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

Children 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.

Toward Automated Detection of Silent Cerebral Infarcts in Children and Young Adults With Sickle Cell Anemia.

BACKGROUND: Silent cerebral infarcts (SCI) in sickle cell anemia (SCA) are associated with future strokes and cognitive impairment, warranting early diagnosis and treatment. Detection of SCI, however, is limited by their small size, especially when neuroradiologists are unavailable. We hypothesized that deep learning may permit automated SCI detection in children and young adults with SCA as a tool to identify the presence and extent of SCI in clinical and research settings. METHODS: We utilized UNet-a deep learning model-for fully automated SCI segmentation. We trained and optimized UNet using brain magnetic resonance imaging from the SIT trial (Silent Infarct Transfusion). Neuroradiologists provided the ground truth for SCI diagnosis, while a vascular neurologist manually delineated SCI on fluid-attenuated inversion recovery and provided the ground truth for SCI segmentation. UNet was optimized for the highest spatial overlap between automatic and manual delineation (dice similarity coefficient). The optimized UNet was externally validated using an independent single-center prospective cohort of SCA participants. Model performance was evaluated through sensitivity and accuracy (%correct cases) for SCI diagnosis, dice similarity coefficient, intraclass correlation coefficient (metric of volumetric agreement), and Spearman correlation. RESULTS: The SIT trial (n=926; 31% with SCI; median age, 8.9 years) and external validation (n=80; 50% with SCI; age, 11.5 years) cohorts had small median lesion volumes of 0.40 and 0.25 mL, respectively. Compared with the neuroradiology diagnosis, UNet predicted SCI presence with 100% sensitivity and 74% accuracy. In magnetic resonance imaging with SCI, UNet reached a moderate spatial agreement (dice similarity coefficient, 0.48) and high volumetric agreement (intraclass correlation coefficient, 0.76; ρ=0.72; P<0.001) between automatic and manual segmentations. CONCLUSIONS: UNet, trained using a large pediatric SCA magnetic resonance imaging data set, sensitively detected small SCI in children and young adults with SCA. While additional training is needed, UNet may be integrated into the clinical workflow as a screening tool, aiding in SCI diagnosis.

Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait.

BACKGROUND: Individuals with sickle cell anemia have heightened risk of stroke and cognitive dysfunction. Given its high prevalence globally, whether sickle cell trait (SCT) is a risk factor for neurological injury has been of interest; however, data have been limited. We hypothesized that young, healthy adults with SCT would show normal cerebrovascular structure and hemodynamic function. METHODS: As a case-control study, young adults with (N=25, cases) and without SCT (N=24, controls) underwent brain magnetic resonance imaging to quantify brain volume, microstructural integrity (fractional anisotropy), silent cerebral infarcts (SCI), intracranial stenosis, and aneurysms. Pseudocontinuous arterial spin labeling and asymmetric spin echo sequences measured cerebral blood flow and oxygen extraction fraction, respectively, from which cerebral metabolic oxygen demand was calculated. Imaging metrics were compared between SCT cases and controls. SCI volume was correlated with baseline characteristics. RESULTS: Compared with controls, adults with SCT demonstrated similar normalized brain volumes (SCT 0.80 versus control 0.81, P=0.41), white matter fractional anisotropy (SCT 0.41 versus control 0.43, P=0.37), cerebral blood flow (SCT 62.04 versus control, 61.16 mL/min/100 g, P=0.67), oxygen extraction fraction (SCT 0.27 versus control 0.27, P=0.31), and cerebral metabolic oxygen demand (SCT 2.71 versus control 2.70 mL/min/100 g, P=0.96). One per cohort had an intracranial aneurysm. None had intracranial stenosis. The SCT cases and controls showed similar prevalence and volume of SCIs; however, in the subset of participants with SCIs, the SCT cases had greater SCI volume versus controls (0.29 versus 0.07 mL, P=0.008). Of baseline characteristics, creatinine was mildly elevated in the SCT cohort (0.9 versus 0.8 mg/dL, P=0.053) and correlated with SCI volume (ρ=0.49, P=0.032). In the SCT cohort, SCI distribution was similar to that of young adults with sickle cell anemia. CONCLUSIONS: Adults with SCT showed normal cerebrovascular structure and hemodynamic function. These findings suggest that healthy individuals with SCT are unlikely to be at increased risk for early or accelerated ischemic brain injury.

