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Myasthenia Gravis (MG) is an autoimmune disease that damages the neuromuscular junction (NMJ), reduces the transmission of nerve impulses to muscles, and thus causes fluctuating muscle weakness and fatigue. The main types of MG are autoantibodies that target necessary components of the postsynaptic membrane, such as acetylcholine receptors (AChRs) and muscle-specific kinase (MuSK). The above immune-mediated alterations disrupt synaptic transmission and reduce muscle contraction. Study the molecular and cellular mechanisms of MG to find genes that regulate the immune system, cause inflammation, or affect NMJ homeostasis and may serve as biomarkers. These biomarkers can provide more information on the course of a disease and help to customise diagnosis and treatment according to this information. The transcriptomic data in this study were obtained from the Gene Expression Omnibus (GEO) database under accession number GSE85452 (GPL10558), which contains peripheral blood gene expression profiles of MG patients and healthy controls. Differential Expression Analysis was conducted to find genes in *M. fitumendi* related to MG. Preprocess and normalise the raw data before the following comparisons. Mendelian Randomisation (MR) was employed to investigate whether the candidate genes causally affected MG risk. PTGS2 was found to be a protective factor (OR < 1) and selected for further study. Gene set enrichment analysis (GSEA) was then carried out to identify related pathways, and single-sample gene set enrichment analysis (ssGSEA) was used to explore associations with the immune system. Single-cell RNA sequencing (scRNA-seq) was performed to find out which cells expressed PTGS2, how the proportions of different cell types in the MG microenvironment were changed, and what inter-cellular communication occurred. A network-based virtual PTGS2 overexpression analysis was also carried out in MG cells with scTenifoldNet. Single-cell gene regulatory networks were built from the raw count data and denoised by tensor decomposition. PTGS2 regulatory activity increased due to a doubling of the weight of the positive regulatory edge. Genes with an adjusted P-value <0.05 were regarded as significantly altered and subjected to KEGG and Gene Ontology enrichment analysis. Using a sensitive threshold of |log₂FC| > 0.38 for the initial screening of the MG transcriptome, a particular set of differentially expressed genes in patients was identified compared with healthy individuals. Mendelian Randomisation analysis also showed that PTGS2 is associated with a reduced risk of MG and has a negative causal association with the disease. Functional enrichment analysis linked PTGS2-associated molecular signatures to immune and inflammatory pathways. Immune infiltration analysis showed variations in the proportion of immune cells in MG, and PTGS2 expression was significantly correlated with several subsets of immune cells. Gene-disease association mapping links PTGS2 to multiple immune-related disorders. Single-cell RNA sequencing also showed cell-type-specific expression and different distributions of PTGS2 in MG patients and healthy controls. Overexpression of virtual PTGS2 mainly modified genes and pathways in the myeloid cell, such as IL-17 signalling, chemotaxis and neutrophil migration. Therefore, PTGS2 may be involved in the regulation of inflammatory myeloid responses in MG. Transcriptome and gene analysis identified PTGS2 as a protective gene for myasthenia gravis. PTGS2 is linked to immune-inflammatory signals, and single-cell data have identified specific cell types in the MG immune microenvironment that express it. Network-based virtual PTGS2 overexpression mainly altered myeloid-associated genes and pathways of IL-17 signalling, chemotaxis and neutrophil migration. PTGS2 may be a biomarker and a possible therapeutic target for MG.
