Journal of the Neurological Sciences

ObjectiveTo compare early cerebrospinal fluid (CSF) cytokine profiles in intracerebral hemorrhage (ICH) versus subarachnoid hemorrhage (SAH), with a focus on angiography-negative SAH (anSAH). MethodsWe conducted a retrospective observational cohort study of adults with spontaneous hemorrhagic stroke (ICH or SAH). For cytokine analyses, we included patients with external ventricular drains (EVDs) and analyzed the first CSF sample obtained within 72 hours of symptom onset. Cytokines were measured using a multiplex bead-based assay and included interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor A (VEGF-A), C-C motif chemokine ligand-2 (CCL2), and granulocyte colony-stimulating factor (G-CSF). Cytokine concentrations were log-transformed due to non-normal distribution. Functional outcomes were assessed using the modified Rankin Scale (mRS) at discharge and 3 months. ResultsCSF cytokine analyses included 120 patients with available CSF samples (43 ICH and 77 SAH), while functional outcome analyses included a broader cohort of 490 patients with ICH or SAH to characterize discharge and 3-month outcomes across hemorrhage subtypes. Compared with SAH, ICH demonstrated higher early CSF log[IL-8] and log[VEGF-A] and had worse functional outcomes at discharge and 3 months. Within SAH, anSAH had higher log[IL-8] and log[VEGF-A] than aSAH, and its cytokine profile more closely aligned with that of primary ICH in hemorrhages without vascular malformations. DiscussionEarly CSF cytokine patterns suggest anSAH shares a more ICH-like inflammatory signature than aneurysmal SAH, supporting anSAH as a potentially biologically distinct SAH phenotype.

BackgroundSuccessful recanalisation without functional independence is a frequent phenomenon following endovascular thrombectomy for large vessel occlusion stroke. AimTo demonstrate safety and efficacy of adjunct tirofiban therapy after endovascular thrombectomy in patients with anterior circulation large vessel occlusion stroke achieving successful recanalization defined as modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3. DesignThe study of adjunct tirofiban treatment after successful endovascular thrombectomy recanalisation (ATTRACTION) is a multicenter, prospective, double-blind, randomized trial enrolling 1360 patients in China. Eligible patients will be randomised 1:1 to either the tirofiban or placebo group. OutcomeThe primary efficacy outcomes is assessed as the proportion of participants with a modified Rankin Scale (mRS) score of 0-2 at 90 days, and the primary safety outcome is symptomatic intracranial haemorrhage within 48 hours from randomisation. ConclusionThis study will provide evidence on the efficacy and safety of sequential tirofiban therapy after successful recanalisation in patients with anterior circulation large vessel occlusion stroke. Trial registration numberNCT06265051 WHAT IS ALREADY KNOWN ON THIS TOPICSuccessful recanalization without functional independence is a frequent phenomenon following endovascular thrombectomy and previous small-sample, retrospective studies supported the administration of adjunct tirofiban therapy in patients after endovascular thrombectomy achieving successful recanalization. WHAT THIS STUDY ADDSThe ATTRACTION trial aims to access the efficacy and safety of adjunct tirofiban therapy and the protocol describes the rationale and design of the trial. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYATTRACTION trial will inform whether tirofiban therapy after successful recanalisation by endovascular thrombectomy can improve patient outcomes.

IntroductionNeurodegenerative dementia syndromes are severely debilitating, progressive and increasing in incidence with an ageing population. A treatable differential diagnosis to neurodegenerative dementia is autoimmune encephalitis (AE), but AE patients are often misdiagnosed, delaying treatment. Previous work in the Netherlands has shown that 0.8% of patients with suspected neurodegenerative dementia suffer from AE. In Sweden, there is considerable variability in the prevalence of AE, possibly indicating under-diagnosis. We hypothesized that some Swedish individuals seeking care for memory impairment might suffer from an undetected AE and that these would show aberrances in available markers of neuroinflammation. MethodsWe retrospectively screened frozen sera from 1041 individuals seen between 2019 and 2023 at the Karolinska University hospital memory clinics in Stockholm for autoantibodies to contactin-associated protein-like 2 (CASPR2), leucine-rich glioma-inactivated 1 (LGI1), gamma-aminobutyric acid receptor B (GABABR), the n-methyl-d-aspartate receptor (NMDA-R) and Immunoglobulin superfamily containing LAMP, OBCAM, and Neurotrimin family member 5 (IgLON5) using live cell-based assays (CBAs) and scored them by microscopy. Serum and CSF from suspected positive patient samples were re-tested and titrated by live CBA, commercial fixed CBAs and tissue based assays. Results8 of the 1021 individuals, or 0.8% of the cohort, tested positive in at least three different tests for antibodies to CASPR2 (n=3), GABABR (n=2), LGI1 (n=1) and NMDAR (n=2). Seven of these patients had not been previously diagnosed with AE. Apart from two CASPR2-antibody positive patients showing neuropathic pain and seizures and neuromyotonia, respectively, the patients lacked clinical signs of encephalitis aside from memory impairment and affect lability. The antibody-positive patients did not differ significantly from autoantibody-negative patients in any available clinical parameter. None showed signs of inflammation on brain magnetic resonance tomography, and 2/7 lacked any sign of neuroinflammation in the CSF with available tests, which is commonly seen in later-onset AE. ConclusionOur work identifies undiagnosed AE patients with subtle symptomatology among Swedish memory clinic visitors, that cannot be sensitively separated from antibody-negative patients with current diagnostic tests. Our results suggest the need for the introduction of more sensitive markers of neuroinflammation to the memory clinic to identify and treat individuals with AE among sufferers of memory impairment.

