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Background and Purpose: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial. Methods: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics. Results: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26–115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack ( P 0 ( P P =0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS. Conclusions: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909.

Background Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown. Aims To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies. Methods At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression. Results Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52–1.7). Conclusions Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide. Registration: https://www.clinicaltrials.gov . Unique identifier: NCT 02313909

Background: Cerebral amyloid angiopathy (CAA) contributes to brain neurodegeneration and cognitive decline, but the relationship between these two processes is incompletely understood. Objective: The purpose of this study is to examine cortical thickness and its association with cognition and neurodegenerative biomarkers in CAA. Methods: Data were collected from the Functional Assessment of Vascular Reactivity study and the Calgary Normative Study. In total, 48 participants with probable CAA, 72 cognitively normal healthy controls, and 24 participants with mild dementia due to AD were included. Participants underwent an MRI scan, after which global and regional cortical thickness measurements were obtained using FreeSurfer. General linear models, adjusted for age and sex, were used to compare cortical thickness globally and in an AD signature region. Results: Global cortical thickness was lower in CAA compared to healthy controls (mean difference (MD) –0.047 mm, 95% confidence interval (CI) –0.088, –0.005, p = 0.03), and lower in AD compared to CAA (MD –0.104 mm, 95% CI –0.165, –0.043, p = 0.001). In the AD signature region, cortical thickness was lower in CAA compared to healthy controls (MD –0.07 mm, 95% CI –0.13 to –0.01, p = 0.02). Within the CAA group, lower cortical thickness was associated with lower memory scores (R2 = 0.10; p = 0.05) and higher white matter hyperintensity volume (R2 = 0.09, p = 0.04). Conclusion: CAA contributes to neurodegeneration in the form of lower cortical thickness, and this could contribute to cognitive decline. Regional overlap with an AD cortical atrophy signature region suggests that co-existing AD pathology may contribute to lower cortical thickness observed in CAA.

Objective: To describe the neuroimaging and other methods for assessing vascular contributions to neurodegeneration in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study, a Canadian multi-center, prospective longitudinal cohort study, including reliability and feasibility in the first 200 participants. Methods: COMPASS-ND includes persons with Alzheimer’s disease (AD; n = 150), Parkinson’s disease (PD) and Lewy body dementias (LBDs) (200), mixed dementia (200), mild cognitive impairment (MCI; 400), subcortical ischemic vascular MCI (V-MCI; 200), subjective cognitive impairment (SCI; 300), and cognitively intact elderly controls (660). Magnetic resonance imaging (MRI) was acquired according to the validated Canadian Dementia Imaging Protocol and visually reviewed by either of two experienced readers blinded to clinical characteristics. Other relevant assessments include history of vascular disease and risk factors, blood pressure, height and weight, cholesterol, glucose, and hemoglobin A1c. Results: Analyzable data were obtained in 197/200 of whom 18 of whom were clinically diagnosed with V-MCI or mixed dementia. The overall prevalence of infarcts was 24.9%, microbleeds was 24.6%, and high white matter hyperintensity (WMH) was 31.0%. MRI evidence of a potential vascular contribution to neurodegeneration was seen in 12.9%–40.0% of participants clinically diagnosed with another condition such as AD. Inter-rater reliability was good to excellent. Conclusion: COMPASS-ND will be a useful platform to study vascular brain injury and its association with risk factors, biomarkers, and cognitive and functional decline across multiple age-related neurodegenerative diseases. Initial findings show that MRI-defined vascular brain injury is common in all cognitive syndromes and is under-recognized clinically.

