Association Between Hippocampal Volumes and Cognition in Cerebral Amyloid Angiopathy.

BACKGROUND AND OBJECTIVES: Accumulating evidence suggests that gray matter atrophy, often considered a marker of Alzheimer disease (AD), can also result from cerebral small vessel disease (CSVD). Cerebral amyloid angiopathy (CAA) is a form of sporadic CSVD, diagnosed through neuroimaging criteria, that often co-occurs with AD pathology and leads to cognitive impairment. We sought to identify the role of hippocampal integrity in the development of cognitive impairment in a cohort of patients with possible and probable CAA. METHODS: Patients were recruited from an ongoing CAA study at Massachusetts General Hospital. Composite scores defined performance in the cognitive domains of memory, language, executive function, and processing speed. Hippocampal subfields' volumes were measured from 3T MRI, using an automated method, and multivariate linear regression models were used to estimate their association with each cognitive domain and relationship to CAA-related neuroimaging markers. RESULTS: One hundred twenty patients, 36 with possible (age mean [range]: 75.6 [65.6-88.9]), 67 with probable CAA (75.9 [59.0-94.0]), and 17 controls without cognitive impairment and CSVD (72.4 [62.5-82.7]; 76.4% female patients), were included in this study. We found a positive association between all investigated hippocampal subfields and memory and language, whereas specific subfields accounted for executive function (CA4 [Estimate = 5.43; 95% CI 1.26-9.61; p = 0.020], subiculum [Estimate = 2.85; 95% CI 0.67-5.02; p = 0.022]), and processing speed (subiculum [Estimate = 1.99; 95% CI 0.13-3.85; p = 0.036]). These findings were independent of other CAA-related markers, which did not have an influence on cognition in this cohort. Peak width of skeletonized mean diffusivity (PSMD), a measure of white matter integrity, was negatively associated with hippocampal subfields' volumes (CA3 [Estimate = -0.012; 95% CI -0.020 to -0.004; p = 0.034], CA4 [Estimate = -0.010; 95% CI -0.020 to -0.0007; p = 0.037], subiculum [Estimate = -0.019; 95% CI -0.042 to -0.0001; p = 0.003]). DISCUSSION: These results suggest that hippocampal integrity is an independent contributor to cognitive impairment in patients with CAA and that it might be related to loss of integrity in the white matter. Further studies exploring potential causes and directionality of the relationship between white matter and hippocampal integrity may be warranted.

Intravenous Thrombolytics in the Treatment of Acute Ischemic Stroke.

Purpose of Review: To review the current evidence and ongoing clinical trials evaluating the efficacy and safety of tenecteplase (TNK), an alternative tissue plasminogen activator (tPA), in the acute management of arterial ischemic stroke (AIS). To date, alteplase is the only tPA approved by the United States FDA for use in AIS. Recent Findings: There have been multiple phase two and three trials investigating the safety and efficacy of TNK in AIS. In patients with AIS due to large vessel occlusion, one randomized controlled trial demonstrated superiority of TNK for vessel recanalization rates and long-term functional outcomes when compared to alteplase. A meta-analysis of all phase two and three trials evaluating TNK in AIS concluded that TNK has a comparable safety and efficacy profile to alteplase. The results of these trials prompted new recommendations in the Acute Stroke Guideline published by the AHA suggesting it may be reasonable to use as an alternative to alteplase. Furthermore, recent real-world data has also reported decreased door-to-needle time with TNK utilization. Summary: In patients with AIS, use of a thrombolytic agent is standard of care and has been shown to reduce neurological disability and improve functional outcome. Randomized controlled trials have demonstrated that TNK is non-inferior to alteplase from a clinical outcome and safety standpoint. The existing data evaluating the efficacy of TNK compared to alteplase in acute AIS within 4.5 h from symptom onset showed no significant difference between these two agents with regard to functional outcome at 90 days but improved median time to treatment and large vessel recanalization in TNK-treated patients. The results from ongoing TNK trials in larger patient cohorts and in wake-up stroke populations will be instrumental to the wide-scale utilization of TNK in acute AIS management.