ObjectivesFunctional neurological symptoms which do not meet clinical definitions of functional neurological disorder (FND) are common in clinical practice. Understanding the distinction between these benign functional symptoms and FND is crucial in defining FND as an entity for study, and as a clinical syndrome. We aimed to measure the frequency of functional symptoms in people who do not have FND. MethodsA survey was administered to 95 clinicians who attended an international conference on FND. Participants were asked to report the occurrence and characteristics of experiences with features of functional sensory or motor symptoms, or dissociation. ResultsOf the 95 people who responded to the survey, 57.4% reported having experienced any functional symptoms, and 47.9% reported having experienced functional motor or sensory symptoms. The symptoms reported were generally short-lived and caused only mild distress and disruption. Most respondents who reported having experienced a functional symptom reported having had multiple events through their lives. InterpretationThe results suggest that the lifetime occurrence of functional neurological symptoms is at least two orders of magnitude higher than the prevalence of FND. The high prevalence of functional symptoms in people who have never had FND challenges the common assumption that the occurrence of functional neurological symptoms is synonymous with FND. We propose that FND is better conceived of as a failure of the mechanisms by which functional neurological symptoms resolve, rather than the occurrence of functional symptoms per se. This reconceptualization implies new research directions for the underlying aetiology of FND.

BackgroundLarge middle cerebral artery (MCA) infarctions can result in life-threatening cerebral edema. Quantitative brain atrophy may improve risk stratification for severe edema. We examined whether quantitative brain atrophy is associated with severe midline shift after large ischemic stroke and whether incorporating atrophy improves prediction beyond established clinical and radiographic predictors. MethodsThis was a retrospective observational cohort study of patients with [&ge;][1/2] MCA ischemic infarction, presentation within 24 hours of last known well, and at least one follow-up head CT, admitted to two academic hospitals with comprehensive stroke centers between 2006 and 2024. The study was approved by the institutional review boards of both centers. Brain atrophy was quantified as the inverse of standardized brain volume on admission head CT. The primary outcome was severe radiographic mass effect, defined as midline shift [&ge;]5 mm on follow-up CT. The secondary outcome was in-hospital mortality. Multivariable regression models assessed associations between quantified atrophy and outcomes. Incremental prognostic value was evaluated by comparing models with and without atrophy using measures of goodness of fit, calibration, and discrimination. ResultsAmong 565 patients (mean age 67.5{+/-}15.7 years; 49.9% female), 223 (39.5%) developed severe mass effect. Greater atrophy was associated with lower odds of midline shift [&ge;]5 mm (OR 0.44, 95% CI 0.34-0.58), but not with in-hospital mortality. Incorporation of atrophy significantly improved prediction of severe mass effect compared to the baseline model (likelihood ratio test {chi}{superscript 2} (1) = 41, p <0.001; AIC 703 vs. 741; BIC 733 vs. 767; AUC 0.68 vs. 0.60). ConclusionsQuantified brain atrophy is independently associated with a reduced risk of severe mass effect after large MCA stroke and improved the performance of established predictive models. Incorporation of this imaging biomarker may enhance early risk stratification, monitoring, and intervention planning for patients at risk of life-threatening cerebral edema.

