Publications by authors named "Hugh S Markus"

357 Publications

Rate of, and risk factors for, white matter hyperintensity growth: a systematic review and meta-analysis with implications for clinical trial design.

J Neurol Neurosurg Psychiatry 2021 Aug 3. Epub 2021 Aug 3.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background: White matter hyperintensities (WMHs) are a highly prevalent MRI marker of cerebral small vessel disease (SVD), which predict stroke and dementia risk, and are being increasingly used as a surrogate marker in clinical trials. However, the influence of study population selection on WMH progression rate has not been studied and the effect of individual patient factors for WMH growth are not fully understood.

Methods: We performed a systematic review and meta-analysis of the literature on progression of WMHs in longitudinal studies to determine rates of WMH growth, and how these varied according to population characteristics and cardiovascular risk factors. We used these data to calculate necessary sample sizes for clinical trials using WMH as an endpoint.

Results: WMH growth rate was highest in SVD (2.50cc/year), intermediate in unselected stroke patients (1.29cc/year) and lower in patients with non-stroke cardiovascular disease, and with cognitive impairment. Age was significantly associated with progression (correlation coefficient 0.15cc/year, 95% CI 0.02 to 0.28cc/year) as was baseline lesion volume (0.6cc/year, 95% CI 0.13 to 1.06 cc/year). Both hypertension (OR 1.72, 95% CI 1.19 to 2.46) and current smoking (OR 1.48, 95% CI 1.02 to 2.16) were associated with WMH growth. Sample sizes for a clinical trial varied greatly with patient population selection and baseline lesion volume; estimates are provided.

Conclusions: WMH progression varies markedly according to the characteristics of the population being studied and this will have a major impact on sample sizes required in a clinical trial. Our sample size estimates provide data for planning clinical trials using WMH as an outcome measure.

Prospero Registration Number: CRD42020191781.
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http://dx.doi.org/10.1136/jnnp-2021-326569DOI Listing
August 2021

Intensive speech therapy after stroke.

Authors:
Hugh S Markus

Int J Stroke 2021 Jul;16(5):495-496

Department of Clinical Neurosciences, University of Cambridge, Cambridge UK.

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http://dx.doi.org/10.1177/17474930211027503DOI Listing
July 2021

Cerebral Amyloid Angiopathy and the Fibrinolytic System: Is Plasmin a Therapeutic Target?

Stroke 2021 Aug 15;52(8):2707-2714. Epub 2021 Jun 15.

Australian Centre for Blood Diseases (C.B.K., R.L.M.), Monash University, Melbourne, Australia.

Cerebral amyloid angiopathy is a devastating cause of intracerebral hemorrhage for which there is no specific secondary stroke prevention treatment. Here we review the current literature regarding cerebral amyloid angiopathy pathophysiology and treatment, as well as what is known of the fibrinolytic pathway and its interaction with amyloid. We postulate that tranexamic acid is a potential secondary stroke prevention treatment agent in sporadic cerebral amyloid angiopathy, although further research is required.
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http://dx.doi.org/10.1161/STROKEAHA.120.033107DOI Listing
August 2021

Editorial.

Authors:
Hugh S Markus

Int J Stroke 2021 Jun;16(4):355

University of Cambridge, Cambridge, UK Email:

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http://dx.doi.org/10.1177/17474930211020263DOI Listing
June 2021

Ischaemic stroke can follow COVID-19 vaccination but is much more common with COVID-19 infection itself.

Authors:
Hugh S Markus

J Neurol Neurosurg Psychiatry 2021 May 25. Epub 2021 May 25.

Department of Clinical Neurosciences, Cambridge University, Cambridge CB2 1TN, UK

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http://dx.doi.org/10.1136/jnnp-2021-327057DOI Listing
May 2021

EXPRESS: COVID-19 AND STROKE â UNDERSTANDING THE RELATIONSHIP AND ADAPTING SERVICES. A GLOBAL WORLD STROKE ORGANISATION PERSPECTIVE.

Int J Stroke 2021 May 18:17474930211006435. Epub 2021 May 18.

Clinics Hospital of Porto Alegre, Porto Alegre, RS, Brazil.

