Background: The role of waste clearance underlying brain injury and cognitive impairment in sickle cell disease (SCD) is understudied. Dilated perivascular spaces, a marker of glymphatic dysfunction, sleep disturbance, and chronic inflammation have been reported in individuals with SCD. We hypothesized that glymphatic clearance is impaired in patients with SCD and associated with infarct burden, microstructural damage, blood-brain barrier (BBB) permeability, and cognitive impairment. Methods: Adults with SCD and controls underwent diffusion tensor image MRI to quantify a nalysis a l ong the p erivascular s pace (ALPS) index (Table, Fig 1A), a proxy for glymphatic clearance. Imaging markers of brain injury were white matter microstructural disruption (increased mean diffusivity, MD) and infarct volume normalized by inverse normal transformation. BBB permeability (Ktrans) was measured using dynamic contrast enhancement MRI. Clinical metrics of inflammation were platelet and white blood cell counts. Cognitive function was measured by Pattern Comparison Processing Speed Test. ALPS index was compared between SCD vs. controls. Pearson correlations measured relationships between ALPS index and imaging, cognitive, and inflammatory variables. Linear regression adjusted for age and sex. Results: ALPS index was lower in SCD (N=41) vs. controls (N=40), before and after adjusting for age and sex (Fig 1B), suggesting impaired glymphatic clearance in SCD. ALPS index was associated with impaired microstructure (MD) before and after adjusting for age and sex in the SCD cohort, with a trend towards association with infarct burden. These associations were not found in controls. ALPS index negatively correlated with processing speed in the SCD cohort only, trending significance (r = 0.29, p=0.07, Fig 1E). Only a small subset had Ktrans (N=22), and no association with ALPS index was found (Fig 1F). ALPS index was negatively correlated with platelets in SCD and white blood cells in controls, suggesting a role of systemic inflammation in association with glymphatic clearance (Fig 2). Conclusion: Preliminary data suggest glymphatic clearance is impaired in SCD and associated with ischemic injury and cognitive dysfunction in SCD. We will test if sleep disturbance mediates the effects of glymphatic impairment on these outcomes, and if glymphatic dysfunction and BBB permeability mediate the effect of inflammation on these outcomes. This will be done by presentation (cohort, N~200).

Background: Multiple studies have found a male prevalence in childhood ischemic stroke regardless of age. Causes for this sex difference are not fully understood. We hypothesized there may be potential differences in hemodynamic reserve, measured by cerebrovascular reactivity (CVR). Methods: Children ages 8-24 years with and without sickle cell anemia (SCA) underwent cerebrovascular reactivity (CVR) measurement using computer-controlled carbon dioxide manipulation during blood-oxygen level dependent (BOLD) MRI, along with MRI- measurements of cerebral blood flow (CBF; multi-post-label delay arterial spin labeling) and oxygen extraction (asymmetric spin echo). Cerebrovascular reactivity (CVR) was assessed voxel-wise within the gray matter (GM) in two ways: Magnitude CVR (mCVR) was defined as the slope of Δ %BOLD signal per Δ mmHg end-tidal CO 2 (ETCO 2 ). We then modeled the dynamic response as the convolution of ETCO 2 with an exponential hemodynamic response function (HRF), yielding two metrics: the time constant τ, representing the latency and speed of the vascular response, and the steady-state CVR (ssCVR), defined as the slope of BOLD signal versus the convolved ETCO 2 regressor, reflecting time-independent reactivity. Group comparisons used the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables, with Benjamini–Hochberg correction for multiple comparisons. A bidirectional stepwise linear regression modeled each CVR, allowing for entry/removal of all potential predictors, with candidate variables including age, sex, SCA status, hemoglobin, GM CBF, GM arterial transit time (ATT), GM OEF, GM cerebral metabolic rate of oxygen utilization (GM CMRO 2 ). Results: CVR data was available in 69 children median age 15 years [IQR 12-18], 46 females. The 17 SCA and 52 control participants were age (p=0.34) and sex (p=0.18) matched. Males had lower mCVR (p=0.009) and ssCVR (p=0.01) than females. On stepwise variable selection for multivariable modeling of mCVR, hemoglobin (p=0.006), sex (p=0.002) and GM arterial transit time (p=0.02) remained significant. In ssCVR, only hemoglobin (p<0.001) and sex (p=0.03) remained significant. Conclusion: Sex influences CVR in youth, even after adjusting for hemoglobin and potential differences in cerebral blood flow in a steady state CVR measurement. Further understanding of this may elucidate mechanisms of sex stroke risk differences in children.