Lifestyle factors, such as smoking cigarettes and alcohol consumption, can influence disease progression in Multiple Sclerosis (MS). This study aimed to investigate the associations of smoking cigarettes and alcohol consumption with clinical parameters in people with MS (pwMS). This is a prospective cohort study, analysing data from the German NationMS cohort. We analysed data of 1374 patients recruited between 2010 and 2017. Main outcomes were Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW) and Paced Auditory Serial Addition Test (PASAT). Secondary outcomes were number of T2 and GD+ lesions. We conducted logistic and linear mixed model regression, adjusted for age, sex, educational level, MS subtype. Smoking cigarettes was associated with increased odds of reaching pre-defined cut-off values for EDSS and T25FW, as well as with increased mean differences across follow-ups. Alcohol consumption was associated with decreased odds of reaching the cut-off for EDSS and T25FW. Findings for PASAT were less consistent. We found no significant associations for T2 and GD+ lesions. This study provides further evidence that smoking cigarettes accelerates MS progression and that pwMS should be advised to quit smoking. However, this negative impact could not be demonstrated for alcohol consumption. Reverse causation cannot be ruled out and further research in this area is warranted. Instead of registration in a primary trial registry, a comprehensive study protocol was published a priori and is available online: https://osf.io/3xscy. How smoking and alcohol consumption affect the progression of multiple sclerosis Background: Lifestyle habits, such as smoking and drinking alcohol, can influence how Multiple Sclerosis (MS) progresses over time. In this study, we wanted to investigate whether smoking and alcohol consumption are linked to changes in physical and mental health in people living with MS. What did the researchers do? We analyzed data from 1,374 patients who were part of a large German long-term study (the NationMS cohort) between 2010 and 2017. We focused on three main areas: the overall level of disability, walking speed, and mental sharpness (memory and concentration). We also looked at MRI brain scans to see if lifestyle factors were linked to the number of MS-related spots or scars (lesions) in the brain. What were the main findings? Our results showed that smoking was linked to a higher chance of worsening physical disability and slower walking speeds. Patients who smoked reached certain stages of disability sooner than non-smokers. Interestingly, alcohol consumption was associated with a lower risk of physical decline in this group. For mental sharpness, the results were not very clear. We found no significant link between smoking or alcohol and the number of lesions visible on MRI scans. What do these findings mean? This study provides more evidence that smoking can speed up the progression of MS. Therefore, people with MS should be encouraged to quit smoking to help manage their condition. While we did not find a negative impact from alcohol consumption, we cannot be certain that alcohol is ‘protective’. It is possible that people who feel healthier are simply more likely to drink alcohol, while those who feel worse stop drinking (a concept called ‘reverse causation’). More research is needed to fully understand these links.
Myelination, driven by differentiation of oligodendrocyte precursor cells, is critical for metabolic and structural support and efficient axonal signal transmission in neurons. Loss of myelin is a hallmark of multiple sclerosis and other devastating demyelinating disorders. As demyelination persists, neurons become increasingly vulnerable, leading to neurodegeneration and chronic disability. Restoring myelin through endogenous repair mechanisms offers a promising therapeutic approach to mitigate progressive neuronal loss. One key regulator of myelination is the G protein-coupled receptor 17, GPR17, whose chronic upregulation in oligodendrocyte precursor cells is commonly seen with myelin injury. In line with single-nucleus transcriptomic data showing predominant expression of GPR17 in committed oligodendrocyte precursor cells, our postmortem immunohistochemical analyses of MS patient tissue revealed a significant upregulation of GPR17+/BCAS1+ oligodendrocyte precursor cells adjacent to and in demyelinated lesions. Importantly, remyelinated lesions lacked GPR17 immunoreactivity, consistent with a model in which sustained GPR17 expression is associated with demyelination and impaired oligodendrocyte precursor cell differentiation. To test the impact of pharmacological GPR17 inhibition on remyelination, we evaluated the effects of a novel, selective GPR17 antagonist in cuprizone-induced murine demyelination models. This toxin-induced approach has been widely used to study mechanisms of de- and remyelination, in the absence of the full inflammatory complexity of demyelinating diseases such as multiple sclerosis. We show that oral treatment results in robust functional recovery consistent with remyelination, as evidenced by improved spatial memory and recovery of visual evoked potential latency delays. GPR17 antagonism also accelerated structural remyelination in the corpus callosum and optic nerve. Together, these findings support a role for pharmacological GPR17 antagonism in promoting remyelination and highlight this G protein-coupled receptor as a promising therapeutic target for demyelinating disorders.
