Falls are a frequent and serious complication after stroke, affecting more than 30% of survivors within the first year. While age and comorbidities are established risk factors for falls, stroke-specific contributors—particularly lesion-related impairments in mobility and gait—are less well understood and may inform targeted secondary prevention. We analyzed data from 94 patients with disabling subacute ischemic stroke enrolled in the prospective BAPTISe cohort, a predefined imaging and biomarker sub-cohort of the multicenter PHYS-STROKE trial. Detailed gait and mobility assessments were performed at baseline. Principal component (PC) analysis reduced seven mobility-related and four gait-related variables into two composite scores: PC1-Mobility and PC1-Gait, explaining 56% and 82% of variance, respectively. PC1-Mobility reflected global disability and functional mobility in daily life, whereas PC1-Gait captured spatiotemporal walking capacity and efficiency. Lesion network mapping (LNM) using a normative connectome identified functional networks associated with each domain. Patient-reported falls up to six months post-enrollment were the primary endpoint. LNM of PC1-Mobility revealed a predominantly cortical network involving pre- and postcentral gyri, superior and middle frontal gyri, and sensorimotor integration areas. In contrast, PC1-Gait was associated with subcortical and infratentorial connectivity, including bilateral thalamus, brainstem, and cerebellum. In multivariable regression, network similarity scores were not independently associated with falls; only older age was significant (adjusted OR1.08, 95%CI1.02–1.15,p=0.013). LNM of fall occurrence showed a cortical network with significant spatial overlap with the PC1-Mobility network(p<0.001). This exploratory, hypothesis-generating study identified distinct lesion-derived functional networks associated with post-stroke mobility and gait impairment. Our findings suggest that falls may be more closely linked to disruptions in cortical networks involved in voluntary motor control and whole-body coordination, rather than subcortical structures primarily modulating gait. These results provide a foundation for future research aimed at improving fall risk stratification and targeted prevention strategies in stroke survivors.

BACKGROUND:Cerebral small vessel disease (CSVD) is a common incidental MRI finding in patients with transient ischemic attack (TIA) and stroke and has been linked to cognitive decline. This study investigated the prevalence of CSVD imaging biomarkers in TIA patients and their association with cognitive performance over 3 years. METHODS:We included 246 TIA patients from the INSPiRE-TMS study (ClinicalTrials.gov: NCT01586702). CSVD was assessed on baseline 3 T MRI using a composite score (0-4) including white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (PVS). Cognitive performance was evaluated using the Montreal Cognitive Assessment (MoCA) at baseline and annually for 3 years. RESULTS:At least one CSVD imaging biomarker was present in 58.5% of patients. Lacunes (36.6%) were the most common, followed by PVS (28.1%), WMH (19.5%), and CMBs (17.9%). Higher CSVD-score was independently associated with greater cognitive decline over 3 years (β = -0.52, 95% CI -0.95- -0.08, p = 0.020), along with older age (β = -0.08, 95% CI -0.13 to -0.03, p = 0.001). CMB burden was the strongest predictive component of the CSVD-score (β = 0.42, 95% CI -0.63 to -0.22, p < 0.001). CSVD-score was particularly associated with decline in the memory domain (adjusted β of -0.18, 95% CI -0.32 to -0.04, p = 0.015). CONCLUSION:CSVD imaging markers are present in over half of TIA patients and are independently associated with cognitive decline up to 3 years, with the strongest effect on memory. Whether the presence of CMBs is the strongest predictive imaging biomarker of cognitive decline in TIA patients requires confirmation in further studies.

