Stroke

Background: Storage symptoms after stroke-isolated urgency, urgency with frequency, and isolated frequency are common but traditionally attributed to a single overactive bladder mechanism via suprapontine disinhibition. However, clinical heterogeneity in symptom presentation suggests distinct underlying mechanisms. We aimed to characterize the neural substrates of three storage symptom subtypes after stroke using comprehensive lesion-symptom mapping. Methods: We prospectively evaluated 1,498 consecutive subacute stroke patients admitted for inpatient rehabilitation (1,105 men, 73.8%; median age 61 years). Storage symptoms were classified into three subtypes: isolated urgency (n=109), urgency with frequency (n=32), and isolated frequency (n=19). Multivariable logistic regression models with Bonferroni correction identified independent predictors across demographic, clinical, white matter hyperintensity (WMH), brain atrophy, and lesion location variables. Results: The three subtypes demonstrated largely distinct sets of independent predictors. The left genu of the corpus callosum (aOR=20.06, 95% CI 7.78-51.74, P<0.001) and the inferior frontal gyrus (aOR=3.48, 95% CI 1.81-6.67, P<0.001) were independently associated with isolated urgency and survived Bonferroni correction, together with a right IFG-insula synergistic effect (OR=21.46, 95% CI 10.49-43.88, P<0.001). Urgency with frequency was associated with a broad fronto-cingulate network-the IFG (aOR=11.45, 95% CI 3.10-42.33, P<0.001, surviving Bonferroni correction) and the ACC (aOR=11.53, 95% CI 2.40-55.49, P=0.002) with diffuse right-hemisphere dominance, older age and brain atrophy. Isolated frequency was associated with anterior corona radiata involvement (aOR=5.46, 95% CI 1.92-15.54, P=0.002) and male sex (aOR=10.62, 95% CI 1.36-82.98, P=0.024), though none reached the strict Bonferroni threshold. Conclusions: These findings identify three mechanistically distinct post-stroke storage symptom subtypes with separable neural substrates, lateralization profiles, and clinical determinants. The triple dissociation across subtypes supports a discrete pathway model over the traditional unitary OAB framework, providing a neuroanatomically grounded basis for subtype-stratified treatment Keywords: storage symptoms; subacute stroke; hemispheric lateralization; structural synergy; lesion-syndrome mapping

BACKGROUND: Subarachnoid hemorrhage (SAH) induces inflammatory responses and subsequent immune cell activation, which may contribute in cerebral vasospasm, microcirculatory impairment and poor neurological outcomes. Although cerebral vasospasm has traditionally been considered a major cause of delayed cerebral ischemia after SAH, therapies targeting angiographic vasospasm have not consistently improved functional outcomes. Early inflammatory responses may contribute to microcirculatory impairment, cerebral vasospasm, and subsequent neurological injury. Herein, we investigated whether interleukin-10 (IL-10), an anti-inflammatory cytokine, improves these outcomes in an experimental SAH model. METHODS: Mice received intramuscular injections of either an adeno-associated virus encoding IL-10 (AAV/IL-10) vector or an AAV expressing green fluorescent protein (AAV/GFP) vector (control). India ink angiography was performed to assess the diameter of the sphenoidal segment of the middle cerebral artery (MCA), the total length of the visible cortical arteries, and cortical staining intensity, as indices of cerebral vasospasm, microcirculatory impairment, and cerebral perfusion, respectively. Perivascular inflammatory cell infiltration and cytokine levels were assessed using immunohistochemistry and ELISA. We also evaluated the therapeutic efficacy of the AAV/IL-10 vector when administered immediately after SAH induction. RESULTS: IL-10 overexpression significantly improved neurological outcomes after SAH and was associated with attenuated cerebral vasospasm and microcirculatory impairment, as well as preservation of cerebral perfusion. It also significantly reduced neutrophil and macrophage infiltration around the internal carotid artery and attenuated SAH-induced elevations in IL-6 and matrix metalloproteinase-3 levels. Mice treated with the AAV/IL-10 vector immediately after SAH induction showed significant improvements in neurological scores and cerebral perfusion. CONCLUSIONS: AAV-mediated IL-10 overexpression improves neurological outcomes after SAH, likely by attenuating inflammatory responses, cerebral vasospasm, and microcirculatory impairment. These findings suggest that IL-10-based anti-inflammatory therapy is a promising therapeutic strategy for SAH.

