Overt Stroke Research Articles

Diffusion-Weighted Magnetic Resonance Imaging Demonstrates White Matter Alterations in Watershed Regions in Children With Moyamoya Without Stroke or Silent Infarct

BackgroundMoyamoya is a disease with progressive cerebral arterial stenosis leading to stroke and silent infarct. Diffusion-weighted magnetic resonance imaging (dMRI) studies show that adults with moyamoya have significantly lower fractional anisotropy (FA) and higher mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) compared with controls, which raises concern for unrecognized white matter injury. Children with moyamoya have significantly lower FA and higher MD in their white matter compared with controls. However, it is unknown which white matter tracts are affected in children with moyamoya. MethodsWe present a cohort of 15 children with moyamoya with 24 affected hemispheres without stroke or silent infarct compared with 25 controls. We analyzed dMRI data using unscented Kalman filter tractography and extracted major white matter pathways with a fiber clustering method. We compared the FA, MD, AD, and RD in each segmented white matter tract and combined white matter tracts found within the watershed region using analysis of variance. ResultsAge and sex were not significantly different between children with moyamoya and controls. Specific white matter tracts affected included inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, thalamofrontal, uncinate fasciculus, and arcuate fasciculus. Combined watershed region white matter tracts in children with moyamoya had significantly lower FA (−7.7% ± 3.2%, P = 0.02) and higher MD (4.8% ± 1.9%, P = 0.01) and RD (8.7% ± 2.8%, P = 0.002). ConclusionsLower FA with higher MD and RD is concerning for unrecognized white matter injury. Affected tracts were located in watershed regions suggesting that the findings may be due to chronic hypoperfusion. These findings support the concern that children with moyamoya without overt stroke or silent infarction are sustaining ongoing injury to their white matter microstructure and provide practitioners with a noninvasive method of more accurately assessing disease burden in children with moyamoya.

Neuroimaging and Cognitive Function in Sickle Cell Disease: A Systematic Review.

Sickle cell disease (SCD) is the most common inherited single-gene disease. Complications include chronic anaemia, reduced oxygen-carrying capability, and cerebral vasculopathy, resulting in silent cerebral infarction, stroke, and cognitive dysfunction with impairments in measures of executive function, attention, reasoning, language, memory, and IQ. This systematic review aims to investigate the association between neuroimaging findings and cognition in children with SCD. Searches of PubMed and Embase were conducted in March 2022. Studies were included if participants were <18 years, if original data were published in English between 1960 and 2022, if any genotype of SCD was included, and if the relationship between cognition and neuroimaging was examined. Exclusion criteria included case studies, editorials, and reviews. Quality was assessed using the Critical Appraisal Skills Programme Case Control Checklist. A total of 303 articles were retrieved; 33 met the eligibility criteria. The presence of overt or silent strokes, elevated blood flow velocities, abnormal functional connectivity, and decreased fMRI activation were associated with neuropsychological deficits in children with SCD when compared to controls. There is a critical need to address the disease manifestations of SCD early, as damage appears to begin at a young age. Most studies were cross-sectional, restricting the interpretation of the directionality of relationships. Future research employing longitudinal neuroimaging and neuropsychological assessments could improve our understanding of the cumulative consequences of SCD on the developing brain.

Iatrogenic Strokes and Covert Brain Infarcts After Percutaneous Cardiac Procedures: An Update.

Millions of cardiac procedures are performed worldwide each year, making the potential complication of periprocedural iatrogenic stroke an important concern. These strokes can occur intraoperatively or within 30 days of a procedure and can be categorised as either overt or covert, occurring without obvious acute neurologic symptoms. Understanding the prevalence, risk factors, and strategies for preventing overt and covert strokes associated with cardiac procedures is imperative for reducing periprocedural morbidity and mortality. In this narrative review, we focus on the impacts of perioperative ischemic strokes for several of the most common interventional cardiac procedures, their relevance from a neurologic standpoint, and future directions for the care and research on perioperative strokes. Depending on the percutaneous procedure, the rates of periprocedural overt strokes can range from as little as 0.01% to as high as 2.9%. Meanwhile, covert brain infarctions (CBIs) occur much more frequently, with rates for different procedures ranging from 10%-84%. Risk factors include previous stroke, atherosclerotic disease, carotid stenosis, female sex, and African race, as well as other patient- and procedure-level factors. While the impact of covert brain infarctions is still a developing field, overt strokes for cardiac procedures lead to longer stays in hospital and increased costs. Potential preventative measures include screening and vascular risk factor control, premedicating, and procedural considerations such as the use of cerebral embolic protection devices. In addition, emerging treatments from the neurologic field, including neuroprotective drugs and remote ischemic conditioning, present promising avenues for preventing these strokes and merit investigation in cardiac procedures.

Mechanisms and Clinical Manifestations of Cognitive Decline in Atrial Fibrillation Patients: Potential Implications for Preventing Dementia.

Atrial fibrillation (AF) patients face an approximate 1.5-fold increased risk of cognitive decline compared with the general population. Among poststroke AF patients, the risk of cognitive decline is even higher with an estimated threefold increase. This article provides a narrative review on the current evidence and highlights gaps in knowledge and areas for future research. Although earlier studies hypothesized that the association between AF and cognitive decline is mainly a consequence of previous ischemic strokes, more recent evidence also suggests such an association in AF patients without a history of clinical stroke. Because AF and cognitive decline mainly occur among elderly individuals, it is not surprising that both entities share multiple risk factors. In addition to clinically overt ischemic strokes, silent brain infarcts and other brain injury are likely mechanisms for the increased risk of cognitive decline among AF patients. Oral anticoagulation for stroke prevention in AF patients with additional stroke risk factors is one of the only proven therapies to prevent brain injury. Whether a broader use of oral anticoagulation, or more intense anticoagulation in some patients are beneficial in this context needs to be addressed in future studies. Although direct studies are lacking, it is reasonable to recommend optimal treatment of comorbidities and risk factors for the prevention of cognitive decline and dementia.