We measured cortical hemodynamics of healthy adults during hypercapnic challenge using an HD-DOT system and RespirAct device. We observed differences in superficial and cortical hemodynamics across spatial and temporal dimensions.

Sickle cell disease (SCD) causes brain injury and cognitive disability. Systemic inflammation and endothelial injury are central to SCD pathophysiology, yet the relationship between systemic drivers of blood-brain barrier (BBB) disruption and brain injury remains understudied. This cross-sectional study assessed whole-brain and regional BBB permeability (Ktrans) using dynamic contrast-enhanced magnetic resonance imaging in 37 adults with SCD in steady-state and 37 non-SCD adults. Cerebral oxygen extraction fraction (OEF) and white matter mean diffusivity (MD) measured tissue hypoxia and microstructural injury, respectively. The SCD cohort showed elevated Ktrans compared with controls (3.6 x10-4min-1 vs. 2.58x10-4min-1, 95% CI median difference [0.36, 1.30]x10-4min-1, P< 0.001), indicating BBB disruption. In SCD, white matter Ktrans was associated with MD (β [95% Cl]: 6.25 [1.72, 10.77], P=0.008), independent of OEF (β [95% Cl]: 0.22 [0.09, 0.35]) and silent cerebral infarcts (β [95% Cl]: 0.01 [0.00, 0.02]). The interaction (P=0.037) between Ktrans and OEF on MD suggested a combined, deleterious effect of BBB disruption and hypoxia on microstructural injury. High-throughput plasma proteomics followed by differential expression analysis, and weighted gene correlation network analysis in a subset of 61 participants revealed 79 proteins associated with BBB permeability belonged to iron homeostasis, response to hypoxia, immune dysregulation, extracellular matrix degradation, lipoprotein homeostasis, and arginine-proline metabolism pathways. All pathways were independently associated with microstructural injury. BBB permeability is a mediator of brain injury for all pathways except extracellular matrix degradation. Targeting specific systemic pathways to protect the BBB may represent a therapeutic approach to preserve brain health in SCD.

Background: Over 50% of sickle cell anemia (SCA) patients will have silent or overt cerebral strokes, which have been linked to cognitive impairment. L-glutamine supplementation has been FDA approved to reduce vaso-occlusive crises frequency. However, glutamine’s effect on stroke and cognitive impairment in SCA is unknown. Measurement of neurometabolites using conventional MR spectroscopy has been limited to a single voxel due to technical challenges. A novel, high-resolution MR spectroscopic imaging (MRSI) technique, termed SPICEx, permits measurement of critical neural substrates and metabolites. In this pilot study, we assessed the neurometabolomic profile of patients with SCA compared to healthy controls using MRSI. Hypothesis: As a marker of stroke risk and brain health, we hypothesized that SCA patients have lower cerebral glutamine compared to controls. Methods: Adults with SCA and healthy controls without history of stroke underwent 3T brain MRI. SPICEx [RG1] produced 3D whole brain (WB) neurometabolite maps (2x3x3 mm 3 , acquisition time 12 minutes) including voxel-wise glutamine. MRI metrics of white matter (WM) microstructural disruption (increased mean diffusivity, MD) were also obtained. Gray matter (GM), WM and WB glutamine measures were compared between SCA vs. controls using Mann-Whitney U test. Spearman’s correlation assessed the relationship between cerebral glutamine, MD, and volume. Results: Of 8 SCA patients and 9 controls, we found lower WB, WM, and WM to WB glutamine ratio in SCA vs. controls (P=0.08, P=0.02, and P=0.01, respectively). Across the cohort, low GM glutamine was associated with reduced GM volume (ρ=0.5, p=0.04), and low WM glutamine was associated with elevated MD, (ρ=–0.5, p=0.04). Two SCA patients were prescribed 8-12 weeks of L-glutamine supplementation, and their WB glutamine increased compared to their first scan. Conclusion: Patients with SCA have reduced cerebral glutamine, likely due to increased energy expenditure from inflammation and erythropoiesis, leading to insufficient amino acid substrates for neural processing. Glutamine is a precursor for glutamate, GABA, and glutathione, the major antioxidant counteracting oxidative stress. The relative reduction of glutamine in the white matter may align with the propensity for silent infarcts occurring in the deep white matter. We are enrolling a larger cohort to investigate the role of L-glutamine supplementation to prevent stroke and cognitive impairment in SCA.

