Publications by authors named "Joanna M Wardlaw"

469 Publications

A Stroke Is a Stroke, With or Without a Visible Infarct.

Authors:
Joanna M Wardlaw

Neurology 2021 Jul 21. Epub 2021 Jul 21.

Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh

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http://dx.doi.org/10.1212/WNL.0000000000012540DOI Listing
July 2021

Relationship between inferior frontal sulcal hyperintensities on brain MRI, ageing and cerebral small vessel disease.

Neurobiol Aging 2021 Jun 21;106:130-138. Epub 2021 Jun 21.

Centre for Clinical Brain Science, Edinburgh Imaging and UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK. Electronic address:

Raised signal in cerebrospinal fluid (CSF) on fluid-attenuated inversion recovery (FLAIR) may indicate raised CSF protein or debris and is seen in inferior frontal sulci on routine MRI. To explore its clinical relevance, we assessed the association of inferior frontal sulcal hyperintensities (IFSH) on FLAIR with demographics, risk factors, and small vessel disease markers in three cohorts (healthy volunteers, n=44; mild stroke patients, n=105; older community-dwelling participants from Lothian birth cohort 1936, n=101). We collected detailed clinical data, scanned all subjects on the same 3T MRI scanner and 3-dimensional FLAIR sequence and developed a scale to rate IFSH. In adjusted analyses, the IFSH score increased with age (per 10-year increase; OR 1.69; 95% CI, 1.42-2.02), and perivascular spaces score in centrum semiovale in stroke patients (OR 1.73; 95% CI, 1.13-2.69). Since glymphatic CSF clearance declines with age and drains partially via the cribriform plate to the nasal lymphatics, IFSH on 3T MRI may be a non-invasive biomarker of altered CSF clearance and justifies further research in larger, more diverse samples.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.06.013DOI Listing
June 2021

Reply to: Rethink the classical view of cerebrospinal fluid production.

Nat Rev Neurol 2021 Jul 12. Epub 2021 Jul 12.

Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1038/s41582-021-00539-zDOI Listing
July 2021

Response to Schroeter ML, Letter, Small vessel disease and social cognition.

Alzheimers Dement 2021 Jun 22. Epub 2021 Jun 22.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1002/alz.12402DOI Listing
June 2021

A Comparison of CVR Magnitude and Delay Assessed at 1.5 and 3T in Patients With Cerebral Small Vessel Disease.

Front Physiol 2021 2;12:644837. Epub 2021 Jun 2.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Background: Cerebrovascular reactivity (CVR) measures blood flow change in response to a vasoactive stimulus. Impairment is associated with several neurological conditions and can be measured using blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI). Field strength affects the BOLD signal, but the effect on CVR is unquantified in patient populations.

Methods: We recruited patients with minor ischemic stroke and assessed CVR magnitude and delay time at 3 and 1.5 Tesla using BOLD MRI during a hypercapnic challenge. We assessed subcortical gray (GM) and white matter (WM) differences using Wilcoxon signed rank tests and scatterplots. Additionally, we explored associations with demographic factors, WM hyperintensity burden, and small vessel disease score.

Results: Eighteen of twenty patients provided usable data. At 3T vs. 1.5T: mean CVR magnitude showed less variance (WM 3T: 0.062 ± 0.018%/mmHg, range 0.035, 0.093; 1.5T: 0.057 ± 0.024%/mmHg, range 0.016, 0.094) but was not systematically higher (Wilcoxon signal rank tests, WM: = -0.33, confidence interval (CI): -0.013, 0.003, = 0.167); delay showed similar variance (WM 3T: 40 ± 12 s, range: 12, 56; 1.5T: 31 ± 13 s, range 6, 50) and was shorter in GM ( = 0.33, CI: -2, 9, = 0.164) and longer in WM ( = -0.59, CI: -16, -2, = 0.010). Patients with higher disease severity tended to have lower CVR at 1.5 and 3T.

Conclusion: Mean CVR magnitude at 3T was similar to 1.5T but showed less variance. GM/WM delay differences may be affected by low signal-to-noise ratio among other factors. Although 3T may reduce variance in CVR magnitude, CVR is readily assessable at 1.5T and reveals comparable associations and trends with disease severity.
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http://dx.doi.org/10.3389/fphys.2021.644837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207286PMC
June 2021

Diffusion-weighted imaging lesions and risk of recurrent stroke after intracerebral haemorrhage.

J Neurol Neurosurg Psychiatry 2021 Jun 8. Epub 2021 Jun 8.

Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.

Objective: To determine whether the presence of diffusion-weighted imaging-positive (DWI+) lesions is associated with recurrent stroke after intracerebral haemorrhage (ICH).

Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) assessed the effect of restarting versus avoiding antiplatelet therapy after ICH on major vascular events for up to 5 years. We rated DWI sequences of MRI done before randomisation for DWI+ lesion presence, masked to outcome and antiplatelet use. Cox proportional hazards regression models were used to quantify associations.

Results: Of 537 participants in RESTART, 247 (median (IQR) age 75.7 (69.6-81.1) years; 170 men (68.8%); 120 started vs 127 avoided antiplatelet therapy) had DWI sequences on brain MRI at a median of 57 days (IQR 19-103) after ICH, of whom 73 (30%) had one or more DWI+ lesion. During a median follow-up of 2 years (1-3), 18 participants had recurrent ICH and 21 had ischaemic stroke. DWI+ lesion presence was associated with all stroke, (adjusted HR 2.2 (95% CI 1.1 to 4.2)) and recurrent ICH (4.8 (95% CI 1.8 to 13.2)), but not ischaemic stroke (0.9 (95% CI 0.3 to 2.5)). DWI+ lesion presence (0.5 (95% CI 0.2 to 1.3)) vs absence (0.6 (95% CI 0.3 to 1.5), p=0.66) did not modify the effect of antiplatelet therapy on a composite outcome of recurrent stroke.