Abstract TP178: Cerebral Infarction after Hematopoietic Stem Cell Transplantation (HSCT) in Adult Patients with Sickle Cell Disease

Introduction: Symptomatic and silent cerebral infarcts (SCIs) are common in children and adults with sickle cell disease (SCD). SCIs are associated with cognitive performance and risk of future symptomatic stroke. The incidence of overt stroke and SCI post HSCT is low in children, but there is limited information in adults. We sought to determine the impact of HSCT on the rate of new symptomatic and silent cerebral infarcts in adults with SCD. Methods: The study population included patients with SCD (HbSS, HbSC, and HbS/beta-thalassemia) that were enrolled in NIH studies (14-H-0077, 09-H-0225) and underwent HSCT from 2004-19 and received pre- and post-transplant MRI studies. MRI FLAIR, T1, and T2 images were reviewed by two independent readers and scored for presence of prior ischemic stroke and silent cerebral infarct (≥ 3mm on T2 or FLAIR images in 2 imaging planes). Changes in SCIs and ischemic strokes were compared before and after transplantation. Results: Eighty-four patients were included in the study, mean age 32.3 yrs. (range 10-65 yrs.) and 57% male. Median follow-up period was 3.3 yrs. (range: 6 months -17 yrs.) for a total of 412 patient-years. Overall, 60% had evidence of SCI and or prior ischemic stroke at transplant; 54% (45/84) with SCI and 23% with imaging evidence of a prior stroke. During the follow-up period, 13% (11/84) patients developed new ischemic injury, two patients developed a new stroke and nine patients developed new SCIs. The post-HSCT incidence rate of new stroke was 0.49 events/100 patient-years, and SCIs was 2.2 events/100 patient-years. Patients who progressed compared to those who did not were older at transplant (36.1 yrs. vs. 31.2 yrs.; p=0.09), had a prior history of stroke (27% vs. 22%, p=0.71), had a prior history of SCI (64% vs. 52%, p=0.47), and a prior history of stenotic vasculopathy (18% vs. 14%, p= 0.65). Conclusions: The incidence of new ischemic events after HSCT for SCD in adults is low. Our rates are comparable to incidence rates reported in children with SCD after HSCT. While rates of progression were higher in patients with prior stroke, SCI, and vasculopathy, we did not find a significant difference between groups.

Clinical Outcome of Transcatheter Aortic Valve Replacement With TriGUARD 3™ Cerebral Embolic Protection Device

ObjectivePeriprocedural stroke during transcatheter aortic valve replacement (TAVR) is a highly feared adverse event. The TriGUARD 3 cerebral embolic protection device (CEPD) may have the potential benefit of reduction of embolic events, but it still remains unclear whether it reduces the incidence of periprocedural stroke or transient ischemic attack (TIA).We aimed to investigate whether the latest TriGUARD 3 CEPD reduces the incidence of clinically overt stroke within 72 h or at discharge after TAVR. MethodsIn this prospective single-center study 117 patients (mean age 80.3 years, 53.8 % male) were included from July 2020 to December 2021. ResultsThe primary efficacy endpoint of this study, periprocedural clinically overt stroke or TIA, within 72 h or at discharge after TAVR with the TriGUARD 3 CEPD occurred in 1/117 pts (0.8 %). Secondary endpoints (device related issues such as life-threatening or disabling bleeding, acute kidney injury, major vascular complications) were reported in 4/117 pts (3.4 %). ConclusionsThis study suggests that the use of the latest TriGUARD 3™ CEPD in transfemoral TAVR seems to be associated with a low rate of clinically overt stroke and a low rate of device related adverse events, reflecting “real world” TAVR practice. However these results should be hypothesis generating and confirmed in a large RCT.

Relationships between cerebral small vessel diseases markers and cognitive performance in stroke-free patients with atrial fibrillation.

Atrial fibrillation (AF) is related to an increased risk of cognitive dysfunction. Besides clinically overt stroke, AF can damage the brain via several pathophysiological mechanisms. We aimed to assess the potential mediating role of cerebral small vessel disease (SVD) and cognitive performance in individuals with AF. Stroke-free individuals with AF from the cardiological outpatient clinic at West China Hospital of Sichuan University were recruited. Extensive neuropsychological testing tools were assessed including global function, domains of attention, executive functions, learning, and memory. 3 T magnetic resonance imaging (MRI) was used for SVD markers assessment of white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS). The correlation between SVD markers and cognitive measures was analyzed by multivariate linear regression models. We finally enrolled 158 participants, of whom 95 (60.1%) were males. In multivariate models, the presence of lacunes independently associated with Montreal Cognitive Assessment (Model 1: ß = 0.52, Model 2: ß = 0.55), Rey Auditory Verbal Learning Test-immediate and delayed recall (Model 1: ß = 0.49; ß = 0.69; Model 2: ß = 0.53; ß = 0.73) as well as Stroop-Acorrect (Model 1: ß = 0.12; Model 2: ß = 0.13), while total WMH severity independently associated with Strooptime-A (Model 1: ß = 0.24; Model 3: ß = 0.27), Strooptime-B (Model 1: ß = 0.17; Model 3: ß = 0.17), Strooptime-C (Model 1: ß = 0.22; Model 3: ß = 0.21) and Shape Trail Test-A (Model 1: ß = 0.17; Model 3: ß = 0.16). In our cohort of stroke-free individuals with AF, lacunes, and WMHs were independently associated with cognitive decline while EPVS and CMBs did not show significance. Assessment of SVD MRI markers might be valuable for cognition risk stratification and facilitate optimal management of patients with AF.

Red cell exchange transfusions increase cerebral capillary transit times and may alter oxygen extraction in sickle cell disease.

