International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

Lindgren, Arne; Braun, Robynne; Majersik, Jennifer J.; Clatworthy, Philip; Mainali, Shraddha; Derdeyn, Colin P.; Maguire, Jane; Jern, Christina; Rosand, Jonathan; Cole, John W.; J, Lee; Khatri, Pooja; Nyquist, Paul; Debette, Stéphanie; Wei, Loo Keat; Rundek, Tatjana; Leifer, Dana; Thijs, Vincent; Lemmens, Robin; Heitsch, Laura; Prasad, Kameshwar; Conde, Jordi Jiménez; Dichgans, Martin; Rost, Natalia S.; Cramer, Steven C.; Bernhardt, Julie; Worrall, Bradford B.; Fernández‐Cadenas, Israel

doi:10.1177/17474930211007288

Cited by 15 publications

(28 citation statements)

References 55 publications

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“…We here only assessed rather coarse-grained behavioral outcomes – with the additional limitation that the NIHS Scale is known to result in higher scores for left-hemispheric lesions. 39 Future studies could therefore specify the impact of WMH and stroke lesion interaction effects on language outcomes or individual NIHSS items as a first step, 40 corroborate the detrimental effects and estimate their clinical relevance further. Conceivably, a more consistent consideration of the WMH burden in models of language-related outcomes may substantially increase the prediction performance.…”

Section: Discussionmentioning

confidence: 99%

Lesions in putative language and attention regions are linked to more severe strokes in patients with higher white matter hyperintensity burden

Bonkhoff

Hong

Bretzner

et al. 2021

Preprint

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ObjectiveTo examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways.MethodsMR neuroimaging and National Institutes of Health Stroke Scale data at index stroke, as well as modified Rankin Scale (mRS) at 3-6 months post-stroke were obtained from MRI-GENIE study of acute ischemic stroke (AIS) patients. Individual WMH volume was automatically derived from FLAIR-images. Stroke lesions were automatically segmented from DWI-images, spatially normalized and parcellated into atlas-defined brain regions. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS>2) were modeled within a purpose-built machine learning and Bayesian regression framework. In particular, interaction effects between stroke lesions and a high versus low WMH burden were integrated via hierarchical model structures. Models were adjusted for the covariates age, age2, sex, total DWI-lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts.ResultsA total of 928 AIS patients contributed to stroke severity analyses (mean age: 64.8(14.5), 40% women), 698 patients to functional outcome analyses (mean age: 65.9(14.7), 41% women). Individual stroke lesions were represented in five anatomically distinct left-hemispheric and five right-hemispheric lesion patterns. Across all patients, acute stroke severity was substantially explained by three of these patterns, that were particularly focused on bilateral subcortical and left-hemispherically pronounced cortical regions. In high WMH burden patients, two lesion patterns consistently emerged as more pronounced in case of stroke severity: the first pattern was centered on left-hemispheric insular, opercular and inferior frontal regions, while the second pattern combined right-hemispheric temporo-parietal regions. Bilateral subcortical regions were most relevant in explaining long term unfavorable outcome. No WMH-specific lesion patterns of functional outcomes were substantiated. However, a higher overall WMH burden was associated with higher odds of unfavorable outcomes.ConclusionsHigher WMH burden increases stroke severity in case of stroke lesions involving left-hemispheric insular, opercular and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporo-parietal regions (potentially linked to attention). These findings may contribute to augment stroke outcome predictions and motivate a WMH burden and stroke lesion pattern-specific clinical management of AIS patients.

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Section: Discussionmentioning

confidence: 99%

Lesions in putative language and attention regions are linked to more severe strokes in patients with higher white matter hyperintensity burden

Bonkhoff

Hong

Bretzner

et al. 2021

Preprint

Self Cite

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“…It is important to consider both stroke outcome which describes the degree of function at specific time points; and stroke recovery which comprises the degree of improvement (or deterioration) over time and may better identify dynamic biological processes. 10 We highlight the importance of dynamic phenotypes that may capture mechanisms involved in the injury-repair timeline following stroke. We discuss how genetic studies, including GWASs, can exploit these phenotypes to uncover genes and pathways that shape stroke outcome, from early brain injury to long-term recovery.…”

Section: Lee Et Almentioning

confidence: 99%

“…But there is a risk that the phenotyping is not harmonized between the studies and may also be of insufficient detail to perform studies of quantitative endophenotypes. 10 GWAS can be used to study copy number variations, and one study reported that genetic imbalance is related to poor 3-month outcome after stroke. 59 Other genetic approaches, such as whole-exome sequencing or whole-genome sequencing, are promising, but the implementation due to high costs is still limited.…”

Section: Using Genetics To Explore Mechanisms Underlying Stroke Outcomementioning

confidence: 99%

Using Human Genetics to Understand Mechanisms in Ischemic Stroke Outcome: From Early Brain Injury to Long-Term Recovery

Fernández‐Cadenas²,

Lindgren

2021

Stroke

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There is a critical need to elucidate molecular mechanisms underlying brain injury, repair, and recovery following ischemic stroke—a global health problem with major social and economic impact. Despite 5 decades of intensive research, there are no widely accepted neuroprotective drugs that mitigate ischemic brain injury, or neuroreparative drugs, or personalized approaches that guide therapies to enhance recovery. We here explore novel reverse translational approaches that will complement traditional forward translational methods in identifying mechanisms relevant to human stroke outcome. Although genome-wide association studies have yielded over 30 genetic loci that influence ischemic stroke risk, only a few genome-wide association studies have been performed for stroke outcome. We discuss important considerations for genetic studies of ischemic stroke outcome—including carefully designed phenotypes that capture injury/recovery mechanisms, anchored in time to stroke onset. We also address recent genome-wide association studies that provide insight into mechanisms underlying brain injury and repair. There are several ongoing initiatives exploring genomic associations with novel phenotypes related to stroke outcome. To improve the understanding of the genetic architecture of ischemic stroke outcome, larger studies using standardized phenotypes, preferably embedded in standard-of-care measures, are needed. Novel techniques beyond genome-wide association studies—including exploiting informatics, multi-omics, and novel analytics—promise to uncover genetic and molecular pathways from which drug targets and other new interventions may be identified.

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“…Such studies require data from thousands of cases, and data collection and outcomes need to be standardized across these different cohorts. 3 An useful framework for design of these studies is presented in a consensus paper from the International Stroke Genetics Consortium in this issue. It makes an important reading for anyone planning to carry out studies in this area.…”

mentioning

confidence: 99%

“…It makes an important reading for anyone planning to carry out studies in this area. 3 A potentially exciting novel treatment approach is environmental enrichment. This has been shown to improve recovery in animal models of stroke, promoting brain plasticity and enhancing sensory motor recovery with the greatest gains made when used in conjunction with motor retraining.…”

mentioning

confidence: 99%

Reducing disability after stroke

Markus¹

2022

International Journal of Stroke

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International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

Cited by 15 publications

References 55 publications

Lesions in putative language and attention regions are linked to more severe strokes in patients with higher white matter hyperintensity burden

Lesions in putative language and attention regions are linked to more severe strokes in patients with higher white matter hyperintensity burden

Using Human Genetics to Understand Mechanisms in Ischemic Stroke Outcome: From Early Brain Injury to Long-Term Recovery

Reducing disability after stroke

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