A year ago the World Stroke Organisation (WSO) highlighted the enormous global impact of the COVID-19 pandemic on stroke care. In this review we consider a year later where we are now, what the future holds, and what the long term effects of the pandemic will be on stroke. Stroke occurs in about 1.4% of patients hospitalised with COVID-19 infection, who show an excess of large vessel occlusion and increased mortality. Despite this association, stroke presentations fell dramatically during the pandemic, although emerging data suggests that total stroke mortality may have risen with increased stroke deaths at home and in care homes. Strategies and guidelines have been developed to adapt stroke services worldwide, and protect healthcare workers. Adaptations include increasing use of telemedicine for all aspects of stroke care. The pandemic is exacerbating already marked global inequalities in stroke incidence and mortality. Lastly the pandemic has had a major impact on stroke research and funding, although it has also emphasised the importnace of large scale collaborative research initiatives.
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http://dx.doi.org/10.1177/17474930211006435DOI Listing
May 2021

Microglial activation and blood-brain barrier permeability in cerebral small vessel disease.

Brain 2021 Jun;144(5):1361-1371

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. The underlying pathogenesis is poorly understood, but both neuroinflammation and increased blood-brain barrier permeability have been hypothesized to play a role, and preclinical studies suggest the two processes may be linked. We used PET magnetic resonance to simultaneously measure microglial activation using the translocator protein radioligand 11C-PK11195, and blood-brain barrier permeability using dynamic contrast enhanced MRI. A case control design was used with two disease groups with sporadic SVD (n = 20), monogenic SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL), and normal controls (n = 20) were studied. Hotspots of increased glial activation and blood-brain barrier permeability were identified as values greater than the 95th percentile of the distribution in controls. In sporadic SVD there was an increase in the volume of hotspots of both 11C-PK11195 binding (P = 0.003) and blood-brain barrier permeability (P = 0.007) in the normal appearing white matter, in addition to increased mean blood-brain barrier permeability (P < 0.001). In CADASIL no increase in blood-brain barrier permeability was detected; there was a non-significant trend to increased 11C-PK11195 binding (P = 0.073). Hotspots of 11C-PK11195 binding and blood-brain barrier permeability were not spatially related. A panel of 93 blood biomarkers relating to cardiovascular disease, inflammation and endothelial activation were measured in each participant; principal component analysis was performed and the first component related to blood-brain barrier permeability and microglial activation. Within the sporadic SVD group both hotspot and mean volume blood-brain barrier permeability values in the normal appearing white matter were associated with dimension 1 (β  =  0.829, P = 0.017, and β  =  0.976, P = 0.003, respectively). There was no association with 11C-PK11195 binding. No associations with blood markers were found in the CADASIL group. In conclusion, in sporadic SVD both microglial activation and increased blood-brain barrier permeability occur, but these are spatially distinct processes. No evidence of increased blood-brain barrier permeability was found in CADASIL.
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http://dx.doi.org/10.1093/brain/awab003DOI Listing
June 2021

Cognitive impact of cerebral microbleeds in patients with symptomatic small vessel disease.

Int J Stroke 2021 May 7:17474930211012837. Epub 2021 May 7.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background And Aim: Whether cerebral microbleeds cause cognitive impairment remains uncertain. We analyzed whether cerebral microbleeds are associated with cognitive dysfunction in patients with symptomatic cerebral small vessel disease, and whether this association is independent of other neuroimaging markers of cerebral small vessel disease.

Methods: We analyzed consecutive patients with MRI-confirmed lacunar stroke included in DNA-Lacunar-2 multicenter study. Cerebral microbleeds were graded using the Brain Observer Microbleed Rating Scale (BOMBS). Neuropsychological assessment was performed using the Brief Memory and Executive Test (BMET). We analyzed the association between cerebral microbleeds, BMET, and the following subdomains: executive function/processing speed and orientation/memory. We also searched for an independent association between cerebral microbleeds and vascular cognitive impairment, defined as BMET ≤ 13.

