Imaging markers of small vessel disease and brain frailty, and outcomes in acute stroke

Appleton, Jason P.; Woodhouse, Lisa J; Adami, Alessandro; Becker, Jennifer; Berge, Eivind; Cala, L.A.; Casado, Ana M.; Caso, Valeria; Christensen, Hanne; Dineen, Robert A.; Gommans, John; Koumellis, Panos; Szatmári, Szabolcs; Sprigg, Nikola; Bath, Philip M; Wardlaw, Joanna M.

doi:10.1212/wnl.0000000000008881

Cited by 101 publications

(145 citation statements)

References 34 publications

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“…Associated short-term with infarct growth ( n = 61) [ 28 ] and poor functional outcomes ( n = 4011) [ 29 ] in stroke, SVD effects outlast the acute phase, contributing increased risk long-term of recurrent ischaemic stroke, disability, dementia, and death ( n = 71,298). [ 30 ]…”

Section: Defining the Natural History Of Clinical Cerebral Small Vessmentioning

confidence: 99%

“…SVD substantially limits independence, contributing to functional impairment, [ 29 ] stroke recurrence, dementia, and mortality after stroke, [ 30 ] as well as functional decline and mortality in non-disabled adults. [ 50 ] SVD is associated with longer hospital lengths of stay in cognitively impaired, [ 51 ] and earlier institutionalization in stroke patients.…”

Section: Defining the Natural History Of Clinical Cerebral Small Vessmentioning

confidence: 99%

“…[ 2 ] These lesions are individually and collectively associated with increased risk of stroke, cognitive decline and dementia, and poor functional outcomes after stroke, and are highly heritable. [ 29 , 30 , 50 , 79 ]…”

Section: Risk Factors For Svd and Its Progressionmentioning

confidence: 99%

“…Several MRI scoring systems can be easily applied by clinicians to characterize SVD severity, many of which can predict clinical outcomes. The Fazekas scale is commonly used to evaluate WMH on MRI and can be used on CT. [ 78 ] Similarly, while less sensitive than MRI-based scores, equivalent CT-based scores for total SVD and “brain frailty” [ 29 ] predict poor functional outcome and cognitive impairment after stroke. [ 29 , 30 ] A simple and pragmatic score that may provide a more complete estimate of the full impact of SVD on the brain is the total SVD score (counting the presence of WMH, lacunes, CMB, and PVS on MRI as an ordinal score of 0 to 4), which could have potential for patient risk stratification.…”

Section: Risk Factors For Svd and Its Progressionmentioning

confidence: 99%

“…The Fazekas scale is commonly used to evaluate WMH on MRI and can be used on CT. [ 78 ] Similarly, while less sensitive than MRI-based scores, equivalent CT-based scores for total SVD and “brain frailty” [ 29 ] predict poor functional outcome and cognitive impairment after stroke. [ 29 , 30 ] A simple and pragmatic score that may provide a more complete estimate of the full impact of SVD on the brain is the total SVD score (counting the presence of WMH, lacunes, CMB, and PVS on MRI as an ordinal score of 0 to 4), which could have potential for patient risk stratification. [ 70 ] Despite the increasing availability of MRI and limitations of CT, CT continues to be the most widely used neuroimaging tool in patients with neurological or neuropsychiatric symptoms, and can provide valuable information for SVD assessment.…”

Section: Risk Factors For Svd and Its Progressionmentioning

confidence: 99%

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Clinical management of cerebral small vessel disease: a call for a holistic approach