Abstract Background and aims This retrospective pooled analysis evaluated the longitudinal association between total cerebral small vessel disease (CSVD) burden, its neuroimaging biomarkers, and post-stroke cognitive trajectory over three years. We sought to define the differential prognostic roles of individual CSVD markers on global and domain-specific cognition. Methods Data were analyzed from 1,376 participants (67.88% with CSVD) across two independent, prospective stroke cohorts (PROSCIS-B and INSPIRE-TMS). CSVD markers were systematically assessed on baseline MRI, these included white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMB), and enlarged perivascular spaces (PVS). Cognitive performance was measured annually for three years using standardized screening tools (MoCA, MMSE, or TICS). Longitudinal associations between CSVD severity (score 1-4) and cognition were assessed using mixed-effects regression models. Results CSVD severity was significantly correlated with progressive deterioration in global cognition over 3 years (ß = -0.19; p = 0.03). WMH severity emerged as an independent predictor of poorer overall cognitive performance (ß = -0.09; p < 0.01). Domain-specific analysis further revealed that lacunes were significantly associated with impaired attention performance (p = 0.02), while WMH burden correlated with diminished naming performance (p = 0.02). Conclusions These findings support the hypothesis that CSVD severity is predictive of progressive cognitive decline following ischemic stroke. Interestingly, WMH burden emerged as the strongest predictor of post-stroke cognitive decline while different CSVD MRI biomarkers seem to have differential effect on different cognitive subdomains. Taken together, these findings support the integration of MRI-based CSVD assessment for optimizing cognitive risk stratification in stroke survivors. Conflict of interest Huma Fatima Ali is a MD/PhD student in International Graduate Program of Medical Neurosciences and associated fellow at Einstein Center of Neurosciences, Charite Universitätsmedizin Berlin, Germany. Matthias Endres reports on grants from Bayer and Ipsen and fees paid to the Charité from Amgen, AstraZeneca, Bayer Healthcare, BMS, Daiichi Sankyo, all outside the submitted work. Heinrich Audebert reports on grants from Pfizer within the submitted word and fees paid from AstraZeneca, Bayer Healthcare, BMS, Boehringer Ingelheim, Novartis, Novo-Nordisk and Pfizer, all outside the submitted work.

BACKGROUND:Neutrophil granulocytes actively contribute to tissue damage after ischemic stroke. The membrane protein CD177 is detectable on variable neutrophil numbers in most individuals (CD177 wild-type [CD177WT] genotype), whereas ≈5% of the general population completely lack CD177 (CD177-deficient [CD177null] genotype). Despite its known relevance in vasculitis, the role of ischemic stroke remains unknown. METHODS:In 2 prospective cohorts of patients with first-ever ischemic stroke (PROSCIS-B [Prospective Cohort With Incident Stroke Berlin], NOFF-S [Neutrophils: Origin, Fate & Function Stroke]), we assessed the effect of CD177null and CD177WT status on stroke severity and outcome (National Institutes of Health Stroke Scale and modified Rankin Scale) over 1 year or 3 months poststroke, respectively. By flow cytometry, we stratified CD177 expression level as CD177neg, CD177dim, and CD177high. The predictive value of the CD177 state was evaluated by multivariable regression and discrimination analyses. RESULTS:In PROSCIS-B (n=579; mean age, 68.1 years; 38.5% women) and NOFF-S (n=236, 68.4 years, 36.9% women), similar rates of patients were CD177null (n=26 [4.5%] and n=10 [4.2%], respectively). Patients with CD177null had a higher probability of unfavorable stroke outcome (modified Rankin Scale score 3-6) than patients with CD177WT (n=8 of 21 [38.1%] versus 90 of 462 [19.5%] with follow-up, P=0.05, in PROSCIS-B; n=8 of 10 [80.0%] versus n=23 of 142 [16.2%] with follow-up, P<0.0001, in NOFF-S). This association remained when adjusted for age, sex, initial stroke severity defined by National Institutes of Health Stroke Scale score, stroke subtype defined by TOAST (Trial of ORG 10172 in Acute Stroke Treatment), and reperfusion treatment (risk ratio, 3.8 [95% CI, 2.0-7.1]; P<0.001, in NOFF-S). In NOFF-S, the proportion of CD177dim neutrophils at admission was negatively associated with stroke severity at admission, while that of CD177high neutrophils predicted a favorable clinical outcome after 3 months. CD177 expression level significantly improved the prediction of stroke outcome in addition to clinical adjustment variables in area under the curve, net reclassification improvement, and integrated discrimination improvement analyses (P=0.004, P=0.001, and P<0.001, respectively, for CD177high). CONCLUSIONS:CD177 expression at admission is an easy-to-measure biomarker for patient stratification. CD177 holds potential as a therapeutic target to modulate immune responses after stroke. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856.