AbstractsO_ST_ABSBackgroundC_ST_ABSSelf-management is essential for stroke survivors to maintain a healthy lifestyle and reduce recurrence risk. Although theory-based self-management interventions are widely recommended, the theoretical frameworks underpinning them and their comparative effectiveness remain unclear. AimsTo systematically identify the theories, models, and frameworks (TMFs) used in self-management interventions for stroke survivors, to explore how they guide interventions, and evaluate their effectiveness on self-management behaviors and self-efficacy. MethodsPubMed, Embase, Web of Science, ProQuest Health & Medical Collection and the Cochrane Library were searched from inception to July 15, 2025. Randomized controlled trials or quasi-experimental studies evaluating theory-based self-management interventions for stroke survivors were included. Two reviewers independently screened studies, extracted data, and assessed risk of bias (Cochrane RoB 2.0). Meta-analyses were performed using random-effects models. ResultsFrom 11,495 records, 32 studies with 3,212 participants were included. Sixteen distinct TMFs were identified; self-efficacy theory was most frequent (13/32), followed by social cognitive theory (6/32). All TMFs were middle-range theories. Meta-analysis showed TMFs-based interventions significantly improved self-management behaviors (SMD = 4.26, 95%CI: 0.20-8.31, I{superscript 2} = 98.2%) and self-efficacy (SMD = 0.60, 95%CI: 0.32-0.88, I{superscript 2} = 72.8%). However, the effect for behaviors is likely inflated due to extreme heterogeneity and theoretical diversity. Theory-specific analysis of self-efficacy theory (k = 8) confirmed significant effects on self-efficacy (SMD = 0.64, 95%CI: 0.21-1.08). ConclusionsThis review identified 16 distinct theoretical models; self-efficacy theory was most frequently applied, followed by social cognitive theory. Theory-based interventions significantly improved self-management behaviours and self-efficacy.

aStructured abstractO_ST_ABSBACKGROUNDC_ST_ABSOver the past couple of decades, the role of infections, as well as the involvement of the immune system, have been highlighted in the development of dementia. METHODData from the Wisconsin Registry for Alzheimers Prevention cohort were utilized for the analysis. A history of medical conditions was searched across the cohort, and known infections and autoimmune conditions were recorded for each participant. These conditions were then compared with the diagnosis and cognitive performances of each participant. Furthermore, plasma markers were analyzed using two different protein quantification methods. RESULTSOur analysis revealed poorer cognitive performances among participants with listed medical conditions. In plasma samples, Ab42/ICAM1 was identified as a protein ratio with significant variation across condition statuses. DISCUSSIONOur study confirmed that infections and autoimmune conditions contribute to cognitive decline. Ab42/ICAM1 was identified as a relevant marker.

PurposeIntracranial atherosclerotic disease-related large vessel occlusion (ICAD-LVO) presents distinct challenges, particularly regarding the high risk of reocclusion and the need for specific management strategies. While several prediction scores exist to differentiate ICAD-LVO from embolic LVO (EMB-LVO), their external validity remains unproven. We aimed to externally validate six established prediction scores for differentiating the two. MethodsWe analyzed data from a prospectively maintained, two-center stroke registry (June 2021-March 2025). Consecutive patients who underwent mechanical thrombectomy and had complete clinical and imaging data necessary for calculating six scores (ISAT, REMIT, ABC2D, ATHE, ICAS-LVO, and Score-ICAD) were included. LVO etiology was defined based on angiographic findings during endovascular treatment. The discriminative performance of each score was assessed using the area under the receiver operating characteristic curve (AUC). ResultsOf 1,288 screened admissions, 91 patients met the inclusion criteria (ICAD-LVO, n = 18; embolic occlusion, n = 73). The AUCs (95% confidence interval) for differentiating etiology were: ISAT, 0.870 (0.664-1.000; P = 0.064); REMIT, 0.793 (0.676-0.911; P <0.001); Score-ICAD, 0.707 (0.582-0.833; P = 0.013); ABC2D, 0.627 (0.504-0.751; P = 0.095); ATHE, 0.600 (0.451-0.749; P = 0.230); and ICAS-LVO, 0.465 (0.301-0.630; P = 0.650). ConclusionIn this external validation, REMIT demonstrated the most robust and statistically significant discrimination between ICAD-LVO and EMB-LVO. Overall, scores incorporating imaging features outperformed those relying on clinical variables. These findings support the concept that ICAD-LVO represents a distinct pathophysiological entity from embolic occlusion and that accurate mechanism inference requires comprehensive imaging assessment of intracranial atherosclerotic disease beyond the occlusion site.