Results: Out of 688 included patients, cerebral microbleeds were detected in 192 (27.9%). After adjusting for white matter hyperintensities severity, lacune count, and other confounders, both the presence and the number of cerebral microbleeds were significantly associated with impaired cognitive performance [β = -13.0; 95% CI = (-25.3, -0.6) and β = -13.1; 95% CI = (-19.8, -6.4), respectively]. On analysis of specific cognitive domains, associations were present for executive function/processing speed [β = -5.8; 95% CI = (-9.3, -2.2) and β = -4.3; 95% CI = (-6.2, -2.4), respectively] but not for orientation/memory [β = -0.4; 95% CI = (-4.0, 3.2) and β = -2.1; 95% CI = (-4.0, 0.1), respectively]. We also found an independent association between the presence and the number of cerebral microbleeds and vascular cognitive impairment [adjusted OR = 1.48; 95% CI = (1.01, 2.18) and OR = 1.43; 95% CI = (1.15, 1.79), respectively].

Conclusion: In a large cohort of symptomatic cerebral small vessel disease patients, after controlling for other neuroimaging markers of cerebral small vessel disease severity, cerebral microbleeds were associated with cognitive dysfunction. Executive function and processing speed were predominantly impaired. This might suggest a causal role of cerebral microbleeds in determining vascular cognitive impairment.
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http://dx.doi.org/10.1177/17474930211012837DOI Listing
May 2021

The copy number variation and stroke (CaNVAS) risk and outcome study.

PLoS One 2021 19;16(4):e0248791. Epub 2021 Apr 19.

University of Maryland School of Medicine, Baltimore, MD, United States of America.

Background And Purpose: The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap.

Methods: Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data.

Results: The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism.

Conclusion: The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055008PMC
April 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

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies.

Lancet Neurol 2021 05 25;20(5):351-361. Epub 2021 Mar 25.

Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease.

Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation.

Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke.

Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk.

Funding: British Heart Foundation.
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http://dx.doi.org/10.1016/S1474-4422(21)00031-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062914PMC
May 2021

Individual markers of cerebral small vessel disease and domain-specific quality of life deficits.

Brain Behav 2021 05 10;11(5):e02106. Epub 2021 Mar 10.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background: Cerebral small vessel disease (SVD) leads to reduced quality of life (QOL), but the mechanisms underlying this relationship remain unknown. This study investigated multivariate relationships between radiological markers of SVD and domain-specific QOL deficits, as well as potential mediators, in patients with SVD.

Methods: Clinical and neuroimaging measures were obtained from a pooled sample of 174 SVD patients from the St. George's Cognition and Neuroimaging in Stroke and PRESsure in established cERebral small VEssel disease studies. Lacunes, white matter hyperintensities, and microbleeds were defined as radiological markers of SVD and delineated using MRI. QOL was assessed using the Stroke-Specific Quality of Life Scale. Multivariate linear regression was used to determine whether SVD markers were associated with domain-specific QOL deficits. Significant associations were further investigated using mediation analysis to examine whether functional disability or cognition was potential mediators.

Results: Multivariate regression analyses revealed that lacunes were associated with total QOL score (β = -8.22, p = .02), as well as reductions in mobility (β = -1.41, p = .008) and language-related subdomains (β = -0.69, p = .033). White matter hyperintensities and microbleeds showed univariate correlations with QOL, but these became nonsignificant during multivariate analyses. Mediation analyses revealed that functional disability, defined as reduced activities of daily living, and executive function, partially mediated the relationship between lacunes and total QOL, as well as mobility-related QOL, but not language-related QOL.

Conclusions: Lacunar infarcts have the most detrimental effect on QOL in SVD patients, particularly in the mobility and language-related subdomains. These effects may be partially explained by a reduction in activities of daily living. These results may inform targeted interventions to improve QOL in patients with SVD.
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http://dx.doi.org/10.1002/brb3.2106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119866PMC
May 2021

Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease.

J Cereb Blood Flow Metab 2021 Mar 17:271678X211004307. Epub 2021 Mar 17.

Translational Molecular Neuroscience Group, Weatherall Institute of Molecular Medicine, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of the ECM contributes to a broad range of neurological disorders. However, despite this importance, our understanding of the ECM composition remains very limited mainly due to difficulties in its isolation. To address this, we developed an approach to extract the cerebrovascular ECM from mouse and human post-mortem normal brain tissues. We then used mass spectrometry with off-line high-pH reversed-phase fractionation to increase the protein detection. This identified more than 1000 proteins in the ECM-enriched fraction, with > 66% of the proteins being common between the species. We report 147 core ECM proteins of the human brain vascular matrisome, including collagens, laminins, fibronectin and nidogens. We next used network analysis to identify the connection between the brain ECM proteins and cerebrovascular diseases. We found that genes related to cerebrovascular diseases, such as , , and were significantly enriched in the cerebrovascular ECM network. This provides unique mechanistic insight into cerebrovascular disease and potential drug targets. Overall, we provide a powerful resource to study the functions of brain ECM and highlight a specific role for brain vascular ECM in cerebral vascular disease.
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http://dx.doi.org/10.1177/0271678X211004307DOI Listing
March 2021

variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants.