Persons with sickle cell disease (SCD) suffer from chronic hemolytic anemia, reduced blood oxygen content, and lifelong risk of silent and overt stroke. Major conventional stroke risk factors are absent in most individuals with SCD, yet nearly 50% have evidence of brain infarcts by the age of 30 years, indicating alternative etiologies for ischemia. We investigated whether radiological evidence of accelerated blood water transit through capillaries, visible on arterial spin labeling (ASL) magnetic resonance imaging, reduces following transfusion-induced increases in hemoglobin and relates to oxygen extraction fraction (OEF). Neurological evaluation along with anatomical and hemodynamic imaging with cerebral blood flow (CBF)-weighted pseudocontinuous ASL and OEF imaging with T2 -relaxation-under-spin-tagging were applied in sequence before and after blood transfusion therapy (n = 32) and in a comparator cohort of nontransfused SCD participants on hydroxyurea therapy scanned at two time points to assess stability without interim intervention (n = 13). OEF was calculated separately using models derived from human hemoglobin-F, hemoglobin-A, and hemoglobin-S. Gray matter CBF and dural sinus signal, indicative of rapid blood transit, were evaluated at each time point and compared with OEF using paired statistical tests (significance: two-sided p < 0.05). No significant change in sinus signal was observed in nontransfused participants (p = 0.650), but a reduction was observed in transfused participants (p = 0.034), consistent with slower red cell transit following transfusion. The dural sinus signal intensity was inversely associated with OEF pretransfusion (p = 0.011), but not posttransfusion. Study findings suggest that transfusion-induced increases in total hemoglobin may lengthen blood transit times through cerebral capillaries and alter cerebral OEF in SCD.

Perioperative ischaemic brain injury and plasma neurofilament light: a secondary analysis of two prospective cohort studies

BackgroundIschaemic brain infarction can occur without acute neurological symptoms (covert strokes) or with symptoms (overt strokes), both associated with poor health outcomes. We conducted a pilot study of the incidence of preoperative and postoperative (intraoperative or postoperative) covert strokes, and explored the relationship of postoperative ischaemic brain injury to blood levels of neurofilament light, a biomarker of neuronal damage. MethodsWe analysed 101 preoperative (within 2 weeks of surgery) and 58 postoperative research MRIs on postoperative days 2–9 from two prospective cohorts collected at the University of Wisconsin (NCT01980511 and NCT03124303). Participants were aged >65 yr and undergoing non-intracranial, non-carotid surgery. ResultsPreoperative covert stroke was identified in 2/101 participants (2%; Bayesian 95% confidence interval [CI], 0.2–5.4). This rate was statistically different from the postoperative ischaemic brain injury rate of 7/58 (12%, 4.9–21.3%; P=0.01) based on postoperative imaging. However, in a smaller group of participants with paired imaging (n=30), we did not identify the same effect (P=0.67). Patients with postoperative brain injury had elevated peak neurofilament light levels (median [inter-quartile range], 2.34 [2.24–2.64] log10 pg ml−1) compared with those without (1.86 [1.48–2.21] log10 pg ml−1; P=0.025). Delirium severity scores were higher in those with postoperative brain injury (19 [17–21]) compared with those without (7 [4–12]; P=0.01). ConclusionAlthough limited by a small sample size, these data suggest that preoperative covert stroke occurs more commonly than previously anticipated. Plasma neurofilament light is a potential screening biomarker for postoperative ischaemic brain injury.

Trials in Progress: Two Randomized, Double-Blind, Multicenter, Placebo-Controlled Trials Investigating the Efficacy of Voxelotor on Cerebral Blood Flow and Neurocognitive Function in Patients with Sickle Cell Disease

Background: Sickle cell disease (SCD) is an inherited blood disorder caused by a point mutation in the beta chain of hemoglobin (Hb) that results in the formation of sickle hemoglobin, HbS. Polymerization of HbS under conditions of deoxygenation causes red blood cell sickling that can lead to hemolytic anemia and vascular occlusion with subsequent end-organ damage, infarction, and cognitive dysfunction. In patients with SCD, cerebral blood flow (CBF) is elevated throughout the brain, with silent cerebral infarcts (SCIs) occurring mainly in brain regions with the lowest CBF. SCIs, overt strokes, and cognitive impairment are some of the most common complications of SCD, all of which have a substantial impact on the education, employment, and quality of life of patients with SCD. Cognitive impairment in patients with SCD can also manifest in those without SCI or overt stroke, suggesting a potential role of chronic anemia and cerebral hemodynamics in neurocognitive dysfunction. Despite progress in the development of therapies for SCD, little is known about their effect on cognitive function and cerebral hemodynamics. Voxelotor is a HbS polymerization inhibitor approved in the United States for the treatment of SCD in patients aged ≥4 years and in the United Kingdom, European Union, and the United Arab Emirates for patients aged ≥12 years. Objective: To understand the impact of voxelotor on brain function in patients with SCD, 2 post-approval studies of voxelotor are currently recruiting and are described here. Methods: The Neurocognitive Function study (NCT05228834) is a phase 3b, randomized, double-blind, placebo-controlled, multicenter trial investigating the effect of once-daily oral voxelotor (Figure) on neurocognitive function in children and adolescents with SCD. The Cerebral Hemodynamics study (NCT05228821) is a phase 4, randomized, double-blind, placebo-controlled, multicenter trial investigating the impact of once-daily oral voxelotor (Figure) on CBF in adolescents and adults with SCD. An overview of the study population, study design, and key endpoints for both studies is provided in the Table. Results: The primary objective of the Neurocognitive Function study is to assess the effect of voxelotor compared with placebo on the neurocognitive function in children and adolescents with SCD (aged 8 to <18 years), which will be evaluated by measuring the change from baseline at week 12 in the executive abilities composite score, as assessed by the National Institutes of Health Toolbox Cognition Module. The primary objective of the Cerebral Hemodynamics study is to assess the efficacy of voxelotor compared with placebo on CBF in adolescents and adults (aged 12-30 years) with homozygous hemoglobin S (HbSS) or sickle beta zero thalassemia (HbSβ0), which will be evaluated by assessing the change from baseline in CBF measured by magnetic resonance imaging at week 12. Conclusions: Treatments that improve neurocognitive dysfunction represent an important unmet need in the management of SCD. Results from the Neurocognitive Function study and the Cerebral Hemodynamics study (the latter will enroll adult patients) will provide important information on the impact that inhibition of HbS polymerization may have on cognitive function and cerebral hemodynamics by improving anemia and hemolysis in patients with SCD. Funding: Global Blood Therapeutics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Quantifying Dilated Perivascular Spaces in Children with Sickle Cell Disease