Background: Evidence regarding delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains sparse. We aimed to identify its predictors and occurrence and evaluate its role in ischemic stroke and functional outcome under treatment with interventional rescue therapy (IRT). Methods: This retrospective single-center study included 628 adults with aSAH from 2014?2023. The primary endpoint was occurrence of refractory DCI (= refractory despite induced hypertension) treated with at least one IRT. Multivariable models evaluated refractory DCI, new ischemic stroke, and poor functional outcome (mRS 3?6) at 6?12 months. Results: Among 628 included patients, 61 who died within 3 days were excluded from DCI analysis; 166/567 (29%) developed refractory DCI. Younger age (OR = 0.98; P<0.001), female sex (OR = 0.57; P=0.007), and higher WFNS grade (OR = 1.18; P=0.011) were independently associated with refractory DCI. Earlier first IRT was associated with longer DCI duration (IRR = 0.88; P<0.001) and more required IRTs (IRR = 0.91; P<0.001). IRT was performed later than day 14 in 29/166 patients (17.5%); none was older than 70 years. Refractory DCI was associated with new ischemic stroke (OR = 4.68; P<0.001) and poor functional outcome (OR = 2.37; P<0.001); earlier first IRT was associated with poor outcome within the refractory DCI subgroup (OR = 0.86; P=0.03). Outcomes after 1?2 IRTs did not differ from those without refractory DCI (P=0.4), whereas ?3 IRTs were associated with poor outcome (P=0.04). Conclusions: Refractory DCI affected 29% of aSAH patients, predominantly younger women and patients with poorer initial neurological status, and extended beyond day 14 in nearly 20% of affected patients, none of whom was older than 70 years. Refractory DCI and earlier onset were associated with poorer radiological and functional outcomes. The absence of a detected outcome difference after 1?2 IRTs suggests that favorable outcomes may remain achievable despite refractory DCI.

Background: Aneurysmal subarachnoid haemorrhage (aSAH) is frequently complicated by delayed cerebral ischaemia (DCI), for which current therapies incompletely target the underlying multifactorial pathophysiology. Transauricular vagus nerve stimulation (taVNS) modulates inflammatory, vasoactive and autonomic pathways and may attenuate secondary brain injury after aSAH. Methods: We conducted a prospective, single-centre, single-blind, randomised, sham-controlled pilot trial in adults within 5 days of aneurysm securing for non-traumatic aSAH. Participants were allocated 1:1 to active taVNS (left tragus) or sham (left earlobe) using a portable device delivered for 45 minutes twice daily over 5 days. Primary outcomes were safety (taVNS-related serious adverse events), acceptability, and compliance; secondary outcomes included inflammatory biomarkers, DCI, in-hospital complications, and functional outcomes to 1 month. Results: Thirty patients were randomised (16 taVNS, 14 sham), with numerically more severe aSAH at baseline in the taVNS arm. No taVNS-related serious adverse events occurred; side effects were generally mild and transient, and over 80% of planned sessions were completed. TaVNS produced greater reductions in serum tumour necrosis factor- and trends towards reductions in interleukin-1{beta} and interleukin-10, with numerically fewer DCI events (6.6% vs 35.7%) and neurological impairments (16.7% vs 53.8%), although functional outcomes were not statistically different at 1 month. Conclusions: Early taVNS after aSAH is safe, acceptable, and feasible in the neurocritical care setting and shows biologically plausible signals warranting evaluation in larger multi-centre trials.

Background The time trend in long-term survival after a stroke is to some extent unknow due to (relatively) short follow up periods in available data. The objective of this study is to identify and quantify differences in long-term stroke survival in Sweden between men and women and patients with different attained educational levels, comparing two time-periods, 2000-2009 and 2010-2022. Methods This study employs total population Swedish register data pertaining to hospital-based care and mortality due to stroke for the period 2000-2022 in order to estimate survival (all-cause mortality) after ischaemic and haemorrhagic stroke, respectively, and pertaining to attained educational level. Kaplan-Meier survival functions are estimated stratifying for time-period, sex and educational level. Cox regressions are employed to quantify mortality hazard ratios between the strata. Age is taken into account in complementary analyses (supplement). Results Taking only time-period (2000-2009 vs 2010-2022) into account resulted in significantly higher survival in the second period for ischaemic stroke patients (HR: 0.84; 95% CI: 0.83-0.84), while no significant difference could be detected for haemorrhagic stroke. Stratifying for sex showed that men gained more than women in terms of reduced mortality hazard rate between the periods. Further stratifying by educational level and estimating survival separately for men and women showed that, for both men and women, patients with the lowest education were relatively worse off (compared to patients with higher education) in the second period. Further analyses, taking age into account, reversed the relative hazard ratio between men and women, but corroborated the result that low education is associated with poorer outcome than high education. Conclusions The results suggest that there are considerable differences in expected long-term survival after stroke between the sexes, but that this may be due to differences in age between the sexes at the time of stroke. Moreover, lower educational level is significantly associated with lower long-time survival.

