Abstract Background and aims Brain health impacts resilience to neurological diseases and is associated with favorable functional outcomes after ischemic stroke (IS). However, the relationship between modifiable vascular risk factors and structural brain health at IS onset has not been explored. Methods We analyzed patients surviving IS with available admission MRI from the GASROS cohort. We quantified brain health using the MRI-based biomarker effective Reserve (eR), a latent variable derived from age, white matter hyperintensity, and normal-appearing brain volume, which is automatically calculated from admission T2-FLAIR sequences. Data on modifiable risk factors were recorded at acute hospital admission. In multivariable regression models, we investigated the associations between brain health and (1) modifiable risk factors; (2) Life’s Essential 8 (LE8) sub scores, and (3) LE8 total score, adjusting for sex. Results We analyzed 511 patients surviving IS (median age 66 [IQR 55-76] years, 34% female). Baseline characteristics included diagnoses of diabetes (20%), hypertension (63%), history of smoking (65%), body mass index (BMI, median: 27 [IQR 24-30]) and NIHSS (median: 2 [IQR 1-6]). Hypertension (aOR [95% confidence interval], 0.50 [0.40-0.64]), lower eGFR (per 10 mL/min/1.73m2 increase, 1.30 [1.24-1.37]), and lower BMI (1.05 [1.03-1.08]) were associated with worse brain health at admission (Figure 1). Calculating LE8 sub scores, higher blood pressure, higher blood glucose, and lower BMI were associated with worse brain health. We observed no association between the total LE8 score and brain health. Conclusions Modifiable vascular risk factors are associated with MRI markers of structural brain health at admission in patients with ischemic stroke. Conflict of interest EL is supported by Swedish Research Council (2023-06531), the Swedish Heart Lung Foundation (no. 20230904, 2024135125). AC: nothing to disclose. LA: nothing to disclose. KA: nothing to disclose. NSR is supported by NINDS U19NS115388 and the MGB AI Cures Grant Award. MDS is supported by AI Cures Grant Award, Heitman Stroke Foundation, and NIA R21AG083559. Figure 1 - belongs to Results

Status epilepticus (SE) is a life-threatening persistent epileptic seizure that can arise from various brain structures, leaving its brain circuit unknown. In this study, we utilize brain imaging changes during SE to reveal the brain architecture and circuit of persistent seizures. Multimodal lesion mapping identified that brain imaging changes during SE localize to a specific predisposed brain architecture characterized by increased metabolic rate, high synaptic and mitochondrial density, glutamate (mGLUR5 and NMDA) and GABA receptors. Gene expression patterns within lesion locations revealed a transcriptomic profile enriched for epilepsy pathologies (including SE), neuronal and synaptic processes, and glutamate signaling. Lesion network mapping demonstrated these same lesions map to a common brain circuit, unifying a traditionally heterogeneous patient population. Findings were validated in an independent cohort and the identified SE circuit distinguished brain imaging changes during SE from other lesion etiologies with excellent accuracy (91%), significantly outperforming all other tested maps. With this SE circuit, we identify therapeutic targets for precision therapy that could modulate this circuit. This study demonstrates brain imaging changes in SE converge on a unified brain circuit that could help diagnostic workup of patients in critical care and guide clinical trials of precision therapy for persistent seizures.

