Frontiers in Neurology最新文献

Background: The therapeutic landscape of multiple sclerosis (MS) is rapidly evolving, with increasing emphasis on early initiation of high-efficacy disease-modifying therapies (heDMTs). However, real-world data on predictors of first-line heDMT use and its outcomes remain scarce in the Middle East.

Objectives: To identify demographic and clinical factors influencing the choice of first-line heDMT vs. platform therapy in relapsing-remitting MS (RRMS) and to evaluate whether initial treatment class impacts disability outcomes and treatment persistence.

Methods: We conducted a retrospective cohort study of 826 RRMS patients treated at a tertiary center in Saudi Arabia between 2016 and 2024. Predictors of initiating heDMT were identified using multivariable logistic regression. Disability status (EDSS category) was analyzed using ordinal logistic regression. Treatment persistence and causes of discontinuation were examined using Kaplan-Meier survival analysis, Cox proportional hazards modeling, and Fine-Gray competing-risks regression.

Results: Of 826 patients, 330 (40%) received heDMTs as first-line therapy. Initiation in the later treatment era (2019-2024) strongly predicted heDMT use compared with the early treatment era (2008-2013; OR = 48.8; p < 0.001), as did cerebellar symptom onset (OR = 2.51; p = 0.025). Age, sex, and comorbidities were not significant predictors. Starting on a heDMT did not translate into higher or lower disability levels compared with platform therapies (OR = 1.08; p = 0.767). However, patients initiating heDMTs demonstrated superior treatment persistence (12-month persistence: 91.7 vs. 83.4%; p < 0.0001) and a markedly lower risk of discontinuation (HR = 0.41; p < 0.001). Competing-risks analysis showed that heDMT users were significantly less likely to discontinue due to inefficacy or adverse events, but more likely to stop for other reasons, such as pregnancy, preference, or supply issues.

Conclusions: First-line use of heDMTs in Saudi Arabia has increased substantially over recent years, particularly among patients with cerebellar onset. While disability outcomes were similar between treatment groups, initiating heDMTs conferred clear advantages in persistence and tolerability. These findings reinforce the paradigm shift toward early intensive MS management and highlight the need for broader access and guideline-driven implementation of heDMTs in the region.

Introduction: Dual-tasking is an emerging topic of study within the field of multiple sclerosis (MS) rehabilitation. Past research on dual-task performance among people with MS (PwMS) is limited by methodological differences and minimal consideration of underlying neurophysiology. Related studies suggest that changes in inhibitory neural activity in the motor cortex may support dual-task performance in healthy adults, as assessed using transcranial magnetic stimulation (TMS). Other TMS work indicates that MS alters corticospinal inhibition, but how and whether it is modulated during dual-tasking in PwMS is unknown. The objective of this exploratory, cross-sectional small-N study was to explore whether changes in corticospinal inhibition that occur during dual-tasking may be different in PwMS compared to non-MS controls.

Methods: Six PwMS (4F; 45.17 ± 15.74 years) and three non-MS controls (2F; 42.33 ± 16.62 years) performed motor and cognitive tasks under single- and dual-task conditions. Each dual-task included a core motor task, which involved maintaining a steady pinch grip force. Performance of this core motor task allowed for assessment of corticospinal inhibition during task performance via measurement of the cortical silent period elicited by TMS. Tasks combined with the core motor task included holding a string of numbers and/or number letter combinations in working memory and a toe-tapping task. Several versions of the tasks were presented alongside the core motor task, each providing different levels of novelty and complexity. Dual-task performance was measured as dual-task cost, considering task performance and cortical silent period duration. Analyses included descriptive statistics and, in line with a small-N study design, examination of individual data.

Results: There was no evidence of greater cognitive-motor interference in PwMS relative to non-MS controls. Task novelty and complexity effects between PwMS and non-MS controls were similar. Despite behavioral similarities, PwMS displayed greater changes in cortical silent period under dual-task conditions compared to non-MS controls that were accentuated under motor-motor dual-task conditions.

Discussion: Findings suggest that while PwMS and non-MS controls may perform similarly during dual-tasking, the neurophysiological mechanisms involved may be different. Further work is needed to elucidate the impact of MS-related changes in the corticospinal system on dual-tasking.