Peak Width of Skeletonized Mean Diffusivity: A Neuroimaging Marker for White Matter Injury.

A leading cause of white matter (WM) injury in older individuals is cerebral small vessel disease (SVD). Cerebral SVD is the most prevalent vascular contributor to cognitive impairment and dementia. Therapeutic progress for cerebral SVD and other WM disorders depends on the development and validation of neuroimaging markers suitable as outcome measures in future interventional trials. Diffusion-tensor imaging (DTI) is one of the best-suited MRI techniques for assessing the extent of WM damage in the brain. But the optimal method to analyze individual DTI data remains hindered by labor-intensive and time-consuming processes. Peak width of skeletonized mean diffusivity (PSMD), a recently developed fast, fully automated DTI marker, was designed to quantify the WM damage secondary to cerebral SVD and reflect related cognitive impairment. Despite its promising results, knowledge about PSMD is still limited in the radiologic community. This focused review provides an overview of the technical details of PSMD while synthesizing the available data on its clinical and neuroimaging associations. From a critical expert viewpoint, the authors discuss the limitations of PSMD and its current validation status as a neuroimaging marker for vascular cognitive impairment. Finally, they point out the gaps to be addressed to further advance the field.

Poststroke Disability: Association Between Sex and Patient-Reported Outcomes.

BACKGROUND: Ischemic stroke (IS) is a leading cause of long-term disability with sex-specific differences in outcomes. Identifying the influential factors that contribute to sex-specific disparities in stroke outcomes, therefore, holds potential to develop individualized interventions for reducing long-term disability. Further, investigating the association between sex and Patient-Reported Outcome Measures (PROMs) provides additional information on the individual impact and heterogeneity of IS. We aimed to identify sex-specific differences in stroke outcomes and relationship with PROMs in IS patients with 3-month follow-up. METHODS: Between February 2017 and February 2020, a total of 410 patients admitted with IS to the Massachusetts General Hospital, in Boston, were enrolled in this prospective cohort. At 3-month poststroke, patients were assessed for Barthel Index, modified Rankin Scale, and PROM-10 questionnaires. T scores for physical and mental health were determined from the summing of PROM-10 responses in each domain. Regression analysis was performed to identify sex-specific determinants of functional and patient-reported outcomes. RESULTS: At baseline, 242 participants were male (mean age, 65 years) and 168 were female (mean age, 70 years). Groups had similar rates of cardiovascular risk factors, admission National Institutes of Health Stroke Scale, and discharge modified Rankin Scale. At follow-up, male participants were more likely to have better rates of T Physical and Barthel Index. In regression analysis, PROMs T Physical (odds ratio, 1.06; P=0.01), Barthel Index (odds ratio, 1.06; P=0.01), and modified Rankin Scale score of ≥2 (odds ratio, 2.60; P=0.01) were associated with female sex. Female sex was also associated with lower scores for PROMs Physical subcomponents and with patient-reported general health and emotional problems. CONCLUSIONS: Women have worse outcomes after ischemic stroke, including objective measures of functional disability and patient-reported outcomes. Incorporating PROMs into IS outcome measures may offer additional insight into sex-specific differences in stroke recovery and outcomes.

The relevance of rich club regions for functional outcome post-stroke is enhanced in women.

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

Radiomics-Derived Brain Age Predicts Functional Outcome After Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: While chronological age is one of the most influential determinants of poststroke outcomes, little is known of the impact of neuroimaging-derived biological "brain age." We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of patients with stroke will be associated with cardiovascular risk factors and worse functional outcomes. METHODS: We extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison with chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs and a logistic regression model of favorable functional outcomes taking RBA as input. RESULTS: We reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age = 62.8 years, 42.0% female patients). T2-FLAIR radiomics predicted chronological ages (mean absolute error = 6.9 years, r = 0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted odds ratios: 0.58, 0.76, 0.48, 0.55; all p-values < 0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes. DISCUSSION: T2-FLAIR radiomics can be used to predict brain age and derive RBA. Older-appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke.