Reliable biomarkers for autoimmune encephalitis (AE) are limited, and emerging CSF markers are not incorporated into current diagnostic criteria. Prognostic tools remain insufficient, highlighting the need for biomarkers that support both early diagnosis and assessment of disease severity and prognosis. In this multicenter prospective cohort study, we analyzed clinical data and paired CSF-serum samples from adults with definite AE enrolled in the German Network for Research on Autoimmune Encephalitis registry and the CSF biobank of Hannover Medical School. Of 2,330 screened individuals, 92 patients with anti-N-methyl-d-aspartate receptor (NMDAR, n = 53), anti-leucine-rich glioma-inactivated 1 (LGI1, n = 20), or anti-contactin-associated protein-like 2 (CASPR2, n = 19) encephalitis were included and followed longitudinally for a median of 38 months. Control groups comprised patients with relapsing multiple sclerosis, varicella-zoster virus encephalitis, and noninflammatory neurologic conditions (each n = 30), as well as antibody-positive patients without AE (n = 15), with the groups frequency-matched for age and sex. Kappa free light chain (KFLC), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and cytokines were measured in paired CSF-serum samples obtained at baseline and during follow-up. Disease severity and disability were assessed using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score and the modified Rankin Scale (mRS). Intrathecal synthesis of KFLC was detected in 94% of anti-NMDAR, 50% of anti-LGI1, and 53% of anti-CASPR2 encephalitis cases, demonstrating higher diagnostic sensitivity than CSF-restricted oligoclonal bands or pleocytosis. Diagnostic specificity across pooled control groups was moderate at 44% but reached 90% when compared with noninflammatory neurologic controls. CSF NfL z-score levels were strongly associated with baseline disease severity, with each 1-standard deviation increase corresponding to an approximately 10-point higher CASE score, independent of clinical covariates (β = 0.61). Longitudinal changes in NfL concentrations in CSF and serum were associated with disease severity and neurologic disability at follow-up (CASE score: adjusted R2 = 0.401; mRS score: adjusted R2 = 0.203). GFAP and cytokines showed limited diagnostic or prognostic utility. Intrathecal KFLC synthesis represents a highly sensitive CSF marker that supports early suspicion of autoimmune encephalitis and prompts antibody testing. NfL provides robust biochemical information on baseline disease severity and longitudinal changes that may aid prognostic assessment across AE subtypes.
Whether surgical haematoma evacuation leads to reduced brain damage in patients with spontaneous supratentorial intracerebral haemorrhage (SSICH) remains unknown. Blood biomarkers reflecting brain damage could aid in prognosticating the clinical outcome and hence support quantifying the benefit of surgical interventions. Blood samples from 10 patients with SSICH in the phase II early minimally invasive image-guided endoscopic evacuation of intracerebral hemorrhage (EMINENT-ICH) pilot study (NCT04805177, completed) were collected longitudinally (at baseline, 24 hours, 3 days, 1 week, 1 month and 6 months after surgical haematoma evacuation). Neurofilament light chain (NfL), glial fibrillar acidic protein (GFAP), calcium-binding protein S100B and the inflammatory markers interferon-gamma, interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10 and tumour necrosis factor alpha were quantified. The perioperative and long-term course of concentrations and association with clinical outcome measures were assessed. A favourable outcome was defined as a modified ranking scale ≤3. Favourable outcome was observed in 60% (6/10) of patients (median age 72.5 years (IQR 67.5-79.8), 70% male), and in 70% (7/10) of patients, the preset goal of a postsurgery haematoma volume below 15 mL was achieved. On average, patients with unfavourable outcomes at 6 months had twofold higher NfL and sixfold higher GFAP concentrations compared with those with favourable outcomes (pNfL=0.127, pGFAP=0.017); concentrations of both markers were higher in patients with unsatisfactory haematoma evacuation (3.7-fold for NfL, p=0.0072 and 12.4-fold for GFAP, p=0.0122). Concentrations of other markers, especially ILs, were not indicative of functional outcomes. Based on our results, we provide preliminary evidence that lower serum NfL and GFAP levels are associated with favourable clinical outcomes and successful haematoma evacuation in SSICH.