BACKGROUND:Endovascular thrombectomy (EVT) dramatically improves clinical outcomes, but the final infarct volume (FIV) on magnetic resonance imaging only accounts for a minority of the treatment effect. An imaging biomarker that more strongly correlates with post-EVT functional outcome would be helpful for clinical prognosis and serve as a surrogate outcome measure in trials of EVT-adjuvant therapies. Here, we aimed to validate a novel magnetic resonance imaging-based metric, infarct density, which leverages post-EVT apparent diffusion coefficient as a marker of infarct severity. METHODS:A retrospective cohort was derived from a single-center prospective EVT registry. Consecutive patients treated with EVT for anterior circulation large vessel occlusion were included from 2018 to 2019 who achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction ≥2b). Magnetic resonance imaging was performed 12 to 48 hours post-EVT and processed via RAPID to quantify FIV using the apparent diffusion coefficient <620 threshold. Lesion volume was also collected using an apparent diffusion coefficient <470 threshold, and infarct density was calculated as: (volume <470/volume <620)×100%. Good outcome was defined as ≤2 on the 90-day modified Rankin Scale. Multivariable logistic regression models quantified the association between clinical/imaging variables and outcome. Receiver operating characteristic analysis quantified model classification performance. RESULTS:Of 319 patients treated with EVT, 272 met inclusion criteria. The mean age was 69±13 years, 41% were female, and 62% achieved a good outcome. After adjusting for clinical and radiographic factors, FIV (adjusted odds ratio, 0.99 per 1 mL [95% CI, 0.98-1.00]; P=0.03) and infarct density (adjusted odds ratio, 0.95 per 1% [95% CI, 0.94-0.97]; P<0.001) were both independently inversely associated with good outcome. The final model incorporating both FIV and infarct density achieved excellent classification performance (area under the curve, 0.87 [95% CI, 0.83-0.91]). Removing infarct density from the model diminished its performance (area under the curve, 0.83 [95% CI, 0.78-0.88]; P=0.01). CONCLUSIONS:Apparent diffusion coefficient-based infarct density after EVT is independently associated with long-term outcome and provides greater prognostic information than FIV alone. Post-EVT infarct density may be useful in clinical care and as a surrogate outcome measure in trials of EVT-adjuvant therapies.

Identifying the anatomy of circuits causal of psychosis could inform treatment targets for schizophrenia. We identified 155 published case reports of brain lesions that caused new-onset psychosis. We mapped connectivity of these lesions using a normative human fMRI connectome. Lesions causing psychosis mapped to a common brain circuit defined by functional connectivity to the posterior subiculum of the hippocampus. This circuit was consistent both across individual symptoms of psychosis (delusions, hallucinations, and thought disorders), and when excluding lesions that touched the hippocampus. In an independent observational study (n=181), lesions connected to this circuit were preferentially associated with psychotic symptoms. A location in the rostromedial prefrontal cortex with high connectivity to this psychosis circuit was identified as a potential target for transcranial magnetic stimulation. Based on these results, we conclude that lesions that cause psychosis have common functional connections to the posterior subiculum of the hippocampus.

Background: Endovascular thrombectomy (EVT) dramatically improves clinical outcomes, but the final infarct volume (FIV) on MRI only accounts for a minority of the treatment effect. An imaging biomarker that more strongly correlates with post-EVT functional outcome would be helpful for clinical prognosis and serve as a surrogate outcome measure in trials of EVT-adjuvant therapies. Here, we aimed to validate a novel MRI-based metric, infarct density, which leverages post-EVT apparent diffusion coefficient (ADC) as a marker of infarct severity. Methods: A retrospective cohort was derived from a single-center prospective EVT registry. Consecutive anterior circulation EVT patients were included from 2018-2019 who achieved successful reperfusion (mTICI ≥2b). MRI was performed 12-48 hours post-EVT and processed via RAPID to quantify FIV using the ADC <620 threshold. Lesion volume was also collected using ADC <470 threshold, and infarct density was calculated as: (volume <470/volume <620)x100%. Good outcome was defined as ≤2 on the 90-day modified Rankin Scale. Multivariable logistic regression models quantified the association between clinical/imaging variables and outcome. ROC analysis quantified model classification performance. Results: Of 319 EVT patients, 272 met inclusion criteria. The mean age was 69 ±13 years, 41% were female, and 62% achieved a good outcome. After adjusting for clinical and radiographic factors, FIV (aOR 0.99 per 1mL; 95%CI: 0.98-1.00; p=0.03) and infarct density (aOR 0.95 per 1%; 95%CI: 0.94-0.97; p<0.001) were both independently inversely associated with good outcome. The final model incorporating both FIV and infarct density achieved excellent classification performance (AUC 0.87; 95%CI: 0.83-0.91). Removing infarct density from the model diminished its performance (AUC 0.83; 95%CI: 0.78-0.88; p=0.01). Conclusion: ADC-based infarct density after EVT is independently associated with long‐term outcome and provides greater prognostic information than FIV alone. Post-EVT infarct density may be useful in clinical care and as a surrogate outcome measure in trials of EVT-adjuvant therapies.

