Homocysteine and small vessel stroke: A mendelian randomization analysis.

OBJECTIVE: Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization. METHODS: We used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B6 (n = 1), and vitamin B12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases). RESULTS: Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p = 6.7 × 10-4 ) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B6 levels were 0.49 (95% CI, 0.34-0.71; p = 1.3 × 10-4 ) and 0.70 (95% CI, 0.52-0.94; p = 0.02), respectively. Genetically higher vitamin B12 levels were not associated with any stroke subtype. INTERPRETATION: These findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501

Circulating Vitamin K₁ Levels in Relation to Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study.

Vitamin K plays a crucial role in blood coagulation, and hypercoagulability has been linked to atherosclerosis-related vascular disease. We used the Mendelian randomization study design to examine whether circulating vitamin K₁ (phylloquinone) levels are associated with ischemic stroke. Four single-nucleotide polymorphisms associated with vitamin K₁ levels were used as instrumental variables. Summary-level data for large artery atherosclerotic stroke (n = 4373 cases), small vessel stroke (n = 5386 cases), cardioembolic stroke (n = 7193 cases), and any ischemic stroke (n = 34,217 cases and 404,630 non-cases) were available from the MEGASTROKE consortium. Genetically-predicted circulating vitamin K₁ levels were associated with large artery atherosclerotic stroke but not with any other subtypes or ischemic stroke as a whole. The odds ratios per genetically predicted one nmol/L increase in natural log-transformed vitamin K₁ levels were 1.31 (95% confidence interval (CI) 1.12⁻1.53; p = 7.0 × 10-4) for large artery atherosclerotic stroke, 0.98 (95% CI 0.85⁻1.12; p = 0.73) for small vessel stroke, 1.01 (95% CI 0.90⁻1.14; p = 0.84) for cardioembolic stroke, and 1.05 (95% CI 0.99⁻1.11; p = 0.11) for any ischemic stroke. These findings indicate that genetic predisposition to higher circulating vitamin K₁ levels is associated with an increased risk of large artery atherosclerotic stroke

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

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

Oxidative phosphorylation and lacunar stroke: Genome-wide enrichment analysis of common variants.

OBJECTIVE: We investigated whether oxidative phosphorylation (OXPHOS) abnormalities were associated with lacunar stroke, hypothesizing that these would be more strongly associated in patients with multiple lacunar infarcts and leukoaraiosis (LA). METHODS: In 1,012 MRI-confirmed lacunar stroke cases and 964 age-matched controls recruited from general practice surgeries, we investigated associations between common genetic variants within the OXPHOS pathway and lacunar stroke using a permutation-based enrichment approach. Cases were phenotyped using MRI into those with multiple infarcts or LA (MLI/LA) and those with isolated lacunar infarcts (ILI) based on the number of subcortical infarcts and degree of LA, using the Fazekas grading. Using gene-level association statistics, we tested for enrichment of genes in the OXPHOS pathway with all lacunar stroke and the 2 subtypes. RESULTS: There was a specific association with strong evidence of enrichment in the top 1% of genes in the MLI/LA (subtype p = 0.0017) but not in the ILI subtype (p = 1). Genes in the top percentile for the all lacunar stroke analysis were not significantly enriched (p = 0.07). CONCLUSIONS: Our results implicate the OXPHOS pathway in the pathogenesis of lacunar stroke, and show the association is specific to patients with the MLI/LA subtype. They show that MRI-based subtyping of lacunar stroke can provide insights into disease pathophysiology, and imply that different radiologic subtypes of lacunar stroke subtypes have distinct underlying pathophysiologic processes.Hugh Markus is supported by an NIHR Senior Investigator award. Hugh Markus and Steve Bevan are supported by the NIHR Cambridge University Hospitals Comprehensive Biomedical Research Centre. Collection of the UK Young Lacunar Stroke Resource was primarily supported by a Functional Genomics grant from the Wellcome Trust with additional support from the Stroke Association. Genotyping and MT were supported by a project grant from the Stroke Association (TSA 2013/01). Dr. Anderson is supported by NIH-NINDS K23 NS086873 and a Fellowship in Therapeutic Investigation sponsored by the Massachusetts General Hospital Department of Neurology and Biogen Idec, Inc.This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/WNL.000000000000226

A comparison of functional and tractography based networks in cerebral small vessel disease.

OBJECTIVE: MRI measures of network integrity may be useful disease markers in cerebral small vessel disease (SVD). We compared the sensitivity and reproducibility of MRI derived structural and functional network measures in healthy controls and SVD subjects. METHODS: Diffusion tractography and resting state fMRI were used to create connectivity matrices from 26 subjects with symptomatic MRI confirmed lacunar stroke and 19 controls. Matrices were constructed at multiple scales based on a multi-resolution cortical atlas and at multiple thresholds for the matrix density. Network parameters were calculated over the multiple resolutions and thresholds. In addition the reproducibility of structural and functional network parameters was determined in a subset of the subjects (15 SVD, 10 controls) who were scanned twice. RESULTS: Structural networks showed a highly significant loss of network integrity in SVD cases compared to controls, for all network measures. In contrast functional networks showed no difference between SVD and controls. Structural network measures were highly reproducible in both cases and controls, with ICC values consistently over 0.8. In contrast functional network measures showed much poorer reproducibility with ICC values in the range 0.4-0.6 overall, and even lower in SVD cases. CONCLUSIONS: Structural networks identify impaired network integrity, and are highly reproducible, in SVD, supporting their use as markers of SVD disease severity. In contrast, functional networks showed low reproducibility, particularly in SVD cases, and were unable to detect differences between SVD cases and controls with this sample size

Apathy, but not depression, is associated with executive dysfunction in cerebral small vessel disease.