Background: Cerebral amyloid angiopathy (CAA) is associated with cognitive decline. CAA has diverse impacts on brain structure and function; however, the brain lesions that mediate the association of CAA with cognition are not understood well. Aims: To determine the degree to which CAA neuroimaging biomarkers mediate the association of CAA with cognitive dysfunction. Methods: We analyzed cross-sectional data of patients with probable CAA and controls without cognitive impairment from the Functional Assessment of Vascular Reactivity study. Neuropsychological tests were grouped into domains of memory, executive function, and processing speed. Candidate CAA neuroimaging biomarkers were pre-specified based on prior literature, consisting of white matter hyperintensity volume, peak width of skeletonized mean diffusivity (PSMD) on diffusion tensor magnetic resonance imaging (MRI), cerebrovascular reactivity (CVR), cortical thickness, and cortical thickness in a meta-region of interest typically affected by Alzheimer’s disease (AD). Cognitive scores and neuroimaging markers were standardized and reported in relation to values in controls. Mediation analysis was used to estimate the total effect of CAA on cognition and the proportion of the total effect that was mediated by neuroimaging biomarkers, controlling for age, sex, and education. Results: There were 131 participants (67 CAA and 64 controls). Mean age was 72.1 ± 7.7 years, and 54.2% were women. As expected, compared to controls, CAA was associated with lower cognition. In mediation analyses, CAA had direct unmediated effects of 48%, 46%, and 52% on all three cognitive domains. The association of CAA with memory was partially mediated by CVR and PSMD, accounting for 18% and 36% of the total effect of CAA. The association of CAA with executive function was partially mediated by PSMD and mean cortical thickness in the AD meta-region of interest (ROI), accounting for 33% and 31% of the total effect of CAA. The association of CAA with processing speed was partially mediated by CVR and PSMD, accounting for 8% and 34% of the total effect of CAA. Among CAA participants, the presence of cortical superficial siderosis was associated with lower processing speed. Conclusion: Altered white matter diffusivity (i.e. PSMD), CVR, and atrophy, taken together, account for about half the effect of CAA on cognition.

Background Cerebral protection remains the cornerstone of successful aortic surgery; however, there is no consensus as to the optimal strategy. Objective To compare the safety and efficacy of innominate to axillary artery cannulation for delivering antegrade cerebral protection during proximal aortic arch surgery. Methods This randomized controlled trial (The Aortic Surgery Cerebral Protection Evaluation CardioLink-3 Trial, ClinicalTrials.gov Identifier: NCT02554032 ), conducted across 6 Canadian centers between January 2015 and June 2018, allocated 111 individuals to innominate or axillary artery cannulation. The primary safety outcome was neuroprotection per the appearance of new severe ischemic lesions on the postoperative diffusion-weighted-magnetic resonance imaging. The primary efficacy outcome was the difference in total operative time. Secondary outcomes included 30-day all-cause mortality and postoperative stroke. Results One hundred two individuals (mean age, 63 ± 11 years) were in the primary safety per-protocol analysis. Baseline characteristics between the groups were similar. New severe ischemic lesions occurred in 19 participants (38.8%) in the axillary versus 18 (34%) in the innominate group (P for noninferiority = .0009). Total operative times were comparable (median, 293 minutes; interquartile range, 222-411 minutes) for axillary versus (298 minutes; interquartile range, 231-368 minutes) for innominate (P for superiority = .47). Stroke/transient ischemic attack occurred in 4 (7.1%) participants in the axillary versus 2 (3.6%) in the innominate group (P = .43). Thirty-day mortality, seizures, delirium, and duration of mechanical ventilation were similar in both groups. Conclusions diffusion-weighted magnetic resonance imaging assessments indicate that antegrade cerebral protection with innominate cannulation is safe and affords similar neuroprotection to axillary cannulation during aortic surgery, although the burden of new neurological lesions is high in both groups.

IntroductionA number of MRI methods have been proposed to be useful, quantitative biomarkers of neurodegeneration in ageing. The Calgary Normative Study (CNS) is an ongoing single-centre, prospective, longitudinal study that seeks to develop, test and assess quantitative magnetic resonance (MR) methods as potential biomarkers of neurodegeneration. The CNS has three objectives: first and foremost, to evaluate and characterise the dependence of the selected quantitative neuroimaging biomarkers on age over the adult lifespan; second, to evaluate the precision, variability and repeatability of quantitative neuroimaging biomarkers as part of biomarker validation providing proof-of-concept and proof-of-principle; and third, provide a shared repository of normative data for comparison to various disease cohorts.Methods and analysisQuantitative MR mapping of the brain including longitudinal relaxation time (T1), transverse relaxation time (T2), T2*, magnetic susceptibility (QSM), diffusion and perfusion measurements, as well as morphological assessments are performed. The Montreal Cognitive Assessment (MoCA) and a brief, self-report medical history will be collected. Mixed regression models will be used to characterise changes in quantitative MR biomarker measures over the adult lifespan. In this report, we describe the study design, strategies to recruit and perform changes to the acquisition protocol from inception to 31 December 2018, planned statistical approach and data sharing procedures for the study.Ethics and disseminationParticipants provide signed informed consent. Changes in quantitative MR biomarkers measured over the adult lifespan as well as estimates of measurement variance and repeatability will be disseminated through peer-reviewed scientific publication.