MR-assisted PET respiratory motion correction using deep-learning based short-scan motion fields.

PURPOSE: We evaluated the impact of PET respiratory motion correction (MoCo) in a phantom and patients. Moreover, we proposed and examined a PET MoCo approach using motion vector fields (MVFs) from a deep-learning reconstructed short MRI scan. METHODS: The evaluation of PET MoCo was performed in a respiratory motion phantom study with varying lesion sizes and tumor to background ratios (TBRs) using a static scan as the ground truth. MRI-based MVFs were derived from either 2000 spokes (MoCo2000 , 5-6 min acquisition time) using a Fourier transform reconstruction or 200 spokes (MoCoP2P200 , 30-40 s acquisition time) using a deep-learning Phase2Phase (P2P) reconstruction and then incorporated into PET MoCo reconstruction. For six patients with hepatic lesions, the performance of PET MoCo was evaluated using quantitative metrics (SUVmax , SUVpeak , SUVmean , lesion volume) and a blinded radiological review on lesion conspicuity. RESULTS: MRI-assisted PET MoCo methods provided similar results to static scans across most lesions with varying TBRs in the phantom. Both MoCo2000 and MoCoP2P200 PET images had significantly higher SUVmax , SUVpeak , SUVmean and significantly lower lesion volume than non-motion-corrected (non-MoCo) PET images. There was no statistical difference between MoCo2000 and MoCoP2P200 PET images for SUVmax , SUVpeak , SUVmean or lesion volume. Both radiological reviewers found that MoCo2000 and MoCoP2P200 PET significantly improved lesion conspicuity. CONCLUSION: An MRI-assisted PET MoCo method was evaluated using the ground truth in a phantom study. In patients with hepatic lesions, PET MoCo images improved quantitative and qualitative metrics based on only 30-40 s of MRI motion modeling data.

Cerebral oxygen metabolic stress is increased in children with sickle cell anemia compared to anemic controls.

Patients with sickle cell anemia (SCA) experience cerebral metabolic stress with an increase in oxygen extraction fraction (OEF) to compensate for reduced oxygen carrying capacity due to anemia. It remains unclear if anemia alone drives this metabolic stress. Using MRI, we collected voxel-wise OEF measurements to test our hypothesis that OEF would be elevated in anemic controls without SCA (AC) compared to healthy controls (HC), but OEF would be even higher in SCA compared to AC. Brain MRIs (N = 159) were obtained in 120 participants (34 HC, 27 AC, 59 SCA). While hemoglobin was lower in AC versus HC (p < 0.001), hemoglobin was not different between AC and SCA cohorts (p = 0.459). Whole brain OEF was higher in AC compared to HC (p < 0.001), but lower compared to SCA (p = 0.001). Whole brain OEF remained significantly higher in SCA compared to HC (p = 0.001) while there was no longer a difference between AC versus HC (p = 0.935) in a multivariate model controlling for age and hemoglobin. OEF peaked within the border zone regions of the brain in both SCA and AC cohorts, but the volume of white matter with regionally elevated OEF in AC was smaller (1.8%) than SCA (58.0%). While infarcts colocalized within regions of elevated OEF, more SCA participants had infarcts than AC (p < 0.001). We conclude that children with SCA experience elevated OEF compared to AC and HC after controlling for the impact of anemia, suggesting that there are other pathophysiologic factors besides anemia contributing to cerebral metabolic stress in children with SCA.

GRAPES: Trivia game increases sickle cell disease knowledge in patients and providers and mitigates healthcare biases.