J Neurol Neurosurg Psychiatry 2021 Jul 12;92(7):694-701. Epub 2021 Mar 12.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, Cambridgeshire, UK

Background: Cysteine-altering variants identical to those causing the rare monogenic form of stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remain unclear.

Methods: Cysteine-altering variants were identified in UK Biobank whole-exome sequencing data (N=200 632). Frequency of stroke, vascular dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. MRIs from those with variants were visually rated, each matched with three controls.

Results: Of 200 632 participants with exome sequencing data available, 443 (~1 in 450) carried 67 different cysteine-altering variants. After adjustment for various covariates, variant carriers had increased risk of stroke (OR: 2.33, p=0.0004) and vascular dementia (OR: 5.00, p=0.007), and increased white matter hyperintensity volume (standardised difference: 0.52, p<0.001) and white matter ultrastructural damage on diffusion MRI (standardised difference: 0.72, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 5.97, p<0.001) and cerebral microbleeds (OR: 4.38, p<0.001). White matter hyperintensity prevalence was most increased in the anterior temporal lobes (OR: 7.65, p<0.001) and external capsule (OR: 13.32, p<0.001).

Conclusions: Cysteine-changing variants are more common in the general population than expected from CADASIL prevalence and are risk factors for apparently 'sporadic' stroke and vascular dementia. They are associated with MRI changes of small vessel disease, in a distribution similar to that seen in CADASIL.
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http://dx.doi.org/10.1136/jnnp-2020-325838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223663PMC
July 2021

COVID-19 and stroke-Understanding the relationship and adapting services. A global World Stroke Organisation perspective.

Int J Stroke 2021 04;16(3):241-247

Department of Neurology, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul and Hospital Moinhos de Vento, Porto Alegre, Brazil.

A year ago the World Stroke Organisation (WSO) highlighted the enormous global impact of the COVID-19 pandemic on stroke care. In this review, we consider a year later where we are now, what the future holds, and what the long-term effects of the pandemic will be on stroke. Stroke occurs in about 1.4% of patients hospitalized with COVID-19 infection, who show an excess of large vessel occlusion and increased mortality. Despite this association, stroke presentations fell dramatically during the pandemic, although emerging data suggest that total stroke mortality may have risen with increased stroke deaths at home and in care homes. Strategies and guidelines have been developed to adapt stroke services worldwide, and protect healthcare workers. Adaptations include increasing use of telemedicine for all aspects of stroke care. The pandemic is exacerbating already marked global inequalities in stroke incidence and mortality. Lastly, the pandemic has had a major impact on stroke research and funding, although it has also emphasized the importance of large scale collaborative research initiatives.
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http://dx.doi.org/10.1177/17474930211005373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044614PMC
April 2021

Response to Carvalho et al.: Diagnosis of monogenic small-vessel disease - "real- world" application of the consensus recommendation of the European Academy of Neurology.

Eur J Neurol 2021 Jun 22;28(6):e37. Epub 2021 Mar 22.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1111/ene.14817DOI Listing
June 2021

Neurofilament light chain predicts future dementia risk in cerebral small vessel disease.

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

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Objectives: Serum neurofilament light chain (NfL) has been proposed as prognostic markers in neurogenerative disease. A cross-sectional study in cerebral small vessel disease (SVD) reported an association with cognition and disability. If NfL is to be used to predict outcome, studies are required to demonstrate baseline NfL predicts future dementia risk. Furthermore, if it is to be used as a surrogate marker in clinical trials, change in NfL over time periods typical of a clinical trial must be linked to clinical progression. In a longitudinal study of patients with lacunar stroke and confluent white matter hyperintensities, we determined whether both baseline, and change, in NfL levels were linked to changes in MRI markers, cognitive decline and dementia risk.

Methods: Patients underwent MRI, cognitive testing and blood taking at baseline and annually for 3 years. Clinical and cognitive follow-up continued for 5 years.