Background: Platform trials are an efficient trial design which enable testing of multiple interventions simultaneously. They could advance knowledge of treatments for intracerebral haemorrhage (ICH). We aimed to investigate the views of clinicians involved in stroke research on recruitment to a future platform trial for ICH. Methods: Between April and July 2025, we conducted a UK-wide online survey of clinicians actively involved in stroke research using convenience sampling through professional organisations. Participants considered factors related to the consent process and research environment and could provide optional free text responses about additional barriers or facilitators to recruitment. We used descriptive statistics for quantitative data and content analysis for qualitative data. Results: Among 73 respondents, 46 (63%) were female, 36 (50%) were stroke physicians, 24 (34%) nurses, 6 (8%) allied health professionals, and 7 (10%) were in other roles. 36 (49%) had >20 years of clinical experience, 45 (61%) reported spending <10% of their role in research. 66 (91%) thought that a platform trial would be a good option for testing interventions for patients with stroke due to ICH. Across 11 modifiable factors, clinicians most frequently rated perceived importance of the research question as a facilitator of recruitment (94%), while clinician preference for specific treatments was most frequently rated as a barrier (48%). Two themes emerged from free text responses: study design and infrastructure. Regarding study design respondents perceived consent procedures (n=9), study materials (n=8), study procedures (n=8), eligibility assessment (n=6), the research question (n=3) and randomization (n=3) as important for a future platform trial. Regarding infrastructure, emergent factors were staffing (n=17), local research culture and capacity (n=9), research governance and delivery (n=6), and training (n=6). Conclusion: The overwhelming majority of respondents from the UK clinical stroke community supported a platform trial for ICH, although the influence of survey responder bias is unknown.

ImportancePrognosticating functional independence after an acute stroke is critical for anticipatory guidance and rehabilitation planning. Here we demonstrate that poor brain health at the time of incident stroke is linked to worse functional outcomes for women compared to men. ObjectiveTo determine if brain health at time of stroke presentation has a differential effect on functional outcomes between men and women. DesignRetrospective cross-sectional study. SettingAnalysis conducted in 2025 with multi-center patient data that included participants from two large acute ischemic stroke cohorts; local (GASROS) and multinational (MRI-GENIE) between the years 2003 and 2011. ParticipantsClinical data collected for enrolled study participants included demographic data, medical history of hypertension, diabetes mellitus, hyperlipidemia, smoking status, acute stroke severity as measured by National Institutes of Health Stroke Scale (NIHSS), stroke etiology, and modified Rankin Scale (mRS) score at 90 days post-stroke. Brain health was quantified as effective reserve derived from acute neuroimaging data. Exposure(s)designated sex, retrieved from registration records. Main OutcomeFunctional outcome was measured by mRS scores at 90 days post-stroke, in men and women with poor, moderate, or good brain health at time of stroke injury. ResultsA total of 1039 patients were included in the analysis, 37.8 % women, median age 67 [interquartile range 56-77]. Women with poor brain health (i.e. lowest quartile of effective reserve) had worse functional outcomes at 90 days (55.6% with mRS>2) compared to men with poor brain health (31.2% with mRS>2: p < 0.001). This difference between men and women was not observed in categories of moderate or good brain health. There was no observed significant difference in stroke severity, volume of acute lesion, burden of white matter hyperintensities, or stroke etiology between men and women with poor brain health. Conclusions and RelevanceBrain health at the time of incident stroke has a differential effect on functional outcomes at 90 days between men and women. Women with poor brain health endure disproportionately worse outcomes compared to men. This highlights an important step in understanding sex-specific vulnerability in early recovery post-stroke, and can inform disposition, rehabilitation services, and resource allocation planning.

BackgroundDystonia is a debilitating movement disorder that is difficult to assess when co-existing with spasticity, as is typical in cerebral palsy (CP). Querying caregivers about their childrens movements is known to increase clinical dystonia identification. However, beyond identification, determining whether dystonia is the predominant vs. accompanying movement feature in a child with CP can guide clinical decision making, particularly regarding surgical candidacy. ObjectiveTo determine whether caregivers movement descriptions differed between children with predominant dystonia, predominant spasticity with accompanying dystonia, and predominant spasticity without dystonia. MethodsIn this cross-sectional study, we used conventional content analysis to codify caregivers descriptions of triggered involuntary movements in children with CP seen in a tertiary care CP center between 4/2023 and 12/2024. Movement feature frequencies were compared across tone types using Chi-square tests with Bonferroni corrections for multiple comparisons. ResultsOf 180 children with CP (mean age 9.2, 47.8% male), caregivers of children with predominant dystonia (50/180, 27.8%) more frequently described movements triggered by negative emotions (p<0.002) and affecting their back, trunk, and whole body (p<0.04). Caregivers of children with predominant spasticity with dystonia (99/180, 55.0%) more frequently described movements affecting a single limb (p<0.04). Caregivers of children without dystonia (31/180, 17.2%) described movements as being slight or small (p<0.008). These differences persisted even for caregivers unaware their child had dystonia (77/149, 51.6%). ConclusionsCaregivers movement descriptions differ between children with different combinations of dystonia and spasticity, which may help inform clinical management and guide communication with families about dystonia.

