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IntroductionWhite matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β1-42 (Aβ42)-positive status.MethodsIndividual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume.ResultsVRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p

IntroductionThe spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns.MethodsIndividual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented.ResultsWMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected.DiscussionAggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.

BackgroundThe United States lacks a timely and accurate nationwide surveillance system for acute ischemic stroke (AIS). We use the Get With The Guidelines-Stroke registry to apply poststratification survey weights to generate national assessment of AIS epidemiology, hospital care quality, and in-hospital outcomes.MethodsClinical data from the Get With The Guidelines-Stroke registry were weighted using a Bayesian interpolation method anchored to observations from the national inpatient sample. To generate a US stroke forecast for 2019, we linearized time trend estimates from the national inpatient sample to project anticipated AIS hospital volume, distribution, and race/ethnicity characteristics for the year 2019. Primary measures of AIS epidemiology and clinical care included patient and hospital characteristics, stroke severity, vital and laboratory measures, treatment interventions, performance measures, disposition, and clinical outcomes at discharge.ResultsWe estimate 552 476 patients with AIS were admitted in 2019 to US hospitals. Median age was 71 (interquartile range, 60-81), 48.8% female. Atrial fibrillation was diagnosed in 22.6%, 30.2% had prior stroke/transient ischemic attack, and 36.4% had diabetes. At baseline, 46.4% of patients with AIS were taking antiplatelet agents, 19.2% anticoagulants, and 46.3% cholesterol-reducers. Mortality was 4.4%, and only 52.3% were able to ambulate independently at discharge. Performance nationally on AIS achievement measures were generally higher than 95% for all measures but the use of thrombolytics within 3 hours of early stroke presentations (81.9%). Additional quality measures had lower rates of receipt: dysphagia screening (84.9%), early thrombolytics by 4.5 hours (79.7%), and statin therapy (80.6%).ConclusionsWe provide timely, reliable, and actionable US national AIS surveillance using Bayesian interpolation poststratification weights. These data may facilitate more targeted quality improvement efforts, resource allocation, and national policies to improve AIS care and outcomes.

Background and objectivesPrior regional or single-center studies have noted that 4% to 7% of eligible patients with acute ischemic stroke (AIS) decline IV tissue plasminogen activator (tPA). We sought to determine the prevalence of tPA declination in a nationwide registry of patients with AIS and to investigate differences in declination by race/ethnicity.MethodsWe used the Get With The Guidelines-Stroke registry to identify patients with AIS eligible for tPA and admitted to participating hospitals between January 1, 2016, and March 28, 2019. We compared patient demographics and admitting hospital characteristics between tPA-eligible patients who received and those who declined tPA. Using multivariable logistic regression, we determined patient and hospital factors associated with tPA declination.ResultsAmong 177,115 tPA-eligible patients with AIS at 1,976 sites, 6,545 patients (3.7%) had tPA declination as the sole documented reason for not receiving tPA. Patients declining treatment were slightly older, were more likely to be female, arrived more often at off-hours and earlier after symptom onset, and were more likely to present to Primary Stroke Centers. Compared with non-Hispanic White, non-Hispanic Black race/ethnicity was independently associated with increased (adjusted odds ratio [aOR] 1.21, 95% CI 1.11-1.31), Asian race/ethnicity with decreased (aOR 0.72, 95% CI 0.58-0.88), and Hispanic ethnicity (any race) with similar odds of tPA declination (OR 0.98, 95% CI 0.86-1.13) in multivariable analysis.DiscussionAlthough the overall prevalence of tPA declination is low, eligible non-Hispanic Black patients are more likely and Asian patients less likely to decline tPA than non-Hispanic White patients. Reducing rates of tPA declinations among non-Hispanic Black patients may be an opportunity to address disparities in stroke care.