Follicular CD4+ T (TFH) cells have been implicated in the pathogenesis of multiple sclerosis (MS). However, studies evaluating follicular CD8+ T (TFC) cells and the relationship between TFH/TFC cells with clinical MS parameters are lacking. Here, the frequency of circulating TFH/TFC cells from healthy and MS subjects was determined by cytometry according the expression of PD-1, CXCR3, CCR6, IL-21, IFN-γ and IL-17 by CXCR5+CD4+/CD8+T-cells. The plasma CXCL13 and NfL levels were quantified by ELISA. The degree of neurological disability and brain lesions were determined by EDSS score and magnetic resonance imaging, respectively. Relapse occurrence was evaluated during 1-year follow-up. Our results demonstrated that PD-1+IL-21+TFH-cell subsets (TFH1, TFH17.1 and TFH17) frequency and the percentage of PD-1+IL-21+TFC17.1 and PD-1-IL-21+TFH17.1/TFC17.1 cells were higher in the MS than in the control group. Different IL-17-expressing PD-1-IL-21+TFH/TFC cell subsets positively correlated with plasma CXCL13 and NfL levels. Also, circulating PD-1-IL-21+TFH17/TFC17 directly correlated with neurological disabilities. While radiological activity of disease positively correlated with percentage of PD-1-IL-21+TFH17.1/TFH17 cells and PD-1-IL-21+TFC1/TFC17.1/TFC17 cells, clinical activity of MS was associated with both elevated levels of CXCL13 and NfL and the frequencies of PD-1-IL-21+TFH17.1/TFH17 and PD-1-IL-21+TFC1/TFC17.1 cells. In summary, our findings suggest that PD-1-TFH/TFC cells able to produce IL-21, IFN-γ and IL-17 could be a signature of MS severity.
Increased disease awareness and advanced serological tests have improved myasthenia gravis (MG) diagnosis. However, the risk of misdiagnosis remains. The aim of this study was to evaluate the rate and causes of MG misdiagnosis in a tertiary MG clinic. We analyzed medical records from patients diagnosed with MG who were referred to our tertiary clinic for a second opinion between 2019 and 2024. Of the 144 patients originally included in the analysis, 15 were excluded due to insufficient data. MG diagnosis was not confirmed in 26/129 patients (20.2%). None of these 26 patients had clinical symptoms consistent with MG; 13 patients (50%) were seronegative; 12 had AChR antibodies (Abs) (detected by radioimmunoassay -RIA in 6 and by ELISA in the other 6 patients); a single patient had MuSK-Abs. Fixed and live cell-based assays were negative in all these 26 cases. Predictors of MG misdiagnosis included absence of MG-typical clinical features, younger age at onset, female sex, non-response to or intolerance of pyridostigmine, Ab testing by ELISA. MG misdiagnosis is not uncommon and often leads to unnecessary treatment. Our findings confirm the relevance of typical clinical pattern, proper antibody assays, and expertise in neurophysiological testing to establish MG diagnosis.
Efgartigimod, an FcRn antagonist for AChR antibody-positive generalized myasthenia gravis (gMG), has not been well explored for thymectomy perioperative management. Compared to conventional IVIg or plasmapheresis, its rapid onset and targeted mechanism may offer certain advantages. This study evaluated Efgartigimod's safety and efficacy in thymectomy for gMG patients with thymoma. We retrospectively analyzed six gMG patients who underwent thymectomy at the China-Japan Union Hospital of Jilin University between April 2024 and March 2025 after receiving perioperative Efgartigimod therapy. We included five females and one male. Our primary endpoints included alterations in Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores, postoperative achievement rate of minimal symptom expression (MSE), incidence of perioperative exacerbation, occurrence of adverse events, and use of corticosteroids. All patients exhibited clinical improvement following sequential pre- and postoperative administration of Efgartigimod; overall reductions were observed in MG-ADL and QMG scores. After postoperative Efgartigimod therapy, four patients achieved MSE. On the first postoperative day, only one patient experienced a transient perioperative exacerbation, which resolved rapidly post-additional Efgartigimod administration; no myasthenic crisis was reported. No drug-related adverse reactions were observed. However, one patient developed a mild upper respiratory tract infection during the perioperative period, which resolved with symptomatic management. Perioperative Efgartigimod administration in patients with gMG and thymoma exhibited rapid preoperative symptom improvement, shortened preoperative preparation time, decreased postoperative disease fluctuation, sustained symptomatic relief, and a favorable safety profile. As an emerging targeted immunotherapeutic strategy, Efgartigimod is efficacious in the perioperative management of gMG patients with thymoma, thereby warranting further validation in prospective studies.