Introduction: Demyelinating lesions, or plaques, can form around axons when mature oligodendrocytes are damaged, often because of viral infections, heavy metal toxicity, or autoimmune disorders. These lesions are associated with cognitive impairment, motor dysfunction, sensory deficits, and memory loss, and may contribute to the progression of neurodegenerative diseases. At present, no therapy exists for demyelinating disorders, and available treatments primarily slow the progression of myelin loss while cognitive and functional deficits persist.

Materials and methods: In this study, we investigated the neuroprotective potential of stigmasterol in a vanadium-induced demyelination. Forty-eight C57BL/6 mice were randomly assigned to three groups and received either saline, vanadium, or vanadium plus stigmasterol for 4 weeks. Behavioral assessments included the elevated plus maze and open field test for anxiety-like behavior, the Barnes maze for learning and memory, and grip strength and rotarod tests for motor function. Immunofluorescence staining and Western blotting were used to evaluate markers of oligodendrocyte lineage (Olig2, PDGFRα), myelin integrity (MBP, MOG, electron microscopy), neuronal survival (NeuN), and glial activation, while inflammatory cytokines (TNF-α, IL-6) were quantified by ELISA.

Results: Our results revealed that vanadium administration induced anxiety-like behavior, impaired behavioral flexibility, reduced motor strength and coordination, and was associated with loss of MBP and MOG expression, decreased PDGFRα and Olig2, and elevated glial activation and inflammatory cytokines. Remarkably, stigmasterol co-treatment ameliorated these behavioral deficits, preserved MBP and MOG expression, increased PDGFRα and Olig2 levels, and attenuated microglial and astrocytic activation along with TNF-α and IL-6 production.

Conclusion: These findings suggest that stigmasterol confers neuroprotection by preserving oligodendrocyte lineage cells, enhancing PDGFRα-mediated precursor recruitment, and maintaining myelin integrity. By mitigating neuroinflammation and promoting remyelination, stigmasterol is a promising therapeutic candidate for metal-induced demyelinating disorders.

Background: Stroke, especially the ischemic type, remains a leading global cause of death and disability, with modifiable risk factors offering prevention opportunities. Trimethylamine N-oxide (TMAO), a gut-derived metabolite, promotes vascular damage and is linked to stroke risk. Although prior studies have explored dose-response relationships, clinically actionable thresholds remain undefined, limiting translational applications. This study aims to advance the field by quantifying a continuous dose-response relationship and determining a specific risk threshold, which is currently lacking, to inform preventive strategies.

Methods: This PRISMA-compliant meta-analysis included 11 observational studies (n = 7,556) and encompassed two components: an overall meta-analysis of 10 studies to compare admission TMAO levels, and a dose-response meta-analysis that was specifically applied to the subset of 4 studies with sufficient data across multiple exposure categories. We pooled standardized mean differences (SMD) for admission TMAO levels and modeled dose-response curves using restricted cubic splines (knots at 2.37/3.45/5.95 μmol/L). Heterogeneity was quantified using the I ²-statistic, sensitivity was assessed using alternative statistical models and dose scaling approaches, and publication bias was evaluated with Egger's test and the trim-and-fill method.

Results: Stroke patients showed significantly higher TMAO vs. controls (SMD = 0.55, 95% CI: 0.35, 0.74; P < 0.00001). Linear dose-response relationship: Each 1 μmol/L TMAO increase raised stroke risk by 8.9% (OR = 1.089, 95% CI: 1.023-1.158; P = 0.007). Risk threshold: TMAO > 3.0 μmol/L significantly increases the risk (OR > 1) and warrants preventive intervention. Cumulative risk escalated: 0 → 5 μmol/L: 53% risk increase (OR = 1.53); 0 → 20 μmol/L: 448% risk increase (OR = 5.48); robustness confirmed by sensitivity analysis (I ² = 35.9%; Cochran Q, P = 0.154).

Conclusion: TMAO exhibits a linear, dose-dependent association with stroke risk, with ≥ 3.0 μmol/L serving as a critical threshold for clinical intervention.