BACKGROUND: Patients with sickle cell disease (SCD) endure healthcare biases that are partially due to a lack of disease-specific education among healthcare providers. Furthermore, there is a paucity of age-appropriate health education materials for patients with SCD. To address this gap, we created the GRAPES tool (Game to Raise Awareness for Patient/Provider/Public Education of SCD; www.tinyurl.com/GRAPESgame) and hypothesized that utilization of the GRAPES tool will improve patient and provider SCD knowledge and mitigate healthcare bias. PROCEDURE: The GRAPES tool is an online, single-player trivia game. A feasibility study was conducted in pediatric patients with SCD at age 10 years or older and registered nurses. All participants were assessed for change in SCD-relevant knowledge and satisfaction post-gameplay. Providers were assessed for change in attitudes toward patients with SCD post-gameplay. RESULTS: Twenty-five patients and 25 providers were enrolled. All participants (P < 0.001), and specifically within the patient (P = 0.019) and provider (P < 0.001) cohorts, showed increased SCD knowledge post-gameplay. Both patients and providers reported high satisfaction with GRAPES. Provider negative attitudes were reduced (P = 0.007) post-gameplay without change in positive attitudes (P = 0.959). Providers demonstrated post-gameplay reduced (P = 0.001) belief that patients' changing behavior around providers indicates inappropriate drug-seeking behavior. CONCLUSIONS: This study demonstrates the feasibility and acceptability of the GRAPES tool as a potential digital, behavioral intervention to provide educational materials for patients and their providers in different clinical settings, improve knowledge about SCD, and decrease stigma against patients with SCD in the healthcare setting.

Rate of Infarct-Edema Growth on CT Predicts Need for Surgical Intervention and Clinical Outcome in Patients with Cerebellar Infarction.

BACKGROUND: Up to 20% of patients with cerebellar infarcts will develop malignant edema and deteriorate clinically. Radiologic measures, such as initial infarct size, aid in identifying individuals at risk. Studies of anterior circulation stroke suggest that mapping early edema formation improves the ability to predict deterioration; however, the kinetics of edema in the posterior fossa have not been well characterized. We hypothesized that faster edema growth within the first hours after acute cerebellar stroke would be an indicator for individuals requiring surgical intervention and those with worse neurological outcomes. METHODS: Consecutive patients admitted to the neurological intensive care unit with acute cerebellar infarction were retrospectively identified. Hypodense regions of infarct and associated edema, "infarct-edema", were delineated by using ABC/2 for all computed tomography (CT) scans up to 14 days from last known well. To examine how rate of infarct-edema growth varied across clinical variables and surgical intervention status, nonlinear and linear mixed-effect models were performed over 2 weeks and 2 days, respectively. In patients with at least two CT scans, multivariable logistic regression examined clinical and radiological predictors of surgical intervention (defined as extraventricular drainage and/or posterior fossa decompression) and poor clinical outcome (discharge to skilled nursing facility, long-term acute care facility, hospice, or morgue). RESULTS: Of 150 patients with acute cerebellar infarction, 38 (25%) received surgical intervention and 45 (30%) had poor clinical outcome. Age, admission National Institutes of Health Stroke Scale (NIHSS) score, and baseline infarct-edema volume did not differ, but bilateral/multiple vascular territory involvement was more frequent (87% vs. 50%, p < 0.001) in the surgical group than that in the medical intervention group. On 410 serial CTs, infarct-edema volume progressed rapidly over the first 2 days, followed by a subsequent plateau. Of 112 patients who presented within two days, infarct-edema growth rate was greater in the surgical group (20.1 ml/day vs. 8.01 ml/day, p = 0.002). Of 67 patients with at least two scans, after adjusting for baseline infarct-edema volume, vascular territory, and NIHSS, infarct-edema growth rate over the first 2 days (odds ratio 2.55; 95% confidence interval 1.40-4.65) was an independent, and the strongest, predictor of surgical intervention. Further, early infarct-edema growth rate predicted poor clinical outcome (odds ratio 2.20; 95% confidence interval 1.30-3.71), independent of baseline infarct-edema volume, brainstem infarct, and NIHSS. CONCLUSIONS: Early infarct-edema growth rate, measured via ABC/2, is a promising biomarker for identifying the need for surgical intervention in patients with acute cerebellar infarction. Additionally, it may be used to facilitate discussions regarding patient prognosis.

Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome.

BACKGROUND AND PURPOSE: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSSbaseline - NIHSS24hours = ΔNIHSS6-24h), to examine its relevance to AIS mechanisms and long-term outcomes. METHODS: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS6-24h. In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS6-24h was examined. Finally, the association of ΔNIHSS6-24h with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA). RESULTS: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median ΔNIHSS6-24h was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS6-24h (R2=0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R2=0.27), but much of the variance remained unexplained. ΔNIHSS6-24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS3-24h was similarly associated with 90-day outcomes. CONCLUSIONS: The dynamic phenotype, ΔNIHSS6-24h, captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS6-24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.

Bulk volume susceptibility difference between deoxyhemoglobin and oxyhemoglobin for HbA and HbS: A comparative study.

PURPOSE: Sickle cell anemia is a blood disorder that alters the morphology and the oxygen affinity of the red blood cells. Cerebral oxygen extraction fraction measurements using quantitative BOLD contrast have been used for assessing inadequate oxygen delivery and the subsequent risk of ischemic stroke in sickle cell anemia. The BOLD signal in MRI studies relies on Δχdo , the bulk volume susceptibility difference between fully oxygenated and fully deoxygenated blood. Several studies have measured Δχdo for normal hemoglobin A (HbA). However, it is not known whether the value is different for sickle hemoglobin. In this study, Δχdo was measured for both HbA and sickle hemoglobin. METHODS: Six sickle cell anemia patients and 6 controls were recruited. Various blood oxygenation levels were achieved through in vivo manipulations to keep the blood close to its natural state. To account for the differences in oxygen affinity, Hill's equations were used to translate partial pressure of oxygen to oxygen saturation for HbA, sickle hemoglobin, and fetal hemoglobin (HbF) separately. The pH and PCO2 corrections were performed. Temperature and magnetic field drift were controlled for. A multivariate generalized linear mixed model with random participant effect was used. RESULTS: Assuming that Δχdo is similar for HbA and HbF and that ΔχmetHb is 5/4 of Δχdo for HbA, it was found that the Δχdo values for HbA and sickle hemoglobin were not statistically significantly different from each other. CONCLUSION: The same Δχdo value can be used for both types of hemoglobin in quantitative BOLD analysis.

Deep learning-based T1-enhanced selection of linear attenuation coefficients (DL-TESLA) for PET/MR attenuation correction in dementia neuroimaging.

PURPOSE: The accuracy of existing PET/MR attenuation correction (AC) has been limited by a lack of correlation between MR signal and tissue electron density. Based on our finding that longitudinal relaxation rate, or R1 , is associated with CT Hounsfield unit in bone and soft tissues in the brain, we propose a deep learning T1 -enhanced selection of linear attenuation coefficients (DL-TESLA) method to incorporate quantitative R1 for PET/MR AC and evaluate its accuracy and longitudinal test-retest repeatability in brain PET/MR imaging. METHODS: DL-TESLA uses a 3D residual UNet (ResUNet) for pseudo-CT (pCT) estimation. With a total of 174 participants, we compared PET AC accuracy of DL-TESLA to 3 other methods adopting similar 3D ResUNet structures but using UTE R2∗ , or Dixon, or T1 -MPRAGE as input. With images from 23 additional participants repeatedly scanned, the test-retest differences and within-subject coefficient of variation of standardized uptake value ratios (SUVR) were compared between PET images reconstructed using either DL-TESLA or CT for AC. RESULTS: DL-TESLA had (1) significantly lower mean absolute error in pCT, (2) the highest Dice coefficients in both bone and air, (3) significantly lower PET relative absolute error in whole brain and various brain regions, (4) the highest percentage of voxels with a PET relative error within both ±3% and ±5%, (5) similar to CT test-retest differences in SUVRs from the cerebrum and mean cortical (MC) region, and (6) similar to CT within-subject coefficient of variation in cerebrum and MC. CONCLUSION: DL-TESLA demonstrates excellent PET/MR AC accuracy and test-retest repeatability.