Neuroimaging markers of patient-reported outcome measures in acute ischemic stroke.

Objectives: To determine the relationship between patient-reported outcome measures (PROMs) and volumetric imaging markers in acute ischemic stroke (AIS). Patients and Methods: Patients presenting at Massachusetts General Hospital between February 14, 2017 and February 5, 2020 with a confirmed AIS by MRI were eligible and underwent a telephone interview including PROM-10 questionnaires 3-15 months after stroke. White matter hyperintensity (VWMH) and brain volumes (VBrain) were automatically determined using admission clinical MRI. Stroke lesions were manually segmented and volumes calculated (VLesion). Multivariable and ordinal regression analyses were performed to identify associations between global and PROM-10 subscores with brain volumetrics and clinical variables. Results: Utilizing data from 167 patients (mean age: 64.7; 41.9% female), higher VWMH was associated with worse global physical (ß=-0.6), global mental (ß=-0.65), physical health (OR=0.68), social satisfaction (OR=0.66), fatigue (OR=0.69) and social activities (OR=0.59) scores. Higher VLesion was associated with poorer global mental (ß=-0.79), mental health (OR=0.68), physical (OR=0.66) and social activities (OR=0.55), and emotional distress (OR=0.68) scores. Higher VBrain was linked to better global mental (ß=0.93), global physical (ß=0.79), mental health (OR=1.54) and physical activities (OR=1.72) scores. Conclusions: Neuroimaging biomarkers were significantly associated with PROMs, where higher VWMH and VLesion led to worse outcome, while higher VBrain was protective. The inclusion of neuroimaging analyses and PROMs in routine assessment provides enhanced understanding of post-stroke outcomes.

Direct to angio-suite large vessel occlusion transfers achieve faster arrival-to-puncture times and improved outcomes.

Introduction: For patients with large vessel occlusion (LVO) stroke, time to treatment with endovascular thrombectomy (EVT) is crucial to prevent infarction and improve outcomes. We sought to evaluate the hub arrival-to-puncture times and outcomes for transferred patients accepted directly to the angio-suite (LVO2OR) versus those accepted through the emergency department (ED) in a hub-and-spoke telestroke network. Methods: Consecutive patients transferred for EVT with spoke CTA-confirmed LVO, spoke ASPECTS >6, and LKW-to-hub arrival <6 hours were identified. Our LVO2OR protocol began implementation in January 2017. The LVO2OR cohort includes patients who underwent EVT from July 2017 to October 2020; the ED cohort includes those from January 2011 to December 2016. Hub arrival-to-puncture time and 90-day modified Rankin Scale (mRS) were prospectively recorded. Results: The LVO2OR cohort was comprised of 91 patients and the ED cohort 90. LVO2OR patients had more atrial fibrillation (AF, 51% vs 32%, p=0.02) and more M2 occlusions (27% vs 10%, p=0.01). LVO2OR patients had faster median hub arrival-to-puncture time (11 vs 92 minutes, p<0.001), faster median telestroke consult-to-puncture time (2.4 vs 3.6 hours, p<0.001), greater TICI 2b-3 reperfusion (92% vs 69%, p<0.001), and greater 90-day mRS <2 (35% vs 21%, p=0.04). In a multivariable model, LVO2OR significantly increased the odds of 90-day mRS <2 (aOR 2.77, 95%CI 1.07,7.20; p=0.04) even when controlling for age, baseline mRS, AF, NIHSS, M2 location, and TICI 2b-3. Conclusion: In a hub-and-spoke telestroke network, accepting transferred patients directly to the angio-suite was associated with dramatically reduced hub arrival-to-puncture time and may lead to improved 90-day outcomes. Direct-to-angio-suite protocols should continue to be evaluated in other regions and telestroke models.