Anti-CRMP5/CV2 antibody disease is a rare cause of optic neuritis, therefore the clinical findings, results of neuroimaging, CSF studies and treatment outcomes have been described in case reports or small case series. Here, we performed a systematic review including all published cases of optic neuritis with positive anti-CRMP5/CV2 antibodies. Twenty-four articles comprising 32 patients were included. Median age was 67 years (60-71); 87.1% of patients had clinically symptomatic bilateral optic neuritis, with 64% having a visual acuity worse than 20/200 and ocular pain was uncommon (4.2%). An associated malignancy was identified in 90.6% of cases, most commonly small-cell lung carcinoma (more than 70%) and breast (5%). Optic disc edema occurred in 83.9%, frequently with vitreous (70.8%) and retinal (35%) inflammation. Orbit MRI was normal in 57.1% of cases, but CSF almost universally showed pleocytosis. Overall mortality was 32.1% (9 of 28 patients) at a median follow-up of 9.5 (4-23) months. Absence of tumor response to oncologic treatment was strongly associated with higher mortality (88.9%) and final visual acuity worse than or equal to 20/200 (71.4%), whereas escalation of immunosuppression, such as immunoglobulin, plasmapheresis, and cyclophosphamide, was not associated with improved outcomes. Further investigation into the mechanisms by which CD8+ cytotoxic T-cell recruitment and activation in the pre-laminar optic nerve is essential to develop targeted therapies that can improve visual outcomes.
Minimal hepatic encephalopathy (MHE) is an underdiagnosed complication of liver cirrhosis, associated with progression to overt hepatic encephalopathy (HE). The Portosystemic Hepatic Encephalopathy Score (PHES) is the recommended diagnostic standard, but its use is hindered by resource constraints and limited accuracy. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are released during neuroaxonal and astrocyte injury and may serve as HE-biomarkers. We investigated NfL and GFAP in cerebrospinal fluid (CSF) and serum across the spectrum of HE and assessed their correlation and diagnostic performance. In this cross-sectional study, 35 patients with cirrhosis and 14 healthy controls (HC) were included. MHE was defined as PHES < -4, and overt HE was graded according to the West Haven Criteria. NfL and GFAP were quantified in CSF and serum using single-molecule array technology. NfL concentrations in CSF and serum increased stepwise from HC to unimpaired patients, MHE, and overt HE (p < 0.0001). CSF- and serum NfL were strongly correlated (rho = 0.888, p < 0.0001), and CSF and serum NfL discriminated MHE and overt HE from unimpaired patients and HC, with AUROCs of 0.877-0.902 and 0.930-0.951, respectively. GFAP showed moderate correlation between CSF and serum (rho = 0.496, p < 0.0004) and discriminatory value in CSF (AUROCs of 0.777-0.800); however, to a lesser extent than NfL. Neuroaxonal injury is detectable in HE by NfL in both CSF and serum. The strong CSF and serum correlation suggests that serum NfL may serve as a minimally invasive biomarker of MHE and overt HE. Cell damage in the brain increases as liver‐related cognitive problems worsen in patients with liver disease. This is shown by a rising level of a marker called neurofilament light chain in both spinal fluid and blood. A new finding is that neurofilament light chain levels in blood closely match those in spinal fluid, meaning a simple blood test could reflect what is happening in the brain. This makes it possible to detect and monitor cognitive impairment without needing invasive spinal fluid tests.