Introduction: The neurological complications of sickle cell disease (SCD) are particularly devastating and range from "overt stroke" to cerebral small vessel disease (CSVD), including silent cerebral infarction (SCI) and cognitive deficits despite the absence of magnetic resonance imaging (MR)-detectable evidence of cerebral injury. This suggests the possibility of additional, possibly covert, mechanisms of injury. Perivascular (Virchow-Robin) spaces (PVS) are fluid filled spaces that surround cerebral vessels penetrating or leaving the brain parenchyma and become visible when enlarged (dilated), due to inflammation or hypertension. The presence of dilated PVS (dPVS) in the basal ganglia (BG) and centrum semiovale (CO) are rare in children and have been associated with multiple neurodegenerative and neuroinflammatory disorders in aging populations. dPVS in the BG specifically are associated with CSVD, while those in the CO are associated with neuroinflammation. However, until now, the presence of dPVS has not been studied in either adults or children with SCD. Our overall objectives were to use MR images from children who were screened and/or participated in the Silent Cerebral Infarct Treatment in SCD (SIT) trial to 1) determine the burden of dPVS in children with SCD, specifically within the basal ganglia and centrum semiovale, and 2) correlate these findings with other markers of CSVD, specifically silent cerebral infarctions. Methods: The SIT trial was a multicenter, randomized clinical trial that evaluated the effect of monthly chronic transfusions to prevent the development of new SCI in children with SCD. As part of the enrollment process, all children underwent an initial MRI. We used both the Wardlaw (currently used as part of the international consensus criteria for evaluating CSVD) and Rotterdam criteria to quantify dPVS burden on T2-weighted screening MR images for 340 participants from the SIT trial. Briefly, both rating scales evaluate dPVS in the BG, CO, and midbrain (MB); the Rotterdam criteria also includes the hippocampus. The Wardlaw criteria categorize dPVS on an ordinal scale from 0 (none) to 4 (> 40) in the BG and CO and 0 or 1 point (absent or present) for the MB, with a total score of 9 as the maximum dPVS burden from all 3 brain regions. The Rotterdam criteria uses a semi-continuous scale and specifies counting dPVS to a total of 20 for each region for a maximum combined dPVD burden score of 80. Additional variables in our analysis were participant's age, hemoglobin, total white blood cell (WBC) count, and presence of SCI at baseline. We categorized dPVS burden score from the Wardlaw rating scale into low (0-2), medium (3-4), and high ( 5) and performed an ordinal multivariate logistic regression with age, sex, presence of SCI, hemoglobin, and total WBC count as independent variables. Results: We completed the two dPVS rating scales on 340 initial (screening) MR images from 340 children screened for the SIT trial, with a median age of 8.3 years (range 5 - 15 years). Eighty-eight (26%) had evidence of at least one SCI. The mean hemoglobin was 8 ± 1.1 g/dL and total WBC count was 12,000 ± 4200 cells/ml. The mean dPVS burden score from the Wardlaw criteria was 3.7 ± 1.7, while for the Rotterdam criteria, the mean was 32 ± 14 (Table). Global and regional dPVS scores from the two rating scales were well correlated (p < 0.001, r = 0.72 - 0.8). dPVS score in the BG and CSO was moderately correlated (p < 0.001, r = 0.45). There was no significant sex difference in dPVS burden (mean Wardlaw rating: males = 3.9 versus females = 3.6, p = 0.08). Multivariate analysis show that increasing age was associated with dPVS burden (p = 0.005), as was increasing hemoglobin, which showed a trend towards association (p = 0.06), potentially due to increased pressure within microvasculature, resulting in extravasation of fluid into the surrounding space. Surprisingly, presence or size of SCI were not associated with dPVS burden. Conclusions: Children with SCD have evidence of more than expected dilated perivascular spaces compared to not only healthy children but also adults, which increase with age. Although likely involved in neurological injury, dilated PVS in children with SCD do not appear to be associated with the presence of CSVD phenotypes such as SCI. We reasoned that in SCD, dPVS may be sequelae of underlying neuroinflammation. Future studies are needed to examine correlation of dPVS with biomarkers of neuroinflammation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of Elevated Tricuspid Regurgitation Velocity with Kidney and Cerebrovascular Disease in Children with Sickle Cell Disease

Introduction: Adult patients with sickle cell disease (SCD) develop progressive end-organ injury leading to multi-organ disease and increased mortality. It is plausible that this multi-organ damage begins in pediatric patients. Tricuspid regurgitation velocity (TRV), measured by echocardiography is a surrogate marker for pulmonary hypertension that is a poor prognostic factor in adults with SCD. The utility of screening echocardiograms as a marker of disease severity is being studied in pediatrics. In this study, we assessed associations between elevated TRV with early development of chronic kidney disease (albuminuria), and cerebrovascular disease (CVD). Methods: We performed an IRB approved cross-sectional study to evaluate the prevalence of elevated TRV ≥ 2.5 m/s and its associations with albuminuria and CVD in patients with SCD ages 1-21 years. We included children with a diagnosis of SCD who had at least one echocardiogram performed during an outpatient clinic visit at steady-state for screening for pulmonary hypertension. We categorized patients as receiving either transfusion therapy (chronic transfusion for >12 months), SCD modifying therapy (hydroxyurea, voxelotor, crizanlizumab, or L-glutamine), or no therapy. Patients on both transfusion and a SCD modifying therapy were defined as being on transfusion therapy. We defined albuminuria as patients with two of three consecutive albumin creatinine ratios ≥30mg/g measured during standard clinic visits. Cerebrovascular disease was defined as having either 1) an overt stroke, 2) silent cerebral stroke defined by MRI, 3) vasculopathy by abnormal magnetic resonance angiography (MRA), 4) transient ischemic event defined by stroke symptoms that resolved within 24 hours, or 5) abnormal TCD (>200 cm/second). We performed bivariate analysis utilizing t-test (or Kruskal-Wallis test) and Cochran-Mantel-Haenszel test for continuous and categorical variables respectively. To determine the association between elevated TRV and albuminuria, and elevated TRV and CVD, logistic regression was fit and adjusted for variables that were significant in the bivariate analysis. Using the TRV <2.5m/sec as the reference group, adjusted odds ratios with their accompanying confidence intervals were calculated for those with albuminuria and those with CVD in separate models. All reported P values were 2-sided. Statistical significance was defined as p<0.05. All analyses were performed using Statistical Analysis Software 9.4, (SAS Institute, Cary, NC). Results: Among 166 children with echocardiography, the prevalence of an elevated TRV was 21%. On bivariate analysis, elevated TRV was significantly associated with persistent albuminuria (OR 2.85 (95% CI: 1.27-6.43) and cerebrovascular disease (OR: 2.46 (95% CI: 1.09-5.53) (Table 1). An elevated TRV was also significantly associated with increased age (15.6 vs 12.9 yrs, p=0.005), lower hemoglobin F% (2.5 vs 4.6%, p=0.01), higher absolute reticulocyte count (0.5 vs 0.4 x 106/ µL p=0.005) and chronic transfusion therapy (p=0.04). After adjusting for age, absolute reticulocyte count, HbF and treatment in a multivariable logistic regression, the associations between elevated TRV with either persistent albuminuria (OR: 1.82 (0.71 - 4.67)) and cerebrovascular disease (OR: 1.15 (0.43-3.10)) were no longer statistically significant (Table 1). Our data suggests that with an odds ratio of 2.9 and a prevalence of elevated TRV of 20%, a prospective study of 166 adolescent patients with SCD would be needed to detect the association between elevated TRV and persistent albuminuria with 80% power and 233 children would be needed to detect this difference with 90% power. Conclusion: This data provides additional evidence that around 20% of pediatric patients have an elevated TRV and those patients may also have an increased risk for developing chronic kidney disease and cerebrovascular disease. A larger, prospective cohort study should be conducted to confirm these findings and determine the role of screening echocardiography in pediatric SCD. At minimum, our data suggests that pediatric patients with known chronic kidney disease or cerebrovascular disease should be screened for cardiac complications. Furthermore, longitudinal studies are needed to evaluate the association between elevated TRV in children with early end-organ complications in adults. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effect of Voxelotor on Cerebral Perfusion and Cerebral Oxygen Metabolism in Adult Patients with Sickle Cell Disease; Preliminary Results of the Coverage Study