Peak width of skeletonized mean diffusivity in cerebral amyloid angiopathy: Spatial signature, cognitive, and neuroimaging associations.

Background: Peak width of skeletonized mean diffusivity (PSMD) is a promising diffusion tensor imaging (DTI) marker that shows consistent and strong cognitive associations in the context of different cerebral small vessel diseases (cSVD). Purpose: Investigate whether PSMD (1) is higher in patients with Cerebral Amyloid Angiopathy (CAA) than those with arteriolosclerosis; (2) can capture the anteroposterior distribution of CAA-related abnormalities; (3) shows similar neuroimaging and cognitive associations in comparison to other classical DTI markers, such as average mean diffusivity (MD) and fractional anisotropy (FA). Materials and methods: We analyzed cross-sectional neuroimaging and neuropsychological data from 90 non-demented memory-clinic subjects from a single center. Based on MRI findings, we classified them into probable-CAA (those that fulfilled the modified Boston criteria), subjects with MRI markers of cSVD not attributable to CAA (presumed arteriolosclerosis; cSVD), and subjects without evidence of cSVD on MRI (non-cSVD). We compared total and lobe-specific (frontal and occipital) DTI metrics values across the groups. We used linear regression models to investigate how PSMD, MD, and FA correlate with conventional neuroimaging markers of cSVD and cognitive scores in CAA. Results: PSMD was comparable in probable-CAA (median 4.06 × 10-4 mm2/s) and cSVD (4.07 × 10-4 mm2/s) patients, but higher than in non-cSVD (3.30 × 10-4 mm2/s; p < 0.001) subjects. Occipital-frontal PSMD gradients were higher in probable-CAA patients, and we observed a significant interaction between diagnosis and region on PSMD values [F(2, 87) = 3.887, p = 0.024]. PSMD was mainly associated with white matter hyperintensity volume, whereas MD and FA were also associated with other markers, especially with the burden of perivascular spaces. PSMD correlated with worse executive function (ß = -0.581, p < 0.001) and processing speed (ß = -0.463, p = 0.003), explaining more variance than other MRI markers. MD and FA were not associated with performance in any cognitive domain. Conclusion: PSMD is a promising biomarker of cognitive impairment in CAA that outperforms other conventional and DTI-based neuroimaging markers. Although global PSMD is similarly increased in different forms of cSVD, PSMD's spatial variations could potentially provide insights into the predominant type of underlying microvascular pathology.

Characterizing reasons for stroke thrombectomy ineligibility among potential candidates transferred in a hub-and-spoke network.

Background: Access to endovascular thrombectomy (EVT) is relatively limited. Hub-and-spoke networks seek to transfer appropriate large vessel occlusion (LVO) candidates to EVT-capable hubs. However, some patients are ineligible upon hub arrival, and factors that drive transfer inefficiencies are not well described. We sought to quantify EVT transfer efficiency and identify reasons for EVT ineligibility. Methods: Consecutive EVT candidates presenting to 25 spokes from 2018-2020 with pre-transfer CTA-defined LVO and ASPECTS ≥6 were identified from a prospectively maintained database. Outcomes of interest included hub EVT, reasons for EVT ineligibility, and 90-day modified Rankin Scale (mRS) ≤2. Results: Among 258 patients, the median age was 70 years (IQR 60-81); 50% were female. 56% were ineligible for EVT after hub arrival. Cited reasons were large established infarct (49%), mild symptoms (33%), recanalization (6%), distal occlusion (5%), sub-occlusive lesion (3%), and goals of care (3%). Late window patients [last known well (LKW) >6 hours] were more likely to be ineligible (67% vs 43%, P<0.0001). EVT ineligible patients were older (73 vs 68 years, p=0.04), had lower NIHSS (10 vs 16, p<0.0001), longer LKW-hub arrival time (8.4 vs 4.6 hours, p<0.0001), longer spoke Telestroke consult-hub arrival time (2.8 vs 2.2 hours, p<0.0001), and received less intravenous thrombolysis (32% vs 45%, p=0.04) compared to eligible patients. EVT ineligibility independently reduced the odds of 90-day mRS≤2 (aOR=0.26, 95%CI=0.12,0.56; p=0.001) when controlling for age, NIHSS, and LKW-hub arrival time. Conclusions: Among patients transferred for EVT, there are multiple reasons for ineligibility upon hub arrival, with most excluded for infarct growth and mild symptoms. Understanding factors that drive transfer inefficiencies is important to improve EVT access and outcomes.

Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics.

Background purpose: A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort. Materials and methods: Analyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome. Results: We analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p FDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p FDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL. Conclusion: Multiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only.

Association of Stroke Lesion Pattern and White Matter Hyperintensity Burden With Stroke Severity and Outcome.

BACKGROUND AND OBJECTIVES: To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. METHODS: MR neuroimaging and NIH Stroke Scale data at index stroke and the modified Rankin Scale (mRS) score at 3-6 months after stroke were obtained from the MRI-Genetics Interface Exploration study of patients with acute ischemic stroke (AIS). Individual WMH volume was automatically derived from fluid-attenuated inversion recovery images. Stroke lesions were automatically segmented from diffusion-weighted imaging (DWI) images, parcellated into atlas-defined brain regions and further condensed to 10 lesion patterns via machine learning-based dimensionality reduction. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS score >2) were modeled within purpose-built Bayesian linear and logistic regression frameworks. Interaction effects between stroke lesions and a high vs low WMH burden were integrated via hierarchical model structures. Models were adjusted for age, age2, sex, total DWI lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts. RESULTS: A total of 928 patients with AIS contributed to acute stroke severity analyses (age: 64.8 [14.5] years, 40% women) and 698 patients to long-term functional outcome analyses (age: 65.9 [14.7] years, 41% women). Stroke severity was mainly explained by lesions focused on bilateral subcortical and left hemispherically pronounced cortical regions across patients with both a high and low WMH burden. Lesions centered on left-hemispheric insular, opercular, and inferior frontal regions and lesions affecting right-hemispheric temporoparietal regions had more pronounced effects on stroke severity in case of high compared with low WMH burden. Unfavorable outcomes were predominantly explained by lesions in bilateral subcortical regions. In difference to the lesion location-specific WMH effects on stroke severity, higher WMH burden increased the odds of unfavorable outcomes independent of lesion location. DISCUSSION: Higher WMH burden may be associated with an increased stroke severity in case of stroke lesions involving left-hemispheric insular, opercular, and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporoparietal regions (potentially linked to attention). Our findings suggest that patients with specific constellations of WMH burden and lesion locations may have greater benefits from acute recanalization treatments. Future clinical studies are warranted to systematically assess this assumption and guide more tailored treatment decisions.

Utilization of Telestroke Prior to and Following the COVID-19 Pandemic.

For over two decades, telestroke has been utilized as a means for improving acute access to a stroke specialist when this expertise is otherwise unavailable. During this time, telestroke use has increased and improvements in care metrics have been widely reported. Several telestroke model variations are utilized; each has different workflow implications. A successful telestroke system should include adequate protocols and training, equipment, documentation system, and tracking of quality metrics. Upfront costs of needed technology and devices, credentialing hurdles, and limited reimbursement are all reported barriers to the utilization of telestroke. Emphasis on safety measures during the COVID-19 pandemic resulted in the dramatic upscaling of telehealth utilization, although overall stroke volumes declined in many areas in the early phases of the pandemic. Going forward, continued reduction in cost of required devices and broadband connections, increased use of automated and advanced analytical software, and a universal licensing and credentialing system are needed to continue the expansion of telestroke use.

Chronic Stroke Sensorimotor Impairment Is Related to Smaller Hippocampal Volumes: An ENIGMA Analysis.