Introduction Endovascular therapy (EVT) use increased following clinical trials publication in 2015, but limited data suggest there may be persistent race and ethnicity differences. Methods and Results We included all patients with acute ischemic stroke arriving within 6 hours of last known well and with National Institute of Health Stroke Scale (NIHSS) score ≥6 between April 2012 and June 2019 in the Get With The Guidelines-Stroke database and evaluated the association between race and ethnicity and EVT use and outcomes, comparing the era before versus after 2015. Of 302 965 potentially eligible patients; 42 422 (14%) underwent EVT. Although EVT use increased over time in all racial and ethnic groups, Black patients had reduced odds of EVT use compared with non-Hispanic White (NHW) patients (adjusted odds ratio [aOR] before 2015, 0.68 [0.58‒0.78]; aOR after 2015, 0.83 [0.76‒0.90]). In-hospital mortality/discharge to hospice was less frequent in Black, Hispanic, and Asian patients compared with NHW. Conversely discharge home was more frequent in Hispanic (29.7%; aOR, 1.28 [1.16‒1.42]), Asian (28.2%; aOR, 1.23 [1.05‒1.44]), and Black (29.1%; aOR, 1.08 [1.00‒1.18]) patients compared with NHW (24%). However, at 3 months, functional independence (modified Rankin Scale, 0-2) occurred less frequently in Black (37.5%; aOR, 0.84 [0.75‒0.95]) and Asian (33%; aOR, 0.79 [0.65‒0.98]) patients compared with NHW patients (38.1%). Conclusions In a large cohort of patients treated with EVT, Black versus NHW patient disparities in EVT use have narrowed over time but still exist. Discharge related outcomes were slightly more favorable in racial and ethnic underrepresented groups; 3-month functional outcomes were worse but improved across all groups with time.

Background and purposeMany older patients presenting with acute ischemic stroke were already taking aspirin before admission. However, the management strategy for patients with aspirin treatment failure has not been fully established.MethodsWe used data from the American Heart Association Get With The Guidelines Stroke Registry to describe discharge antithrombotic treatment patterns among Medicare beneficiaries with ischemic stroke who were taking aspirin before their stroke and were discharged alive from 1734 hospitals in the United States between October 2012 and December 2017.ResultsOf 261 634 ischemic stroke survivors, 100 016 (38.2%) were taking aspirin monotherapy before stroke. Among them, 44.4% of patients remained on aspirin monotherapy at discharge (20.9% 81 mg, 18.2% 325 mg, 5.3% other or unknown dose). The next most common therapy choice was dual antiplatelet therapy (24.6%), followed by clopidogrel monotherapy (17.8%). The remaining 13.2% of patients were discharged on either aspirin/dipyridamole, warfarin, or nonvitamin K antagonist oral anticoagulants with or without antiplatelet, or no antithrombotic therapy at all.ConclusionsNearly half of patients with ischemic stroke while on preventive therapy with aspirin are discharged on aspirin monotherapy without changing antithrombotic class, while the other half are discharged on clopidogrel monotherapy, dual antiplatelet therapy, or other less common agents. These findings emphasize the need for future research to identify best management strategies for this very common and complex clinical scenario.