We present our Stage-1 Registered Report as a full clinical trial article with all methods in past tense and including mock results, table and figures for the primary analysis. To remind the reader that this Stage-1 article is written before data collection, we highlight in color that these mock results are only for illustrative purposes and will be replaced by the actual results in the Stage-2 Registered Report. Background In patients experiencing out-of-hospital cardiac arrest, optimization of oxygen delivery during cardiopulmonary resuscitation is a critical. Although both positive end-expiratory pressure (PEEP) and zero end-expiratory pressure (ZEEP) are employed during CPR, their respective impacts on clinically relevant outcomes is yet to be clearly established. Methods This investigator-initiated, pragmatic, registry-based, multicenter, triple-blind randomized controlled superiority trial evaluates whether applying 8 cm H2O PEEP during cardiopulmonary resuscitation improves outcomes compared with ZEEP in adults with non-traumatic, non-drowning out-of-hospital cardiac arrest. Pre-randomized CPR kits (1:1 PEEP vs. sham) were used by ambulance sites during manual ventilation throughout the resuscitation process. The primary analysis was conducted in the principal stratum of patients who received either a supraglottic airway or endotracheal tube. The primary outcome was neurological status at hospital discharge measured by a utility-weighted score on the modified Rankin Scale. Secondary outcomes included prehospital return of spontaneous circulation, 30-day survival, and 6-month quality of life. The primary safety outcome was clinically significant pneumothorax.

Background: Atrial fibrillation detected after stroke (AFDAS) is frequently diagnosed after embolic stroke of undetermined source (ESUS) and has important implications for secondary stroke prevention. Although prediction scores have been proposed to identify patients at increased risk of AFDAS, prospective evidence supporting their implementation to guide rhythm monitoring in routine clinical practice is limited. Methods: In this prospective, population-based implementation cohort study, adults with ESUS were enrolled between January 2022 and December 2024 across all stroke centers in Styria, Austria. The Graz AF Risk Score was prospectively implemented as part of a risk-adapted diagnostic pathway for cardiac rhythm monitoring. Patients with a score [&ge;]4 were recommended for implantable loop recorder monitoring, whereas monitoring in those with scores <4 remained at the treating physician's discretion. The primary outcome was AFDAS detection; recurrent ischemic stroke and recurrent stroke etiology were secondary outcomes. Results: Among 784 patients (median age 73 years [IQR 64-80], 45.7% women), AFDAS was detected in 166 patients (21.2%) during a median follow-up of 26.3 months (IQR 20-34). AFDAS detection was substantially higher in patients with a Graz AF Risk Score [&ge;]4 than <4 (38.1% vs. 3.9%; p<0.001). After adjustment for age, sex and ILR monitoring, a score [&ge;]4 independently predicted AFDAS (HR 6.3, 95% CI 3.5-11.2; p<0.001) and recurrent ischemic stroke (HR 2.2, 95% CI 1.1-4.1; p=0.023). Only one recurrent stroke in patients with a score <4 was attributable to atrial fibrillation (AF) (1/18, 5.6%). Conclusions: Prospective implementation of the Graz AF Risk Score identified patients with ESUS at markedly different risks of AFDAS. A Graz AF Risk Score [&ge;]4 was also independently associated with recurrent ischemic stroke. These findings support a risk-adapted approach to cardiac rhythm monitoring after ESUS.

Background: The condition of a patient with acute stroke often changes within hours of ICU admission. Prognostic work here targets fixed endpoints predicted from admission data, and trajectory phenotyping assigns one label per patient. We used longitudinal ICU data to identify interpretable dynamic clinical states, characterize transitions between them, and relate the current state to later events. Methods: Retrospective cohort study of 6368 adults with acute stroke in MIMIC IV v3.1. The first 72 h were divided into twelve 6-hour windows, and a hidden Markov model was fitted to 21 neurological, physiological and organ support variables. State number was chosen against criteria fixed before fitting: statistical fit, restart stability, state occupancy and clinical interpretability. Generalized estimating equations related the current state to new mechanical ventilation and vasopressor use within 12 h, and to ICU death within 72 h. Eleven sensitivity analyses assessed the robustness of the state solution. Results: Four states were selected: neurologically preserved-low support, neurological impairment low support, impairment renal dysfunction and impairment-respiratory support (63.3%, 7.8%, 11.8% and 17.1% of windows). Within 72 h, 40.3% of patients changed state at least once, and transitions ran in both directions rather than along a single severity gradient. States were identified without outcome data, yet ICU mortality by last state ranged from 2.9% to 43.9%. Adjusted for age, sex, subtype and Charlson index, the current state remained associated with organ-support escalation and death. State prevalence differed by at most 1.1 percentage points between training and test sets, and 10 of 11 sensitivity analyses gave a stable four-state solution (ARI 0.754 0.955). Conclusions: The early ICU course of acute stroke can be represented as movement among a small number of clinically interpretable states. The representation was reproducible in a held out set and across admission eras, but requires validation in an independent database before any clinical use.