BACKGROUND:Falls affect over 30% of stroke survivors within the first year, yet lesion-related mobility and gait impairments underlying fall risk remain poorly understood. This study aimed to identify lesion-derived functional networks associated with impaired mobility, gait, and fall risk in subacute stroke, and to determine whether disruption to these networks is associated with falls during the six-month follow-up. METHODS:We analyzed data from 94 patients with disabling subacute ischemic stroke from the prospective Baptize cohort, an imaging sub-cohort of the multicenter PHYS-STROKE trial. Principal component (PC) analysis reduced seven mobility-related and four gait-related baseline variables into two composites: PC1-Mobility and PC1-Gait, explaining 56% and 82% of variance, respectively. PC1-Mobility indexed global disability, whereas PC1-Gait reflected spatiotemporal walking capacity. Lesion network mapping (LNM) identified functional networks associated with each domain. Patient-reported falls up to six months post-enrollment were the primary endpoint. RESULTS:LNM revealed that the mobility-related network predominantly involved cortical regions, whereas the gait-related network was linked to subcortical and infratentorial connectivity. In binary multivariable logistic regression, network similarity scores were not associated with falls; only older age was significant (adjusted OR 1.08, 95% CI 1.02-1.16, p = 0.01). LNM of fall occurrence identified a cortical network with significant spatial overlap with the mobility-related network (p < 0.001). CONCLUSION:This exploratory, hypothesis-generating study identified distinct functional networks for post-stroke mobility and gait impairment. Falls may be more closely linked to disruptions in cortical networks supporting voluntary motor control and whole-body coordination than to subcortical gait-modulating structures, potentially informing fall risk stratification and targeted prevention. TRIAL REGISTRATION:ClinicalTrials.gov identifiers: BAPTISe: NCT01954797, PHYS-STROKE: NCT01363856.

Introduction Following a cerebrovascular event, the associated risks for further major adverse cerebro- and cardiovascular events and death (MACE) and important aspects of cognitive, mental and patient-reported outcomes are currently not understood, particularly long-term. Here, we present the study design of the ongoing Berlin Long-term Observation of Vascular Events (BeLOVE) stroke stratum and report data of the first study phase.Methods and analysis BeLOVE is a prospective, longitudinal, observational, hospital-based cohort study. Its stroke stratum enrols adult patients with acute ischaemic stroke, transient ischaemic attack (TIA) or non-traumatic intracerebral haemorrhage. Patients undergo deep phenotyping including cerebral and cardiac MRI, ECG, echocardiography and bio-sampling including multi-omics analyses. Regular, standardised follow-ups take place annually over a period of up to 10 years and record the frequency of MACE as the primary outcome.Secondary outcomes include the frequency, progression and interactions of functional impairments, namely post-stroke cognition, pain, depression, seizures and their relationship to quality of life.The first study phase included 758 patients (median 69 years, 37% female). At 2-year follow-up, the cumulative incidence (95% CI) of the composite primary endpoint MACE was 0.107 (0.085 to 0.132) and that of first ischaemic stroke, first myocardial infarction and death were 0.066 (0.049 to 0.086), 0.015 (0.008 to 0.026) and 0.040 (0.027 to 0.056), respectively.Ethics and dissemination Each participant will provide informed written consent during the acute in-hospital phase. Data will be available for research purposes via a written request to the data use and access committee.Trial registration number German Clinical Trials Register: http://www.drks.de/DRKS00023323 on 4 November 2020.

Post-stroke pain (PSP) affects nearly half of stroke survivors, severely compromising quality of life. The causes of PSP remain underexplored, although there is likely a complex interplay of lesion effects, psychological factors, and mobility that play a role in its development. The aim of the study was to investigate clinical characteristics associated with PSP, as well as structural and functional correlates of PSP using lesion symptom (LSM) and network mapping (LNM). We analyzed data from the INSPiRE-TMS cohort, encompassing 1022 minor ischemic stroke patients. Pain severity and psychological factors (EQUATION 5D-3L questionnaire) were assessed annually for up to 3 years. In a sub-group of 391 patients with available imaging data, LSM and LNM analyses were conducted to identify neural correlates of PSP. Overall, 47% of patients reported pain 1-year post-stroke. Multivariable regression analyses identified baseline anxiety as associated with PSP assessed at 1-year post-stroke (OR 2.90, 95% CI 1.17-7.17, p = 0.021). LSM did not identify any voxels associated with new severe pain. LNM identified a network involving the anterior cingulate cortex, thalamus, and insular cortex. Adjusting for anxiety highlighted distinct network contributions, suggesting interactive effects of psychological states on pain perception. Automated comparison to large metanalytical findings using Neurosynth associated the terms 'pain' and 'nociception' most strongly to the identified network. PSP is closely associated with psychological factors such as anxiety. LNM of PSP revealed disruptions in a pain-related neural network consistent with prior pain research. These results warrant external validation and could guide future network-targeted neuromodulation therapies. Trial Registration: ClinicalTrials.gov identifier: NCT01586702.