Conclusions: DWI+ lesion presence in ICH survivors is associated with recurrent ICH, but not with ischaemic stroke. We found no evidence of modification of effects of antiplatelet therapy on recurrent stroke after ICH by DWI+ lesion presence. These findings provide a new perspective on the significance of DWI+ lesions, which may be markers of microvascular mechanisms associated with recurrent ICH.

Trial Registration Number: ISRCTN71907627.
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http://dx.doi.org/10.1136/jnnp-2021-326116DOI Listing
June 2021

Thrombolysis outcomes according to arterial characteristics of acute ischemic stroke by alteplase dose and blood pressure target.

Int J Stroke 2021 Jun 24:17474930211025436. Epub 2021 Jun 24.

211065The George Institute for Global Health, Faculty of Medicine, 7800University of New South Wales, Sydney, Australia.

Background: We explored the influence of low-dose intravenous alteplase and intensive blood pressure lowering on outcomes of acute ischemic stroke according to status/location of vascular obstruction in participants of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED).

Methods: ENCHANTED was a multicenter, quasi-factorial, randomized trial to determine efficacy and safety of low- versus standard-dose intravenous alteplase and intensive- versus guideline-recommended blood pressure lowering in acute ischemic stroke patients. In those who had baseline computed tomography or magnetic resonance imaging angiography, the degree of vascular occlusion was grouped according to being no (NVO), medium (MVO), or large (LVO). Logistic regression models were used to determine 90-day outcomes (modified Rankin scale [mRS] shift [primary], other mRS cut-scores, intracranial hemorrhage, early neurologic deterioration, and recanalization) by vascular obstruction status/site. Heterogeneity in associations for outcomes across subgroups was estimated by adding an interaction term to the models.

Results: There were 940 participants: 607 in alteplase arm only, 243 in blood pressure arm only, and 90 assigned to both arms. Compared to the NVO group, functional outcome was worse in LVO (mRS shift, adjusted OR [95% CI] 2.13 [1.56-2.90]) but comparable in MVO (1.34 [0.96-1.88]) groups. There were no differences in associations of alteplase dose or blood pressure lowering and outcomes across NVO/MVO/LVO groups (mRS shift: low versus standard alteplase dose 0.84 [0.54-1.30]/0.48 [0.25-0.91]/0.99 [0.75-2.09], P = 0.28; intensive versus standard blood pressure lowering 1.32 [0.74-2.38]/0.78 [0.31-1.94]/1.24 [0.64-2.41], P = 0.41), except for a borderline significant difference for intensive blood pressure lowering and increased early neurologic deterioration (0.63 [0.14-2.72]/0.17 [0.02-1.47]/2.69 [0.90-8.04], P = 0.05).

Conclusions: Functional outcome by dose of alteplase or intensity of blood pressure lowering is not modified by vascular obstruction status/site according to analyses from ENCHANTED, although these results are compromised by low statistical power. http://www.clinicaltrials.gov. Unique identifiers: NCT01422616.
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http://dx.doi.org/10.1177/17474930211025436DOI Listing
June 2021

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Eur J Epidemiol 2021 Jun 6. Epub 2021 Jun 6.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
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http://dx.doi.org/10.1007/s10654-021-00759-zDOI Listing
June 2021

Correlations in post-mortem imaging-histopathology studies of sporadic human cerebral small vessel disease: A systematic review.

Neuropathol Appl Neurobiol 2021 May 26. Epub 2021 May 26.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Aims: Sporadic human cerebral small vessel disease (SVD) commonly causes stroke and dementia but its pathogenesis is poorly understood. There are recognised neuroimaging and histopathological features. However, relatively few studies have examined the relationship between the radiological and pathological correlates of SVD; better correlation would promote greater insight into the underlying biological changes.

Methods: We performed a systematic review to collate and appraise the information derived from studies that correlated histological with neuroimaging-defined SVD lesions. We searched for studies describing post-mortem imaging and histological tissue examination in adults, extracted data from published studies, categorised the information and compiled this narrative.

Results: We identified 38 relevant studies, including at least 1146 subjects, 342 of these with SVD: 29 studies focussed on neuroradiological white matter lesions (WML), six on microinfarcts and three on dilated perivascular spaces (PVS) and lacunes. The histopathology terminology was diverse with few robust definitions. Reporting and methodology varied widely between studies, precluding formal meta-analysis. PVS and 'oedema' were frequent findings in WML, being described in at least 94 and 18 radiological WML, respectively, in addition to myelin pallor. Histopathological changes extended beyond the radiological lesion margins in at least 33 radiological WML. At least 43 radiological lesions not seen pathologically and at least 178 histological lesions were not identified on imaging.

Conclusions: Histopathological assessment of human SVD is hindered by inconsistent methodological approaches and unstandardised definitions. The data from this systematic review will help to develop standardised definitions to promote consistency in human SVD research.
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http://dx.doi.org/10.1111/nan.12737DOI Listing
May 2021

Associations Between White Matter Hyperintensity Burden, Cerebral Blood Flow and Transit Time in Small Vessel Disease: An Updated Meta-Analysis.