BACKGROUND AND PURPOSE:Parenchymal hematomas (PHs) represent an important complication in ischemic stroke after endovascular thrombectomy (EVT), but the risk factors are incompletely understood. Neuroimaging data preintervention, such as infarct topography, may help elucidate predisposing factors and inform more nuanced patient care intra- and postprocedurally. METHODS:Large vessel occlusion patients with pre-EVT MRI were included from a single quaternary center. Diffusion-weighted imaging (DWI) lesions underwent manual segmentation and registration onto a standard brain space for topographical mapping. The presence of PH postintervention was determined. Associations between infarct topography, clinical characteristics, and PH were evaluated. RESULTS:A total of 165 patients (median age: 69; 56% female) were identified. Intravenous alteplase was administered to 52%, 70% achieved thrombolysis in cerebral infarction 2b-3 reperfusion, and 8% had PH postintervention. The preintervention DWI lesions were 48% (38%-60%) white matter, 23% (6%-47%) cortex, and 15% (4%-28%) basal ganglia. Basal ganglia infarct volume was independently associated with PH (adjusted odds ratio = 1.342, 95% confidence interval 1.002-1.797, p = 0.049), accounting for white matter and cortex infarct volume, among other key factors. Basal ganglia infarct volume was associated with susceptibility-weighted imaging vessel sign (betaadjusted = 0.233, p = 0.006) and the National Institutes of Health Stroke Scale (betaadjusted = 0.220, p = 0.012), controlling for other factors. CONCLUSIONS:Preintervention basal ganglia infarct volume may provide important insights into the risk of PH after intervention. Improved understanding of the biology of basal ganglia infarction and hemorrhagic transformation has implications for the management of patients undergoing EVT and may represent a future therapeutic target for neuroprotective strategies.

Once taken into consideration, sex differences in neurological diseases emerge in abundance: (i) Stroke severity is significantly higher in females than in males, (ii) Alzheimer's disease (AD) pathology is more pronounced in females, and (iii) conspicuous links with hormonal cycles led to female-specific diagnoses, such as catamenial migraines and epilepsy. While these differences receive increasing attention in isolation, they likely link to similar processes in the brain. Hence, this review aims to present an overview of the influences of sex chromosomes, hormones, and aging on male and female brains across health and disease, with a particular focus on AD and stroke. The focus here on advancements across several fields holds promise to fuel future research and to lead to an enriched understanding of the brain and more effective personalized neurologic care for all.

Importance Identifying anatomy causally involved in psychosis could inform therapeutic neuromodulation targets for schizophrenia. Objective To assess whether lesions that cause secondary psychosis have functional connections to a common brain circuit. Design, Setting, and Participants This case-control study mapped functional connections of published cases of lesions causing secondary psychosis compared with control lesions unassociated with psychosis. Published cases of lesion-induced psychosis were analyzed in a computational laboratory. Participants had documented brain lesions associated with new-onset psychotic symptoms without a history of psychosis. Control cases included 1156 patients with lesions not associated with psychosis. Generalizability across lesional datasets was assessed using an independent cohort of 181 patients with brain lesions who subsequently underwent neurobehavioral testing. Data were analyzed from June 2022 to April 2024. Exposures Lesions causing secondary psychosis. Main Outcomes and Measures Psychosis or no psychosis. Results A total of 153 lesions from published cases were determined to be causal of psychosis, 42 of which were described as schizophrenia or schizophrenia-like (71 [46%] patients were male, 82 [54%] female; mean [SD] age, 50.0 [20.8] years). Lesions that caused secondary psychosis mapped to a common brain circuit defined by functional connectivity to the posterior subiculum of the hippocampus (84% functional overlap, family-wise error [FWE] rate corrected P < 5 x 10(-5)). At a lower statistical threshold (>75% overlap, FWE-corrected P < 5 x 10(-4)), this circuit included the ventral tegmental area, retrosplenial cortex, lobule IX and dentate nucleus of the cerebellum, and the mediodorsal and midline nuclei of the thalamus. This circuit was consistent when derived from schizophrenia-like cases (spatial r = 0.98). We repeated these analyses after excluding lesions intersecting the hippocampus (n = 47) and found a consistent functional connectivity profile (spatial r = 0.98) with the posterior subiculum remaining the center of connectivity (>75% overlap, FWE-corrected P < 5 x 10(-5)), demonstrating a circuit-level effect. In an independent observational cohort of patients with penetrating head trauma (n = 181), lesions associated with symptoms of psychosis exhibited significantly similar connectivity profiles to the lesion-derived psychosis circuit (suspiciousness, P = .03; unusual thought content, P = .046). Voxels in the rostromedial prefrontal cortex are highly correlated with this psychosis circuit (spatial r = 0.82), suggesting the rostromedial prefrontal cortex as a promising transcranial magnetic stimulation target for psychosis. Conclusions and Relevance Lesions that cause secondary psychosis affect a common brain circuit in the hippocampus. These results can help inform therapeutic neuromodulation targeting.