IntroductionNeurocognitive impairment (NCI) remains common among people living with HIV (PWH), particularly in low- and middle-income countries where accurate diagnostic tools are limited. In Peru, the lack of locally validated neuropsychological (NP) normative data in Spanish poses a major barrier to diagnosing HIV-associated NCI, especially among PWH who develop NCI at younger ages. This study aimed to develop regression-based NP norms for young and middle-aged Spanish-speaking adults in Lima, Peru and validate the norms in demographically similar PWH to improve diagnostic precision of HIV-associated NCI. MethodsA total of 164 healthy adults without HIV from Lima completed a comprehensive NP battery assessing memory, attention, executive function, and language, which are commonly affected in HIV-associated NCI. Multiple regression models were used to consider the influence of age, years of education, and sex on raw scores, yielding standardized demographically-adjusted norms for the population. The resulting norms were then applied to 310 PWH from Lima and then compared with previously published norms for Spanish speaking adults to evaluate performance differences. ResultsAge and education were the strongest predictors of performance across tests, while sex had minimal influence. Compared to people without HIV, PWH had significantly lower educational attainment (mean 12.6 vs. 13.7 years) and exhibited significantly worse performance on normed scores of Benson Figure Copy, Benson Figure Delayed Recall, Color Trails 1 and 2, Hopkins Verbal Learning Test - Revised, and WAIS-III Digit Symbol Coding, Digit Span, and Symbol Search. There were statistically significant differences between T-scores on nearly all tests between our population-specific norms and previously published norms in both directions, indicating potential over- and under-detection errors when applying norms from non-local samples. DiscussionOur findings highlight the utility of locally derived norms in detecting subtle cognitive changes among young and middle-aged PWH compared with previously published norms for Spanish-speakers. Application of these norms reveals significant between-group differences that may go undetected using non-local normative data or raw scores. Future efforts should focus on rural norm development and inclusion of individuals with lower educational backgrounds in Peru and other Latin American countries.

Repetitive head impacts (RHI) from contact and collision sports have been associated with later-life cognitive and neurobehavioral impairments, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE). RHI-associated clinical sequelae among female former soccer players, specifically, are not well understood. This cross-sectional study aimed to examine the relationship of RHI exposure proxies (e.g., total years of soccer play, highest level of play, and estimated cumulative heading frequency) with clinical measures (e.g., subjective cognitive complaints, objective cognitive performance, behavioral dysregulations, and depressive symptoms) among 3,174 women, aged 40 years or above, enrolled in the Head Impact and Trauma Surveillance Study (HITSS), all of whom played organized soccer. HITSS participants completed an online battery that elicited self-reported cognitive and behavioral complaints and depressive symptoms, and that assessed cognitive performing via computerized tests. Multivariable linear and logistic regression models estimated associations between soccer-related RHI proxies and outcome measures, adjusting for age and education. Among the former soccer players, longer duration of soccer play, higher level of play, and greater estimated cumulative heading frequency were significantly associated with worse self-reported cognitive functioning, greater behavioral dysregulation, and elevated depressive symptom severity (range of significant unstandardized B coefficients: 0.02 to 0.52). Higher estimated cumulative heading exposure was associated with higher odds of clinically meaningful elevations on subjective measures (OR range: 1.05 to 1.13) There were no associations between any of the RHI proxies and performance on the objective computerized cognitive assessments. Among middle-aged women who played organized soccer, cumulative RHI exposure was associated with small but statistically significant effects for measures of subjective cognitive complaints, behavioral functioning, and depressive symptoms. We found no associations for objective outcomes of cognitive function. Continued monitoring of this large cohort of female former soccer players will improve understanding of long-term consequences of soccer play.