Front Neurol 2021 4;12:647848. Epub 2021 May 4.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Cerebral small vessel disease (SVD) is a major contributor to stroke and dementia, characterized by white matter hyperintensities (WMH) on neuroimaging. WMH are associated with reduced cerebral blood flow (CBF) cross-sectionally, though longitudinal associations remain unclear. We updated a 2016 systematic review, identifying 30 new studies, 27 cross-sectional ( = 2,956) and 3 longitudinal ( = 440). Cross-sectionally, 10/27 new studies ( = 1,019) included sufficient data for meta-analysis, which we meta-analyzed with 24 previously reported studies ( = 1,161), total 34 ( = 2,180). Our meta-analysis showed that patients with lower CBF had worse WMH burden (mean global CBF: standardized mean difference (SMD): -0.45, 95% confidence interval (CI): -0.64, -0.27). Longitudinally, associations between baseline CBF and WMH progression varied: the largest study (5 years, = 252) found no associations, while another small study (4.5 years, = 52) found that low CBF in the periventricular WMH penumbra predicted WMH progression. We could not meta-analyse longitudinal studies due to different statistical and methodological approaches. We found that CBF was lower in WMH than in normal-appearing white matter in an additional meta-analysis (5 cross-sectional studies; = 295; SMD: -1.51, 95% CI: -1.94, -1.07). These findings highlight that relationships between resting CBF and WMH are complex. Further longitudinal studies analyzing regional CBF and subsequent WMH change are required to determine the role of CBF in SVD progression.
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http://dx.doi.org/10.3389/fneur.2021.647848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129542PMC
May 2021

Comparison of structural MRI brain measures between 1.5 and 3 T: Data from the Lothian Birth Cohort 1936.

Hum Brain Mapp 2021 Aug 19;42(12):3905-3921. Epub 2021 May 19.

Lothian Birth Cohorts Group, The University of Edinburgh, Edinburgh, UK.

Multi-scanner MRI studies are reliant on understanding the apparent differences in imaging measures between different scanners. We provide a comprehensive analysis of T -weighted and diffusion MRI (dMRI) structural brain measures between a 1.5 T GE Signa Horizon HDx and a 3 T Siemens Magnetom Prisma using 91 community-dwelling older participants (aged 82 years). Although we found considerable differences in absolute measurements (global tissue volumes were measured as ~6-11% higher and fractional anisotropy [FA] was 33% higher at 3 T than at 1.5 T), between-scanner consistency was good to excellent for global volumetric and dMRI measures (intraclass correlation coefficient [ICC] range: .612-.993) and fair to good for 68 cortical regions (FreeSurfer) and cortical surface measures (mean ICC: .504-.763). Between-scanner consistency was fair for dMRI measures of 12 major white matter tracts (mean ICC: .475-.564), and the general factors of these tracts provided excellent consistency (ICC ≥ .769). Whole-brain structural networks provided good to excellent consistency for global metrics (ICC ≥ .612). Although consistency was poor for individual network connections (mean ICCs: .275-.280), this was driven by a large difference in network sparsity (.599 vs. .334), and consistency was improved when comparing only the connections present in every participant (mean ICCs: .533-.647). Regression-based k-fold cross-validation showed that, particularly for global volumes, between-scanner differences could be largely eliminated (R range .615-.991). We conclude that low granularity measures of brain structure can be reliably matched between the scanners tested, but caution is warranted when combining high granularity information from different scanners.
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http://dx.doi.org/10.1002/hbm.25473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288101PMC
August 2021

Sources of systematic error in DCE-MRI estimation of low-level blood-brain barrier leakage.

Magn Reson Med 2021 Oct 18;86(4):1888-1903. Epub 2021 May 18.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Purpose: Dynamic contrast-enhanced (DCE) -MRI with Patlak model analysis is increasingly used to quantify low-level blood-brain barrier (BBB) leakage in studies of pathophysiology. We aimed to investigate systematic errors due to physiological, experimental, and modeling factors influencing quantification of the permeability-surface area product PS and blood plasma volume v , and to propose modifications to reduce the errors so that subtle differences in BBB permeability can be accurately measured.

Methods: Simulations were performed to predict the effects of potential sources of systematic error on conventional PS and v quantification: restricted BBB water exchange, reduced cerebral blood flow, arterial input function (AIF) delay and error. The impact of targeted modifications to the acquisition and processing were evaluated, including: assumption of fast versus no BBB water exchange, bolus versus slow injection of contrast agent, exclusion of early data from model fitting and correction. The optimal protocol was applied in a cohort of recent mild ischaemic stroke patients.

Results: Simulation results demonstrated substantial systematic errors due to the factors investigated (absolute PS error ≤ 4.48 × 10 min ). However, these were reduced (≤0.56 × 10 min ) by applying modifications to the acquisition and processing pipeline. Processing modifications also had substantial effects on in-vivo normal-appearing white matter PS estimation (absolute change ≤ 0.45 × 10 min ).

Conclusion: Measuring subtle BBB leakage with DCE-MRI presents unique challenges and is affected by several confounds that should be considered when acquiring or interpreting such data. The evaluated modifications should improve accuracy in studies of neurodegenerative diseases involving subtle BBB breakdown.
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http://dx.doi.org/10.1002/mrm.28833DOI Listing
October 2021

Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts.

Lancet Neurol 2021 06 23;20(6):448-459. Epub 2021 Apr 23.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Background: Post-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute ischaemic stroke and use this information to develop a prediction model.