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Background and purposeDepression is common after stroke and is often treated with antidepressant medications (AD). ADs have also been hypothesised to improve stroke recovery, although recent randomised trials were neutral. We investigated the patterns of in-hospital AD initiation after ischaemic stroke and association with clinical and readmission outcomes.MethodsAll Medicare fee-for-service beneficiaries aged 65 or older hospitalised for ischaemic stroke in participating Get With The Guidelines-Stroke hospitals between April and December 2014 were eligible for this analysis. Outcome measures included days alive and not in a healthcare institution (home time), all-cause mortality and readmission within 1-year postdischarge. Propensity score (PS)-adjusted logistic regression models were used to evaluate the associations between AD use and each outcome measure. We also compared outcomes in patients prescribed selective serotonin reuptake inhibitors (SSRIs) AD versus those prescribed non-SSRI ADs.ResultsOf 21 805 AD naïve patients included in this analysis, 1835 (8.4%) were started on an AD at discharge. Patients started on an AD had higher rates of depression and prior ischaemic stroke, presented with higher admission National Institutes of Health Stroke Scale score and were less likely to be discharged home. Similarly, patients started on an SSRI had lower rates of discharge to home. Adjusting for stroke severity, patients started on an AD had worse all-cause mortality, all-cause readmission, major adverse cardiac events, readmission for depression and decreased home-time. However, AD use was also associated with an increased risk for the sepsis, a falsification endpoint, suggesting the presence of residual confounding.ConclusionsPatients with ischaemic stroke initiated on AD therapy are at increased risk of poor clinical outcomes and readmission even after PS adjustment, suggesting that poststroke depression requiring medication is a poor prognostic sign. Further research is needed to explore the reasons why depression is associated with worse outcome, and whether AD treatment modifies this risk or not.

BackgroundThe safety and effectiveness of oral anticoagulation (OAC) after an ischemic stroke in older patients with heart failure (HF) without atrial fibrillation remains uncertain.MethodsUtilizing Get With The Guidelines Stroke national clinical registry data linked to Medicare claims from 2009-2014, we assessed the outcomes of eligible patients with a history of HF who were initiated on OAC during a hospitalization for an acute ischemic stroke. The cumulative incidences of adverse events were calculated using Kaplan-Meier curves and adjusted Cox proportional hazard ratios were compared between patients discharged on or off OAC.ResultsA total of 8,261 patients from 1,370 sites were discharged alive after an acute ischemic stroke and met eligibility criteria. Of those, 747 (9.0%) were initiated on OAC.  Patients on OAC were younger (77.2±8.0 vs. 80.5±8.9 years, p

Abstract Background: The U.S. lacks a stroke surveillance system. This study develops a method to transform an existing registry into a nationally representative database to evaluate acute ischemic stroke care quality.Methods: Two statistical approaches were used to develop post-stratification weights for the Get With The Guidelines-Stroke registry by anchoring population estimates to the National Inpatient Sample. Post-stratification survey weights were estimated using a raking procedure and Bayesian interpolation methods. Weighting methods were adjusted to limit the dispersion of weights and make reasonable epidemiologic estimates of patient characteristics, quality of hospital care, and clinical outcomes. Standardized differences in national estimates were reported between the two post-stratification methods for anchored and non-anchored patient characteristics to evaluate estimation quality. Primary measures evaluated were patient and hospital characteristics, stroke severity, vital and laboratory measures, disposition, and clinical outcomes at discharge. Results: A total of 1,388,296 acute ischemic strokes occurred between 2012 and 2014. Raking and Bayesian estimates of clinical data not recorded in administrative databases were estimated within 5% to 10% of the margins of expected values. Median weights for the raking method were 1.386 and the weights at the 99th percentile were 6.881 with a maximum weight of 30.775. Median Bayesian weights were 1.329 and the 99th percentile weights were 11.201 with a maximum weight of 515.689. Conclusions: Leveraging existing databases with patient registries to develop post-stratification weights is a reliable approach to estimate acute ischemic stroke epidemiology and monitoring for stroke quality of care nationally. These methods may be applied to other diseases or settings to better monitor population health.