Experimental autoimmune encephalomyelitis (EAE) is a powerful and broadly used model to study multiple sclerosis (MS). Like most models, it has advantages and limitations; its advantages include that it can be induced in many species, the pathological mechanisms identified for EAE often overlap with MS, and it has been used for pre-clinical screening for therapeutics that are now used for individuals with MS. Further, there are many approaches for EAE induction, including active immunization with myelin proteins emulsified with immune adjuvants or passive transfer of EAE-specific T cells, allowing focus on the T cell-dependent aspects of disease. EAE also has its limitations, such as variability in incidence and severity. Use of additional adjuvants such as pertussis toxin (PTx) have been employed to hasten onset and exacerbate disease severity, but there also might be conditions under which PTx use would not be indicated, such as avoiding PTx-induced inhibition of Giα receptor signaling. Together these data demonstrate that further refinement of the model is needed, and we hypothesized that mannitol could serve as a PTx replacement since both mannitol and PTx can compromise the blood brain barrier (BBB). The objective of this study was to directly compare EAE induced with no additional adjuvants with EAE induced with intraperitoneal injections of PTx or ad libitum access to mannitol in the drinking water. Our data show that either PTx or mannitol exacerbated EAE disease demonstrating that mannitol treatment can be considered for active EAE induction in lieu of PTx.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS. A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I2 statistic. A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD = -0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD = -0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant. This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder. PROSPERO identifier CRD420251076035.
The 2024 revision of the McDonald criteria allows the diagnosis of multiple sclerosis (MS) based on dissemination in space alone when ≥4 typical lesion locations are present, raising the question of how lesion burden influences the incremental diagnostic value of cerebrospinal fluid (CSF) analysis. To evaluate the incremental diagnostic value of intrathecal IgG oligoclonal bands (IgGOB) according to lesion burden at MS diagnosis. In this retrospective, cross-sectional, single-centre study, 341 patients undergoing diagnostic evaluation for suspected MS were included. Logistic regression models assessed the associations among lesion burden, intrathecal IgG synthesis and MS diagnosis. Lesion burden was strongly associated with MS diagnosis (β = 1.55, p < 0.0001). CSF-restricted IgGOB positivity was associated with lesion burden, but not with disease duration. In a multivariable logistic regression model, both lesion burden (p < 0.0001) and CSF-restricted IgGOB (p < 0.0001) remained independently associated with MS diagnosis (AUC = 0.988). The incremental diagnostic contribution of intrathecal IgG synthesis progressively decreased as lesion burden increased. The incremental diagnostic value of intrathecal IgG synthesis is strongly influenced by lesion burden. These findings support a context-dependent interpretation of CSF analysis within the 2024 McDonald diagnostic criteria.
Early life represents a critical window for maturation of the gut microbiota, mucosal immunity, and neuroimmune pathways underpinning the gut-brain axis (GBA). Probiotic, prebiotic, and synbiotic interventions have been proposed to modulate these processes; however, their mechanistic effects on GBA-relevant biomarkers in humans remain unclear. We conducted a systematic review of randomized controlled trials (RCTs) evaluating microbiota-directed interventions in infants aged 0-36 months, focusing on biological pathways implicated in gut-brain communication. Searches of PubMed/MEDLINE, Scopus, and Web of Science identified six eligible RCTs including 1148 randomized participants, of whom 923 contributed data to at least one GBA-relevant biomarker. Outcomes were synthesized across six mechanistic domains: intestinal microbiota composition and functional proxies, microbial metabolites, mucosal immunity, systemic cytokines, intestinal inflammation and permeability, and hypothalamic-pituitary-adrenal (HPA) axis activity. Across trials, interventions were associated with localized mucosal effects, including selective enrichment of Bifidobacterium and Lactobacillus, modest reductions in fecal pH, and modest, variably reported increases in fecal secretory sIgA. In contrast, short-chain fatty acids (SCFAs) were inconsistently reported and showed no robust between-group differences. Systemic cytokines, fecal calprotectin, permeability markers, basal salivary cortisol, and neurodevelopmental outcomes remained unchanged. Methodological heterogeneity, frequent values below assay detection limits, and developmental variability precluded quantitative meta-analysis. Available RCT evidence, although limited and heterogeneous, suggests that early-life microbiota-directed interventions may be associated with compartmentalized microbial and mucosal immune modulation without measurable propagation to systemic neuroimmune or neurodevelopmental pathways in healthy or mildly symptomatic infants. These findings support a model of developmental neuroimmune gating within the early-life GBA, defined here as the physiological restriction of signal propagation from mucosal to systemic and central pathways during early life, and highlight the need for standardized biomarker frameworks, dynamic neuroendocrine assessments, and studies in higher-risk populations to clarify mechanistic relevance.
