Abstract Background Studies of circulating neurofilament light chain (NfL) and cognition have predominantly examined population-average associations, leaving individuals with relatively preserved cognition despite elevated biomarker burden insufficiently characterized. We investigated whether educational, socioeconomic, and behavioral resources were associated with this NfL–cognition discordance phenotype in older adults. Methods We conducted a cross-sectional complex-survey analysis of participants aged 60–75 years in the 2013–2014 National Health and Nutrition Examination Survey (NHANES). The primary analytic cohort included 502 participants with valid serum NfL measurements and complete cognitive assessments. Serum NfL was adjusted for age, sex, and estimated glomerular filtration rate, whereas global cognition was adjusted for age, sex, and test language. Participants were classified into four joint NfL–cognition phenotypes, with the primary analysis comparing participants with relatively preserved-cognition discordance against those with concordant impairment among individuals with elevated adjusted NfL. Survey-weighted regression models incorporated multiple imputation and prespecified robustness analyses. Results The weighted proportion meeting the study-defined criteria for relatively preserved-cognition discordance was 16.3% (95% CI, 12.0%–21.4%), whereas 8.9% (95% CI, 5.5%–13.6%) met the criteria for concordant impairment. These proportions are conditional on the internally defined NfL and cognition thresholds and should not be interpreted as clinical prevalence estimates. Among participants with elevated adjusted NfL, educational attainment was the only candidate correlate associated with relatively preserved cognition in the primary categorical analysis (overall p = 0.010). Compared with less than high school education, the odds of relatively preserved cognition increased across higher educational categories, whereas poverty-income ratio and recreational physical activity were not associated with the categorical phenotype. In complementary continuous analyses, education, poverty-income ratio, and physical activity were associated with better-than-expected cognition. Higher adjusted NfL showed a generally inverse pattern across cognitive outcomes, with the clearest evidence for global cognition (β=−0.117; 95% CI, − 0.206 to − 0.028) and Digit Symbol Substitution Test (DSST) performance (β=−0.086; 95% CI, − 0.172 to − 0.001). Findings were generally consistent across most stable prespecified sensitivity analyses, alternative cognitive definitions, inverse-probability weighting, and leave-one-primary-sampling-unit-out analyses, although evidence was attenuated under some alternative threshold definitions. Conclusions Among U.S. adults aged 60–75 years with elevated adjusted serum NfL in the NHANES serum-NfL subsample, cognitive performance was heterogeneous. Educational attainment was the most consistent correlate of relatively preserved-cognition discordance, although the data did not show that education modified the association between NfL and cognition. Joint consideration of biomarker burden and cognitive performance may provide complementary information beyond evaluating either measure alone. The phenotype framework should presently be regarded as an analytical research approach rather than a clinically deployable classification system, and longitudinal validation in independent cohorts is required.
Abstract Background Current longitudinal real-world data on secondary progressive multiple sclerosis (SPMS) remains limited, as most studies utilize cross-sectional designs that do not combine objective metrics with patient-reported outcomes like fatigue and depression. Therefore, integrating multidimensional assessments over time is essential to accurately capture disease evolution and treatment efficacy. Objectives To longitudinally evaluate clinical, cognitive, and functional progression in Egyptian patients with active SPMS over 12 months. Methods This prospective study included 46 Egyptian patients with active SPMS (69.6% females; mean age 43.5 years; mean disease duration 13.9 years). Patients were evaluated at baseline and followed for 12 months at 6-month intervals using Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test (T25FWT), Nine-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), Modified Fatigue Impact Scale (MFIS), and Beck Depression Inventory (BDI). Results Male sex and earlier multiple sclerosis (MS) onset were associated with earlier SPMS conversion and higher early relapse rates. Over 12 months, EDSS increased significantly, with concomitant worsening in motor performance, fatigue, depression, and cognition. Faster progression was observed in patients with baseline spinal cord involvement and higher relapse frequency. Conclusion Disease progression in SPMS is multidimensional. Integrating functional, cognitive, and patient-reported measures is crucial for comprehensive assessment and early detection of progression.
Abstract Background Acute ischemic stroke (AIS) remains a leading cause of death and disability worldwide. Because neuroinflammation contributes substantially to ischemic brain injury, minocycline has been investigated as a potential adjunctive therapy owing to its anti-inflammatory and neuroprotective properties. Methods This systematic review and meta-analysis (PROSPERO: CRD420261340165 ) was conducted in accordance with PRISMA guidelines. We included randomized controlled trials (RCTs) enrolling adults with AIS that compared oral or intravenous minocycline plus standard care versus placebo plus standard care. The primary outcome was functional outcome assessed by the modified Rankin Scale (mRS) at 90 days. Random-effects meta-analysis with Hartung-Knapp adjustment was performed, and trial sequential analysis (TSA) was conducted for all-cause mortality. Results Five RCTs involving 2,073 patients were included. Minocycline did not significantly improve excellent functional outcome (mRS ≤1; RR 1.52, p =0.271), functional independence (mRS ≤2; RR 1.32, p =0.214), or moderate functional outcome (mRS ≤3; RR 1.05, p =0.282) at 90 days compared with placebo. Likewise, no significant differences were observed in early neurological improvement at day 7 (NIHSS; p =0.248) or functional independence at 90 days assessed by the Barthel Index ( p =0.246). Minocycline was associated with lower all-cause mortality (RR 0.71, 95% CI 0.57–0.89; p =0.01); however, TSA indicated that the available evidence remains underpowered and insufficient for definitive conclusions. No significant differences were found in recurrent stroke or hemorrhagic transformation. Conclusion In conclusion, our findings suggest that minocycline is biologically credible, but it did not demonstrate a consistent benefit in functional or neurological outcomes after AIS (very low-to-low certainty evidence). Minocycline was associated with reduced all-cause mortality (moderate-certainty evidence), although trial sequential analysis indicates this finding remains inconclusive. With respect to the specific safety outcomes assessed—all-cause mortality, recurrent stroke, and hemorrhagic transformation—our findings do not raise safety concerns; however, safety was not comprehensively evaluated across the broader spectrum of known minocycline-associated adverse effects (e.g., hepatic toxicity, gastrointestinal intolerance, hypersensitivity reactions, vestibular symptoms), which were not systematically reported across the included trials. We therefore view minocycline as a promising adjunct that now needs better targeted, biomarker-informed, reperfusion-aware trials rather than immediate universal use in acute ischemic stroke.