Functional Connectivity Decreases with Metabolic Stress in Sickle Cell Disease.

OBJECTIVE: Children with sickle cell disease (SCD) experience cognitive deficits even when unaffected by stroke. Using functional connectivity magnetic resonance imaging (MRI) as a potential biomarker of cognitive function, we tested our hypothesis that children with SCD would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, indicated by elevated oxygen extraction fraction, would have the lowest connectivity. METHODS: We prospectively obtained brain MRIs and cognitive testing in healthy controls and children with SCD. RESULTS: We analyzed data from 60 participants (20 controls and 40 with sickle cell disease). There was no difference in global cognition or cognitive subdomains between cohorts. However, we found decreased functional connectivity within the sensory-motor, lateral sensory-motor, auditory, salience, and subcortical networks in participants with SCD compared with controls. Further, as white matter oxygen extraction fraction increased, connectivity within the visual (p = 0.008, parameter estimate = -0.760 [95% CI = -1.297, -0.224]), default mode (p = 0.012, parameter estimate = -0.417 [95% CI = -0.731, -0.104]), and cingulo-opercular (p = 0.009, parameter estimate = -0.883 [95% CI = -1.517, -0.250]) networks decreased. INTERPRETATION: We conclude that there is diminished functional connectivity within these anatomically contiguous networks in children with SCD compared with controls, even when differences are not seen with cognitive testing. Increased white matter oxygen extraction fraction was associated with decreased connectivity in select networks. These data suggest that elevated oxygen extraction fraction and disrupted functional connectivity are potentially presymptomatic neuroimaging biomarkers for cognitive decline in SCD. ANN NEUROL 2020;88:995-1008.

Hydroxyurea reduces cerebral metabolic stress in patients with sickle cell anemia.

Chronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs; OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared with patients not receiving disease-modifying therapy, we prospectively obtained brain magnetic resonance imaging scans with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT. There was no difference in whole-brain CBF among the 3 cohorts (P = .148). However, whole-brain OEF was significantly different (P < .001): participants without disease-modifying therapy had the highest OEF (median 42.9% [interquartile range (IQR) 39.1%-49.1%]), followed by HU treatment (median 40.7% [IQR 34.9%-43.6%]), whereas CTT treatment had the lowest values (median 35.3% [IQR 32.2%-38.9%]). Moreover, the percentage of white matter at highest risk for ischemia, defined by OEF greater than 40% and 42.5%, was lower in the HU cohort compared with the untreated cohort (P = .025 and P = .034 respectively), but higher compared with the CTT cohort (P = .018 and P = .029 respectively). We conclude that HU may offer neuroprotection by mitigating cerebral metabolic stress in patients with SCA, but not to the same degree as CTT.

Silent infarcts in sickle cell disease occur in the border zone region and are associated with low cerebral blood flow.

