Citations

Abstract Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.

OBJECTIVE Ivy sign is a radiographic finding on FLAIR MRI sequences and is associated with slow cortical blood flow in moyamoya. Limited data exist on the utility of the ivy sign as a diagnostic and prognostic tool in pediatric patients, particularly outside of Asian populations. The authors aimed to investigate a modified grading scale with which to characterize the prevalence and extent of the ivy sign in children with moyamoya and evaluate its efficacy as a biomarker in predicting postoperative outcomes, including stroke risk. METHODS Pre- and postoperative clinical and radiographic data of all pediatric patients (21 years of age or younger) who underwent surgery for moyamoya disease or moyamoya syndrome at two major tertiary referral centers in the US and Israel, between July 2009 and August 2019, were retrospectively reviewed. Ivy sign scores were correlated to Suzuki stage, Matsushima grade, and postoperative stroke rate to quantify the diagnostic and prognostic utility of ivy sign. RESULTS A total of 171 hemispheres in 107 patients were included. The median age at the time of surgery was 9 years (range 3 months–21 years). The ivy sign was most frequently encountered in association with Suzuki stage III or IV disease in all vascular territories, including the anterior cerebral artery (53.7%), middle cerebral artery (56.3%), and posterior cerebral artery (47.5%) territories. Following surgical revascularization, 85% of hemispheres with Matsushima grade A demonstrated a concomitant, statistically significant reduction in ivy sign scores (OR 5.3, 95% CI 1.4–20.0; p = 0.013). Postoperatively, revascularized hemispheres that exhibited ivy sign score decreases had significantly lower rates of postoperative stroke (3.4%) compared with hemispheres that demonstrated no reversal of the ivy sign (16.1%) (OR 5.5, 95% CI 1.5–21.0; p = 0.008). CONCLUSIONS This is the largest study to date that focuses on the role of the ivy sign in pediatric moyamoya. These data demonstrate that the ivy sign was present in approximately half the pediatric patients with moyamoya with Suzuki stage III or IV disease, when blood flow was most unstable. The authors found that reversal of the ivy sign provided both radiographic and clinical utility as a prognostic biomarker postoperatively, given the statistically significant association with both better Matsushima grades and a fivefold reduction in postoperative stroke rates. These findings can help inform clinical decision-making, and they have particular value in the pediatric population, as the ability to minimize additional radiographic evaluations and tailor radiographic surveillance is requisite.

Abstract Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Background and Purpose— Kidney dysfunction is common among patients hospitalized for ischemic stroke. Understanding the association of kidney disease with poststroke outcomes is important to properly adjust for case mix in outcome studies, payment models and risk-standardized hospital readmission rates. Methods— In this cohort study of fee-for-service Medicare patients admitted with ischemic stroke to 1579 Get With The Guidelines-Stroke participating hospitals between 2009 and 2014, adjusted multivariable Cox proportional hazards models were used to determine the independent associations of estimated glomerular filtration rate (eGFR) and dialysis status with 30-day and 1-year postdischarge mortality and rehospitalizations. Results— Of 204 652 patients discharged alive (median age [25th–75th percentile] 80 years [73.0–86.0], 57.6% women, 79.8% white), 48.8% had an eGFR ≥60, 26.5% an eGFR 45 to 59, 16.3% an eGFR 30 to 44, 5.1% an eGFR 15 to 29, 0.6% an eGFR <15 without dialysis, and 2.8% were receiving dialysis. Compared with eGFR ≥60, and after adjusting for relevant variables, eGFR <45 was associated with increased 30-day mortality with the risk highest among those with eGFR <15 without dialysis (hazard ratio [HR], 2.09; 95% CI, 1.66–2.63). An eGFR <60 was associated with increased 1-year poststroke mortality that was highest among patients on dialysis (HR, 2.65; 95% CI, 2.49–2.81). Dialysis was also associated with the highest 30-day and 1-year rehospitalization rates (HR, 2.10; 95% CI, 1.95–2.26 and HR, 2.55; 95% CI, 2.44–2.66, respectively) and 30-day and 1-year composite of mortality and rehospitalization (HR, 2.04; 95% CI, 1.90–2.18 and HR, 2.46; 95% CI, 2.36–2.56, respectively). Conclusions— Within the first year after index hospitalization for ischemic stroke, eGFR and dialysis status on admission are associated with poststroke mortality and hospital readmissions. Kidney function should be included in risk-stratification models for poststroke outcomes.