Methods: In this large-scale multicohort lesion-symptom mapping study, we pooled and harmonised individual patient data from 12 cohorts through the Meta-analyses on Strategic Lesion Locations for Vascular Cognitive Impairment using Lesion-Symptom Mapping (Meta VCI Map) consortium. The identified cohorts (as of Jan 1, 2019) comprised patients with acute symptomatic infarcts on CT or MRI (with available infarct segmentations) and a cognitive assessment up to 15 months after acute ischaemic stroke onset. PSCI was defined as performance lower than the fifth percentile of local normative data, on at least one cognitive domain on a multidomain neuropsychological assessment or on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios (ORs) for PSCI that were mapped onto a three-dimensional brain template to visualise PSCI risk per location. For the prediction model of PSCI risk, a location impact score on a 5-point scale was derived from the VLSM results on the basis of the mean voxel-wise coefficient (ln[OR]) within each patient's infarct. We did combined internal-external validation by leave-one-cohort-out cross-validation for all 12 cohorts using logistic regression. Predictive performance of a univariable model with only the location impact score was compared with a multivariable model with addition of other clinical PSCI predictors (age, sex, education, time interval between stroke onset and cognitive assessment, history of stroke, and total infarct volume). Testing of visual ratings was done by three clinicians, and accuracy, inter-rater reliability, and intra-rater reliability were assessed with Cohen's weighted kappa.

Findings: In our sample of 2950 patients (mean age 66·8 years [SD 11·6]; 1157 [39·2%] women), 1286 (43·6%) had PSCI. We achieved high lesion coverage of the brain in our analyses (86·9%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (after false discovery rate correction, q<0·01; voxel-wise ORs >20). On cross-validation, the location impact score showed good correspondence, based on visual assessment of goodness of fit, between predicted and observed risk of PSCI across cohorts after adjusting for cohort-specific PSCI occurrence. Cross-validations showed that the location impact score by itself had similar performance to the combined model with other PSCI predictors, while allowing for easy visual assessment. Therefore the univariable model with only the location impact score was selected as the final model. Correspondence between visual ratings and actual location impact score (Cohen's weighted kappa: range 0·88-0·92), inter-rater agreement (0·85-0·87), and intra-rater agreement (for a single rater, 0·95) were all high.

Interpretation: To the best of our knowledge, this study provides the first comprehensive map of strategic infarct locations associated with risk of PSCI. A location impact score was derived from this map that robustly predicted PSCI across cohorts. Furthermore, we developed a quick and reliable visual rating scale that might in the future be applied by clinicians to identify individual patients at risk of PSCI.

Funding: The Netherlands Organisation for Health Research and Development.
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http://dx.doi.org/10.1016/S1474-4422(21)00060-0DOI Listing
June 2021

Rates, risks and routes to reduce vascular dementia (R4vad), a UK-wide multicentre prospective observational cohort study of cognition after stroke: Protocol.

Eur Stroke J 2021 Mar 11;6(1):89-101. Epub 2020 Oct 11.

Department of Neurology, Lancashire Teaching Hospitals NHS Foundation Trust & Lancaster Medical School, Lancaster University, UK.

Background: Stroke commonly affects cognition and, by definition, much vascular dementia follows stroke. However, there are fundamental limitations in our understanding of vascular cognitive impairment, restricting understanding of prevalence, trajectories, mechanisms, prevention, treatment and patient-service needs.

Aims: Rates, Risks and Routes to Reduce Vascular Dementia (R4VaD) is an observational cohort study of post-stroke cognition. We aim to recruit a wide range of patients with stroke, presenting to geographically diverse UK hospitals, into a longitudinal study to determine rates of, and risk factors for, cognitive and related impairments after stroke, to assess potential mechanisms and improve prediction models.

Methods: We will recruit at least 2000 patients within six weeks of stroke with or without capacity to consent and collect baseline demographic, clinical, socioeconomic, lifestyle, cognitive, neuropsychiatric and informant data using streamlined patient-centred methods appropriate to the stage after stroke. We will obtain more detailed assessments at four to eight weeks after the baseline assessment and follow-up by phone and post yearly to at least two years. We will assess diagnostic neuroimaging in all and high-sensitivity inflammatory markers, genetics, blood pressure and diffusion tensor imaging in mechanistic sub-studies. R4VaD will provide reliable data on long-term cognitive function after stroke, stratified by prior cognition, stroke- and patient-related variables and improved risk prediction. It will create a platform enabling sharing of data, imaging and samples. Participants will be consented for re-contact, facilitating future clinical trials and providing a resource for the stroke and dementia research communities.
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http://dx.doi.org/10.1177/2396987320953312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995325PMC
March 2021

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3.

Eur Stroke J 2021 Mar 5;6(1):81-88. Epub 2020 Jun 5.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Background: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood-brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease. The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood-brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543.

Summary: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy.
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http://dx.doi.org/10.1177/2396987320929617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995323PMC
March 2021

Lacunar Stroke Lesion Extent and Location and White Matter Hyperintensities Evolution 1 Year Post-lacunar Stroke.