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper-limb sensorimotor impairment. We investigated associations between non-lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross-sectional T1-weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta-Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA-UE (Fugl-Meyer Assessment of Upper Extremity). Robust mixed-effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni-corrected, P<0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional (P=0.005; ß=0.16) but not contralesional (P=0.96; ß=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; ß=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; ß=-0.26) and contralesional (P=0.006; ß=-0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; ß=-0.21) and extent of sensorimotor damage (P=0.003; ß=-0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women.

Sex-specific lesion pattern of functional outcomes after stroke.

Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.

Association of Infarct Topography and Outcome After Endovascular Thrombectomy in Patients With Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: The care of patients with large vessel occlusion (LVO) stroke has been revolutionized by endovascular thrombectomy (EVT). While EVT has a large effect size, most patients treated with EVT remain disabled or die within 90 days. A better understanding of outcomes may influence EVT selection criteria, novel therapies, and prognostication. We sought to identify associations between outcomes and brain regions involved in ischemic lesions. METHODS: For this cohort study, consecutive patients with LVO who were treated with EVT and underwent post-EVT MRI were identified from a tertiary referral center (2011-2019). Acute ischemic lesions were manually segmented from diffusion-weighted imaging and spatially normalized. Individual lesions were parcellated (atlas-defined 94 cortical regions, 14 subcortical nuclei, 20 white matter tracts) and reduced to 10 essential lesion patterns with the use of unsupervised dimensionality reduction techniques. Ninety-day modified Rankin Scale (mRS) score (>2) was modeled via bayesian regression, taking the 10 lesion patterns as inputs and controlling for lesion size, age, sex, acute NIH Stroke Scale (NIHSS) score, alteplase, prior stroke, intracerebral hemorrhage, and good reperfusion (Thrombolysis in Cerebral Infarction 2b-3). In comparative analyses, 90-day mRS score was modeled considering covariates only, and compartment-wise relevances for acute stroke severity and 90-day mRS score were evaluated. RESULTS: There were 151 patients with LVO identified (age 68 ± 15 years, 52% female). The median NIHSS score was 16 (interquartile range 13-20); 56% had mRS score >2. Lesion locations predictive of 90-day mRS score involved bilateral but left hemispherically more pronounced precentral and postcentral gyri, insular and opercular cortex, and left putamen and caudate (area under the curve 0.91, highest probability density interval [HPDI] covering 90% certainty 0.90-0.92). The lesion location model outperformed the simpler model relying on covariates only (bayesian model comparison of 97% weight to the model with vs 3% weight to the model without lesion location). While lesions affecting subcortical nuclei had the highest relevance for stroke severity (posterior distribution mean 0.75, 90% HPDI 0.256-1.31), lesions affecting white matter tracts had the highest relevance for 90-day mRS score (0.656, 90% HPDI 0.0864-1.12). DISCUSSION: These data describe the significance for outcomes of specific brain regions involved in ischemic lesions on MRI after EVT. Future work in additional datasets is needed to confirm these granular findings.

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

Radiomic signature of DWI-FLAIR mismatch in large vessel occlusion stroke.

BACKGROUND AND PURPOSE: Ischemic diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR) mismatch may be useful in guiding acute stroke treatment decisions given its relationship to onset time and parenchymal viability; however, it relies on subjective grading. Radiomics is an emerging image quantification methodology that may objectively represent continuous image characteristics. We propose a novel radiomics approach to characterize DWI-FLAIR mismatch. METHODS: Ischemic lesions were visually graded for FLAIR positivity (absent, subtle, obvious) among consecutive large vessel occlusion stroke patients who underwent hyperacute MRI. Radiomic features were extracted from within the lesions on DWI and FLAIR. The DWI-FLAIR mismatch radiomics signature was built with features systematically selected by a cross-validated ElasticNet linear regression model of mismatch. RESULTS: We identified 103 patients with mean age 68 ± 16 years; 63% were female. FLAIR hyperintensity was absent in 25%, subtle in 55%, and obvious in 20%. Inter-rater agreement for visual grading was moderate (Κ = .58). The radiomics signature of DWI-FLAIR mismatch included native FLAIR histogram kurtosis and local binary pattern-filtered FLAIR gray-level cluster shade; both correlated with visual grading (ρ = -.42, p < .001 and ρ = .40, p < .001, respectively). CONCLUSIONS: Radiomics can describe DWI-FLAIR mismatch and may provide objective, continuous biomarkers for infarct evolution using clinical-grade images. These novel biomarkers may prove useful for treatment decisions and future research.