Results: NfL data were available for 113 subjects for baseline analysis, and 90 patients for the longitudinal analysis. Baseline NfL predicted cognitive decline (global cognition β-0.335, SE=0.094, p=0.001) and risk of converting to dementia (HR=1.676 (95% CI 1.183 to 2.373), p=0.004). In contrast to imaging, there was no change in NfL values over the follow-up period.

Conclusions: Baseline NfL predicts changes in MRI markers, cognitive decline and dementia rate over a 5 years follow-up period in SVD, suggesting NfL may be a useful prognostic marker. However, change in NfL values was not detected, and therefore NfL may not be a useful surrogate marker in clinical trials in SVD.
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http://dx.doi.org/10.1136/jnnp-2020-325681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142459PMC
February 2021

Modifiable Lifestyle Factors and Risk of Stroke: A Mendelian Randomization Analysis.

Stroke 2021 Mar 4;52(3):931-936. Epub 2021 Feb 4.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (E.L.H., H.S.M.).

Background And Purpose: Assessing whether modifiable risk factors are causally associated with stroke risk is important in planning public health measures, but determining causality can be difficult in epidemiological data. We evaluated whether modifiable lifestyle factors including educational attainment, smoking, and body mass index are causal risk factors for ischemic stroke and its subtypes and hemorrhagic stroke.

Methods: We performed 2-sample and multivariable Mendelian randomization to assess the causal effect of 12 lifestyle factors on risk of stroke and whether these effects are independent.

Results: Genetically predicted years of education was inversely associated with ischemic, large artery, and small vessel stroke, and intracerebral hemorrhage. Genetically predicted smoking, body mass index, and waist-hip ratio were associated with ischemic and large artery stroke. The effects of education, body mass index, and smoking on ischemic stroke were independent.

Conclusions: Our findings support the hypothesis that reduced education and increased smoking and obesity increase risk of ischemic, large artery, and small vessel stroke, suggesting that lifestyle modifications addressing these risk factors will reduce stroke risk.
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http://dx.doi.org/10.1161/STROKEAHA.120.031710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903981PMC
March 2021

Global stroke challenges: From COVID-19 to intracerebral hemorrhage and atrial fibrillation.

Authors:
Hugh S Markus

Int J Stroke 2021 02;16(2):121-122

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1177/1747493021990599DOI Listing
February 2021

Apathy after stroke: Diagnosis, mechanisms, consequences, and treatment.

Int J Stroke 2021 Jul 4;16(5):510-518. Epub 2021 Feb 4.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Apathy is a reduction in goal-directed activity in the cognitive, behavioral, emotional, or social domains of a patient's life and occurs in one out of three patients after stroke. Despite this, apathy is clinically under-recognized and poorly understood. This overview provides a contemporary introduction to apathy in stroke for researchers and practitioners, covering topics including diagnosis, neurobiological mechanisms, associated consequences, and potential treatments for apathy. Apathy is often misdiagnosed as other post-stroke conditions such as depression. Accurate differential diagnosis of apathy, which manifests as reductions in initiative, and depression, which manifests as negative emotionality, is important as it informs prognosis. Research on the neurobiology of apathy suggests that there are few consistent associations between stroke lesion location and the development of apathy. These may be resolved by adopting a network neuroscience approach, which models apathy as a pathology arising from structural or functional damage to brain networks underlying motivated behavior. Importantly, networks can be affected by physiological changes related to stroke, including the acute infarct but also diaschisis and neurodegeneration. Aside from neurobiological changes, apathy is also associated with other negative outcome measures such as functional disability, cognitive impairment, and emotional distress, suggesting that apathy is indicative of a worse prognosis following stroke. Unfortunately, high-quality trials aimed at treating apathy are scarce. Antidepressants may have limited effects on apathy. Acetylcholine and dopamine pharmacotherapy, behavioral interventions, and transcranial magnetic stimulation may be more promising avenues for treatment.
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http://dx.doi.org/10.1177/1747493021990906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267086PMC
July 2021

Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease: A Mendelian Randomization Study.

Neurology 2021 03 25;96(13):e1732-e1742. Epub 2021 Jan 25.