Background: Adherence with home-based exercise rehabilitation among stroke patients is generally low. Promoting a behavioral shift from passive compliance to active participation in home-based exercise rehabilitation is crucial to address this challenge. However, there is currently a lack of in-depth exploration of the mechanisms underlying this behavioral shift among stroke patients. This study aims to explore the behaviors and influencing factors related to home-based exercise rehabilitation among stroke survivors, thereby providing a reference for the development of personalized home-based exercise rehabilitation programs.

Methods: Seventeen stroke patients who visited the neurology outpatient clinic of a tertiary Grade A hospital in Nanjing, China, from October 2024 to May 2025 were recruited for semi-structured interviews. The Colaizzi seven-step analysis method was applied for thematic analysis and theme extraction.

Results: Analysis of the interview data yielded three core themes and 12 sub-themes. These included: (1) the multidimensional influence of personal characteristics and past experiences (limited body structure and function, driven by family responsibilities, self-decision-making ability, preferences for exercise rehabilitation, and economic pressure burden); (2) the driving and constraints of behavior-related cognition (perceived effects of rehabilitation effects, rehabilitation self-efficacy, adaptability of the rehabilitation environment, and multidimensional information asymmetry); and (3) the moderating effect of behavior-related emotional responses (rehabilitation of emotional experience, family support, and peer support).

Conclusion: Home-based exercise rehabilitation behavior among stroke patients is influenced by multiple complex and interrelated factors. Healthcare professionals should fully consider individual differences among patients, develop tailored exercise rehabilitation programs, and strengthen diversified external support systems to improve adherence to home-based exercise rehabilitation and ultimately enhance long-term rehabilitation outcomes.

Background: Atrial cardiomyopathy (ACM) and cerebral small vessel disease (CSVD) share common risk factors (e.g., hypertension, diabetes, dyslipidemia, aging) and pathophysiological mechanisms (e.g., inflammatory response, oxidative stress).

Objective: This study aimed to investigate the relationship between ACM and the total CSVD burden in patients with acute ischemic stroke (AIS).

Methods: We retrospectively enrolled eligible hospitalized AIS patients. Imaging markers were measured based on MRI data, including periventricular and deep white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), lacunes, cerebral microbleeds (CMBs), and brain atrophy. The total CSVD burden was calculated using the Wardlaw score. A P-wave terminal force in lead V1 (PTFV1) > 5,000 μV·ms was used to define atrial cardiomegaly (ACM), and a PTFV1 ≤ 5,000 μV·ms was adopted to define non-atrial cardiomegaly (NACM). Univariate and multivariate ordinal logistic regression analyses estimated the correlation between ACM and total CSVD burden.

Results: Among 323 enrolled patients (mean age 67.67 years, 63.7% male), 83 were classified as ACM. Patients with ACM had significantly higher total Wardlaw scores (OR = 1.79, 95% CI = 1.07-3.02, p = 0.026). Age, hypertension, and NIHSS score were also independent risk factors for increased total burden [OR = 1.05 (95% CI = 1.02-1.07, p < 0.001), 2.09 (95% CI = 1.29-3.42, p = 0.003), and 1.13 (95% CI = 1.03-1.24, p = 0.009), respectively].

Conclusion: This study found a suggestive association between ACM and total CSVD burden in AIS patients, underscoring the importance of assessing ACM for evaluating CSVD risk factors in this patient population.

Background: Understanding the factors related to early neurological improvement (ENI) is crucial in managing atrial fibrillation-related ischemic stroke (AF-stroke), as ENI indicates better long-term outcomes. We investigated the association between endothelial function, measured via flow-mediated dilation (FMD), and the occurrence of ENI in patients with AF-stroke.

Methods: We reviewed patients with acute AF-stroke within 7 days of FMD between April 2019 and April 2025. ENI was defined as a ≥2-point decrease in National Institutes of Health Stroke Scale (NIHSS) or ≥1-point reduction in motor NIHSS items within 24 h in non-thrombolysis patients. For thrombolysis patients, ENI was a ≥8-point reduction or NIHSS 0-1 at 24 h. FMD was measured during hospitalization and expressed as %FMD = (peak diameter - baseline diameter) / Baseline diameter × 100. Multivariable analysis identified the factors associated with ENI and explored their relationship with FMD.