BackgroundLong-term outcomes for Medicare beneficiaries hospitalised with transient ischaemic attack (TIA) and role of ABCD2 score in identifying high-risk individuals are not studied.MethodsWe identified 40 825 Medicare beneficiaries hospitalised from 2011 to 2014 for a TIA to a Get With The Guidelines (GWTG)-Stroke hospital and classified them using ABCD2 score. Proportional hazards models were used to assess 1-year event rates of mortality and rehospitalisation (all-cause, ischaemic stroke, haemorrhagic stroke, myocardial infarction, and gastrointestinal and intracranial haemorrhage) for high-risk versus low-risk groups adjusted for patient and hospital characteristics.ResultsOf the 40 825 patients, 35 118 (86%) were high risk (ABCD2 ≥4) and 5707 (14%) were low risk (ABCD2=0-3). Overall rate of mortality during 1-year follow-up after hospital discharge for the index TIA was 11.7%, 44.3% were rehospitalised for any reason and 3.6% were readmitted due to stroke. Patients with ABCD2 score ≥4 had higher mortality at 1 year than not (adjusted HR 1.18, 95% CI 1.07 to 1.30). Adjusted risks for ischaemic stroke, all-cause readmission and mortality/all-cause readmission at 1 year were also significantly higher for patients with ABCD2 score ≥4 vs 0-3. In contrast, haemorrhagic stroke, myocardial infarction, gastrointestinal bleeding and intracranial haemorrhage risk were not significantly different by ABCD2 score.ConclusionsThis study validates the use of ABCD2 score for long-term risk assessment after TIA in patients aged 65 years and older. Attentive efforts for community-based follow-up care after TIA are needed for ongoing prevention in Medicare beneficiaries who were hospitalised for TIA.

The MarkVCID consortium was formed under cooperative agreements with the National Institute of Neurologic Diseases and Stroke (NINDS) and National Institute on Aging (NIA) in 2016 with the goals of developing and validating biomarkers for the cerebral small vessel diseases associated with the vascular contributions to cognitive impairment and dementia (VCID). Rigorously validated biomarkers have consistently been identified as crucial for multicenter studies to identify effective strategies to prevent and treat VCID, specifically to detect increased VCID risk, diagnose the presence of small vessel disease and its subtypes, assess prognosis for disease progression or response to treatment, demonstrate target engagement or mechanism of action for candidate interventions, and monitor disease progression during treatment. The seven project sites and central coordinating center comprising MarkVCID, working with NINDS and NIA, identified a panel of 11 candidate fluid- and neuroimaging-based biomarker kits and established harmonized multicenter study protocols (see companion paper "MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols" for full details). Here we describe the MarkVCID neuroimaging protocols with specific focus on validating their application to future multicenter trials. MarkVCID procedures for participant enrollment; clinical and cognitive evaluation; and collection, handling, and instrumental validation of fluid samples are described in detail in a companion paper. Magnetic resonance imaging (MRI) has long served as the neuroimaging modality of choice for cerebral small vessel disease and VCID because of its sensitivity to a wide range of brain properties, including small structural lesions, connectivity, and cerebrovascular physiology. Despite MRI's widespread use in the VCID field, there have been relatively scant data validating the repeatability and reproducibility of MRI-based biomarkers across raters, scanner types, and time intervals (collectively defined as instrumental validity). The MRI protocols described here address the core MRI sequences for assessing cerebral small vessel disease in future research studies, specific sequence parameters for use across various research scanner types, and rigorous procedures for determining instrumental validity. Another candidate neuroimaging modality considered by MarkVCID is optical coherence tomography angiography (OCTA), a non-invasive technique for directly visualizing retinal capillaries as a marker of the cerebral capillaries. OCTA has theoretical promise as a unique opportunity to visualize small vessels derived from the cerebral circulation, but at a considerably earlier stage of development than MRI. The additional OCTA protocols described here address procedures for determining OCTA instrumental validity, evaluating sources of variability such as pupil dilation, and handling data to maintain participant privacy. MRI protocol and instrumental validation The core sequences selected for the MarkVCID MRI protocol are three-dimensional T1-weighted multi-echo magnetization-prepared rapid-acquisition-of-gradient-echo (ME-MPRAGE), three-dimensional T2-weighted fast spin echo fluid-attenuated-inversion-recovery (FLAIR), two-dimensional diffusion-weighted spin-echo echo-planar imaging (DWI), three-dimensional T2*-weighted multi-echo gradient echo (3D-GRE), three-dimensional T2 -weighted fast spin-echo imaging (T2w), and two-dimensional T2*-weighted gradient echo echo-planar blood-oxygenation-level-dependent imaging with brief periods of CO2 inhalation (BOLD-CVR). Harmonized parameters for each of these core sequences were developed for four 3 Tesla MRI scanner models in widespread use at academic medical centers. MarkVCID project sites are trained and certified for their instantiation of the consortium MRI protocols. Sites are required to perform image quality checks every 2 months using the Alzheimer's Disease Neuroimaging Initiative phantom. Instrumental validation for MarkVCID MRI-based biomarkers is operationally defined as inter-rater reliability, test-retest repeatability, and inter-scanner reproducibility. Assessments of these instrumental properties are performed on individuals representing a range of cerebral small vessel disease from mild to severe. Inter-rater reliability is determined by distribution of an independent dataset of MRI scans to each analysis site. Test-retest repeatability is determined by repeat MRI scans performed on individual participants on a single MRI scanner after a short (1- to 14-day) interval. Inter-scanner reproducibility is determined by repeat MRI scans performed on individuals performed across four MRI scanner models. OCTA protocol and instrumental validation The MarkVCID OCTA protocol uses a commercially available, Food and Drug Administration-approved OCTA apparatus. Imaging is performed on one dilated and one undilated eye to assess the need for dilation. Scans are performed in quadruplicate. MarkVCID project sites participating in OCTA validation are trained and certified by this biomarker's lead investigator. Inter-rater reliability for OCTA is assessed by distribution of OCTA datasets to each analysis site. Test-retest repeatability is assessed by repeat OCTA imaging on individuals on the same day as their baseline OCTA and a different-day repeat session after a short (1- to 14-day) interval. Methods were developed to allow the OCTA data to be de-identified by the sites before transmission to the central data management system. The MarkVCID neuroimaging protocols, like the other MarkVCID procedures, are designed to allow translation to multicenter trials and as a template for outside groups to generate directly comparable neuroimaging data. The MarkVCID neuroimaging protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the neuroimaging MarkVCID kits will undergo biological validation to determine its ability to measure important aspects of VCID such as cognitive function. The analytic methods for the neuroimaging-based kits and the results of these validation studies will be published separately. The results will ultimately determine the neuroimaging kits' potential usefulness for multicenter interventional trials in small vessel disease-related VCID.