SARS-CoV-2 infection may result in persistent neuropsychiatric symptoms beyond the acute phase, often discussed under the umbrella term "Long COVID". These manifestations commonly include mood disturbances, post-traumatic stress symptoms, cognitive impairment, sleep disturbances, and fatigue, with substantial effects on daily functioning and quality of life. Despite these concerns, the pathophysiological mechanisms underlying these sequelae remain poorly understood, and the lack of specific biomarkers hampers the development of targeted interventions. This review synthesizes recent advances in the clinical presentation, underlying mechanisms, diagnostic approaches, and therapeutic strategies for neuropsychiatric sequelae of Long COVID. We also discuss current challenges and outline future research priorities to facilitate the establishment of standardized diagnostic criteria and the development of effective, mechanism-based therapies.
In patients with progressive multiple sclerosis (PMS), previous studies reported increased cerebrospinal fluid (CSF) concentrations of inflammatory biomarkers, but these correlated only weakly with structural damage. We aimed to identify inflammatory CSF biomarkers that associate with tissue damage in PMS. We performed four substudies: [1] A cross-sectional exploratory study of patients with primary (PPMS) or secondary progressive MS (SPMS) (n = 38) in whom we explored correlations between CSF concentrations of 1128 proteins and CSF neurofilament light chain (NFL) and myelin basic protein. [2] A cross-sectional confirmatory study where a protein of main interest, chitinase-1 (CHIT1), was analyzed in 104 patients with PPMS (n = 78) or SPMS (n = 26) and compared with 38 symptomatic controls. [3] Associations between CSF concentrations of CHIT1 and other disease biomarkers including CSF- and magnetic resonance imaging (MRI)-based measures of white matter injury in patients with PPMS (n = 59). [4] A longitudinal study of effects of treatment with methylprednisolone, natalizumab, dimethyl fumarate, or placebo on CHIT1 in CSF in patients with PMS. Substudy [1] identified three proteins that correlated with CSF NFL: soluble B-cell maturation antigen, CC chemokine ligand 22, and CHIT1. CHIT1 showed a strong correlation with CSF NFL (ρ = 0.61, q = 0.008) and was selected for further analyses. Substudy [2] showed that patients with progressive MS had higher CSF concentrations of CHIT1 than symptomatic controls (all p < 0.001). In substudy [3], CSF concentrations of CHIT1 correlated with increased lesion volume (p < 0.001) and decreased magnetization transfer ratio (p = 0.001) of lesions, decreased fractional anisotropy (p < 0.001) and increased mean diffusivity of normal-appearing white matter (p = 0.044) and lesions (p = 0.005) in patients with PPMS. Substudy [4] showed that natalizumab treatment reduced CSF CHIT1 concentrations (p = 0.005) in PMS. CSF CHIT1 concentrations are associated with neuroaxonal and white matter injury in patients with PPMS and responsive to disease-modifying therapy in PMS.
Levodopa did not enhance early motor recovery at 3 months after stroke in the Enhancement of Stroke Rehabilitation with Levodopa (ESTREL) trial. However, whether levodopa modifies the time course of recovery, leading to a delayed benefit remains unclear. Here, we examined levodopa's effects on the trajectories of motor recovery up to 6 months after stroke. The ESTREL trial, a double-blind, randomised controlled clinical trial, compared a 39-day regimen of levodopa/carbidopa (100 mg/25 mg, 3×/day) to placebo alongside standardised task-oriented training. We longitudinally analysed Fugl-Meyer Motor Assessment (FMA) total scores (primary outcome), mRS and NIHSS (secondary outcomes) at baseline (0-7 days post stroke), 5 weeks, 3 and 6 months using linear mixed-effects models including timepoint, treatment allocation and their interaction. In total, 576 of 610 (94%) participants (median age 73 years; 40% female) were analysed. FMA scores improved over time in both groups (P < .001), with no overall levodopa effect across visits (estimate 0.65 points, 95% CI, -3.3 to 4.6; P = .75). There was no indication that levodopa modified the recovery trajectory (χ2 = 0.52, df = 3, P = .91), and estimated levodopa-placebo differences in FMA changes across visit intervals were small, ranging from -0.7 to +0.8 points, with confidence intervals crossing zero. Secondary outcomes showed similar longitudinal improvement, without evidence of a treatment effect. In this post hoc analysis of ESTREL participants with repeated FMA assessments, motor impairment improved from the first days after stroke up to 6 months. Levodopa added to task-oriented inpatient rehabilitation did not improve motor recovery or alter its trajectory over this period. NCT03735901, available at ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT03735901?cond=NCT03735901&rank=1.