BACKGROUND The optimal antiplatelet regimen in patients with acute coronary syndrome (ACS) and multivessel disease undergoing drug-coated balloon (DCB) angioplasty remains unclear. METHODS This was a prespecified subgroup analysis of the REC-CAGEFREE II trial, which was conducted at 41 sites in China and randomized 1948 exclusively DCB-treated participants with ACS to stepwise dual antiplatelet therapy (DAPT) de-escalation or standard DAPT. The primary endpoint was net adverse clinical events (NACE; including all-cause death, stroke, myocardial infarction, revascularization, and BARC type 3 or 5 bleeding) at 12 months. Participants were stratified into multivessel and single-vessel subgroups according to angiographic characteristics. RESULTS Overall, 720/1948 (37.0%) patients had multivessel disease. The multivessel subgroup was associated with a significantly higher risk of NACE compared with the single-vessel subgroup (12.5% versus 6.7%, HR IPTW:1.84, 95%CI:1.35-2.51, P<0.001). No significant interaction was observed between vessel status (multivessel or single-vessel) and treatment allocation with respect to NACE (Pinteraction=0.542). In the multivessel subgroup, NACE occurred in 44/368 (12.1%) and 45/352 (12.9%) in the stepwise de-escalation and standard DAPT groups (HR IPTW:0.95, 95%CI:0.62-1.75, P=0.818), respectively. In the single-vessel subgroup, NACE occurred in 43/607 (7.1%) and 39/621 (6.3%) in the stepwise de-escalation and standard groups (HR IPTW:1.12, 95%CI:0.72-1.70, P=0.611), respectively. For the prespecified hierarchical secondary endpoint, win ratio analyses yielded more wins for stepwise de-escalation in both subgroups. CONCLUSIONS Among patients with ACS undergoing DCB-only angioplasty, those with multivessel disease were associated with a higher risk of NACE than those with single-vessel disease. Stepwise DAPT de-escalation and standard DAPT exhibited similar risk-benefit profiles in both subgroups.

BACKGROUND: Cerebral ischemia following subarachnoid hemorrhage (SAH) has traditionally been considered transient because functional alterations of the cerebral microcirculation are thought to be self-limiting. However, we identified a previously unrecognized vasculopathy, perivascular fibrosis of the cerebral microcirculation (PFCM), characterized by excessive type I collagen deposition after SAH. This study investigated the mechanisms underlying PFCM and its subsequent effects on cerebral hemodynamics. METHODS: In vivo SAH was modeled in mice by autologous blood injection, whereas oxygenated hemoglobin (OxyHb) exposure was used to mimic SAH in vitro. Pericyte-deficient mice (Pdgfr{beta}+/-) and pericyte-specific vestigial-like family member 3 (VGLL3) conditional knockout mice (Vgll3{Delta}PC) were generated. Pericyte contractility was measured by nanoindentation and traction force microscopy. Molecular mechanisms were examined using Western blotting, immunofluorescence, CUT&Tag, RNA-seq, transmission electron microscopy, and molecular docking. PFCM, impaired dilation of the cerebral microcirculation, and cerebral autoregulation were assessed by two-photon imaging, transcranial Doppler with continuous blood pressure monitoring, super-resolution ultrasound imaging, and photoacoustic imaging. RESULTS: After SAH, mice developed long-term cerebral autoregulation dysfunction marked by impaired dilation of the cerebral microcirculation, with the abnormality being most evident within the relatively lower blood pressure range. The marked reduction in PFCM in Pdgfr{beta}+/- mice indicated that pericytes were the principal cellular contributors. Mechanistically, OxyHb-induced cytoskeletal remodeling in vitro increased pericyte contractility and promoted nuclear translocation of SAH-upregulated VGLL3. This was followed by increased genomic occupancy, Col1a1 transcriptional activation, and type I collagen deposition. Pericyte-specific VGLL3 knockout abolished PFCM and, consequently, significantly alleviated long-term cerebral autoregulation dysfunction. CONCLUSIONS: Our findings identify PFCM mediated by pericytic VGLL3 as a novel vasculopathy leading to long-term cerebral autoregulation dysfunction after SAH.

Background: Unruptured intracranial aneurysms (UIAs) are increasingly identified incidentally, and management balances rupture risk against treatment risk. UIA diagnosis has been linked to psychological distress, but psychotropic medication initiation after UIA discovery has not been compared across the full UIA management spectrum. Methods: We conducted a retrospective cohort study using IBM MarketScan claims (CCAE, MDCD, and MDCR; 2009-2023) among adults with a UIA diagnosis, continuous enrollment for 365 days before and after the index date, and no SAH/rupture on or before the index date. We compared the prevalence of 6 mental-health diagnoses before versus after UIA discovery and used adjusted logistic regression to examine psychotropic medication initiation within 365 days by management strategy (untreated observation as the reference). Results: Among 54,945 patients (untreated, 78.5%; endovascular, 11.3%; clipping, 3.0%; other/uncertain, 7.2%), prevalence of every mental-health diagnosis was higher after UIA discovery, most for depression (+4.6 percentage points) and anxiety (+4.5 points). Medication initiation was most common for benzodiazepines (8.7%). Endovascular treatment was associated with higher adjusted odds of benzodiazepine (aOR, 1.21), SSRI (aOR, 1.20), and sedative-hypnotic (aOR, 1.25) initiation.Surgical clipping demonstrated the broadest association, with higher odds across 5 of 6 classes, including benzodiazepines (aOR, 1.71) and sedative-hypnotics (aOR, 1.86). Benzodiazepines had the lowest 1-year persistence (10.5%) despite being the most commonly initiated class. Findings were consistent across sensitivity analyses, with the exception of the increase in panic disorder, which was no longer observed after applying a 30-day post-index lag. Conclusions: Mental-health diagnoses and psychotropic medication initiation increased after UIA discovery, and medication initiation was most pronounced among patients treated with surgical clipping. These findings support psychological assessment as part of aneurysm management regardless of strategy.