Silent cerebral infarcts (SCIs) are associated with cognitive impairment in sickle cell anemia (SCA). SCI risk factors include low hemoglobin and elevated systolic blood pressure; however, mechanisms underlying their development are unclear. Using the largest prospective study evaluating SCIs in pediatric SCA, we identified brain regions with increased SCI density. We tested the hypothesis that infarct density is greatest within regions in which cerebral blood flow is lowest, further restricting cerebral oxygen delivery in the setting of chronic anemia. Neuroradiology and neurology committees reached a consensus of SCIs in 286 children in the Silent Infarct Transfusion (SIT) Trial. Each infarct was outlined and coregistered to a brain atlas to create an infarct density map. To evaluate cerebral blood flow as a function of infarct density, pseudocontinuous arterial spin labeling was performed in an independent pediatric SCA cohort. Blood flow maps were aligned to the SIT Trial infarct density map. Mean blood flow within low, moderate, and high infarct density regions from the SIT Trial were compared. Logistic regression evaluated clinical and imaging predictors of overt stroke at 3-year follow-up. The SIT Trial infarct density map revealed increased SCI density in the deep white matter of the frontal and parietal lobes. A relatively small region, measuring 5.6% of brain volume, encompassed SCIs from 90% of children. Cerebral blood flow was lowest in the region of highest infarct density (P < .001). Baseline infarct volume and reticulocyte count predicted overt stroke. In pediatric SCA, SCIs are symmetrically located in the deep white matter where minimum cerebral blood flow occurs.

Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia.

Blood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO2). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO2, thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; P < .001) and decreased Hb S (from 39.7% to 24.3%; P < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; P = .004) and OEF (from 34.4% to 31.2%; P < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA (P < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels.

Increased complications of chronic erythrocytapheresis compared with manual exchange transfusions in children and adolescents with sickle cell disease.

BACKGROUND: Children and adolescents with sickle cell disease (SCD) are at high risk of strokes and are frequently treated with red blood cell (RBC) transfusions. The goal is to suppress hemoglobin (Hb) S while minimizing transfusion-induced iron overload. RBCs may be given via simple transfusion, manual exchange transfusion (MET), or erythrocytapheresis (aRBCX). Chronic transfusion practices vary among institutions. METHODS: This single-institution, retrospective cohort study compares Hb S control and therapy complication rates between MET and aRBCX in a cohort of children and adolescents with SCD and stroke during a 5-year period from 2008 through 2012. Duration and mode of transfusion therapy, achievement of Hb S suppression goal, iron burden by ferritin levels, and catheter complications were evaluated. RESULTS: Thirty-seven children were included in analysis. The prevalence of catheter complications was 75% in aRBCX recipients compared with 0% in MET recipients (P < 0.001). There was no significant difference between modalities in achieving Hb S suppression or ferritin goals, but those receiving aRBCX had a greater likelihood of discontinuing chelation therapy. Among aRBCX recipients, adherence to >90% of transfusion appointments was associated with achieving Hb S suppression goals. CONCLUSION: aRBCX may have increased complication risks compared with MET for chronic transfusion therapy in SCD. Risks and benefits of aRBCX and MET should be considered when selecting a chronic transfusion modality. Transfusion therapy modalities should be compared in prospective studies for stroke prevention in children with SCD.

Neuroinflammation and amyloid deposition in the progression of mixed Alzheimer and vascular dementia.

BACKGROUND: Alzheimer's disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) pathologies coexist in patients with cognitive impairment. Abnormal amyloid beta (Aß) deposition is the hallmark pathologic biomarker for AD. Neuroinflammation may be a pathophysiological mechanism in both AD and VCID. In this study, we aimed to understand the role of neuroinflammation and Aß deposition in white matter hyperintensities (WMH) progression and cognitive decline over a decade in patients with mixed AD and VCID pathologies. METHODS: Twenty-four elderly participants (median [interquartile range] age 78 [64.8, 83] years old, 14 female) were recruited from the Knight Alzheimer Disease Research Center. 11C-PK11195 standard uptake value ratio (SUVR) and 11C-PiB mean cortical binding potential (MCBP) were used to evaluate neuroinflammation and Aß deposition in-vivo, respectively. Fluid-attenuated inversion recovery MR images were acquired to obtain baseline WMH volume and its progression over 11.5 years. Composite cognitive scores (global, processing speed and memory) were computed at baseline and follow-up over 7.5 years. Multiple linear regression models evaluated the association between PET biomarkers (11C-PK11195 SUVR and 11C-PiB MCBP) and baseline WMH volume and cognitive function. Moreover, linear mixed-effects models evaluated whether PET biomarkers predicted greater WMH progression or cognitive decline over a decade. RESULTS: Fifteen participants (62.5%) had mixed AD (positive PiB) and VCID (at least one vascular risk factor) pathologies. Elevated 11C-PK11195 SUVR, but not 11C-PiB MCBP, was associated with greater baseline WMH volume and predicted greater WMH progression. Elevated 11C-PiB MCBP was associated with baseline memory and global cognition. Elevated 11C-PK11195 SUVR and elevated 11C-PiB MCBP independently predicted greater global cognition and processing speed declines. No association was found between 11C-PK11195 SUVR and 11C-PiB MCBP. CONCLUSIONS: Neuroinflammation and Aß deposition may represent two distinct pathophysiological pathways, and both independently contributed to the progression of cognitive impairment in mixed AD and VCID pathologies. Neuroinflammation, but not Aß deposition, contributed to WMH volume and progression.