From the Institute for Stroke and Dementia Research (M.K.G., R.M., M.D.), Department of Neurology (M.K.G), University Hospital, and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-University, Munich, Germany; Stroke Research Group, Department of Clinical Neurosciences (E.L.H., H.S.M.), and MRC Epidemiology Unit (C.L., N.J.W.), University of Cambridge, UK; Department of Epidemiology (N.F.), UNC Gillings Global School of Public Health, Chapel Hill, NC; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Objective: We employed Mendelian randomization to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.

Methods: We selected instruments for genetic predisposition to T2D (74,124 cases, 824,006 controls), HbA1c levels (n = 421,923), fasting glucose levels (n = 133,010), insulin resistance (n = 108,557), and β-cell dysfunction (n = 16,378) based on published genome-wide association studies. Applying 2-sample Mendelian randomization, we examined associations with ischemic stroke (60,341 cases, 454,450 controls), intracerebral hemorrhage (1,545 cases, 1,481 controls), and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke), as well as with related phenotypes (carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy).

Results: Genetic predisposition to T2D and higher HbA1c levels were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke. Similar associations were also noted for carotid atherosclerotic plaque, fractional anisotropy, a white matter disease marker, and markers of brain atrophy. We further found associations of genetic predisposition to insulin resistance with large artery and small vessel stroke, whereas predisposition to β-cell dysfunction was associated with small vessel stroke, intracerebral hemorrhage, lower gray matter volume, and total brain volume.

Conclusions: This study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show associations of genetically predicted insulin resistance and β-cell dysfunction with large artery and small vessel stroke that might have implications for antidiabetic treatments targeting these mechanisms.

Classification Of Evidence: This study provides Class II evidence that genetic predisposition to T2D and higher HbA1c levels are associated with a higher risk of large artery and small vessel ischemic stroke.
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http://dx.doi.org/10.1212/WNL.0000000000011555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055310PMC
March 2021

in 2021.

Authors:
Hugh S Markus

Int J Stroke 2021 01;16(1):5-6

University of Cambridge, UK Email:

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http://dx.doi.org/10.1177/1747493020981348DOI Listing
January 2021

International Journal of Stroke- the global stroke journal.

Authors:
Hugh S Markus

Int J Stroke 2020 12;15(9):935-936

University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1177/1747493020972522DOI Listing
December 2020

Inherited risk of dementia and the progression of cerebral small vessel disease and inflammatory markers in cognitively healthy midlife adults: the PREVENT-Dementia study.

Neurobiol Aging 2021 02 2;98:124-133. Epub 2020 Nov 2.

Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

Cerebral small vessel disease (SVD) and inflammation are increasingly recognized as key contributors to Alzheimer's disease (AD), although the timing, trajectory, and relation between them early in the disease process is unclear. Therefore, to investigate very early-stage changes, we compared 158 healthy midlife adults with and without inherited AD predisposition (APOE4 carriership (38% positive), parental family history (FH) of dementia (54% positive)) on markers of SVD (white matter hyperintensities (WMH), cerebral microbleeds), and inflammation (C-reactive protein (CRP), fibrinogen), cross-sectionally and longitudinally over two years. While WMH severity was comparable between groups at baseline, longitudinal progression of WMH was greater in at-risk groups (APOE4+ and FH+). Topographically, APOE4 was associated exclusively with deep, but not periventricular, WMH progression after adjusting for FH. Conversely, APOE4 carriers displayed lower CRP levels than noncarriers, but not fibrinogen. Furthermore, interaction analysis showed that FH moderated the effect of SVD and inflammation on reaction time, an early feature of SVD, but not episodic memory or executive function. Findings suggest that vascular and inflammatory changes could occur decades before dementia onset, and may be of relevance in predicting incipient clinical progression.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895800PMC
February 2021

Tracking the global burden of stoke and dementia: World Stroke Day 2020.

Int J Stroke 2020 10;15(8):817-818

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1177/1747493020959186DOI Listing
October 2020

Stroke in COVID-19: A systematic review and meta-analysis.

Int J Stroke 2021 02 11;16(2):137-149. Epub 2020 Nov 11.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, UK.

Background: Coronavirus disease 2019 (COVID-19) has become a global pandemic, affecting millions of people. However, the relationship between COVID-19 and acute cerebrovascular diseases is unclear.

Aims: We aimed to characterize the incidence, risk factors, clinical-radiological manifestations, and outcome of COVID-19-associated stroke.