Introduction: As more patients with stroke, including those with large cores, are treated with endovascular thrombectomy (EVT), understanding the pathophysiology of hemorrhagic transformation (HT) is becoming increasingly important. Pre-EVT infarct topography may have implications for treatment decisions acutely (e.g. stenting) and for post EVT care (e.g. antithrombotics and blood pressure goals). We sought to identify associations between HT and brain regions involved in ischemic lesions. Methods: Consecutive patients with LVO treated with EVT who underwent pre-EVT MRI were identified from two tertiary referral centers (2011-2019). Acute ischemic lesions were extracted through a deep learning enabled pipeline from DWI and spatially normalized. Individual lesions were parcellated (atlas-defined 94 cortical regions, 14 subcortical nuclei, 20 white matter tracts) and reduced to ten essential lesion patterns using unsupervised dimensionality reduction techniques. HT, defined as ECASS PH1 or PH2, was modeled via Bayesian regression, taking the ten lesion patterns as inputs, and controlling for total lesion volume, age, sex, initial NIH Stroke Scale (NIHSS), thrombolysis treatment, good reperfusion (TICI2b-3), acute stenting, last known well-to-puncture time, diabetes mellitus, hypertension, coronary artery disease, smoking, atrial fibrillation, and site of enrollment. Results: A total of 567 (mean age 69 ±15 years; 45% female) patients had pre-EVT DWI without significant artifacts that could undergo lesion segmentation and registration. The median NIHSS was 16 (IQR 11-20) and mean total infarct volume was 22.5 ±36.7ml. Thrombolysis was administered in 51% and good reperfusion was achieved in 83%. HT occurred in 10%. Lesion locations predictive of HT ( Figure ) involved bilateral caudate, putamen, pallidum, and anterior thalamic radiation; and, right more than left thalamus, corticospinal tract, and inferior fronto-occipital fasciculus (area under the curve: 0.73). Conclusions: These data from a large, multicenter cohort with precise MRI-defined infarcts underscore the significance for HT of specific brain regions involved in ischemic lesions before EVT. An understanding of this pathophysiology can inform not only current clinical practice but also the development of future novel therapeutic strategies to prevent HT and reperfusion injury as more patients with large infarct cores are treated with EVT.

The global burden of neurologic disorders is rising, driven by aging populations and improved survival following acute neurologic events. As a result, more individuals are living with long-term disabilities from conditions such as stroke, dementia, and other neurodegenerative diseases. Despite significant advances in neurology, there remains an urgent need for a preventive approach to mitigate these trends. Growing evidence highlights the effectiveness of preventive strategies, including lifestyle modifications and risk factor management, in preserving brain health and reducing the risk of stroke, neurodegenerative conditions, and cognitive decline. Preventive neurology operates within a multilevel framework, ranging from direct patient-centered interventions to systemic policy actions requiring organizational and societal support. Neurologists are uniquely positioned as advocates for brain health, promoting preventive strategies in line with the American Academy of Neurology's Brain Health Initiative. This article explores how neurologists can drive change across individual, family, community, and policy levels by leveraging their clinical expertise, community engagement, and health policy influence. Sustainable progress in brain health will also require system-level changes that integrate preventive goals into the fabric of health care delivery, public health infrastructure, and policy frameworks. Special attention is given to underserved populations, who bear a disproportionate burden of neurologic diseases. Through targeted interventions, public health initiatives, and collaborative care models, preventive neurologists can shape brain health outcomes across the lifespan. Training neurologists with a preventive focus will integrate brain health promotion into standard neurology practice, complementing disease management. By addressing the root causes and risk factors of neurologic conditions, preventive neurology provides a pathway to improving quality of life while reducing the global health care burden.