BackgroundMRI plays an essential role in diagnosing and monitoring neurological diseases. Conventional protocols rely on multiple sequences to obtain complementary contrasts, increasing scan time, cost, and tolerability. Generating multiple contrasts from a single acquisition may streamline workflow while maintaining clinical utility. PurposeTrain attention-based convolutional neural networks (ACNNs) to generate clinical-quality FLAIR, MPRAGE, R2*, and derived contrasts from a single Gradient Echo Plural Contrast Imaging (GEPCI) acquisition, enabling multi-contrast imaging from one scan. Study TypeRetrospective. Population43 MRI scans from individuals with multiple sclerosis (25/18 F/M, 49{+/-}11 years old). Field Strength/Sequence3T MRI was used to obtain 3D GEPCI, MPRAGE, and FLAIR sequences. AssessmentTechnical quality of the AI-generated contrasts was evaluated against directly acquired MRI images using structural similarity index (SSIM). Quantitative accuracy for R2* maps was evaluated using normalized root-mean-square error (NRMSE). Clinical image quality was assessed by expert physicians. Lesion volumes and counts were obtained using automated segmentation. ResultsAI-generated FLAIR and MPRAGE images achieved mean SSIM values of 0.923{+/-}0.028 and 0.935{+/-}0.022, respectively. The generated R2* maps achieved a mean SSIM of 0.996{+/-}0.006, with quantitative accuracy reflected by an NRMSE of 0.031{+/-}0.020. Physicians rated GEPCI-FLAIR images at 4.2 and GEPCI-MPRAGE images at 4.5 (on a 1-to-5 scale), both exceeding the clinically routine standard of 4.0. Lesion volume and count comparisons from automated segmentation showed strong agreement between AI-generated and ground-truth measurements (R{superscript 2}=0.988 and R{superscript 2}=0.933, respectively). ConclusionAI-GEPCI generated multiple clinically relevant MRI contrasts from a single GEPCI acquisition with high similarity to corresponding acquired images. Radiological reviews and quantitative analyses supported the feasibility of producing high-quality, intrinsically co-registered multi-contrasts for comprehensive brain evaluation.

Amyotrophic Lateral Sclerosis (Lou Gehrigs disease) is a progressive neurodegenerative disease affecting hundreds of thousands of people worldwide. It is characterized by the degeneration of the neurons in the brain and spinal cord of the patients, leading to a loss of control of muscles. Over time, without nerves to stimulate them muscles tend to atrophy. ALS may occur sporadically or run in families; many mutations have been identified for the latter. Treatment of ALS is mostly limited to three approved therapeutic agents: riluzole, edaravone, and tauroursidiol/ sodium phenylbutyrate. Among these, riluzole remains the most effective despite its early discovery. There are no conclusive meta-analysis comparing riluzole monotherapy to all possible co-therapies present. In this work we have attempted to address such a concern and observed that no adjunct therapy significantly improved the performance of riluzole. However, mitochondrial/ oxidative stress modulator and neuroimmune/ neuroexcitability modulator co-therapy exhibited positive trends. Surprisingly, trials were mainly confined to the USA and European countries, indicating unequal demographic representation in ASL research. We have concluded that large double blinded inter-continental RCTs to be carried out for better understanding of the scenario.

IntroductionThe ischaemic penumbra is the principal therapeutic target in acute ischaemic stroke (AIS). Although perfusion imaging enables identification of salvageable tissue, its availability is limited and iodinated contrast exposure carries risk. Validated blood-based biomarkers could serve as scalable surrogates for imaging-defined penumbra. ObjectiveWe conducted a systematic review and meta-analysis to assess the association between blood-based biomarkers reported in the literature and the ischaemic penumbra. MethodsWe searched Ovid MEDLINE, Embase (Ovid), PsycINFO (Ovid), and Web of Science until December 3, 2025, for studies involving human subjects with AIS aged over 18 years or animal subjects that reported the presence of infarct and ischaemic penumbra. The primary outcome was the difference in mean biomarker levels in subjects with and without ischaemic penumbrae as defined by the study authors. We used the QUADAS-2 tool to assess risk of bias. We calculated each biomarkers pooled standardized mean difference (SMD) and 95% CI where possible. Protein-protein interaction network (PPI) and pathway analyses were conducted in Cytoscape and the enrichR R package (PROSPERO: CRD42023453175). ResultsWe identified 11 studies (1765 human subjects and 8 nonhuman primates) that assessed 53 candidate blood-based biomarkers. Two studies had a low risk of bias, while nine had a risk of bias. A meta-analysis was conducted for seven biomarkers in humans from four studies. Of these, three biomarkers demonstrated significant association with penumbrae in humans: mid-regional pro-adrenomedullin (MR-proADM; SMD 0.80 [95% CI 0.49 to 1.10]), interleukin-10 (IL-10; SMD 1.94 [0.85 to 3.03]), and neuron-specific enolase (NSE; SMD -0.71 [-1.40 to -0.01]). However, substantial statistical heterogeneity was observed for several pooled biomarkers (I{superscript 2} >90%), limiting confidence in effect size precision. Amongst biomarkers where meta-analysis was not possible, 37 biomarkers showed significant association with presence of a penumbra. Oxygen radical absorbance capacity after perchloric acid treatment (ORACPCA; SMD 0.31 [0.01 to 0.60]) showed significant association with penumbra presence; 34 genes (e.g., STK26 r = 0.58, p = 0.003; MGA r = 0.58, p = 0.004; IL1B r = -0.59, p = 0.003; NUP98 r = -0.71, p < 0.001), circOGDH (r = 0.962, p = 0.002), and NT-proBNP (r = 0.199, p < 0.001) were significantly correlated with penumbra volume. PPI analysis identified IL-1{beta} as the most highly connected node (10 interactions), followed by IL-10 and HDAC1/HCAR2. Cdc42 was reported to be significantly associated with penumbrae in nonhuman primates, but there were insufficient data to calculate SMD. Pathway enrichment revealed positive associations with angiogenesis and IL-12 signalling, and negative associations with leukocyte migration, chemokine signalling, and platelet activation. ConclusionsCurrently reported biomarkers of ischaemic penumbra are not ready for clinical implementation. Although implicated pathways converge on inflammatory regulation, haemostasis, and cerebral perfusion, rigorous prospective validation is required before integration into prehospital or emergency triage workflows.