While poly ADP-ribose polymerase (PARP) inhibitors represent a promising treatment strategy in early phase trials of patients with high-grade glioma (HGG), the clinical outcomes exhibit variability, mainly due to drug-specific pharmacokinetics and insufficient biological stratification involving MGMT and IDH status. We aimed to investigate the safety and efficacy of PARP inhibitors in grade 3 and 4 gliomas. A systematic review and data synthesis were conducted. Records were extracted from PubMed, Scopus, Web of Science, and Embase from inception to May 24th, 2025, and included in accordance with predetermined eligibility criteria. Twelve studies, including 795 patients, were included. The pooled disease control rate (DCR) among patients with HGG was 27%; however, this estimate was associated with substantial heterogeneity and an extremely wide prediction interval (PI: 0.4-97.1%), indicating that the pooled value should not be interpreted as a stable estimate of expected clinical benefit in future studies or individual patient populations. The pooled grade ≥ 3 adverse event rate was 13% with a wide PI (2.2-51.2%), although heterogeneity was also substantial. Fixed-time survival outcomes and molecular/treatment subgroup analyses were summarized descriptively. Several subgroup findings, including those related to IDH status, MGMT promoter methylation, disease setting, and concomitant therapy, should be interpreted as exploratory because of limited study numbers, single-arm trial designs, inconsistent clinical contexts, and substantial between-study heterogeneity. Available evidence suggests that PARP inhibitors have investigational activity and an overall acceptable safety profile in selected glioma populations, but the certainty of evidence is very low. Because pooled estimates were imprecise and accompanied by wide prediction intervals, these analyses should be regarded as descriptive and hypothesis-generating rather than clinically definitive. Larger randomized, biomarker-stratified trials with harmonized outcome definitions are required before PARP inhibitors can be assigned a clear therapeutic role in HGG.
Anti-adenylate kinase 5 (AK5) encephalitis is a rare, predominantly limbic autoimmune disorder featuring subacute cognitive and psychiatric decline. Given the limited literature and MRI's suboptimal sensitivity to neuroinflammation, often precluding timely therapeutic escalation, we sought to delineate the clinical and multimodal imaging spectrum of this condition and propose stage-specific management protocols. Two female patients (aged 15 and 65 years) with subacute cognitive and psychiatric-behavioral disturbances were prospectively evaluated with serial MMSE, CASE and mRS clinical assessments at symptom onset and follow-up. All patients received intravenous methylprednisolone and immunoglobulin, with rituximab administered in one of the cases. Serum and CSF were tested for anti-AK5 antibodies using CBA and TBA. Brain MRI and 18F-DPA714 PET/MRI were performed to assess structural and microglial activation and aggregation patterns. Both patients exhibited prominent anterograde amnesia, psychiatric manifestations, and sleep disturbances. Anti-AK5 antibodies were detected in the serum of both patients via CBA at titers of 1:100 and 1:30, respectively. MRI demonstrated bilateral hippocampal/temporal lobe atrophy with mild T2/FLAIR hyperintensities. 18F-DPA714 PET/MRI revealed increased tracer uptake in the brainstem, frontal, occipital, and hippocampal regions. After intravenous methylprednisolone and immunoglobulin, with rituximab, the adolescent patient showed marked clinical and cognitive recovery (MMSE: 18 to 28; CASE: 6 to 0 in one year). Conversely, the older patient demonstrated limited improvement, with persistent amnesia and neuropsychiatric symptoms. This case series defines the clinical spectrum of anti-AK5 encephalitis, supporting 18F-DPA714 PET/MRI for detecting neuroinflammation correlating with clinical manifestations. Adjunctive CD20-targeted therapy showed efficacy in one patient, warranting B-cell immunotherapy research in larger cohorts.