Front Neurol 2021 5;12:640498. Epub 2021 Mar 5.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Lacunar strokes are a common type of ischemic stroke. They are associated with long-term disability, but the factors affecting the dynamic of the infarcted lesion and the brain imaging features associated with them, reflective of small vessel disease (SVD) severity, are still largely unknown. We investigated whether the distribution, volume and 1-year evolution of white matter hyperintensities (WMH), one of these SVD features, relate to the extent and location of these infarcts, accounting for vascular risk factors. We used imaging and clinical data from all patients [ = 118, mean age 64.9 (SD 11.75) years old] who presented to a regional hospital with a lacunar stroke syndrome within the years 2010 and 2013 and consented to participate in a study of stroke mechanisms. All patients had a brain MRI scan at presentation, and 88 had another scan 12 months after. Acute lesions (i.e., recent small subcortical infarcts, RSSI) were identified in 79 patients and lacunes in 77. Number of lacunes was associated with baseline WMH volume (B = 0.370, SE = 0.0939, = 0.000174). RSSI volume was not associated with baseline WMH volume (B = 3.250, SE = 2.117, = 0.129), but predicted WMH volume change (B = 2.944, SE = 0.913, = 0.00184). RSSI location was associated with the spatial distribution of WMH and the pattern of 1-year WMH evolution. Patients with the RSSI in the centrum semiovale ( = 33) had significantly higher baseline volumes of WMH, recent and old infarcts, than patients with the RSSI located elsewhere [median 33.69, IQR (14.37 50.87) ml, 0.001 ≤ ≤ 0.044]. But patients with the RSSI in the internal/external capsule/lentiform nucleus experienced higher increase of WMH volume after a year [ = 21, median (IQR) from 18 (11.70 31.54) ml to 27.41 (15.84 40.45) ml]. Voxel-wise analyses of WMH distribution in patients grouped per RSSI location revealed group differences increased in the presence of vascular risk factors, especially hypertension and recent or current smoking habit. In our sample of patients presenting to the clinic with lacunar strokes, lacunar strokes extent influenced WMH volume fate; and RSSI location and WMH spatial distribution and dynamics were intertwined, with differential patterns emerging in the presence of vascular risk factors. These results, if confirmed in wider samples, open potential avenues in stroke rehabilitation to be explored further.
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http://dx.doi.org/10.3389/fneur.2021.640498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976454PMC
March 2021

Post-stroke Cognition at 1 and 3 Years Is Influenced by the Location of White Matter Hyperintensities in Patients With Lacunar Stroke.

Front Neurol 2021 1;12:634460. Epub 2021 Mar 1.

Centre for Clinical Brain Sciences, UK Dementia Research Institute at the University of Edinburgh, Edinburgh, United Kingdom.

Lacunar strokes are a common type of ischemic stroke. They are known to have long-term cognitive deficits, but the influencing factors are still largely unknown. We investigated if the location of the index lacunar stroke or regional WMH and their change at 1 year could predict the cognitive performance at 1 and 3 years post-stroke in lacunar stroke patients. We used lacunar lesion location and WMH-segmented data from 118 patients, mean age 64.9 who had a brain MRI scan soon after presenting with symptoms, of which 88 had a repeated scan 12 months later. Premorbid intelligence (National Adult Reading Test) and current intelligence [Addenbrooke's Cognitive Exam-Revised (ACE-R)] were measured at 1, 12, and 36 months after the stroke. ANCOVA analyses adjusting for baseline cognition/premorbid intelligence, vascular risk factors, age, sex and total baseline WMH volume found that the recent small subcortical infarcts (RSSI) in the internal/external capsule/lentiform nucleus and centrum semiovale did not predict cognitive scores at 12 and 36 months. However, RSSI location moderated voxel-based associations of WMH change from baseline to 1 year with cognitive scores at 1 and 3 years. WMH increase in the external capsule, intersection between the anterior limb of the internal and external capsules, and optical radiation, was associated with worsening of ACE-R scores 1 and 3 years post-stroke after accounting for the location of the index infarct, age and baseline cognition.
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http://dx.doi.org/10.3389/fneur.2021.634460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956970PMC
March 2021

Cerebrovascular Reactivity Measurement Using Magnetic Resonance Imaging: A Systematic Review.

Front Physiol 2021 25;12:643468. Epub 2021 Feb 25.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Cerebrovascular reactivity (CVR) magnetic resonance imaging (MRI) probes cerebral haemodynamic changes in response to a vasodilatory stimulus. CVR closely relates to the health of the vasculature and is therefore a key parameter for studying cerebrovascular diseases such as stroke, small vessel disease and dementias. MRI allows measurement of CVR but several different methods have been presented in the literature, differing in pulse sequence, hardware requirements, stimulus and image processing technique. We systematically reviewed publications measuring CVR using MRI up to June 2020, identifying 235 relevant papers. We summarised the acquisition methods, experimental parameters, hardware and CVR quantification approaches used, clinical populations investigated, and corresponding summary CVR measures. CVR was investigated in many pathologies such as steno-occlusive diseases, dementia and small vessel disease and is generally lower in patients than in healthy controls. Blood oxygen level dependent (BOLD) acquisitions with fixed inspired CO gas or end-tidal CO forcing stimulus are the most commonly used methods. General linear modelling of the MRI signal with end-tidal CO as the regressor is the most frequently used method to compute CVR. Our survey of CVR measurement approaches and applications will help researchers to identify good practice and provide objective information to inform the development of future consensus recommendations.
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http://dx.doi.org/10.3389/fphys.2021.643468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947694PMC
February 2021

Imaging Advances: Acute-on-Chronic Stroke.

Stroke 2021 Apr 1;52(4):1486-1489. Epub 2021 Mar 1.

Centre for Clinical Brain Sciences, Edinburgh Imaging and UK Dementia Research Institute, University of Edinburgh, United Kingdom (J.M.W.).

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http://dx.doi.org/10.1161/STROKEAHA.121.033449DOI Listing
April 2021

Neuropsychiatric symptoms associated with cerebral small vessel disease: a systematic review and meta-analysis.