Background— We explored regional variation in 30-day ischemic stroke mortality and readmission rates and the extent to which regional differences in patients, hospitals, healthcare resources, and a quality of care composite care measure explain the observed variation. Methods and Results— This ecological analysis aggregated patient and hospital characteristics from the Get With The Guidelines–Stroke registry (2007–2011), healthcare resource data from the Dartmouth Atlas of Health Care (2006), and Medicare fee-for-service data on 30-day mortality and readmissions (2007–2011) to the hospital referral region (HRR) level. We used linear regression to estimate adjusted HRR-level 30-day outcomes, to identify HRR-level characteristics associated with 30-day outcomes, and to describe which characteristics explained variation in 30-day outcomes. The mean adjusted HRR-level 30-day mortality and readmission rates were 10.3% (SD=1.1%) and 13.1% (SD=1.1%), respectively; a modest, negative correlation ( r =−0.17; P =0.003) was found between one another. Demographics explained more variation in readmissions than mortality (25% versus 6%), but after accounting for demographics, comorbidities accounted for more variation in mortality compared with readmission rates (17% versus 7%). The combination of hospital characteristics and healthcare resources explained 11% and 16% of the variance in mortality and readmission rates, beyond patient characteristics. Most of the regional variation in mortality (65%) and readmission (50%) rates remained unexplained. Conclusions— Thirty-day mortality and readmission rates vary substantially across HRRs and exhibit an inverse relationship. While regional variation in 30-day outcomes were explained by patient and hospital factors differently, much of the regional variation in both outcomes remains unexplained.

Background and Purpose— The recommended treatment for ischemic stroke is tPA (tissue-type plasminogen activator). Although sickle cell disease (SCD) represents no known contraindication to tPA, National Heart Lung and Blood Institute of the National Institutes of Health recommended acute exchange transfusion for stroke in SCD, not tPA. Data on safety and outcomes of tPA in patients are needed to guide tPA use in SCD. Methods— We matched patients from the American Heart Association and American Stroke Association Get With The Guidelines-Stroke registry with SCD to patients without SCD and compared usage, complications, and discharge outcomes after tPA. Multivariable logistic regression models using generalized estimating equations were used to assess outcomes. Results— From 2 016 652 stroke patients admitted to Get With The Guidelines-Stroke sites in the United States, 832 SCD and 3328 non-SCD controls with no differences in admission National Institutes of Health Stroke Scale or blood pressure were identified. Neither the fraction receiving thrombolytic therapy (8.2% for SCD versus 9.4% non-SCD) nor symptomatic intracranial hemorrhage (4.9% of SCD versus 3.2% non-SCD; P =0.4502) was different. There was no difference in a prespecified set of outcome measures for those with SCD compared with controls. Conclusions— Coexistent SCD had no significant impact on the safety or outcome of thrombolytic therapy in acute ischemic stroke. Although the sample size is relatively small, these data suggest that adults with SCD and acute ischemic stroke should be treated with thrombolysis, if they otherwise qualify. Addition studies, however, should track the intracranial hemorrhage rate and provide information on other SCD-related care such as transfusion.

Background Healthcare resources vary geographically, but associations between hospital‐based resources and acute stroke quality and outcomes remain unclear. Methods and Results Using Get With The Guidelines‐Stroke and Dartmouth Atlas of Health Care data, we examined associations between healthcare resource availability, stroke care, and outcomes. We categorized hospital referral regions with high‐, medium‐, or low‐resource levels based on the 2006 national per‐capita availability median of 6 relevant acute stroke care resources. Using multivariable logistic regression, we examined healthcare resource level and in‐hospital quality and outcomes. Of 1 480 308 admitted ischemic stroke patients (2006–2013), 28.8% were hospitalized in low‐, 44.4% in medium‐, and 26.9% in high‐resource hospital referral regions. Quality‐of‐care/timeliness metrics, adjusted length of stay, and in‐hospital mortality were similar across all resource levels. Conclusions Significant variation exists in regional availability of healthcare resources for acute ischemic stroke treatment, yet among Get With the Guidelines‐Stroke hospitals, quality of care and in‐hospital outcomes did not differ by regional resource availability.