BackgroundPersons with epilepsy are at increased risk of depression/anxiety. Older antiseizure medications (ASMs) had drug-drug interactions that complicated pharmacotherapy of depression/anxiety; newer ASMs lack this drawback but can have psychiatric side effects. Anxiety/depression are increasingly recognized and treated pharmacologically. We hypothesized that the likelihood of treatment with selective serotonin uptake inhibitors (SSRI) would have increased in adult-onset epilepsy when prescription habits shifted towards newer ASMs. MethodsWe linked national health registers and included 28569 persons with epilepsy incident in 2006-2020 and 68509 age- and sex matched controls. We assessed the risk of starting SSRI treatment compared to age- and sex-matched controls across three incidence periods: 2006-2010, 2011-2015, and 2016-2020. Cox regression was used to estimate adjusted hazard ratios (HRs), and subgroup analyses explored age, sex, and comorbidities. Specialist psychiatric care was also assessed as a measure of more severe depression. Analysis including persons with SSRI-use before the epilepsy diagnosis were used for sensitivity analyses. FindingsPersons with epilepsy had higher risks of starting SSRIs compared to controls; 1986/9561 (20.8%) received SSRI during follow-up after epilepsy in 2006-2010 and 2020/9165 (22.0%) in 2016-2020; adjusted HRs were 1.92 (95%CI:1.79 - 2.06) in 2006-2010, 1.84 (95%CI:1.72-1.97) in 2011-2015, and 1.81 (95%CI:1.69 - 1.94) in 2016-2020. Among individuals aged 18-30 years at their epilepsy diagnosis, the proportion receiving SSRIs remained the same between the first and last calendar periods (18.2%). Because of increased treatment of controls, the adjusted HRs of SSRI-treatment decreased from 2.33, (95% CI:1.96 - 2.78) to 1.63, (95% CI 1.39 to 1.91). The HR of specialist psychiatric care was not significantly different between the time periods. Most comorbidities were consistently associated with increased likelihood of SSRI treatment, whereas intellectual disability decreased the likelihood in some periods. InterpretationWe found no evidence of overall increased SSRI initiation or psychiatric care after the shift to newer ASMs. Person with epilepsy remain more likely to receive SSRI treatment, but probably not to a level matching the higher prevalence of depression. Increased SSRI treatment of younger age adults has not been matched by increased treatment of young adults with epilepsy. This suggests a potentially widening treatment gap and a need for increased recognition of depression in young adults with epilepsy. FundingSwedish Research Council (2023-02816), Swedish state through the ALF-agreement (ALFGBG-1006343), Knut och Ragnvi Jacobsson foundation, Swedish Society for Medical Research (S18-0040), Swedish Society of medicine (SLS-881501), Epilepsifonden, Rune och Ulla Amlovs stiftelse.