Lancet Psychiatry 2021 03 1;8(3):225-236. Epub 2021 Feb 1.

Centre for Clinical Brain Sciences and UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Cerebral small vessel disease, a common cause of vascular dementia, is often considered clinically silent before dementia or stroke become apparent. However, some individuals have subtle symptoms associated with acute MRI lesions. We aimed to determine whether neuropsychiatric and cognitive symptoms vary according to small vessel disease burden.

Methods: In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, and PsycINFO for articles published in any language from database inception to Jan 24, 2020. We searched for studies assessing anxiety, apathy, delirium, emotional lability, fatigue, personality change, psychosis, dementia-related behavioural symptoms or cognitive symptoms (including subjective memory complaints), and radiological features of cerebral small vessel disease. We extracted reported odds ratios (OR), standardised mean differences (SMD), and correlations, stratified outcomes by disease severity or symptom presence or absence, and pooled data using random-effects meta-analyses, reporting adjusted findings when possible. We assessed the bias on included studies using the Risk of Bias for Non-randomized Studies tool. This study is registered with PROSPERO, CRD42018096673.

Findings: Of 7119 papers identified, 81 studies including 79 cohorts in total were eligible for inclusion (n=21 730 participants, mean age 69·2 years). Of these 81 studies, 45 (8120 participants) reported effect estimates. We found associations between worse white matter hyperintensity (WMH) severity and apathy (OR 1·41, 95% CI 1·05-1·89) and the adjusted SMD in apathy score between WMH severities was 0·38 (95% CI 0·15-0·61). Worse WMH severity was also associated with delirium (adjusted OR 2·9, 95% CI 1·12-7·55) and fatigue (unadjusted OR 1·63, 95% CI 1·20-2·22). WMHs were not consistently associated with subjective memory complaints (OR 1·34, 95% CI 0·61-2·94) and unadjusted SMD for WMH severity between these groups was 0·08 (95% CI -0·31 to 0·47). Anxiety, dementia-related behaviours, emotional lability, and psychosis were too varied or sparse for meta-analysis; these factors were reviewed narratively. Overall heterogeneity varied from 0% to 79%. Only five studies had a low risk of bias across all domains.

Interpretation: Apathy, fatigue, and delirium associated independently with worse WMH, whereas subjective cognitive complaints did not. The association of anxiety, dementia-related behaviours, emotional lability, and psychosis with cerebral small vessel disease require further investigation. These symptoms should be assessed longitudinally to improve early clinical detection of small vessel disease and enable prevention trials to happen early in the disease course, long before cognition declines.

Funding: Chief Scientist Office of the Scottish Government, UK Dementia Research Institute, Fondation Leducq, Stroke Association Garfield-Weston Foundation, Alzheimer's Society, and National Health Service Research Scotland.
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http://dx.doi.org/10.1016/S2215-0366(20)30431-4DOI Listing
March 2021

Low-Dose vs Standard-Dose Alteplase in Acute Lacunar Ischemic Stroke: The ENCHANTED Trial.

Neurology 2021 03 3;96(11):e1512-e1526. Epub 2021 Feb 3.

From The George Institute for Global Health, Faculty of Medicine (Z.Z., C.D., C.X., S. Yoshimura, C.C., T.T.-Y., A.M., X.C., M.L.H., M.W., J.C., C.S.A.), and South Western Clinical School (M.W.P.), University of New South Wales Sydney, Australia; Department of Radiology (Z.Z., J.X.), Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China; Department of Neurology (C.D., C.C., C.S.A.), Royal Prince Alfred Hospital, Sydney Health Partners; Sydney Medical School (C.D., C.C.), University of Sydney, Australia; Department of Neurosurgery (C.X.), West China Hospital, Sichuan University, Chengdu, China; Department of Cerebrovascular Medicine (S. Yoshimura, T.T.-Y.), National Cerebral and Cardiovascular Center, Osaka; Department of Neurology and Neuroscience (T.T.-Y.), Nagoya City University Graduate School of Medical Science, Japan; Department of Neurology (S. You), the Second Affiliated Hospital of Soochow University, Suzhou, China; The George Institute for Global Health, School of Public Health (M.W.), Imperial College, London; Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Center (T.G.R.), University of Leicester, UK; Melbourne Brain Centre, Royal Melbourne Hospital University Department of Medicine (M.W.P.), University of Melbourne, Australia; Departments of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, Cumming School of Medicine (A.M.D.), University of Calgary, Canada; Westmead Applied Research Centre (R.I.L.), University of Sydney, Australia; Division of Neuroimaging Sciences, Edinburgh Imaging and Centre for Clinical Brain Sciences (G.M., J.M.W.), and UK Dementia Research Institute (J.M.W.), University of Edinburgh; and The George Institute China at Peking University Health Science Center (C.S.A.), Beijing, China.

Objective: To determine any differential efficacy and safety of low- vs standard-dose IV alteplase for lacunar vs nonlacunar acute ischemic stroke (AIS), we performed post hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose arm.

Methods: In a cohort of 3,297 ENCHANTED participants, we identified those with lacunar or nonlacunar AIS with different levels of confidence (definite/according to prespecified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin Scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration or death) and treatment effects of low- vs standard-dose alteplase across lacunar and nonlacunar AIS with adjustment for baseline covariables.

Results: Of 2,588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n = 490) or nonlacunar AIS (n = 2,098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% confidence interval] 0.60 [0.47-0.77]) and other clinical or safety outcomes compared to participants with nonlacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- vs standard-dose alteplase on all outcomes across lacunar and nonlacunar AIS (all ≥0.07).