Results: Among the 169 patients diagnosed with AF-stroke, 77 (44.4%) experienced ENI. Those with ENI had higher NIHSS (7 [4-13] vs. 2 [1-5], p < 0.001), more confluent (38.7% vs. 25.5%) and scattered with confluent pattern (29.3% vs. 18.1%, p = 0.007), and higher %FMD (6.5% ± 2.5% vs. 5.3 ± 2.2%, p = 0.001). Multivariable analysis revealed a higher initial NIHSS score (adjusted odds ratio [aOR]: 1.329, p < 0.001) and a history of smoking (aOR: 4.532, p = 0.004), and higher %FMD score (aOR: 1.179; p = 0.043) were independently associated with ENI. Subgroup analysis demonstrated a stronger association between high %FMD and ENI in patients with concomitant vascular risk factors, such as hypertension and dyslipidemia.

Conclusion: Endothelial function was associated with ENI in patients with AF-stroke.

Introduction: RNA methylation modifications, including N1 methyladenosine (m1A), N6-methyladenosine (m6A), 5-methylcytosine (m5C), and 7-methylguanosine (m7G) methylation, have been increasingly implicated in nervous system disorders. The aim of this study was to explore key m1A/m6A/m5C/m7G-related genes in neuropathic pain (NP).

Methods: NP-related gene expression data were downloaded from a public database. Differentially expressed m1A/m6A/m5C/m7G-related genes between the NP and control samples were screened. Subsequently, the RNA methylation-related clusters of NP were identified. Differentially expressed genes (DEGs) between different clusters were identified; this was followed by functional enrichment, weighted gene co-expression network, and protein-protein interaction analyses. Moreover, m1A/m6A/m5C/m7G-related DEGs were validated in a rat NP model constructed using spinal nerve ligation surgery.

Results: Six m1A/m6A/m5C/m7G-related DEGs were identified between NP and normal samples, namely, Fto, Mettl3, Nsun2, Ythdf3, Wdr4, and Eif4e. Based on these RNA methylation-related genes, two distinct NP clusters were identified. The DEGs between the clusters were involved in multiple pathways, such as the MAPK and FoxO signaling pathways. Among the DEGs, 12, including Txn1 and Rps3a, were identified as key genes. Furthermore, upregulation of Fto expression and downregulation of Mettl3, Nsun2, and Ythdf3 expression were observed in NP rats compared with those in control rats.

Discussion: Our findings reveal that genes associated with RNA methylation modifications, including Fto, Mettl3, Nsun2, and Ythdf3, may be involved in NP progression. Additionally, two RNA methylation-related DEG clusters were identified, and key pathways, such as the MAPK and FoxO signaling pathways, may participate in NP progression.

Background: In children with Rett syndrome, this study aimed to (1) describe gross motor skill trajectories; and (2) analyse the influences of genetic variant and comorbidities.

Methods: This was a prospective longitudinal study conducted at the Danish National Center for Rett Syndrome 2008 to 2022. The Rett Syndrome Gross Motor Scale (RSGMS) was administered, and clinical data collected at each visit. Mixed-effects linear regression models were used to analyze the effects of age, genetic variant and comorbidities on gross motor skills. Clinical records data were reviewed.

Results: Data for 33 children with a mean age of 7.3 years (SD 1.2) at first visit were followed for a mean duration of 6.8 years (SD 2.1). The mean RSGMS score was 24.0 (SD 13.2, total of 45) at baseline. Adjusting for age and genetic variant, all severity levels of epilepsy, autonomic breathing dysfunction and scoliosis, except for surgically corrected scoliosis, were associated with a 4-point decrease in RSGMS score every 5 years. Acute escalation of seizures, change in muscle tone, orthopedic surgeries and bone fracture could be associated capacity to maintain gross motor skills.

Conclusion: We identified decline in gross motor skills during childhood. This novel natural history data can assist with interpretation of changes in gross motor skills following the administration of new therapeutics.