G protein-coupled receptor (GPCR) directed regulatory autoantibodies (RABs) have previously been linked to poor functional outcome after ischemic stroke. We investigated the impact of anti-α1/α2/β1/β2 receptor, endothelin B receptor, angiotensin II receptor type 2, and CXCR3 receptor directed RABs on functional outcome and recurrent events after ischemic stroke. Data were derived from the Prospective Cohort with Incident Stroke Berlin (PROSCIS-B; NCT01363856). RABs were measured by ELISA (CellTrend) from sera collected within seven days of first-ever stroke. High RAB levels (quartile [Q]4 vs. Q1-3) and low levels (Q1 vs. Q2-4) were compared to reference groups. Quartile subgroups were characterized at baseline. Functional outcome, measured by the Modified Rankin Scale (mRS) at one year, was evaluated with ordinal logistic regression. Cox proportional hazard models were used to assess risk for a combined endpoint (stroke, myocardial infarction, death) over three years. 562 patients were included (mean age 67 (SD= 13); 38

Dizziness and vertigo are common and debilitating neurological symptoms among patients visiting the emergency department (ED). Possibly because the symptoms are not captured by standard stroke severity tools such as the NIHSS (National Institutes of Health Stroke Scale), their network-level neuroanatomical correlates—particularly potential supratentorial contributions—remain incompletely characterized. Therefore, we aim to investigate the neuroanatomical substrates of post-stroke dizziness and vertigo. This retrospective analysis included patients with acute ischemic stroke from the randomized controlled INSPiRE-TMS trial. Each patient underwent MRI within seven days of symptom onset, and stroke severity was assessed using the NIHSS at hospital admission. Patients were assessed for broadly defined new-onset dizziness/vertigo associated with the acute cerebrovascular event. Lesion symptom mapping (LSM) and lesion network mapping (LNM) were used to investigate associations between lesion location, functional connectivity, and dizziness/vertigo. Among 484 patients, 32 https://clinicaltrials.gov/ct2/show/NCT01586702 ); first registry in April 2012; first patient recruitment: September 2011.

Background: Post-stroke depression (PSD) affects up to one-third of stroke survivors, significantly impacting rehabilitation success and quality of life. However, its underlying pathophysiology remains unclear. Methods: We analyzed two independent, prospective ischemic stroke cohorts (PROSCIS-B [NCT01363856][1] and BAPTISe [NCT01954797][2]; total N=377) to identify brain regions and networks associated with depressive symptoms post-stroke. Lesion-symptom mapping (LSM) assessed associations between lesion location and depressive symptoms measured via the Center for Epidemiologic Studies Depression Scale (CES-D) up to 12 months post-stroke, while lesion network mapping (LNM) evaluated lesion connectivity with brain networks. We explored correlations between spatial similarity to the LNM-identified network and CES-D scores using linear regression models. Results: LSM revealed no significant associations between lesion location and depressive symptoms. In contrast, LNM showed that lesion connectivity to brain regions?including the frontal pole, middle and inferior frontal gyri, inferior temporal gyrus, supramarginal gyrus, angular gyrus, frontal orbital cortex, and thalamus?correlated with CES-D scores (r=0.12, p=0.02). These regions overlapped with canonical resting-state networks, such as the frontoparietal (Dice coefficient [DC] = 0.28), salience (DC = 0.27), and default-mode networks (DC = 0.20), as well as a previously published depression circuit (DC = 0.43). Conclusions: Lesion location alone was not associated with depressive symptoms post-stroke. However, lesion connectivity analysis revealed associations with brain networks, particularly the frontoparietal, salience, and default-mode networks, suggesting that disruption to these circuits may contribute to the development of PSD up to one-year post-stroke. ### Competing Interest Statement ME reports grants from Bayer and fees paid to the Charité from Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Amgen, GSK, Sanofi, Covidien, and Novartis, all outside of the submitted work. CO reports grants from Boehringer Ingelheim and Peak Profiling and honoraria for lectures and/or scientific advice from Boehringer-Ingelheim, Janssen, Limes Klinikgruppe, Neuraxpharm, Oberberg Kliniken and Peak Profiling. ### Funding Statement The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: AKu and AK are participants in the Berlin Institute of Health-Charité Clinical Scientist Program funded by the Charité-Universitätsmedizin Berlin and the Berlin Institute of Health. ME received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC-2049-390688087 and Collaborative Research Center ReTune TRR 295- 424778381. ME received additional funding from Bundesministerium für Bildung und Forschung (BMBF; German Ministry for Education and Research) for the Center for Stroke Research Berlin. CO received funding from the German Research Foundation (OT 209/7-3; 14-1, 19-1, 21-1, EXC 2049), the European Commission (IMI2 859366), the German Federal Ministry of Education and Research (KS2017-067), the Berlin Institute of Health (B3010350), and the Wellcome Trust. AHN reports receiving research funding from the Corona Stiftung, the Else Kröner-Fresenius-Stiftung, and the German Center for Cardiovascular Research (DZHK), and was funded by the Berlin Institute of Health-Charité Clinical Scientist Program of the Charité-Universitätsmedizin Berlin and the Berlin Institute of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants provided informed consent. The studies were conducted in accordance to the Declaration of Helsinki and were approved by the local ethics committee in Berlin. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data supporting the results of this study is available upon reasonable request from the corresponding author. Code availability: Open source software was used for the pre-processing and analysis of the data, including: Lead-DBS (https://github.com/netstim/leaddbs), FSL 6.0.6.4 (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/) and ANTsPy (https://github.com/ANTsX/ANTsPy). The code used to perform AIC, and cross-validations has been made publicly available at https://osf.io/pgnwh/?view_only=015d9716f84d478eb6e2c5cf7d41fff3. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01363856&atom=%2Fmedrxiv%2Fearly%2F2025%2F01%2F06%2F2024.12.31.24319837.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01954797&atom=%2Fmedrxiv%2Fearly%2F2025%2F01%2F06%2F2024.12.31.24319837.atom