Background: The relative merits of infrainguinal bypass and primary major lower limb amputation (MLLA) for chronic limb-threatening ischaemia (CLTI) remain uncertain, and the baseline profiles of patients selected for each strategy are poorly described. Methods: A systematic review and meta-analysis were undertaken in accordance with PRISMA 2020 and prospectively registered (PROSPERO: CRD42022356094). MEDLINE, Embase, CENTRAL, and CINAHL were searched from inception to March 2025. Prospective studies of adults with CLTI undergoing primary infrainguinal bypass or primary MLLA were eligible. Mortality, major adverse cardiovascular events (MACE) and subsequent amputation outcomes were synthesised using random-effects meta-analysis of proportions. Baseline comorbidity profiles were also extracted. Results: Twenty-seven studies involving 6,576 patients were included: 5,779 underwent infrainguinal bypass and 797 underwent MLLA. After bypass, pooled mortality was 3.7% at 30 days (95% CI 2.8%-4.9%, I2 = 49.4%), 18.5% at 1 year (95% CI 15.6%-21.9%, I2 = 62.3%), and 54.3% at 5 years (95% CI 50.5%-58.0%, I2 = 0%). After MLLA, pooled mortality was 9.2% at 30 days (95% CI 4.1%-19.3%, I2 = 73.5%), 28.5% at 1 year (95% CI 13.3%-51.0, I2 = 70.8%), and 39.9% at 2 years (95% CI 0.3%-99.3, I2 = 90.5%), although longer-term estimates were limited by sparse data and marked heterogeneity. Thirty-day MACE was 6.5% (95% CI 4.3%-9.7, I2 = 63.5%) after bypass and 2.8% after MLLA (95% CI 0.1%-37.6%, I2 = 0%). Early subsequent major amputation after bypass occurred in 3.9% of patients (95% CI 2.0%-7.7%, I2 = 91.2%), rising to 16.2% at 1 year (95% CI 12.6%-20.5%, I2 = 82.0%) and 33.3% at 3 years (95% CI 20.1%-49.8%, I2 = 0%). Early re-amputation after MLLA occurred in 10.9% of patients (95% CI 4.5%-24.4%, I2 = 40.3%). Baseline comorbidity burden was high in both groups, with substantial heterogeneity across studies. Conclusions: CLTI carries a poor prognosis regardless of treatment strategy. Infrainguinal bypass is associated with lower early mortality and better early limb preservation than primary MLLA, but long-term survival remains poor and later limb failure is common. Primary MLLA is not a low-risk alternative. Better contemporary comparative evidence utilising modern causal inference approaches is needed to support individualised decision-making.

Purpose. Prognostic assessments after acute brain injury are largely narrative, and how prognostic language relates to subsequent care has not been measured at scale. We quantified where it is written and its association with a subsequent code-status limitation. Materials and Methods. Multidatabase observational study of adults with acute brain injury or a related neurologic emergency, using MIMIC-IV (2008-2019; discharge summaries and radiology reports) and a timestamped MIMIC-III cohort (notes and code-status orders). The exposure was documented prognostic language; outcomes were its association with a subsequent full-code-to-limitation transition, note-stream location, and completeness of documented command-following relative to structured Glasgow Coma Scale (GCS) motor scores. Results. Among 31,993 admissions (27,054 patients; median age, 69 years; 54.9% male), prognostic language in the timestamped cohort (MIMIC-III) was associated with a subsequent code-status limitation after multivariable adjustment (adjusted hazard ratio, 4.3; 95% CI, 2.9-6.5; unadjusted 14-day cumulative incidence, 40% vs 8.5%), including the comfort-measures component (3.9), a higher-risk subgroup (4.4), and after acute-physiology adjustment (4.1); the association was concentrated in the first 3 days. Non-prognostic severity language showed no comparable association (hazard ratios, 1.1-1.3). Prognostic language localized almost entirely to the narrative (4.9% of discharge summaries vs 0.015% of radiology reports); command-following was undocumented in 55.7% of summaries, and no final-24-hour GCS motor score was charted in 72.8%. Conclusions. Documented prognostic language after acute brain injury was written in the narrative, not structured fields, and was associated with a subsequent code-status limitation after multivariable adjustment. This observational association cannot establish causation but warrants prospective study.