Clancy

Appleton

Arteaga

et al. 2020

Chinese Medical Journal

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Cerebral small vessel disease (SVD) is a common global brain disease that causes cognitive impairment, ischemic or hemorrhagic stroke, problems with mobility, and neuropsychiatric symptoms. The brain damage, seen as focal white and deep grey matter lesions on brain magnetic resonance imaging (MRI) or computed tomography (CT), typically accumulates “covertly” and may reach an advanced state before being detected incidentally on brain scanning or causing symptoms. Patients have typically presented to different clinical services or been recruited into research focused on one clinical manifestation, perhaps explaining a lack of awareness, until recently, of the full range and complexity of SVD. In this review, we discuss the varied clinical presentations, established and emerging risk factors, relationship to SVD features on MRI or CT, and the current state of knowledge on the effectiveness of a wide range of pharmacological and lifestyle interventions. The core message is that effective assessment and clinical management of patients with SVD, as well as future advances in diagnosis, care, and treatment, will require a more “joined-up”’ approach. This approach should integrate clinical expertise in stroke neurology, cognitive, and physical dysfunctions. It requires more clinical trials in order to improve pharmacological interventions, lifestyle and dietary modifications. A deeper understanding of the pathophysiology of SVD is required to steer the identification of novel interventions. An essential prerequisite to accelerating clinical trials is to improve the consistency, and standardization of clinical, cognitive and neuroimaging endpoints.

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Section: Defining the Natural History Of Clinical Cerebral Small Vessmentioning

confidence: 99%

Section: Defining the Natural History Of Clinical Cerebral Small Vessmentioning

confidence: 99%

Section: Risk Factors For Svd and Its Progressionmentioning

confidence: 99%

Section: Risk Factors For Svd and Its Progressionmentioning

confidence: 99%

Section: Risk Factors For Svd and Its Progressionmentioning

confidence: 99%

See 3 more Smart Citations

Clinical management of cerebral small vessel disease: a call for a holistic approach

Clancy

Appleton

Arteaga

et al. 2020

Chinese Medical Journal

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Assessment of Discrepancies Between Follow-up Infarct Volume and 90-Day Outcomes Among Patients With Ischemic Stroke Who Received Endovascular Therapy

et al. 2021

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IMPORTANCE Some patients have poor outcomes despite small infarcts after endovascular therapy (EVT), while others with large infarcts do well. Understanding why these discrepancies occur may help to optimize EVT outcomes. OBJECTIVETo validate exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment-related, and posttreatment factors associated with discrepancies between follow-up infarct volume (FIV) and 90-day functional outcome. DESIGN, SETTING, AND PARTICIPANTS This cohort study is a post hoc analysis of the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, a double-blind, randomized, placebo-controlled, international, multicenter trial conducted from March 2017 to August 2019. Patients who participated in ESCAPE-NA1 and had available 90-day modified Rankin Scale (mRS) scores and 24-hour to 48-hour posttreatment follow-up parenchymal imaging were included. EXPOSURES Small FIV (volume Յ25th percentile) and large FIV (volume Ն75th percentile) on 24-hour computed tomography/magnetic resonance imaging. Baseline factors, outcomes, treatments, and poststroke serious adverse events (SAEs) were compared between discrepant cases (ie, patients with 90-day mRS score Ն3 despite small FIV or those with mRS scores Յ2 despite large FIV) and nondiscrepant cases. MAIN OUTCOMES AND MEASURES Area under the curve (AUC) and goodness of fit of prespecified logistic models, including pretreatment (eg, age, cancer, vascular risk factors) and treatment-related and posttreatment (eg, SAEs) factors, were compared with stepwise regression-derived models for ability to identify small FIV with higher mRS score and large FIV with lower mRS score. RESULTS Among 1091 patients (median [IQR] age, 70.8 [60.8-79.8] years; 549 [49.7%] women;median [IQR] FIV, 24.9 mL [6.6-92.2 mL]), 42 of 287 patients (14.6%) with FIV of 7 mL or less (ie, Յ25th percentile) had an mRS score of at least 3; 65 of 275 patients (23.6%) with FIV of 92 mL or greater (ie, Ն75th percentile) had an mRS score of 2 or less. Prespecified models of pretreatment factors (ie, age, cancer, vascular risk factors) associated with low FIV and higher mRS score performed similarly to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42). SAEs, specifically infarct in new territory, recurrent stroke, pneumonia, and congestive heart failure, were associated with low FIV and higher mRS scores; stepwise models also identified 24-hour hemoglobin as treatment-related/posttreatment factor (continued) Key Points Question Why do some patients have poor outcomes despite small infarcts after endovascular therapy, while others with large infarcts fare better? Findings In this cohort study of 1091 patients who received endovascular therapy as part of a randomized clinical trial, discrepancies between infarct volume and function...