Background: Cerebral small vessel disease (CSVD) is a common incidental finding on cerebral MRI in patients with transient ischemic attack (TIA) and stroke and has been linked to increased cerebrovascular risk and cognitive decline. This study aimed to investigate the prevalence of CSVD imaging biomarkers in TIA patients and evaluate their association with cognitive function over three years following the ischemic event. Methods: A cohort of 246 TIA patients from the INSPiRE-TMS (ClinicalTrials.gov: [NCT01586702][1]) study were included. The CSVD-score ? including white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (PVS) ? was assessed on baseline MRI. Cognitive performance was assessed via the Montreal Cognitive Assessment (MoCA) at baseline and annual outpatient visits up to 3 years. Results: CSVD was present in 58.5% of TIA patients. The most prevalent imaging biomarker was lacunes (36.6%), followed by PVS (28.1%), WMH (19.5%) and CMBs (17.9%). Cumulative CSVD-score (range 0-4) was an independently associated with cognitive decline up to 3 years (? = -0.53, 95% CI -0.97 ? -0.09, p = 0.018), alongside advanced age (? = -0.08, 95% CI -0.13 ? -0.03, p=0.001). CMB burden was the strongest predictive component of the CSVD-score (? = 0.42, 95% CI -0.63 ? -0.21, p < 0.001). Specifically, CSVD-score had a significant negative effect on the memory domain of cognitive function with an adjusted ? of -0.18 (95% CI -0.32 ? -0.04, p = 0.014). Conclusion: Imaging biomarkers of CSVD are present in more than half of TIA patients and are an independent predictor of cognitive decline up to 3 years, with the strongest effect on the memory domain of cognitive function. Whether the presence of CMBs is the strongest predictive imaging biomarker of cognitive decline in TIA patients requires confirmation in further studies. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ClinicalTrials.gov of the INSPiRE-TMS study: [NCT01586702][1] ### Funding Statement The INSPiRE-TMS study was funded within the grant of the German Federal Ministry of Education and Research (BMBF) for the Center for Stroke Research Berlin and co-funded with unrestricted grants of Pfizer and the German Stroke Foundation. No additional funding was received towards this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The INSPIRE-TMS study protocol was created in accordance with the Declaration of Helsinki and approved by the ethics committee of the Charité Universitätsmedizin Berlin (EA2/084/11) with additional approval obtained by the respective ethics committees at all participating centres. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data supporting the results of this study can be provided upon reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01586702&atom=%2Fmedrxiv%2Fearly%2F2025%2F03%2F11%2F2025.03.05.25323459.atom

