS and abnormal spermatozoa. Methods: In this study, independent single nucleotide polymorphisms (SNPs) strongly associated with multiple sclerosis (MS) were identified by mining public genome-wide association study repositories and used as instrumental variables to explore causality. The causal effect of MS on sperm abnormalities was systematically assessed using two-sample Mendelian randomization (MR) techniques, and various analytical models such as inverse variance weighting (IVW), MR-Egger and MR-PRESSO were implemented to dissect the association. In addition, a wide range of sensitivity tests, including Cochran's Q test to detect heterogeneity, MR-Egger intercept analysis to assess bias, leave-one-out to test model robustness, and funnel plot analysis to detect potential publication bias, were implemented to ensure the robustness and reliability of the causal inference results. Results: There was a significant causal relationship between MS and abnormal sperm (OR 1.090, 95% CI [1.017–1.168], p = 0.014); The accuracy and robustness of the results were confirmed by sensitivity analysis. Conclusion: Here we show that there appears to be a causal relationship between multiple sclerosis and abnormal spermatozoa. MS as a chronic disease has a higher risk of concomitant sperm abnormalities in its male patients, and reproductive and fertility issues in men with MS should receive special attention from clinicians. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Specifically, it has been recognized as an essential pro-inflammatory cytokine implicated in multiple sclerosis (MS) pathogenesis and progression. MS is a chronic immune-mediated disease of the central nervous system, characterized by multifocal acute and chronic inflammatory demyelination in white and grey matter, along with neuroaxonal loss. A recent concept in the field of MS research is disability resulting from Progression Independent of Relapse Activity (PIRA). PIRA recognizes that disability accumulation since the early phase of the disease can occur independently of relapse activity overcoming the traditional dualistic view of MS as either a relapsing-inflammatory or a progressive-neurodegenerative disease. Several studies have demonstrated an upregulation in TNF expression in both acute and chronic active MS brain lesions. Additionally, elevated TNF levels have been observed in the serum and cerebrospinal fluid of MS patients. TNF appears to play a significant role in maintaining chronic intrathecal inflammation, promoting axonal damage neurodegeneration, and consequently contributing to disease progression and disability accumulation. In summary, this review highlights the current understanding of TNF and its receptors in MS progression, specifically focusing on the relatively unexplored PIRA condition. Further research in this area holds promise for potential therapeutic interventions targeting TNF to mitigate disability in MS patients. [ABSTRACT FROM AUTHOR]

AbstractOne of the most prevalent neurodegenerative diseases is Alzheimer’s disease (AD). The hallmarks of AD include the accumulation of amyloid plaques and neurofibrillary tangles, which cause related secondary diseases, progressive neurodegeneration, and ultimately death. The most prevalent cell type in the human central nervous system, astrocytes, are crucial for controlling neuronal function. Glial fibrillary acidic protein (GFAP) is released from tissue into the bloodstream due to astrocyte breakdown in neurological diseases. Increased levels of GFAP in the serum can function as blood markers and be an effective prognostic indicator to help diagnose neurological conditions early on, from stroke to neurodegenerative diseases. The human central nervous system (CNS) is greatly affected by diseases associated with blood GFAP levels. These include multiple sclerosis, intracerebral hemorrhage, glioblastoma multiforme, traumatic brain injuries, and neuromyelitis optica. GFAP demonstrates a strong diagnostic capacity for projecting outcomes following an injury. Furthermore, the increased ability to identify GFAP protein fragments helps facilitate treatment, as it allows continuous screening of CNS injuries and early identification of potential recurrences. GFAP has recently gained attention due to data showing that the plasma biomarker is effective in identifying AD pathology. AD accounts for 60–70% of the approximately 50 million people with dementia worldwide. It is critical to develop molecular markers for AD, whose number is expected to increase to about 3 times and affect humans by 2050, and to investigate possible targets to confirm their effectiveness in the early diagnosis of AD. In addition, most diagnostic methods currently used are image-based and do not detect early disease, i.e. before symptoms appear; thus, treatment options and outcomes are limited. Therefore, recently developed methods such as point-of-care (POC), on-site applications, and enzyme-linked immunosorbent assay-polymerase chain reaction (ELISA-PCR) that provide both faster and more accurate results are gaining importance. This systematic review summarizes published studies with different approaches such as immunosensor, lateral flow, POC, ELISA-PCR, and molecularly imprinted polymer using GFAP, a potential blood biomarker to detect neurological disorders. Here, we also provide an overview of current approaches, analysis methods, and different future detection strategies for GFAP, the most popular biosensing field. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by inflammation and autoimmune responses. This review explores the participation of T cells, particularly certain CD3+CD20+ T cells, in the clinical manifestations of MS and highlights their presence in diagnosed patients. These T cells show aberrant expression of CD20, normally considered a B-cell marker. In this review, relevant journal articles available in PubMed and CINAHL were identified by employing diverse search terms, such as MS, CD3+CD20+ T cells, the incidence and significance of CD3+CD20+ T cells in MS patients, and the impact of rituximab treatment. The search was limited to articles published in the ten-year period from 2014 to 2024. The results of this review suggest that most scholars agree on the presence of CD3+CD20+ T cells in cerebrospinal fluid. Emerging concepts relate to the fundamental role of CD20-expressing T cells in determining the target and efficacy of MS therapeutics and the presence of T cells in the cerebrospinal fluid of MS patients. The results clearly show that CD20+ T cells indicate disease chronicity and high disease activity. [ABSTRACT FROM AUTHOR]

A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration. [ABSTRACT FROM AUTHOR]