OBJECTIVE: To determine the prevalence of apathy and depression in cerebral small vessel disease (SVD), and the relationships between both apathy and depression with cognition. To examine whether apathy is specifically related to impairment in executive functioning and processing speed. METHODS: 196 patients with a clinical lacunar stroke and an anatomically corresponding lacunar infarct on MRI were compared to 300 stroke-free controls. Apathy and depression were measured using the Geriatric Depression Scale, and cognitive functioning was assessed using an SVD cognitive screening tool, the Brief Memory and Executive Test, which measures executive functioning/processing speed and memory/orientation. Path analysis and binary logistic regression were used to assess the relation between apathy, depression and cognitive impairment. RESULTS: 31 participants with SVD (15.8%) met criteria for apathy only, 23 (11.8%) for both apathy and depression, and 2 (1.0%) for depression only. In the SVD group the presence of apathy was related to global cognition, and specifically to impaired executive functioning/processing speed, but not memory/orientation. The presence of depression was not related to global cognition, impaired executive functioning/processing speed or memory/orientation. CONCLUSIONS: Apathy is a common feature of SVD and is associated with impaired executive functioning/processing speed suggesting the two may share biological mechanisms. Screening for apathy should be considered in SVD, and further work is required to develop and evaluate effective apathy treatment or management in SVD.This work was supported by a Priority Program Grant from the Stroke Association (TSA PPA 2015-02; www.stroke.org.uk). The BMET Study was supported by a grant from the Stroke Association (TSA2008/10). Valerie Lohner is supported by a Stroke Association/British Heart Foundation Program Grant (TSA BHF 2010/01; www.bhf.org.uk). Rebecca Brookes is supported by a BHF Project Grant (PG/13/30/30005). Recruitment to the BMET Study was supported by the English National Institute of Health Research (NIHR) Clinical Stroke Research Network (www.crn.nihr.ac.uk/stroke). Hugh Markus is supported by an NIHR Senior Investigator award (www.nihr.ac.uk) and his work is supported by the Cambridge University Hospital Comprehensive NIHR Biomedical Research Unit (www.cambridge-brc.org.uk)

Brief Screening of Vascular Cognitive Impairment in Patients With Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Without Dementia.

BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of cerebral small vessel disease leading to early-onset stroke and dementia, with younger patients frequently showing subclinical deficits in cognition. At present, there are no targeted cognitive screening measures for this population. However, the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA) have shown utility in detecting cognitive impairment in sporadic small vessel disease. This study assesses the BMET and the MoCA as clinical tools for detecting mild cognitive deficits in CADASIL. METHODS: Sixty-six prospectively recruited patients with CADASIL, and 66 matched controls completed the BMET, with a subset of these also completing the MoCA. Receiver operating characteristic curves were calculated to examine the sensitivity and specificity of clinical cutoffs for the detection of vascular cognitive impairment and reduced activities of daily living. RESULTS: Patients with CADASIL showed more cognitive impairment overall and were poorer on both executive/processing and memory indices of the BMET relative to controls. The BMET showed good accuracy in predicting vascular cognitive impairment (85% sensitivity and 84% specificity) and impaired instrumental activities of daily living (92% sensitivity and 77% specificity). The MoCA also showed good predictive validity for vascular cognitive impairment (80% sensitivity and 78% specificity) and instrumental activities of daily living (75% sensitivity and 76% specificity). The most important background predictor of vascular cognitive impairment was a history of stroke. CONCLUSIONS: The results indicate that the BMET and the MoCA are clinically useful and sensitive screening measures for early cognitive impairment in patients with CADASIL.Stroke Association (Grant ID: TSA2008/10), British Heart Foundation (Grant ID: PG/13/30/30005), Stroke Association/British Heart Foundation (Grant ID: TSA BHF 2010/01), Agency for Science, Technology and Research, Singapore, National Institute for Health Research (Senior Investigator award), Cambridge University Hospital Comprehensive National Institute for Health Research Biomedical Research UnitThis is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1161/STROKEAHA.116.01376

Encephalopathy in a Large Cohort of British Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients.

Background and Purpose- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke usually presenting with migraine with aura, lacunar infarcts, and cognitive impairment. Acute encephalopathy is a less recognized presentation of the disease. Methods- Data collected prospectively from 340 consecutively recruited symptomatic patients with diagnosis of CADASIL seen in a British National CADASIL clinic was retrospectively reviewed and original clinical records and imaging obtained. An encephalopathic event was defined as an acute event of an altered state of consciousness in a patient with CADASIL, manifesting with signs of brain dysfunction, which warranted hospital admission in the absence of any other cause. Clinical characteristics, risk factors, and outcome of encephalopathic presentations were studied. Results- A total of 35 of 340 (10.3%) participants had a history of 50 encephalopathic events which was the first hospital presentation of CADASIL in 33 (94.3%) patients. Most commonly reported features during episodes were visual hallucinations (44%), seizures (22%), and focal neurological deficits (60%).Complete recovery within 3 months was reported in 48(96%) episodes. In 62% of episodes, there was a history of migraine or migraine aura directly preceding the encephalopathy. In 2 out of 15 cases where magnetic resonance imaging during episodes was available, unilateral focal cortical swelling was seen. A past history of migraine was independently associated with encephalopathy (odds ratio=12.3 [95% CI, 1.6-93.7]; P=0.015). Conclusions- In up to 10% of CADASIL patients, a reversible encephalopathy is the first presentation leading to diagnosis. The strong association with migraine suggests a shared pathogenesis. Focal cortical swelling may be seen on magnetic resonance imaging during the acute episode