BACKGROUND:Predicting functional recovery after ischemic stroke is vital for guiding clinical care. This study investigated whether lesion network mapping (LNM), a technique for modeling symptom-specific brain networks, can improve outcome prediction of functional recovery up to one-year post-stroke. METHODS:We pooled data from two prospective stroke cohorts (1000Plus and PROSCIS-B; N = 565). Seven NIHSS-derived symptom networks were generated using LNM based on NIHSS sub-scores on admission (i.e., consciousness, language, motor, sensory, vision, neglect and ataxia). Lesion masks derived from MRI (within 7 days) were intersected with each symptom network to calculate individual network damage scores. Functional outcome was defined by the modified Rankin Scale (mRS) at 3 months (1000Plus) or 12 months (PROSCIS-B). Ordinal logistic regression models were performed to evaluate additional predictive value of LNM: Model 1 included age, lesion volume, and presence of selected neurological deficits; Model 2 included age, lesion volume, and NIHSS-derived network damage scores. Models were compared using pseudo-R2 and AIC. RESULTS:Patients had a mean age of 68 years and a median NIHSS of 3 (IQR 1-5). LNM revealed distinct, symptom-specific networks, with corresponding damage scores that were higher in patients exhibiting the respective deficits compared to those without. However, inclusion of these scores did not enhance the predictive accuracy of functional outcomes beyond that achieved with clinical variables alone (Model 1 vs. Model 2: pseudo-R2: 0.0468 vs. 0.0159; AIC:1730.598 vs. 1769.222). CONCLUSIONS:LNM-derived scores reflected symptom topography but did not enhance prediction of functional recovery. While promising as a mechanistic tool, the clinical utility of LNM-based damage metrics for prognostication remains limited and requires further validation.

Ischemic stroke can lead to neuropsychiatric sequelae such as depression and post-traumatic stress disorder (PTSD), resulting in poorer functional outcomes. The POST-stroke PSYchological DIStress PostPsyDis; NCT01187342) study aimed to investigate whether ischemic lesions in the striatum increase the risk of depression and PTSD after stroke. This monocenter, observational, case-control study included 84 ischemic stroke patients with striatal (n = 54) and non-striatal ischemic brain lesions (n = 30). Primary study endpoints included symptoms of depression (assessed via the Geriatric Depression Scale; GDS-30) and PTSD (assessed via the Posttraumatic Symptom Scale; PTSS-10) 90 days post-stroke. A normative functional connectome was used to obtain a measure of striatal connectivity to the rest of the brain (“striatal network”). Network damage scores were used to estimate damage of each lesion to the striatal network. Patients with striatal lesions had higher GDS-30 scores at 90 days post-stroke (median 5.6 vs. 3.0; Cohen’s d = 0.39; p = 0.057), indicating a small to moderate effect. However, no meaningful group differences were observed in the incidence of depression or PTSD. In multivariable regression analyses, striatal infarction had an adjusted beta coefficient (β) of 1.9 (95 https://clinicaltrials.gov/study/NCT01187342 .

BACKGROUND:Poststroke depression affects up to one-third of stroke survivors, significantly impacting recovery and quality of life. However, its pathophysiology remains unclear. METHODS:We analyzed 2 independent, prospective ischemic stroke cohorts (PROSCIS-B [Prospective Cohort of Incident Stroke Berlin] and BAPTISe [Biomarkers and Perfusion-Training-Induced Changes After Stroke]; n=377) enrolled at the Charité Hospital, Germany, to identify brain regions and networks associated with depressive symptoms poststroke. Lesion-symptom mapping assessed associations between lesion location and depressive symptoms measured by the Center for Epidemiological Studies Depression Scale at 6 (BAPTISe) or 12 (PROSCIS-B) months poststroke. Lesion-network mapping evaluated lesion connectivity with brain networks. A mixed-effects model, including cohort as a random effect, assessed the relationship between network similarity (Pearson correlation) and Center for Epidemiological Studies Depression Scale scores. Dice coefficients (DC) quantified spatial overlap with canonical resting-state networks. RESULTS:Lesion-symptom mapping showed no significant associations between lesion location and depressive symptoms. In contrast, lesion-network mapping revealed that lesion connectivity to brain regions including the frontal pole, middle and inferior frontal gyri, inferior temporal gyrus, supramarginal gyrus, angular gyrus, frontal orbital cortex, and thalamus weakly correlated with Center for Epidemiological Studies Depression Scale scores (β, 11.4 [95%CI, 1.8-21.1]; P=0.02). These regions overlapped with the frontoparietal (DC=0.28), salience (DC=0.27), and default mode (DC=0.20) networks, as well as a published depression circuit (DC=0.43). However, these findings did not replicate across data sets. CONCLUSIONS:Lesion location alone was not associated with poststroke depression. However, connectivity-based analyses implicated disruption of large-scale brain networks in the development of depressive symptoms. The failure to validate this association across data sets underscores the need for further studies with more comparable patient populations-particularly in terms of stroke severity and harmonized assessment time-points-to confirm these findings and their clinical relevance. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01954797.