Background: Sickle cell disease (SCD) is characterized by hemolytic anemia and a hyperdynamic circulation resulting in impaired cerebral hemodynamics and perfusion, culminating in ischemic damage of the brain. SCD is strongly associated with overt strokes or silent cerebral infarctions (SCI) which have been related to elevated flow in the median cerebral artery in children measured by transcranial Doppler. Patients with SCD have an increased cerebral blood flow (CBF) to maintain adequate oxygen delivery (OD). Previously, we and others have demonstrated with special MRI techniques that despite the maintained OD, cerebral metabolic rate of oxygen (CMRO2) is reduced in SCD due to reduced oxygen extraction fraction (OEF), which in turn is strongly related to CBF and hemoglobin (Hb) level. Voxelotor is a small molecule that reversibly binds to Hb and increases its oxygen affinity, thereby decreasing Hb polymerization and sickling. The resulting decreased hemolytic anemia can potentially ameliorate cerebral hemodynamics and perfusion, the increased oxygen affinity may reduce the offloading of oxygen. The aim of our study is to assess the effects of voxelotor on markers of cerebral perfusion and oxygen metabolism. In addition, the effect of voxelotor on the hyperdynamic cardiac function was assessed. Methods: This single-arm, interventional trial is being conducted in a tertiary hospital in Amsterdam, The Netherlands. Adult SCD patients with the severe genotypes of HbSS and HbSβ0-thalassemia were eligible for inclusion. Other major inclusion criteria were: Hb ≤ 10.5 g/dL and in case of hydroxyurea use, a stable dose for at least 90 days. Major exclusion criteria were: regular transfusions or a transfusion within 90 days prior to inclusion, hospitalization for vaso-occlusive crisis ≤ 14 days before inclusion. At baseline and after 3 months of voxelotor treatment (1500 mg pd), MRI scans, echocardiography and laboratory assessments were performed. Time-encoded arterial spin labeling was performed to obtain CBF measurements, gray matter CBF was derived by using white matter and gray matter masks. T2 relaxation under spin tagging was performed in order to calculate OEF. Oxygen delivery and CMRO2 were calculated: formula, CBF x OD, with the OD calculated from OEF and oxygen content. Maximal tricuspid regurgitation velocity (TRVmax) was assessed by trans-thoracic echocardiography as a marker of hyperdynamic circulation. N-Terminal pro-B-type natriuretic peptide (NT-proBNP) was measured as a marker of cardiac stress/dilatation. Parametric data are presented with mean and SD and analyzed by a paired T-test and non-parametric data with median and IQR, and analyzed by a Wilcoxon signed-rank test. Results: Preliminary results of 15 patients (HbSS/HbSβ0-thalassemia, 11/4, mean age 38 years (SD 10), 4 female) who completed their 3 month follow-up are presented here. Upon 3 months of voxelotor treatment, Hb levels significantly increased, 7.6 g/dL, (IQR 6.9 - 8.2) compared to 10.0 g/dL (IQR; p < 0.001), and hemolysis significantly reduced, represented by reticulocyte count, bilirubin and LDH levels (p = < 0.05; Table 1). After 3 months of treatment also a significant increase in oxygen delivery from 6.4 to 8.2 ml O2/100g/min (p = 0.006) was observed, which was primarily due to the increased Hb levels. However, CBF and CMRO2 did not change significantly after 3 months of voxelotor treatment (Table 2) while OEF decreased significantly at 3 months as compared to baseline (from 28.9% to 23.2%, p = 0.002) (Table 2). No significant changes in NT-proBNP levels and TRVmax were observed (Table 1) although a significant decrease was observed in patients with NT-proBNP-levels >160 at baseline (213 (IQR 161 - 254) ng/L vs 152 (IQR 50 -163) ng/L; p = 0.028)). Conclusion: In this preliminary study, no changes in cerebral hemodynamics (CBF) and oxygen metabolic rate (CMRO2) were observed, despite an increased cerebral oxygen delivery due to improvement of Hb levels. CMRO2 remained unchanged as a result of diminished OEF, based on the calibration according to the Li-Bush model, most likely due to the increased oxygen affinity attributed to voxelotor. With respect to the cardiac measures of the circulatory state, no effect on NT-proBNP levels and TRVmax was observed although a significant decrease in NT-proBNP-levels was observed in a post-hoc analysis of patients with elevated NTproBNP levels at baseline. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cognitive Dysfunction Worsens with Age in Patients with Sickle Cell Disease in the Modern Treatment Era