Abstract Introduction Bipolar disorder is a chronic psychiatric condition characterized by high heterogeneity and variable clinical severity, the manifestation of which may be influenced by certain sociodemographic factors and psychoactive substance use. This study aims to evaluate the association between these factors and an operational marker of the clinical course of bipolar disorder in a population receiving psychiatric care. Population and methods This is a cross-sectional study conducted between March 2024 and December 2025 among 98 patients with bipolar disorder type 1 or 2, according to DSM-5 criteria, who were hospitalized at the Arrazi University Psychiatric Hospital in Salé, Morocco. Sociodemographic, clinical, and substance use data were collected from medical records and semi-structured questionnaires administered directly to the patients. The substances assessed included tobacco, cannabis, alcohol, and cocaine, taking into account current use at the time of assessment. Polysubstance use was defined as the simultaneous use of at least two substances. The complex operational marker was defined by the presence of at least 3 lifetime hospitalizations and at least two of the following manifestations: hyperactivity, aggression, or irritability. Univariate and multivariate statistical analyses were conducted to identify factors associated with a more complex clinical course of bipolar disorder. The marker was present in 30 participants (30.6%). All participants signed informed consent forms, and the study was approved by the Research Ethics Committee of the Faculty of Medicine and Pharmacy in Rabat, Morocco. Results The results of this study highlight the prevalence of substance use, which was 55.1% for tobacco, 34.7% for cannabis, and 37.8% for alcohol. In bivariate analysis, tobacco use was significantly associated with the operational marker of clinical course of bipolar disorder ( p = 0.016; crude OR: 3.09; 95% CI [1.21–7.92]). After multivariate adjustment, current cannabis use was associated with the presence of the marker (ORa = 2.981; 95% CI 1.063–8.358; p = 0.038). Additionally, an association was observed between disease duration and the presence of the marker (ORa = 1.054; 95% CI 1.002–1.109; p = 0.040). Conclusion This study explored associations between certain factors and an operational marker of a recurrent and complex clinical course of bipolar disorder. Current cannabis use and a longer duration of illness were associated with the presence of the operational marker. These results should be interpreted with caution given the cross-sectional and exploratory nature of the study.
Abstract Background Despite three decades of neuroprotective failures in acute ischaemic stroke (AIS), edaravone dexborneol (EDB) achieved regulatory approval in China by demonstrating superiority over edaravone monotherapy. The only prior meta-analysis evaluated a single functional endpoint, excluded four subsequent studies including the pivotal TASTE-2 trial, and performed no comparator stratified analyses leaving the totality of evidence uncharacterised. Methods A PROSPERO registered systematic review and meta-analysis searched PubMed, Embase, Scopus, clinical trials.gov and Cochrane through May 2026. Eligible studies were randomised controlled trials and comparative observational studies of EDB in adult AIS patients. Co-primary outcomes were 90-day excellent functional recovery (mRS 0–1) and functional independence (mRS 0–2). Random effects meta-analysis, GRADE certainty rating, and Trial Sequential Analysis (TSA) were applied throughout. Results Eleven studies enrolling 4706 patients seven RCTs and four comparative observational studies were included. EDB significantly improved mRS 0–1 (RR 1.14, 95% CI 1.08–1.20; p < 0.00001; I 2 = 0%; 9 studies; n = 4,474; GRADE: HIGH) and mRS 0–2 (RR 1.08, 95% CI 1.03–1.13; p = 0.001; I 2 = 1%; 8 studies; n = 4089; GRADE: HIGH). TSA showed that accrued information exceeded the required information size for both endpoints (555.4% for mRS 0–1; 505.3% for mRS 0–2), and the O’Brien–Fleming benefit boundary was crossed for mRS 0–1 (Z = 4.70), confirming evidentiary sufficiency for this endpoint. For mRS 0–2, the required information size was reached within the earliest contributing trial, so the sequential boundary could be assessed only at the first information fraction, where it was not crossed (Z = 1.56); TSA-based sufficiency is therefore not claimed for mRS 0–2. Ninety day mortality was non-significantly reduced (RR 0.87, 95% CI 0.67–1.13; GRADE: MODERATE), with only 32.4% of the required information size accrued. Adverse event rates were equivalent (RR 1.01); symptomatic intracranial haemorrhage was numerically lower with EDB (RR 0.73, 95% CI 0.49–1.07). All seven RCTs carried a low risk of bias, indicating a consistently high methodological quality across the included evidence base. Conclusion EDB produces a TSA-confirmed improvement in 90-day excellent functional recovery (mRS 0–1). For functional independence (mRS 0–2), the pooled effect was significant with GRADE HIGH certainty, but TSA could not confirm evidentiary sufficiency because the sequential boundary was assessable only at the earliest information fraction, where it was not crossed, so further corroboration is warranted; a reassuring though not fully conclusive safety profile was observed; certainty for mortality and several secondary and safety outcomes remains lower and is detailed below. Definitive inference on mortality requires blinded, adequately powered, multinational trials.