Thalamic aphasia results from focal thalamic lesions that cause dysfunction of remote but functionally connected cortical areas due to language network perturbation. However, specific local and network-level neural substrates of thalamic aphasia remain incompletely understood. Using lesion symptom mapping, we demonstrate that lesions in the left ventrolateral and ventral anterior thalamic nucleus are most strongly associated with aphasia in general and with impaired semantic and phonemic fluency and complex comprehension in particular. Lesion network mapping (using a normative connectome based on fMRI data from 1000 healthy individuals) reveals a Thalamic aphasia network encompassing widespread left-hemispheric cerebral connections, with Broca's area showing the strongest associations, followed by the superior and middle frontal gyri, precentral and paracingulate gyri, and globus pallidus. Our results imply the critical involvement of the left ventrolateral and left ventral anterior thalamic nuclei in engaging left frontal cortical areas, especially Broca's area, during language processing. A lesion symptom mapping and lesion network mapping study suggests that lesions in the left ventral thalamic nuclei, linked to thalamic aphasia, map onto a common left-hemispheric network, with Broca's area showing the strongest associations.

Clonal hematopoiesis (CH) is common among older people and associated with an increased risk of atherosclerosis, inflammation, and shorter overall survival. Age and inflammation are major risk factors for ischemic stroke, yet the association of CH with risk of secondary vascular events and death is unknown. We investigated CH in peripheral blood DNA from 581 patients with first-ever ischemic stroke from the Prospective Cohort with Incident Stroke-Berlin study (PROSCIS-B) using error-corrected targeted sequencing. The primary composite endpoint (CEP) consisted of recurrent stroke, myocardial infarction, and all-cause mortality. 348 somatic mutations with a variant allele frequency ≥ 1% were identified in 236/581 patients (41%). CH was associated with large-artery atherosclerosis stroke (P = 0.01) and white matter lesion (P < 0.001). CH-positive patients showed increased levels of pro-inflammatory cytokines such as IL-6, IFN-γ, hsCRP, and VCAM-1. CH-positive patients had a higher risk for the primary CEP (HR: 1.55, 95%-CI 1.04 - 2.31, P = 0.03), which was more pronounced in patients with larger clones. CH clone size remained an independent risk factor (HR 1.30, 95%-CI 1.04 - 1.62, P = 0.022) in multivariable Cox regression. While our data show that in particular larger and TET2- or PPM1D-mutated clones are associated with increased risk of recurrent vascular events and death, this risk is partially mitigated by a common germline variant of the IL-6 receptor (IL-6R p.D358A). The CH mutation profile is accompanied by a pro-inflammatory profile opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.