Introduction Patients with sickle cell disease (SCD) suffer from cognitive dysfunction compared to those unaffected by the disease. Such cognitive dysfunction in patients with SCD is further exacerbated by the occurrence of overt stroke or silent cerebral infarcts (SCIs). Fortunately, treatments such as hydroxyurea and red blood cell (RBC) transfusion for patients with SCD have been shown to be neuroprotective. Studies that predate guidelines recommending all patients with HbSS or HbS beta thalassemia null genotypes receive primary disease modification with hydroxyurea report that cognitive dysfunction worsens with age in patients with SCD. However, there is limited investigation into cognitive trajectories across the lifespan during the modern treatment era for patients with SCD. While neuroprotective interventions are widely recommended, we hypothesize that patients with SCD will continue to experience cognitive decline. Methods Patients >5 years of age with any genotype of SCD, excluding those receiving chronic RBC transfusions, were included in these analyses. Cognitive data, as measured by the NIH Toolbox-Cognitive Battery (NIHTB-CB) and the Wechsler Abbreviated Scale Intelligence 2nd edition (WASI-II), were combined from three prospective research studies at a single institution. A subgroup of participants had multiple timepoints of data collected. Multivariate general linear mixed-level models, accounting for multiple timepoints per participant, were used to predict each cognitive subdomain while controlling for the independent variables of age and sex. Age squared (age2) was included in models if necessary to account for a second-order polynomial fit. Significance was defined as α<0.05 and the Benjamini-Hochberg procedure was used to correct for multiple comparison. Results Data was collected from 123 participants with SCD between 2014-2022. The cohort was 45.4% male (56/123 participants). Thirty-four participants had 2 timepoints and 7 participants had 3 timepoints of cognitive data included in the analyses, for 164 total timepoints. First and last-timepoints were separated by 1-4 years for the NIHTB-CB and 1-8 years for the WASI-II tests. The average (SD, range) number of months between the first and last encounters was 31.2 (10.9, 14.2-47.7) for completion of NIHTB-CB testing and 43.9 (22.2, 14.2-89.3) for completion of WASI-II testing. Table 1 describes the cohort. The average (SD, range) hemoglobin at all timepoints was: 9.0 (1.6, 5.6-13.3). The number (percent) of participants taking hydroxyurea and the mean (SD, range) dosage for all timepoints was: 97/164 (59.1%), 380.9mg (649.4, 11.0-2000.0). Using multivariate general linear mixed-level models to predict each cognitive subdomain and composite score provided in the NIHTB-CB and WASI-II, the Flanker Inhibitory Control and Attention (age p=0.0164), Oral Reading (age p=0.0006, age2 p=0.0018), Pattern Comparison Processing Speed (age p=0.0210, age2 p=0.0206, sex p=0.0041), Crystallized Composite (age p=0.0038, age2 p=0.0063) and Total Composite (age p=0.0215, age2 p=0.0219) scores decreased with age while controlling for the effect of sex (Table 1, Figure 1). There was not a significant relationship between age and cognitive outcome measure for the Picture Vocabulary, List Sorting Working Memory, Dimensional Change Card Sorting, Picture Sequence Memory, Fluid Composite, Matrix Reasoning or Full-Scale IQ tests. Conclusion We conclude that cognitive abilities, encompassing executive function abilities (Flanker Inhibitory Control and Attention Test), non-executive function abilities (Oral Reading Test and Crystallized Composite) and processing speed (Pattern Comparison Processing Speed Test), decrease as patients with sickle cell disease age during the modern treatment era. Further analyses are required to determine the impact of age on cognitive outcomes while controlling for the presence of infarction, primary disease modification, hemoglobin and additional biologic covariates. These preliminary analyses support further investigation into the pathophysiology of SCD on both brain development and aging, and consideration of neurocognitive outcomes in the development of new therapeutics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Silent Cerebral Infarction during Immune TTP Remission - Prevalence, Predictors and Impact on Cognition

BACKGROUND: Immune thrombotic thrombocytopenic purpura (iTTP) survivors are at increased risk cardiovascular events including stroke, which is associated with low remission ADAMTS13 activity. In the prospective Neurologic Sequelae of TTP (NeST) study, we evaluated the prevalence of silent cerebral infarction (SCI, ischemic lesions on brain MRI without overt neurodeficits that are a risk factor for future stroke), identified risk factors for SCI, and examined the association of SCI with cognitive impairment, which is prevalent in iTTP survivors. METHODS: We prospectively enrolled adult (age ≥ 18 years) patients with iTTP based on ADAMTS13 activity <10% during an acute episode. All study assessments were performed after achieving hematological remission. Participants undergo annual study visits that include: 1) Brain MRI: SCI is defined as a infarct like lesion (punctate T2 and FLAIR hyperintensity) ≥3 mm in size without corresponding neurodeficits., 2) NIH ToolBox Cognition battery, an extensively-validated tool that tests multiple cognitive domains including executive function (dimensional change card sort test, flanker inhibitory control and attention test), processing speed (pattern comparison test), episodic memory (picture sequence memory test), working memory (list sorting working memory test), language (oral reading recognition, picture vocabulary test). Fully-corrected T scores (normative mean 50, SD 10) adjusted for age, sex, race and educational attainment are computed for individual tests as well as composite scores for fluid cognition, crystallized cognition and total cognition. Mild and major cognitive impairment are defined as a T scores that are 1-2 SD below mean and > 2 SD below mean for any domain, respectively; 3) the Beck depression inventory was also completed since depression is a potential confounder that is common in iTTP and may contribute to impaired cognition. RESULTS: Between September 2020 and July 2022, 39 iTTP patients were enrolled; 32 patients completed MRI (2 excluded due to metal implant/shrapnel, 4 stopped for anxiety/claustrophobia). Median age was 48 years, 71% were female, and 23% had previous stroke (including during acute iTTP). Prevalence and predictors of SCI: MRI showed SCI in 53.1% (Figure 1). Only 47% (8/17) patients with SCI had prior overt stroke. Age [OR 1.07 (95% CI 1.01-1.15, P=0.025) and history of stroke [OR 12.8 (95% CI 1.07-152.9), P=0.044] were associated with SCI in a logistic regression model adjusted for number of iTTP episodes [OR 1.14 (95% CI 0.71-1.86), P=0.570], hypertension [OR 0.77 (95% CI 0.14 - 4.25), P=0.768], and Black race [OR 2.10 (95% CI 0.16-28.20], P=0.574]. SCI is associated with cognitive impairment: Mild and major cognitive impairment were present in 23.1% and 30.8%, respectively. Deficits most commonly involved executive function (flanker inhibitory control and attention test, dimensional change card sort test) and processing speed (pattern comparison test). Compared to patients without SCI, those with SCI had higher rates of cognitive impairment (70.5% vs. 26.7%) including major impairment (52.9% vs. 6.7%) (P=0.014) (Figure 2). In logistic regression models adjusted for age and prior stroke, SCI was associated with major cognitive impairment [OR 18.13 (95% CI 1.3-259.1), P=0.033] as well as mild cognitive impairment [OR 7.76 (95% CI 1.03-58.29]. Patient with SCI had lower composite scores on the NIH ToolBox cognition battery [fluid cognition composite 41 vs. 55, P=0.009, crystallized composite 50 vs. 60, P=0.033, total composite 46 vs, 59, P=0.004), as well as lower scores on tests of executive function (flanker inhibitory control and attention, P=0.020) and processing speed (pattern comparison test, P=0.004), which are most commonly affected in iTTP. Patients with SCI did not have higher mean Beck Depression inventory scores (12.0 ± 7.8 vs. 11.67 ± 11.5, P = 0.659) than those without SCI suggesting that the association with cognitive performance is not due to higher rates of depression in this group. CONCLUSIONS: MRI evidence of brain infarction is common in patients with iTTP with or without a clinical history of stroke. Ongoing follow up with serial MRI continues and will inform whether SCI are progressive in remission and whether low remission ADAMTS13 is a targetable risk factor. The strong association of SCI with impaired cognition suggests that these 'silent infarcts' are neither silent nor innocuous. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Identifying Patterns of Neurocognitive Dysfunction through Direct Comparison of Patients with Leukemia, CNS Tumors, and Sickle Cell Disease