Background One third of all patients with acute ischemic strokes have a pre-existing disability. Patients with pre-existing disabilities have historically been excluded from landmark clinical trials of acute stroke interventions, leading to ongoing controversy about the risks and benefits of acute stroke interventions such as endovascular thrombectomy (EVT). To address this controversy, we compared long-term outcomes and end-of-life care in large vessel occlusion (LVO) patients with moderate-to-severe baseline disability treated with EVT versus medical management alone. Methods Patients who presented with an LVO to our comprehensive stroke center between January 2017 and December 2020 were retrospectively identified from a prospectively maintained database. Moderate-to-severe baseline disability was defined as a pre-stroke modified Rankin Scale (mRS) of 3-5. Delta mRS was defined as the difference between the 90-day and baseline mRS. Logistic and ordinal regressions were performed to evaluate the relationships between EVT and outcomes. An analysis of rates and reasons for transitions to comfort care was also performed, where applicable. Results A total of 175/1008 (17%) LVO patients with moderate-to-severe baseline disability were identified. The median age was 82 (IQR 70-89), and 59% were female. Thirty-two patients (18%) with moderate-to-severe baseline disability were treated with EVT. EVT was independently associated with improved delta mRS (B=-1.048; 95%CI=-1.777,-0.318; p=0.005) accounting for age and NIHSS. However, EVT did not reduce the odds of transitioning to comfort care (aOR=0.794; 95%CI=0.347,1.818; p=0.585) accounting for age and NIHSS. Seventy-six (43%) patients were transitioned to comfort care during their hospitalization. Of the 99 who were not transitioned to comfort care, 18 were treated with EVT, and EVT was independently associated with improved delta mRS (B=-2.794; 95%CI=-4.002,-1.586; p<0.0001). The median time from presentation to transition to comfort care was 2 days (IQR 1-7) in the non-EVT group, compared to 7 (IQR 4-11) in the EVT group (H(1)=5.46, p=0.019). The primary reasons for transitions to comfort care were poor perceived prognosis and medical complications. Conclusions Among patients with moderate-to-severe baseline disability, EVT is associated with less post-stroke accumulated disability without limiting transitions to comfort care. EVT is compatible with goal-concordant care and should not be routinely withheld because of baseline disability alone.

Importance:Brain health may facilitate resilience to detrimental consequences from neurological diseases. Infarct volume is associated with poor functional outcome after acute ischemic stroke (AIS), but potential mediating effects through stroke-related brain health loss have not been investigated. Objective:To determine whether stroke-related brain health loss, quantified by change in MRI derived effective Reserve (eR), mediates the effect of acute infarct volume on functional outcome after AIS. Design:Observational multicenter cohort study. Setting:We analyzed data from the GASROS (n=488) and MRI-GENIE (n=560) cohorts, collected 2003-2011. Participants:Adult patients consecutively diagnosed with AIS, with available admission MRI. Exposure:At admission, white matter hyperintensity (WMH) and normal-appearing brain volumes were assessed on T2-FLAIR, and acute infarct volume on diffusion weighted imaging. WMH was normalized by brain volume, creating WMH load. We quantified brain health using eR, a latent variable incorporating age, WMH load, and normal-appearing brain volume. ΔeR reflected the change in eR when acute infarct volume was included, representing stroke-related brain health decline. Mediation analysis was used to determine if ΔeR mediates the effect of infarct volume on functional outcome (modified Rankin Scale [mRS] at 90 days). Main Outcome Measure:Proportion of mediating effect. Results:We included 1,048 patients (median age 67y, 38% females). At baseline, median NIHSS score was 3 (IQR 1-7), median infarct volume 3.1mL (IQR 0.9-15.5). At 90 days, median mRS score was 1 (IQR 1-3) and 51 (5%) patients had died. In mediation analysis, ΔeR significantly mediated 36% (95% CI 16-56%) of the total effect of infarct volume on functional outcome (direct effect (ß=0.15 [95% CI 0.09-0.22], p<0.001; indirect effect mediated through ΔeR: ß=0.09 [95% CI 0.04 to 0.14], p=0.001). In subgroup-analyses, the mediative effect was apparent among female but not male, and among patients aged >67y but not ≤67y. Conclusions and Relevance:Stroke-related structural brain health loss mediates about one third of the effect of acute infarct volume on functional outcome after ischemic stroke, with important sex and age differences. Brain health significantly influences outcome and recovery potential, and may be considered a key biomarker when modeling outcome after AIS.