Background:Anti-NMDA-receptor GluN1 antibodies (NMDAR1-abs) are present in an autoimmune encephalitis with severe neuropsychiatric symptoms. We aimed to estimate the impact of serum NMDAR1-abs on depressive symptoms years after first-ever ischemic stroke (IS). Methods:Data were used from the PROSpective Cohort with Incident Stroke-Berlin (PROSCIS-B; NCT01363856). Serum NMDAR1-abs (IgM/IgA/IgG) were measured within 7 days after IS using cell-based assays. We defined seropositivity as titers ≥1:10, thereof low titers as ≤1:100 and high titers as >1:100. We used the Center for Epidemiological Studies-Depression (CES-D) scale to measure depressive symptoms at year one, two and three following IS. We calculated crude and confounder adjusted weighted generalized linear models to quantify the impact of NMDAR1-abs on CES-D assessed at three annual time-points. Results:NMDAR1-abs were measured in 583 PROSCIS-B IS patients (mean age = 67 [SD = 13]; 42%female; median NIHSS = 2 [IQR = 1-4]) of whom 76 (13%; IgM: n = 49/IgA: n = 43/IgG: n = 2) were seropositive, 55 (9%) with low and 21 (4%) with high titers. CES-D regarded over all follow-up time-points was higher in seropositive patients (βcrude = 2.56 [95%CI = -0.34 to 5.45]; βadjusted = 2.26 [95%CI = -0.68 to 5.20]) and effects were highest in patients with high titer (low titers: βcrude = 1.42 [95%CI = -1.79 to 4.62], βadjusted = 0.53 [95%CI = -2.47 to 3.54]; high titers: βcrude = 5.85 [95%CI = 0.20 to 11.50]; βadjusted = 7.20 [95%CI = 0.98 to 13.43]). Conclusion:Patients with serum NMDAR1-abs (predominantly IgM&IgA) suffer more severe depressive symptoms after mild-to-moderate IS compared to NMDAR1-abs seronegative patients.

BackgroundAccurate prediction of clinical outcomes in individual patients following acute stroke is vital for healthcare providers to optimize treatment strategies and plan further patient care. Here, we use advanced machine learning (ML) techniques to systematically compare the prediction of functional recovery, cognitive function, depression, and mortality of first-ever ischemic stroke patients and to identify the leading prognostic factors.MethodsWe predicted clinical outcomes for 307 patients (151 females, 156 males; 68 ± 14 years) from the PROSpective Cohort with Incident Stroke Berlin study using 43 baseline features. Outcomes included modified Rankin Scale (mRS), Barthel Index (BI), Mini-Mental State Examination (MMSE), Modified Telephone Interview for Cognitive Status (TICS-M), Center for Epidemiologic Studies Depression Scale (CES-D) and survival. The ML models included a Support Vector Machine with a linear kernel and a radial basis function kernel as well as a Gradient Boosting Classifier based on repeated 5-fold nested cross-validation. The leading prognostic features were identified using Shapley additive explanations.ResultsThe ML models achieved significant prediction performance for mRS at patient discharge and after 1 year, BI and MMSE at patient discharge, TICS-M after 1 and 3 years and CES-D after 1 year. Additionally, we showed that National Institutes of Health Stroke Scale (NIHSS) was the top predictor for most functional recovery outcomes as well as education for cognitive function and depression.ConclusionOur machine learning analysis successfully demonstrated the ability to predict clinical outcomes after first-ever ischemic stroke and identified the leading prognostic factors that contribute to this prediction.

Background White matter hyperintensities (WMH) are the result of cerebral small vessel disease and may increase the risk of cognitive impairment (CI), recurrent stroke, and depression. We aimed to explore the association between selected cerebrovascular risk factors (CVRF) and WMH load as well as the effect of increased WMH burden on recurrent vascular events, CI, and depression in first-ever ischemic stroke patients. Methods 431 from the PROSpective Cohort with Incident Stroke (PROSCIS) were included; Age-Related White Matter Changes (ARWMC) score was used to assess WMH burden on FLAIR. The presence of CVRF (defined via blood pressure, body-mass-index, and serological markers of kidney dysfunction, diabetes mellitus, and hyperlipoproteinemia) was categorized into normal, borderline, and pathological profiles based on commonly used clinical definitions. The primary outcomes included recurrent vascular events (combined endpoint of recurrent stroke, myocardial infarction and/or death), CI 3 years post-stroke, and depression 1-year post-stroke. Results There was no clear association between CVRF profiles and WMH burden. High WMH lesion load (ARWMC score ≥ 10) was found to be associated with CI (adjusted OR 1.05 [95% CI 1.00–1.11]; p < 0.02) in a mixed-model analysis. Kaplan–Meier survival analysis showed a visible increase in the risk of recurrent vascular events following stroke; however, after adjustment, the risk was non-significant (HR 1.5 [95% CI 0.76–3]; p = 0.18). WMH burden was not associated with depression 1-year post stroke (adjusted OR 0.72 [95% CI 0.31–1.64]; p = 0.44). Conclusion Higher WMH burden was associated with a significant decline in cognition 3 years post-stroke in this cohort of first-ever stroke patients.