Background. Innovations in pediatric oncology have led to advances that take the place of older, more toxic therapies, making it possible for more children to survive. As this population grows, it is essential to monitor and carefully study late effects. Perhaps most insidious and far reaching in its effect on the daily lives of survivors is neurocognitive dysfunction that impacts school performance, occupational attainment, and quality of life. The populations at greatest risk for neurocognitive dysfunction in the pediatric hematology oncology population include children with central nervous system (CNS) tumors, leukemia (ALL), and sickle cell disease (SCD). What is known about neurocognitive dysfunction in these populations has come from studying these groups separately and with heterogeneous tools, putting each group on a different "measuring stick." Methods. The current study seeks to quantify and compare the magnitude and type of neurocognitive dysfunction between groups of children with CNS tumors, pre-B ALL, and SCD by employing a common methodology to directly compare these groups to each other. Neurocognitive function was assessed using the NIH Toolbox Cognition Battery. Children between the ages of 7-12 were included without pre-existing neurological disorders. Children with CNS tumors or pre-B ALL were within 18 months of completing therapy. Children with SCD possessed the SS or Sβ0 genotype, regularly took hydroxyurea, had no history of overt stroke, and did not receive chronic transfusions. NIH Toolbox Cognition Battery scores are presented as age-adjusted standard scores with a mean of 100, standard deviation of 15. Effect sizes were calculated using Cohen's d statistic. We hypothesized that these groups would perform significantly differently from normative data and differently from each other, with children with CNS tumors showing the greatest deficits, followed by children with SCD, with children with ALL showing the fewest deficits. Results. Fifty-three patients were included in analysis (n = 11 CNS tumor, n = 27 ALL, n = 15 SCD). Children with ALL demonstrated a large, negative effect in processing speed (median=86, IQR 65-95; Cohen's d = -0.93) and medium, negative effects in working memory (median=91, IQR 84.5-105.5, d = -0.6) and attentional control (median= 92, IQR 80-102, d = -0.6; Figure 1). Children with CNS tumors experienced medium deficits in cognitive flexibility (median=90, IQR 84-97, d = -0.67) and large, negative effects in processing speed (median=77, IQR 69-95, d = -1.53) and attentional control (median=88, IQR 76.5-93, d = -0.8). Children with SCD demonstrated medium, negative effects in episodic memory (median=92.5, IQR 85-102.8, d = -0.5). For the overall cognitive fluid composite score, children with SCD performed in the average range (median=99.5, IQR 83.2-105), while children diagnosed with malignancies demonstrated poorer performance with large effect sizes (ALL median=87, IQR 82-95, d = -0.87; CNS tumor median=84, IQR 74.5-95.5, d = -1.07). Conclusions. Preliminary analyses suggest that at-risk groups of children with ALL, CNS tumors, and SCD experience neurocognitive deficits differently from one another in multiple domains. Future studies should employ findings like these to develop and implement disease- and domain-specific interventions to reverse or alleviate neurocognitive deficits. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Organ Function After HCT for SCD: A Report From the Sickle Cell Transplant Advocacy and Research Alliance

Hematopoietic cell transplantation (HCT) is an established cure for sickle cell disease (SCD) supported by long-term survival, but long-term organ function data are lacking. We sought to describe organ function and assess predictors for dysfunction in a retrospective cohort (n=247) through the Sickle cell Transplant Advocacy and Research alliance. Patients with <1-year follow-up or graft rejection/second HCT were excluded. Organ function data were collected from last follow-up. Primary measures were organ function, comparing pre- and post-HCT. Bivariable and multivariable analyses were performed for predictors of dysfunction. Median age at HCT was 9.4 years; the majority had HbSS (88.2%) and severe clinical phenotype (65.4%). Most received matched related (76.9%) bone marrow (83.3%) with myeloablative conditioning (MAC; 57.1%). Acute and chronic graft-versus-host disease (GVHD) developed in 24.0% and 24.8%. Thirteen patients (5.3%) died ≥1 year after HCT, primarily from GVHD or infection. More post-HCT patients had low ejection or shortening fractions than pre-HCT (0.6%→6.0%, P=.007 and 0%→4.6%, P=.003). The proportion with lung disease remained stable. Eight patients (3.2%) had overt stroke; most had normal (28.3%) or stable (50.3%) brain magnetic resonance imaging. On multivariable analysis, cardiac dysfunction was associated with MAC (odds ratio [OR]=2.71; 95% confidence interval [CI], 1.09-6.77; P=.033) and severe acute GVHD (OR=2.41; 95% CI, 1.04-5.62; P=.041). Neurologic events were associated with central nervous system indication (OR=2.88; 95% CI, 2.00-4.12; P < .001). Overall organ dysfunction was associated with age ≥16 years (OR=2.26; 95% CI, 1.35-3.78; P=.002) and clinically severe disease (OR=1.64; 95% CI, 1.02-2.63; P=.043). In conclusion, our results support consideration of HCT at younger age and use of less intense conditioning.