Sex-specific differences in presentations and determinants of outcomes after endovascular thrombectomy for large vessel occlusion stroke.

INTRODUCTION: Sex-specific differences in ischemic stroke outcomes are prevalent. We sought to investigate sex differences in the determinants of reperfusion and functional outcomes after endovascular thrombectomy (EVT) for emergent large vessel occlusion ischemic stroke (ELVO). METHODS: Patients presenting to a single referral center with an anterior circulation ELVO that underwent EVT from 2011 to 2019 were included in this retrospective analysis. Sex differences in history, presentation, adequate reperfusion (TICI 2b-3), and 90-day good outcome [delta modified Rankin Scale (mRS) ≤ 2 from pre-stroke] were examined. Multivariable logistic regression analyses were performed to assess sex-specific associations with outcomes. RESULTS: Three hundred and eighty-one consecutive ELVO patients were identified. Women (N = 193) were older (75 vs 64 years, p < 0.0001), had more pre-stroke disability (17% vs 9%, p = 0.032), more atrial fibrillation (41% vs 30%, p = 0.033), but less carotid atherosclerosis (8% vs 16%, p = 0.027). Rates of TICI 2b-3 and good outcome were similar between sexes. Carotid atherosclerosis (OR 0.315, 95% CI 0.130, 0.762) and dissection (OR 0.124, 95% CI 0.027, 0.569) independently decreased the odds of TICI 2b-3 among men but not women. Older age, more severe stroke, and not achieving TICI 2b-3 independently decreased the odds of good outcome among both sexes, while prior stroke (OR 0.258, 95% CI 0.083, 0.797) and hemorrhagic transformation (OR 0.111, 0.021, 0.592) were determinants exclusive to men. CONCLUSION: In a real-world analysis of ELVO stroke patients treated with EVT, we found that despite advanced age and more pre-stroke disability, women have comparable reperfusion rates and functional outcomes compared to men. Sex-specific determinants of reperfusion and functional outcome were identified that require further study.

Global white matter structural integrity mediates the effect of age on ischemic stroke outcomes.

BACKGROUND: The relationship of global white matter microstructural integrity and ischemic stroke outcomes is not well understood. AIMS: To investigate the relationship of global white matter microstructural integrity with clinical variables and functional outcomes after acute ischemic stroke. METHODS: A retrospective analysis of neuroimaging data from 300 acute ischemic stroke patients with magnetic resonance imaging brain obtained within 48 hours of stroke onset and long-term functional outcomes (modified Rankin, mRS) was performed. Peak width of skeletonized mean diffusivity (PSMD), as a measure of global white matter microstructural injury, was calculated in the hemisphere contralateral to the acute infarct. Multivariable linear and logistic regression analyses were performed to identify variables associated with PSMD and excellent functional outcome (mRS < 2) at 90 days, respectively. Mediation analysis was then pursued to characterize how PSMD mediates the effect of age on acute ischemic stroke functional outcomes. RESULTS: White matter hyperintensity volume, age, pre-stroke disability, and normal-appearing white matter mean diffusivity were independently associated with increased PSMD. In logistic regression analysis, increased infarct volume and PSMD were independent predictors of excellent functional outcome. Additionally, the effect of age on functional outcomes was indirectly mediated by PSMD (P < 0.001). CONCLUSIONS: As a marker of global white matter microstructural injury, increased PSMD mediates the effect of increased age to contribute to poor acute ischemic stroke functional outcomes. PSMD could serve as a putative radiographic marker of brain age for stroke outcomes prognostication.