Conclusions: We found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard dose for definite/probable lacunar AIS.

Classification Of Evidence: This study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safety over standard-dose alteplase.

Clinical Trial Registration: Clinicaltrials.gov identifier NCT01422616.
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http://dx.doi.org/10.1212/WNL.0000000000011598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032382PMC
March 2021

A four-dimensional computational model of dynamic contrast-enhanced magnetic resonance imaging measurement of subtle blood-brain barrier leakage.

Neuroimage 2021 04 23;230:117786. Epub 2021 Jan 23.

Centre for Clinical Brain Sciences, Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK. Electronic address:

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to quantify and map the spatial distribution of blood-brain barrier (BBB) leakage in neurodegenerative disease, including cerebral small vessel disease and dementia. However, the subtle nature of leakage and resulting small signal changes make quantification challenging. While simplified one-dimensional simulations have probed the impact of noise, scanner drift, and model assumptions, the impact of spatio-temporal effects such as gross motion, k-space sampling and motion artefacts on parametric leakage maps has been overlooked. Moreover, evidence on which to base the design of imaging protocols is lacking due to practical difficulties and the lack of a reference method. To address these problems, we present an open-source computational model of the DCE-MRI acquisition process for generating four dimensional Digital Reference Objects (DROs), using a high-resolution brain atlas and incorporating realistic patient motion, extra-cerebral signals, noise and k-space sampling. Simulations using the DROs demonstrated a dominant influence of spatio-temporal effects on both the visual appearance of parameter maps and on measured tissue leakage rates. The computational model permits greater understanding of the sensitivity and limitations of subtle BBB leakage measurement and provides a non-invasive means of testing and optimising imaging protocols for future studies.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065875PMC
April 2021

Multinational Survey of Current Practice from Imaging to Treatment of Atherosclerotic Carotid Stenosis.

Cerebrovasc Dis 2021 13;50(1):108-120. Epub 2021 Jan 13.

Department of Radiology, Walter Reed National Military Medical Center and Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.

Background: In the last 20-30 years, there have been many advances in imaging and therapeutic strategies for symptomatic and asymptomatic individuals with carotid artery stenosis. Our aim was to examine contemporary multinational practice standards.

Methods: Departmental Review Board approval for this study was obtained, and 3 authors prepared the 44 multiple choice survey questions. Endorsement was obtained by the European Society of Neuroradiology, American Society of Functional Neuroradiology, and African Academy of Neurology. A link to the online questionnaire was sent to their respective members and members of the Faculty Advocating Collaborative and Thoughtful Carotid Artery Treatments (FACTCATS). The questionnaire was open from May 16 to July 16, 2019.

Results: The responses from 223 respondents from 46 countries were included in the analyses including 65.9% from academic university hospitals. Neuroradiologists/radiologists comprised 68.2% of respondents, followed by neurologists (15%) and vascular surgeons (12.9%). In symptomatic patients, half (50.4%) the respondents answered that the first exam they used to evaluate carotid bifurcation was ultrasound, followed by computed tomography angiography (CTA, 41.6%) and then magnetic resonance imaging (MRI 8%). In asymptomatic patients, the first exam used to evaluate carotid bifurcation was ultrasound in 88.8% of respondents, CTA in 7%, and MRA in 4.2%. The percent stenosis upon which carotid endarterectomy or stenting was recommended was reduced in the presence of imaging evidence of "vulnerable plaque features" by 66.7% respondents for symptomatic patients and 34.2% for asymptomatic patients with a smaller subset of respondents even offering procedural intervention to patients with <50% symptomatic or asymptomatic stenosis.

Conclusions: We found heterogeneity in current practices of carotid stenosis imaging and management in this worldwide survey with many respondents including vulnerable plaque imaging into their decision analysis despite the lack of proven benefit from clinical trials. This study highlights the need for new clinical trials using vulnerable plaque imaging to select high-risk patients despite maximal medical therapy who may benefit from procedural intervention.
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http://dx.doi.org/10.1159/000512181DOI Listing
January 2021

Corrigendum: Intracranial Bleeding After Reperfusion Therapy in Acute Ischaemic Stroke Patients Randomized to Glyceryl Trinitrate vs. Control: An Individual Patient Data Meta-Analysis.

Front Neurol 2020 26;11:625572. Epub 2020 Nov 26.

Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom.

[This corrects the article DOI: 10.3389/fneur.2020.584038.].
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http://dx.doi.org/10.3389/fneur.2020.625572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726315PMC
November 2020

Brain network reorganisation and spatial lesion distribution in systemic lupus erythematosus.

Lupus 2021 Feb 13;30(2):285-298. Epub 2020 Dec 13.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Objective: This work investigates network organisation of brain structural connectivity in systemic lupus erythematosus (SLE) relative to healthy controls and its putative association with lesion distribution and disease indicators.

Methods: White matter hyperintensity (WMH) segmentation and connectomics were performed in 47 patients with SLE and 47 healthy age-matched controls from structural and diffusion MRI data. Network nodes were divided into hierarchical tiers based on numbers of connections. Results were compared between patients and controls to assess for differences in brain network organisation. Voxel-based analyses of the spatial distribution of WMH in relation to network measures and SLE disease indicators were conducted.