Background and Objectives: Recurrence following burr-hole drainage of chronic subdural haematoma (cSDH) occurs in 10-25% of cases, sustained by neovascularisation of the subdural neomembrane supplied by the middle meningeal artery (MMA). MMA embolisation reduces recurrence; whether incidental burr-hole intersection of MMA branches during drainage confers similar benefit is unknown. Methods: We performed a multicentre retrospective cohort study of consecutive adults undergoing burr-hole drainage for cSDH at two UK tertiary neurosurgical centres. Postoperative thin-slice CT was used to classify burr-hole intersection of the underlying MMA groove (no hit, distal-branch hit or main-branch hit) and measure perpendicular burr-hole-to-MMA-groove distance. Co-primary outcomes were radiological recurrence and recurrence requiring intervention. Patient-clustered multivariable logistic regression adjusted for prespecified clinical covariates and treating site. Results: 227 patients (284 operated hemispheres) were included. Radiological recurrence decreased from 34.4% with no branch hit to 22.9% with main-branch intersection, with the gradient confined predominantly to unilateral cSDH. Main-branch intersection was associated with lower adjusted odds of radiological recurrence in unilateral cSDH (adjusted OR 0.30, 95% CI 0.11- 0.81; P = .018), with a similar but non-significant association in the overall cohort (adjusted OR 0.53, 95% CI 0.26-1.07; P = .075). Burr-hole-to-MMA-groove distance demonstrated a more consistent association: in the overall cohort, each 5-mm increase independently increased the odds of radiological recurrence (adjusted OR 1.38, 95% CI 1.04-1.82; P = .025). In unilateral cSDH, each 5-mm increase was independently associated with both radiological recurrence (adjusted OR 1.45, 95% CI 1.03-2.04; P = .034) and recurrence requiring intervention (adjusted OR 1.52, 95% CI 1.05-2.20; P = .027). Conclusion: Main-branch intersection of the middle meningeal artery during routine burr-hole surgery is associated with lower recurrence of unilateral cSDH, while the accompanying burr-hole-to-MMA-groove distance gradient provides biologically plausible support for a dose-response relationship. Together, these findings provide mechanistic rationale for prospective evaluation of intentional neuronavigation-guided MMA targeting (BURR-MMA; NCT07549893).

Background: Aerobic exercise is recommended during stroke rehabilitation to improve cardiorespiratory fitness and support recovery; however, participation rates remain low. While institutional and system-level barriers have been widely examined, less is known about how individual patient factors influence engagement in aerobic exercise during rehabilitation. Objectives: We aimed to determine whether depressive symptoms, apathy, self-efficacy and outcome expectations for exercise, perceived barriers, or past exercise history were associated with aerobic exercise participation in stroke rehabilitation. Methods: In this prospective cohort sub-study, adults admitted to in- or out-patient stroke rehabilitation at three urban hospitals completed validated questionnaires assessing depressive symptoms, apathy, exercise self-efficacy, outcome expectations for exercise, perceived barriers to being active, and premorbid exercise history. Participants were separated into two groups for analysis: those who completed aerobic exercise during rehabilitation and those who did not. Equivalence testing and between-group comparisons were performed. Results: Sixty-two participants were enrolled; 16 participated in aerobic exercise and 46 did not. Groups were not equivalent on any individual-level factors. Compared to non-participants, those who performed aerobic exercise had significantly higher depressive symptom scores (p=0.0025) and lower self-efficacy for exercise (p=0.0087). Non-participants demonstrated significantly higher apathy (p=0.0007). No significant differences were found for outcome expectations, perceived barriers, or exercise history. Conclusion: Depressive symptoms and lower self-efficacy did not impede aerobic exercise participation during rehabilitation. Increased apathy, however, was associated with non-participation. Findings highlight the need for individually tailored aerobic exercise prescriptions that consider motivational and affective factors to optimize engagement during stroke rehabilitation.