IntroductionA number of magnetic resonance (MR) imaging methods have been proposed to be useful, quantitative biomarkers of neurodegeneration in aging. The Calgary Normative Study (CNS) is an ongoing single-centre, prospective, longitudinal study that seeks to develop, test and assess quantitative MR methods as potential biomarkers. The CNS has three objectives: first and foremost, to evaluate and characterize the dependence of the selected quantitative neuroimaging biomarkers on age over the adult lifespan; secondly, to evaluate the precision, variability and repeatability of quantitative neuroimaging biomarkers as part of biomarker validation providing proof of-concept and proof-of-principle; and thirdly, provide a shared repository of normative data for comparison to various disease cohorts.Methods and AnalysisQuantitative MR mapping of the brain including longitudinal relaxation time (T1), transverse relaxation time (T2), T2*, magnetic susceptibility (QSM), diffusion and perfusion measurements, as well as morphological assessments are performed. The Montreal Cognitive Assessment (MoCA) and a brief, self-report medical history will be collected. Mixed regression models will be used to characterize changes in quantitative MR biomarker measures over the adult lifespan. In this report on study design, we report interim prevalence and demographic information of recruitment from 28 May 2013 to 31 December 2018.Ethics and DisseminationParticipants provide signed informed consent. Changes in quantitative MR biomarkers measured over the adult lifespan as well as estimates of measurement variance and repeatability will be disseminated through peer-reviewed scientific publication.STRENGTHS AND LIMITATIONSBoth cross-sectional and longitudinal quantitative MR data is being acquired in a large sample normal aging population to characterize changes in these potential neuroimaging biomarkers over the adult lifespan.Clinical and multiple quantitative imaging data are being collected and shared with the research community.Measures of repeatability and a process to update the imaging protocol are included in the study design.Associated self-reported medical history and cognitive assessments are limited

Summary Background In non-surgical settings, covert stroke is more common than overt stroke and is associated with cognitive decline. Although overt stroke occurs in less than 1% of adults after non-cardiac surgery and is associated with substantial morbidity, we know little about perioperative covert stroke. Therefore, our primary aim was to investigate the relationship between perioperative covert stroke (ie, an acute brain infarct detected on an MRI after non-cardiac surgery in a patient with no clinical stroke symptoms) and cognitive decline 1 year after surgery. Methods NeuroVISION was a prospective cohort study done in 12 academic centres in nine countries, in which we assessed patients aged 65 years or older who underwent inpatient, elective, non-cardiac surgery and had brain MRI after surgery. Two independent neuroradiology experts, masked to clinical data, assessed each MRI for acute brain infarction. Using multivariable regression, we explored the association between covert stroke and the primary outcome of cognitive decline, defined as a decrease of 2 points or more on the Montreal Cognitive Assessment from preoperative baseline to 1-year follow-up. Patients, health-care providers, and outcome adjudicators were masked to MRI results. Findings Between March 24, 2014, and July 21, 2017, of 1114 participants recruited to the study, 78 (7%; 95% CI 6–9) had a perioperative covert stroke. Among the patients who completed the 1-year follow-up, cognitive decline 1 year after surgery occurred in 29 (42%) of 69 participants who had a perioperative covert stroke and in 274 (29%) of 932 participants who did not have a perioperative covert stroke (adjusted odds ratio 1·98, 95% CI 1·22–3·20, absolute risk increase 13%; p=0·0055). Covert stroke was also associated with an increased risk of perioperative delirium (hazard ratio [HR] 2·24, 95% CI 1·06–4·73, absolute risk increase 6%; p=0·030) and overt stroke or transient ischaemic attack at 1-year follow-up (HR 4·13, 1·14–14·99, absolute risk increase 3%; p=0·019). Interpretation Perioperative covert stroke is associated with an increased risk of cognitive decline 1 year after non-cardiac surgery, and perioperative covert stroke occurred in one in 14 patients aged 65 years and older undergoing non-cardiac surgery. Research is needed to establish prevention and management strategies for perioperative covert stroke. Funding Canadian Institutes of Health Research; The Ontario Strategy for Patient Oriented Research support unit; The Ontario Ministry of Health and Long-Term Care; Health and Medical Research Fund, Government of the Hong Kong Special Administrative Region, China; and The Neurological Foundation of New Zealand.