Macroperiodic Oscillations Are Associated With Seizures Following Acquired Brain Injury in Young Children.

PURPOSE: Seizures occur in 10% to 40% of critically ill children. We describe a phenomenon seen on color density spectral array but not raw EEG associated with seizures and acquired brain injury in pediatric patients. METHODS: We reviewed EEGs of 541 children admitted to an intensive care unit between October 2015 and August 2018. We identified 38 children (7%) with a periodic pattern on color density spectral array that oscillates every 2 to 5 minutes and was not apparent on the raw EEG tracing, termed macroperiodic oscillations (MOs). Internal validity measures and interrater agreement were assessed. We compared demographic and clinical data between those with and without MOs. RESULTS: Interrater reliability yielded a strong agreement for MOs identification (kappa: 0.778 [0.542-1.000]; P < 0.0001). There was a 76% overlap in the start and stop times of MOs among reviewers. All patients with MOs had seizures as opposed to 22.5% of the general intensive care unit monitoring population ( P < 0.0001). Macroperiodic oscillations occurred before or in the midst of recurrent seizures. Patients with MOs were younger (median of 8 vs. 208 days; P < 0.001), with indications for EEG monitoring more likely to be clinical seizures (42 vs. 16%; P < 0.001) or traumatic brain injury (16 vs. 5%, P < 0.01) and had fewer premorbid neurologic conditions (10.5 vs. 33%; P < 0.01). CONCLUSIONS: Macroperiodic oscillations are a slow periodic pattern occurring over a longer time scale than periodic discharges in pediatric intensive care unit patients. This pattern is associated with seizures in young patients with acquired brain injuries.

Child Neurology Applicants Place Increasing Emphasis on Quality of Life Factors.

BACKGROUND: Medical education, residency training, and the structure of child neurology residency training programs are evolving. We sought to evaluate how training program selection priorities of child neurology residency applicants have changed over time. METHODS: An electronic survey was sent to child neurology residents and practicing child neurologists via the Professors of Child Neurology distribution list in the summer of 2018. It was requested that the survey be disseminated to current trainees and alumni of the programs. The survey consisted of seven questions assessing basic demographics and a list of factors applicants consider when choosing a residency. RESULTS: There were 284 responses with a higher representation of individuals matriculating into residency in the last decade. More recent medical school graduates had a lower probability of considering curriculum as an important factor for residency selection (odds ratio [OR], 0.746; 95% confidence interval [95% CI], 0.568 to 0.98; P = 0.035) and higher priority placed on interaction with current residents over the course of the interview day (OR, 2.207; 95% CI, 1.486 to 3.278; P < 0.0001), sense of resident happiness and well-being (OR, 2.176; 95% CI, 1.494 to 3.169; P < 0.0001), and perception of city or geography of the residency program (OR, 1.710; 95% CI, 1.272 to 2.298; P < 0.001). CONCLUSIONS: Over time, child neurology residency applicants are putting more emphasis on quality of life factors over curriculum. To accommodate these changes, child neurology residency programs should prioritize interactions with residents during the interview process and resident wellness initiatives throughout residency training.