Background Mirror therapy (MT)-specifically paradigms using mirror visual feedback (MVF)-is widely used in neurorehabilitation; however, mechanistic implementations vary substantially in movement content, rhythmicity and attentional demands. This protocol describes an acute mechanistic, within-participant fNIRS screening study designed to compare three prespecified upper-limb mirror-therapy task paradigms and to quantify associated subjective experience after each condition in healthy adults during a single visit. Methods and analysis This is a single-centre, within-participant, randomised crossover study conducted at Wuhan Wuchang Hospital (Wuhan, China). Healthy adults aged 18-35 years will complete three task conditions once each in a counterbalanced order using a 3*3 Latin-square scheme: UMT1 (task-oriented rhythmic functional movement), UMT2 (open-ended free movement with auditory control), and UMT3 (non-functional rhythmic movement). fNIRS will be acquired using the NirSmart-6000A system during a standardised block design. The primary outcome is ROI-level HbO activation quantified as GLM-derived {beta} estimates within the prespecified primary ROIs (bilateral SM1/M1 and bilateral PMC). Secondary outcomes include ROI-level windowed {Delta}HbO (5-20 s post-onset relative to the immediately preceding rest; descriptive only), ROI-level {Delta}HbR, and post-condition subjective ratings (illusion, immersion, confusion and fatigue; 1-7 Likert). Condition effects will be analysed using linear mixed-effects models with fixed effects for condition and period and prespecified multiplicity-adjusted pairwise contrasts. Ethics and dissemination Ethics approval was obtained from the Ethics Committee of Wuchang Hospital Affiliated to Wuhan University of Science and Technology (Approval No.: 2025-112-01; approved on 2025-08-21). The study is expected to be minimal risk. Findings will be disseminated through publication of this protocol manuscript and subsequent results manuscripts and conference presentations. Trial registration number Chinese Clinical Trial Registry (ChiCTR2600116634). This study is conducted as a prespecified mechanistic sub-study under the overarching registered project.

Background: Serial glial fibrillary acidic protein (GFAP) trajectories have become an important framework for contextualizing evolving secondary-injury pathophysiology after moderate-to-severe traumatic brain injury (msTBI). However, total GFAP pools release and clearance signals that may be less useful for longitudinal bedside decisions than a proteoform-resolved assay. We compared total GFAP with neoGFAP, defined here as calpain-generated GFAP proteoforms intended to index active astroglial proteolysis during the subacute phase. Methods: We analyzed 651 serial serum samples from 95 msTBI patients from a previously described single-site cohort. Total GFAP and neoGFAP were measured on the same MSD platform from 6 to 240 hours after injury. Early (6 to 72 h) and late (96 to 240 h) windows, data-derived tertiles, and serial trajectory summaries were calculated directly from serial samples. Models were benchmarked against age plus admission post-resuscitation Glasgow Coma Scale (GCS) and the admission IMPACT extended risk score using five-fold stratified cross-validation. Outcomes were unfavorable outcome (GOSE 1 to 4), less-than-good recovery (GOSE 1 to 6), Disability Rating Scale (DRS) [&ge;]15, mortality, and neuroimaging worsening at 6 months. Results: The cohort contributed 95 serial biomarker profiles, with 90 participants evaluable for 6-month GOSE and 89 for DRS. Unfavorable outcome occurred in 57/90 (63.3%), and less-than-good recovery in 79/90 (87.8%). For unfavorable outcome, IMPACT plus early neoGFAP reached AUROC 0.85 versus 0.84 for IMPACT plus early total GFAP and 0.81 for IMPACT alone. For less-than-good recovery, IMPACT plus late neoGFAP achieved AUROC 0.90 versus 0.84 for late total GFAP and 0.82 for IMPACT alone. Secondary analyses for DRS, mortality, and neuroimaging worsening showed smaller differences. Conclusions: In this retrospective analysis, neoGFAP provided clearer incremental value than total GFAP for recovery-oriented monitoring, especially when late-window reassessment of patients who remained at risk for less-than-good recovery was required. Results support prospective testing of neoGFAP as a pathophysiology-informed adjunct to serial bedside decision making, repeat-assessment thresholds, and recovery stratification.

BACKGROUND People with type 2 diabetes mellitus (T2DM) are at higher risk of cerebral small vessel disease and left ventricular hypertrophy (LVH), potentially contributing to cognitive decline and dementia. We aimed to describe brain volume and cognitive trajectories over 2 years in a cohort of people with T2DM and to determine whether LVH causes increased brain atrophy and cognitive decline. METHODS Diabetes and Dementia (D2) study is a multicentre observational cohort study in Melbourne, Australia. Participants aged >50 years were recruited via 2 hospital outpatient clinics, 3 private clinics, and study advertisements. Participants with pre-existing cognitive impairment, life-limiting medical illness, and severe chronic renal impairment were excluded. Participants attended study visits for brain MRI, transthoracic echocardiography (TTE), and cognitive testing at baseline and 2 years. The exposure was LVH determined on baseline TTE. Pre-specified outcomes were total brain volume (TBV) change and cognitive decline (z-score change?-1 in any cognitive domain) over 2 years. Regression analyses examined associations between baseline variables and outcomes. A causal inference approach was utilized using inverse probability of treatment weighting to standardize for confounding covariates, excluding participants for non-positivity on age and baseline TBV. RESULTS Participants were recruited 20May2016 to 20March2020: 2378 screened, 702 eligible, 196 consented, 150 baseline and 123 2-year assessments with complete MRI, TTE, and cognitive data (17.4% attrition). At baseline, LVH was associated with female sex, older age, lower educational attainment, lower mood, hypertension, obesity, beta-blocker use, and smaller TBV. Participants with baseline cognitive impairment exhibited greater brain atrophy. Lower educational attainment, hypertension, and lower baseline cognitive scores were associated with cognitive decline. Causal inference analysis included 62 participants with no LVH (20(32%) women; mean [SD]=66.9[5.9] years), and 31 with LVH (17(55%) women, 67.4[5.4] years). LVH caused lower TBV change: standardized mean difference (95% CI) 6.3 (0.1, 12.5) cm3, P=.048. LVH had no effect on cognitive decline. CONCLUSIONS Brain atrophy and cognitive decline were associated with baseline cognitive impairment. LVH caused less brain atrophy and cognitive decline in people with T2DM. We conclude that guideline-directed LVH therapies such as beta-blockers have both cardioprotective (remodelling) and neuroprotective effects. TRIAL REGISTRATION ACTRN12616000546459 UTN: U1111-1181-6659