Trimethylamine N-oxide is associated with impaired cognitive function in patients with atrial fibrillation

Abstract Introduction Since patients with atrial fibrillation (AF) are predisposed to suffer from major adverse cerebrovascular events (MACE), they are more likely to suffer MACE linked sequelae, such as cognitive impairment. We hypothesised that the gut microbiome derivate trimethylamine N-oxide (TMAO) may amplify this pathomechanism given its hypercoagulative, proinflammatory and proatherogenic effects. Methods Patients of the Swiss-AF cohort with determined TMAO plasma levels, cognitive scores (n=2'379) and cerebral magnetic resonance imaging (cMRI) (n=1'722) collected at baseline were included. TMAO levels were measured by liquid chromatography-mass spectrometry (HPLC). Overall cognitive performance was evaluated using the Cognitive Construct (CoCo) score reflecting different cognitive functions measured by four validated neuropsychological assessments, namely the Montreal Cognitive Assessment (MoCA), Trail Making Test (TMT parts A and B), Semantic Fluency Test (SFT) and Digital Symbol Substitution Test (DSST). The scores were compared with the quartiles of patients' TMAO plasma levels (Q1: 0.6–4, Q2: 4–5.8, Q3: 5.8–9.1, Q4: 9.1–164μmol/l) in linear effect models. All models were adjusted for multiple covariates correlating with this association: For TMAO (overall meat consumption &amp;gt;3 times per week, physical activity, glomerular filtration rate, presence of diabetes mellitus), cognitive function (EQ-5D-5L score, geriatric depression scale, education level) and cerebral affects (white matter lesions volume and total brain volume in cMRI). The relevance of high TMAO plasma levels in different stroke groups in cMRI (i.e., clinically overt, silent, or no stroke) were analysed in a subgroup analysis. The subgroups were additionally adjusted for total brain volume to eliminate the effect of simultaneous decrease of cerebral white matter. Results After multivariable adjustment, AF patients in the highest quartile of TMAO levels performed significantly poorer in the global cognitive score (CoCo: estimate −0.11, 95% CI [−0.17, −0.05], p=0.002) compared to patients in the lowest quartile. This was observed also in the MoCA, SFT, DSST, TMT-A and TMT-B. In the subgroup analysis, an association between the highest TMAO quartile (compared with the lowest quartile) and lower CoCo score was found in the group of patients with overt strokes (−0.18, 95% CI [−0.33, −0.04], p=0.012). Weak evidence of the same association was found in the group of patients with silent strokes (−0.13, 95% CI [−0.25, 0.002], p=0.053) and patients with no strokes (−0.08, 95% CI [−0.16, 0.01], p=0.07). After adjustment for decreased brain volume, the association remained for silent strokes (−0.14, 95% CI [−0.28, −0.01], p=0.036) indicating the impact of TMAO in this subgroup. Conclusion TMAO plasma levels were associated with cognitive impairment in patients with AF. Longitudinal data will clarify dynamics and likely causality between TMAO and cognitive impairment. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Swiss National Science Foundation

Signals for reduced cognitive function are associated with subtle signs of atrial cardiomyopathy and left ventricular diastolic dysfunction – insights from a large population based study

Abstract Background/Introduction In recent years, it has been proposed that a thrombogenic atrial substrate due to various alterations in (left) atrial morphology and function could contribute to atrial thromboembolism even in the absence of (clinically overt) atrial fibrillation. This so-called atrial cardiomyopathy may pose a risk of stroke and cognitive decline beyond the presence of atrial fibrillation. Purpose To define the association of echocardiographic parameters of left atrial cardiomyopathy and left ventricular diastolic dysfunction with cognitive function in individuals free of clinically overt atrial fibrillation or stroke. Methods Data from the first 10,000 participants of a large German population-based cohort study were analysed. Of these, 8264 individuals underwent standardized transthoracic echocardiography and cognitive function testing at baseline. Parameters of left ventricular systolic and diastolic function as well as left atrial function were systematically assessed, including left atrial global peak strain. Cognitive function was quantified using the Animal Naming Test and the Trail Making Test A and B. We performed linear regression analyses with incremental adjustment to examine the association of echocardiographic parameters with the performance on the neuropsychological tests. Results After exclusion of 463 individuals with known AF and 309 individuals with prior/known stroke or severe depression, 7492 individuals were analysed (mean age 61.9±8.4 years, 52.3% women, median left ventricular ejection fraction 59% [25th/75th percentile 56/62%], median left atrial volume index 25.0 ml/m2 [25th/75th percentile 20/30 ml/m2]). In multivariable-adjusted analyses, E/e'-ratio was significantly associated with a worse performance on the Animal Naming Test (−0.24 per one standard deviation [SD] increase, 95% confidence interval [CI] −0.42 to −0.06), the Trail Making Test A (0.76 per one SD increase, 95% CI 0.35–1.17) and B (1.1 per one SD increase, 95% CI 0.09–2.11). Left atrial strain was associated with worse performance on Trail Making Test B (−1.39 per one SD increase, 95% CI −2.46 to −0.32). Increased left atrial volume index was associated with worse performance on the ANT (0.2, 95% CI 0.03–0.37). Conclusions Subtle echocardiographic signs of atrial cardiomyopathy and left ventricular diastolic dysfunction are associated with worse performance on cognitive function tests in a German middle-aged population. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): The Hamburg City Health Study (HCHS) is supported by the University Medical Center Hamburg-Eppendorf and by various grants from different institutions/organizations.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease

AbstractChildren with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.