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Mediation of Age and Thrombectomy Outcome by Neuroimaging Markers of Frailty in Patients With Stroke

Benali,

Singh,

Fladt

et al. 2024

JAMA Netw Open

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ImportanceAge is a leading predictor of poor outcomes after brain injuries like stroke. The extent to which age is associated with preexisting burdens of brain changes, visible on neuroimaging but rarely considered in acute decision-making or trials, is unknown.ObjectivesTo explore the mediation of age on functional outcome by neuroimaging markers of frailty (hereinafter neuroimaging frailty) in patients with acute ischemic stroke receiving endovascular thrombectomy (EVT).Design, Setting, and ParticipantsThis cohort study was a post hoc analysis of the Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) randomized clinical trial, which investigated intravenous (IV) nerinetide in patients who underwent EVT within a 12-hour treatment window. Patients from 48 acute care hospitals in 8 countries (Canada, US, Germany, Korea, Australia, Ireland, UK, and Sweden) were enrolled between March 1, 2017, and August 12, 2019. Markers of brain frailty (brain atrophy [subcortical or cortical], white matter disease [periventricular or deep], and the number of lacunes and chronic infarctions) were retrospectively assessed while reviewers were blinded to other imaging (eg, computed tomography angiography, computed tomography perfusion) or outcome variables. All analyses were done between December 1, 2022, and January 31, 2023.ExposuresAll patients received EVT and were randomized to IV nerinetide (2.6 mg/kg of body weight) and alteplase (if indicated) treatment vs best medical management.Main Outcome and MeasuresThe primary outcome was the proportion of the total effect of age on 90-day outcome, mediated by neuroimaging frailty. A combined mediation was also examined by clinical features associated with frailty and neuroimaging markers (total frailty). Structural equation modeling was used to create latent variables as potential mediators, adjusting for baseline, early ischemic changes; stroke severity; onset-to-puncture time; nerinetide treatment; and alteplase treatment.ResultsAmong a total of 1105 patients enrolled in the study, 1102 (median age, 71 years [IQR, 61-80 years]; 554 [50.3%] male) had interpretable imaging at baseline. Of these participants, 549 (49.8%) were treated with IV nerinetide. The indirect effect of age on 90-day outcome, mediated by neuroimaging frailty, was associated with 85.1% of the total effect (β coefficient, 0.04 per year [95% CI, 0.02-0.06 per year]; P &lt; .001). When including both frailty constructs, the indirect pathway was associated with essentially 100% of the total effect (β coefficient, 0.07 per year [95% CI, 0.03-0.10 per year]; P = .001).Conclusions and RelevanceIn this cohort study, a secondary analysis of the ESCAPE-NA1 trial, most of the association between age and 90-day outcome was mediated by neuroimaging frailty, underscoring the importance of features like brain atrophy and small vessel disease, as opposed to chronological age alone, in predicting poststroke outcomes. Future trials could include such frailty features to stratify randomization or improve adjustment in outcome analyses.

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Imaging markers of small vessel disease and brain frailty, and outcomes in acute stroke

Cited by 101 publications

References 34 publications

Clinical management of cerebral small vessel disease: a call for a holistic approach

Clinical management of cerebral small vessel disease: a call for a holistic approach

Assessment of Discrepancies Between Follow-up Infarct Volume and 90-Day Outcomes Among Patients With Ischemic Stroke Who Received Endovascular Therapy

Mediation of Age and Thrombectomy Outcome by Neuroimaging Markers of Frailty in Patients With Stroke

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