Results: Despite inter-individual differences in brain network organization observed across the study sample, the connectome networks of SLE patients had larger proportion of connections in the peripheral nodes. SLE patients had statistically larger numbers of links in their networks with generally larger fractional anisotropy weights (i.e. a measure of white matter integrity) and less tendency to aggregate than those of healthy controls. The voxels exhibiting connectomic differences were coincident with WMH clusters, particularly the left hemisphere's intersection between the anterior limb of the internal and external capsules. Moreover, these voxels also associated more strongly with disease indicators.

Conclusion: Our results indicate network differences reflective of compensatory reorganization of the neural circuits, reflecting adaptive or extended neuroplasticity in SLE.
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http://dx.doi.org/10.1177/0961203320979045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854491PMC
February 2021

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Hyperdense artery sign, symptomatic infarct swelling and effect of alteplase in acute ischaemic stroke.

Stroke Vasc Neurol 2021 Jun 27;6(2):238-243. Epub 2020 Nov 27.

Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK

Background: Alteplase improves functional outcomes of patients with acute ischaemic stroke, but its effects on symptomatic infarct swelling, an adverse complication of stroke and the influence of CT hyperdense artery sign (HAS) are unclear. This substudy of the Third International Stroke Trial aimed to investigate the association between HAS and symptomatic infarct swelling and effect of intravenous alteplase on this association.

Methods: We included stroke patients whose prerandomisation scan was non-contrast CT. Raters, masked to clinical information, assessed baseline (prerandomisation) and follow-up (24-48 hours postrandomisation) CT scans for HAS, defined as an intracranial artery appearing denser than contralateral arteries. Symptomatic infarct swelling was defined as clinically significant neurological deterioration ≤7 days after stroke with radiological evidence of midline shift, effacement of basal cisterns or uncal herniation.

Results: Among 2961 patients, HAS presence at baseline was associated with higher risk of symptomatic infarct swelling (OR 2.21; 95% CI 1.42 to 3.44). Alteplase increased the risk of swelling (OR 1.69; 95% CI 1.11 to 2.57), with no difference between patients with and those without baseline HAS (p=0.49). In patients with baseline HAS, alteplase reduced the proportion with HAS at follow-up (OR 0.67; 95% CI 0.50 to 0.91), where HAS disappearance was associated with reduced risk of swelling (OR 0.25, 95% CI 0.14 to 0.47).

Conclusion: Although alteplase was associated with increased risk of symptomatic infarct swelling in patients with or without baseline HAS, it was also associated with accelerated clearance of HAS, which in return reduced swelling, providing further mechanistic insights to underpin the benefits of alteplase.
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http://dx.doi.org/10.1136/svn-2020-000569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258046PMC
June 2021

Response by Doubal et al to Letter Regarding Article, "Cilostazol for Secondary Prevention of Stroke and Cognitive Decline: Systematic Review and Meta-Analysis".

Stroke 2020 12 23;51(12):e377. Epub 2020 Nov 23.

Centre for Clinical Brain Sciences and UK Dementia Research Institute, University of Edinburgh, Scotland.

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http://dx.doi.org/10.1161/STROKEAHA.120.032520DOI Listing
December 2020

Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder.

Brain Behav Immun 2021 02 19;92:39-48. Epub 2020 Nov 19.

Division of Psychiatry, University of Edinburgh, Edinburgh, UK.

Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers. Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; N = 271, N = 609). Serum CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (β = 0.145, P = 6 × 10) and energy levels (β = 0.101, P = 0.027), along with reduced entorhinal cortex thickness (β = -0.095, P = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, β= -0.12 to -0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (βaverage = -0.15 versus βaverage = 0.01 respectively). These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.
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http://dx.doi.org/10.1016/j.bbi.2020.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910280PMC
February 2021

Intracranial Bleeding After Reperfusion Therapy in Acute Ischaemic Stroke Patients Randomized to Glyceryl Trinitrate vs. Control: An Individual Patient Data Meta-Analysis.

Front Neurol 2020 20;11:584038. Epub 2020 Oct 20.

Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom.

Thrombolysis, with or without thrombectomy, for acute ischaemic stroke is associated with an increased risk of intracranial bleeding. We assessed whether treatment with glyceryl trinitrate (GTN), a nitric oxide donor, may influence the associated bleeding risk. We searched for completed randomized controlled trials of GTN vs. no GTN in acute ischaemic stroke with data on reperfusion treatments (thrombolysis and/or thrombectomy). The primary efficacy outcome was functional status as assessed by the modified Rankin Scale (mRS) at day 90; the primary safety outcome was intracranial bleeding. Secondary safety outcomes included symptomatic intracranial hemorrhage and haemorrhagic transformation of infarction. Individual patient data were pooled and meta-analysis performed using ordinal or binary logistic regression with adjustment for trial and prognostic variables both overall and in those randomized within 6 h of symptom onset. Three trials met the eligibility criteria. Of 715 patients with ischaemic stroke who underwent thrombolysis (709, >99%) or thrombectomy (24, 3.4%), 357 (49.9%) received GTN and 358 (50.1%) received no GTN. Overall, there was no difference in the distribution of the mRS at day 90 between GTN vs. no GTN (OR 0.94, 95% CI 0.72-1.23; = 0.65); similarly, there was no difference in intracranial hemorrhage rates between treatment groups (OR 0.90, 95% CI 0.43-1.89; = 0.77). In those randomized to GTN vs. no GTN within 6 h of symptom onset, there were numerically fewer bleeding events, but these analyses did not reach statistical significance. In ischaemic stroke patients treated predominantly with thrombolysis, transdermal GTN was safe, but did not influence functional outcome at 90 days.
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http://dx.doi.org/10.3389/fneur.2020.584038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606455PMC
October 2020