Stroke remains a leading cause of mortality and long-term disability worldwide, yet rapid diagnosis is often limited by the shortage of trained radiologists, particularly in resource-constrained settings. Automated analysis of CT imaging offers a potential solution, but existing methods often struggle to achieve clinically generalisable performance while jointly addressing multiple diagnostic tasks. Here we present the Intelligent Integrated Stroke Diagnosis System IISDS, an end-to-end deep learning framework built upon StrokeGNN, a graph-based architecture that integrates 3D contextual feature extraction with U-Net-based 2D lesion segmentation to enable comprehensive stroke analysis from non-contrast CT scans. IISDS performs stroke subtype classification, lesion segmentation and lesion volume estimation within a unified pipeline. To develop and validate the system, we collected and curated BGD-ISD through a collaboration between AI researchers, neurologists, radiologists and clinicians, resulting in a large multi-centre dataset comprising 1,507 CT scans from 597 stroke cases acquired across six hospitals and medical centres in Bangladesh. Across BGD-ISD and multiple publicly available datasets, IISDS achieves state-of-the-art performance on all tasks, improving segmentation accuracy by [&ge;]0.011 Dice score, reducing lesion volume estimation error by [&ge;]0.3 average symmetric surface distance (ASSD), and increasing classification performance by [&ge;]0.018 area under the receiver operating characteristic curve (AUC) compared with existing approaches. These results demonstrate the potential of graph-based deep learning to enable clinically generalisable, automated and scalable stroke diagnosis from CT imaging, supporting rapid clinical decision-making, particularly in healthcare environments with limited access to expert radiological interpretation.

Background: The Boston Criteria v2.0 represent the gold standard for diagnosing Cerebral Amyloid Angiopathy (CAA), but their application is currently precluded in mixed small vessel disease (SVD), where deep and lobar hemorrhages coexist. The aims of this study are: (i) to determine which cerebrospinal fluid (CSF) biomarker (A{beta}42, A{beta}40, A{beta}42/40 ratio) is the best candidate to support the CAA diagnosis; (ii) to define a data-driven cut-off, and (iii) to explore if a biomarker-integrated classification significantly improves the phenotypical concordance with the suspected predominant SVD (CAA vs. arteriosclerosis). Methods: We analyzed data from a retrospective multicenter cohort of patients with suspected CAA, defined as probable CAA (Boston criteria v2.0) but allowing deep hemorrhagic lesions, and with available CSF biomarkers. We visually quantified MRI-visible SVD markers (e.g., cerebral microbleeds [CMB], cortical superficial siderosis [cSS], lacunes) and their association with MRI-visible SVD features. We employed a Gaussian Mixture Model (GMM) to identify a data-driven threshold for amyloid positivity (A+). Then, we compared the prevalence of MRI-visible manifestations of SVD between subgroups applying different frameworks, namely the current MRI-based classification (probable CAA vs. mixed SVD) and a CSF biomarker-integrated classification (A+ vs. A-). Results: We enrolled 121 patients (age: 72 [66-77] years; 60% probable CAA, 40% mixed SVD with suspected CAA). The CSF A{beta}42/40 ratio showed a bimodal distribution and consistent associations with all CAA-specific radiological features. The CSF biomarker-integrated reclassification, particularly using the GMM cut-off, significantly improved the distinction between subgroups regarding CAA- and arteriosclerosis-related MRI features (e.g., cSS presence: probable CAA vs. mixed SVD: aOR=2.84 [95%CI 1.27-6.39], p=0.011; A+ vs. A-: aOR=12.68 [95%CI 4.31-37.32], p<0.001; deep lacunes presence: probable CAA vs. mixed SVD: aOR=0.20 [95%CI 0.08-0.50], p<0.001; A+ vs. A-: aOR=0.04 [95%CI 0.01-0.11], p<0.001). Notably, patients classified as A+ never demonstrated more than four deep CMBs. Discussion: A CSF biomarker-integrated classification may improve the classification of CAA compared with the current MRI-based framework. These findings are cohort-specific and would benefit from further validation, especially with a neuropathological reference. Still, these results support a future transition toward an integrated biological-radiological framework, which may refine in vivo CAA diagnosis, particularly in mixed SVD.