Background and objectives STXBP1-related disorder (STXBP1-RD), caused by pathogenic variants in the STXBP1 gene, is a rare neurodevelopmental condition, characterized by early-onset seizures, developmental delay, intellectual disability (ID), and prominent motor dysfunction. Despite the high prevalence of motor symptoms, systematic gait characterization remains limited. We therefore aimed to quantitively assess gait in individuals with STXBP1-RD. Methods In this cross-sectional study, we included ambulatory patients aged 6 years or older with genetically confirmed STXBP1-RD. Instrumented 3D Gait Analysis (i3DGA) was performed to objectively quantify gait. Functional mobility was assessed with the Functional mobility scale (FMS) and Mobility Questionnaire 28 (MobQues28). Caregiver health-related quality of life was evaluated using the PedsQL-Family Impact Module (PedsQL-FIM). We explored associations between gait, functional mobility, STXBP1-variant type and clinical features (ID, age at seizure onset, seizure frequency, age at onset of independent walking). Correspondence between i3DGA and the Edinburgh Visual Gait Score (EVGS), an observational gait assessment, was investigated. Results Eighteen participants were included. Compared to typically developing peers, individuals with STXBP1-RD had significantly reduced walking speed, step and stride length. Gait patterns were highly variable, with the most frequent pattern being an externally rotated foot progression angle (FPA), present in 11/18 participants. At home, 93.75% of the participants (16/18) walked independently, yet community mobility was more variable: 11/16 (68.75%) walked independently, 2/16 (12.50%) with aid and 3/16 (18.75%) used a wheelchair, indicating increasing limitations with distance and environmental complexity. Earlier acquisition of independent walking strongly predicted later unassisted ambulation at community level (p<0.001). Median MobQues28 score was 57.14% and median PedsQL-FIM score was 60.42%, indicating a moderate level of mobility limitations and reduced health-related quality of life of caregivers. EVGS was highly positive correlated with i3DGA (p= 0.001). Discussion Quantitative gait analysis in individuals with STXBP1-RD demonstrates heterogenous kinematic deviations, with an externally rotated FPA emerging as the most common pattern. Age at independent walking was a clinically relevant predictor of later functional mobility. EVGS showed strong correspondence with i3DGA and may offer a more practical, semi-quantitative assessment for broader use. These findings inform clinical decision-making and guide the selection of scalable outcome measures for natural history studies and interventional trials.

BackgroundThe Montreal Cognitive Assessment (MoCA) is a recommended brief screening tool to detect cognitive impairment in people with Parkinsons disease (PD). ObjectiveTo compare English and Bengali MoCA performance in Bangladeshi individuals with PD in East London. MethodsThis cross-sectional study involved participants completing both English and Bengali MoCA. Analyses included ANCOVA, paired and unpaired t-tests, and Bland-Altman methods in full and age-matched samples. ResultsFifty PD participants and 22 healthy controls (HC) were included in the full analysis. Both groups scored higher on Bengali than English MoCA (mean difference [~]4 points, p<0.001). Age-matched analyses (n= 29 PD and 22 HC) detected PD-control differences with the Bengali but not English version (p=0.02). Bengali scores aligned more closely with multidisciplinary assessments, though mean scores remained below normative cut-offs. ConclusionBengali MoCA improves detection of cognitive differences over English but still overestimates impairment, supporting the need for culturally adapted tools and population-specific cut-offs.

Cerebral small vessel diseases (CSVDs) are a group of disorders affecting the small arteries, veins, and capillaries supplying the white matter and deep grey matter structures. They are the most common form of cerebrovascular disease, accounting for almost half of vascular dementia cases worldwide and approximately 20% of stroke incidence. Whilst genetic testing is a routine diagnostic tool for monogenic CSVDs, less than 20% of patients have a causal variant in known CSVD genes. We performed whole exome sequencing on 117 patients suspected of monogenic CSVD that had previously tested negative for pathogenic variants in seven well-characterised CSVD genes (NOTCH3, HTRA1, COL4A1, COL4A2, TREX1, GLA, and FOXC1). Targeted analysis was conducted on known and associated CSVD genes as well as candidate genes causative of conditions with symptomatic overlap to CSVD. Burden analysis focusing on rare, functional variants was used to identify novel associations when compared against a cohort of 1035 non-neurological control samples. We identified 18 candidate disease-causing variants across nine CSVD-associated genes and a significant burden of rare and rare, likely disease-causing heterozygous variants in ABCC6. Two genes identified from stroke and neurodegenerative disease gene panels, MYH11 (adjusted P=1x10-2) and NOTCH1 (adjusted P=1x10-2), also had a significant burden of candidate disease-causing variants. Additionally, we identified novel associations for seven genes (COL7A1, HMCN1, LAMA1, MMP9, TENM4, TNC, TTN) with monogenic CSVD. Our findings implicate several genes as potentially causal of monogenic CSVD, highlighting the need for more extensive genetic screening in suspected CSVD cases and also functional characterisation of novel implicated variants to determine their mechanistic role in CSVD pathogenesis.