Abstract: Background: The U.S. lacks a stroke surveillance system. This study develops a method to transform an existing registry into a nationally representative database to evaluate acute ischemic stroke care quality.Methods: Two statistical approaches were used to develop post-stratification weights for the Get With The Guidelines-Stroke registry by anchoring population estimates to the National Inpatient Sample. Post-stratification survey weights were estimated using a raking procedure and Bayesian interpolation methods. Weighting methods were adjusted to limit the dispersion of weights and make reasonable epidemiologic estimates of patient characteristics, quality of hospital care, and clinical outcomes. Standardized differences in national estimates were reported between the two post-stratification methods for anchored and non-anchored patient characteristics to evaluate estimation quality. Primary measures evaluated were patient and hospital characteristics, stroke severity, vital and laboratory measures, disposition, and clinical outcomes at discharge. Results: A total of 1,388,296 acute ischemic strokes occurred between 2012 and 2014. Raking and Bayesian estimates of clinical data not recorded in administrative databases were estimated within 5% to 10% of the margins of expected values. Median weights for the raking method were 1.386 and the weights at the 99th percentile were 6.881 with a maximum weight of 30.775. Median Bayesian weights were 1.329 and the 99th percentile weights were 11.201 with a maximum weight of 515.689. Conclusions: Leveraging existing databases with patient registries to develop post-stratification weights is a reliable approach to estimate acute ischemic stroke epidemiology and monitoring for stroke quality of care nationally. These methods may be applied to other diseases or settings to better monitor population health.