Methods: Three medical databases were systematically reviewed for published articles on acute cerebrovascular diseases in COVID-19 (December 2019-September 2020). The review protocol was previously registered (PROSPERO ID = CRD42020185476). Data were extracted from articles reporting ≥5 stroke cases in COVID-19. We complied with the PRISMA guidelines and used the Newcastle-Ottawa Scale to assess data quality. Data were pooled using a random-effect model.

Summary Of Review: Of 2277 initially identified articles, 61 (2.7%) were entered in the meta-analysis. Out of 108,571 patients with COVID-19, acute CVD occurred in 1.4% (95%CI: 1.0-1.9). The most common manifestation was acute ischemic stroke (87.4%); intracerebral hemorrhage was less common (11.6%). Patients with COVID-19 developing acute cerebrovascular diseases, compared to those who did not, were older (pooled median difference = 4.8 years; 95%CI: 1.7-22.4), more likely to have hypertension (OR = 7.35; 95%CI: 1.94-27.87), diabetes mellitus (OR = 5.56; 95%CI: 3.34-9.24), coronary artery disease (OR = 3.12; 95%CI: 1.61-6.02), and severe infection (OR = 5.10; 95%CI: 2.72-9.54). Compared to individuals who experienced a stroke without the infection, patients with COVID-19 and stroke were younger (pooled median difference = -6.0 years; 95%CI: -12.3 to -1.4), had higher NIHSS (pooled median difference = 5; 95%CI: 3-9), higher frequency of large vessel occlusion (OR = 2.73; 95%CI: 1.63-4.57), and higher in-hospital mortality rate (OR = 5.21; 95%CI: 3.43-7.90).

Conclusions: Acute cerebrovascular diseases are not uncommon in patients with COVID-19, especially in those whom are severely infected and have pre-existing vascular risk factors. The pattern of large vessel occlusion and multi-territory infarcts suggests that cerebral thrombosis and/or thromboembolism could be possible causative pathways for the disease.
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http://dx.doi.org/10.1177/1747493020972922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859578PMC
February 2021

Is periodontitis a risk factor for ischaemic stroke, coronary artery disease and subclinical atherosclerosis? A Mendelian randomization study.

Atherosclerosis 2020 11 4;313:111-117. Epub 2020 Oct 4.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background And Aims: Observational studies have reported an association between periodontitis and cardiovascular disease but whether this association is causal is uncertain. We therefore used Mendelian randomization to test whether periodontitis is causally associated with stroke, coronary artery disease, or subclinical atherosclerosis.

Methods: A two-sample Mendelian randomization analysis was carried out using five single nucleotide polymorphisms previously associated with periodontitis in genome-wide association studies. Summary data were drawn from MEGASTROKE and combined with de novo analyses of UK Biobank for stroke and its major subtypes (up to 44,221 cases, 739,957 controls) and CARDIoGRAMplusC4D and UK Biobank for coronary artery disease (122,733 cases, 424,528 controls). We used existing data on carotid intima-media thickness in UK Biobank as a marker of subclinical atherosclerosis (N = 22,179). Causal estimates were obtained using inverse-variance weighted Mendelian randomization. Sensitivity analyses were performed using weighted median and MR-Egger approaches.

Results: No association was found between periodontitis and any stroke (odds ratio [OR] per doubling in the odds of periodontitis 0.99, 95% confidence interval [CI] 0.97 to 1.02), ischaemic stroke (OR 1.00, 95% CI 0.97 to 1.03) or its major subtypes (p > 0.4), or coronary artery disease (OR 1.01, 95% CI 0.99 to 1.03). Similarly, we found no association for periodontitis and subclinical atherosclerosis (β -0.002, 95% CI -0.004 to 0.001). These results were consistent across a series of sensitivity analyses.

Conclusions: These findings provide no robust evidence for a causal relationship between periodontitis and stroke or coronary artery disease. This suggests that associations reported in observational studies may represent confounding.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660116PMC
November 2020

Improving stroke care through education: The World Stroke Academy.

Int J Stroke 2020 10;15(7):703

Stroke Outcomes and Decision Neuroscience Unit, Department of Medicine, University of Toronto, Toronto, Canada.

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http://dx.doi.org/10.1177/1747493020954748DOI Listing
October 2020
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