Stroke is less common in children than in adults, yet equally devastating. Nevertheless, children with symptoms of acute stroke commonly present to community hospitals or adult stroke centers where experience and institutional protocols for pediatric stroke diagnosis and management may be limited. Despite advances in pediatric stroke awareness and the implementation of stroke pathways in many children's hospitals, significant gaps remain in the timely recognition, diagnosis, and management of pediatric stroke. A key contributing factor is the lack of system-level infrastructure to guide pediatric acute stroke care. This special report examines the challenges and barriers to achieving Pediatric Stroke Readiness at a national level in the United States and presents 5 engagement case studies highlighting efforts to establish processes and networks for pediatric stroke management across diverse care settings. The cases emphasize the development and implementation of systems of care in which pediatric stroke centers collaborate with first responders, community hospitals, and adult stroke centers to improve the delivery of acute stroke care for children. The strategies underscore different engagement approaches and identify opportunities for future research and quality improvement. These case studies also illustrate educational materials and clinical pathways that may serve as resources for others pursuing similar initiatives.

ABSTRACT:DeepBrainNet, a machine learning tool, uses magnetic resonance imaging (MRI) to predict an individual's brain age, allowing calculation of the brain age gap (predicted chronological age) for use as a biomarker of brain health. We tested the DeepBrainNet tool in sickle cell anemia (SCA) on 210 brain MRIs from 130 children (90 with SCA; 40 healthy controls) to investigate the hypothesis that children with SCA would have a younger predicted brain age than healthy controls as an index of aberrant brain development. DeepBrainNet estimates brain age from 80 axial slices of each brain, with the median used as global brain age. Global brain age gap was not different between patients with SCA and controls (P = .956). However, the estimated difference in regional brain age gap between SCA without stroke and controls was -1.26 (95% confidence interval, -2.34 to -0.19; P = .021) years after adjusting for chronological age, indicating regionally reduced brain age in SCA. The DeepBrainNet model architecture was modified to create a SCA classifier that distinguished axial brain slices from controls vs SCA without stroke history (accuracy, 0.69; area under the curve, 0.7). We conclude that there is a regional decrease in brain age in children with SCA without stroke compared with controls, suggesting altered brain development. Furthermore, DeepBrainNet can be used to train a classifier to accurately classify the presence of SCA in children without infarcts with only the input of clinically available MRI sequences. These data highlight that machine learning tools could potentially be used to improve upon risk prediction algorithms and assessment of treatment effect with further development.

OBJECTIVES:We evaluate the association between pre-extracorporeal membrane oxygenation (ECMO) markers of impaired oxygen delivery, as quantified by the impaired oxygen delivery index (iD o2 ; Etiometry, Boston, MA) and neurologic outcomes in infants supported on ECMO. DESIGN:A single-center retrospective cohort study using demographic and clinical data along with iD o2 metrics calculated at 120-minute intervals before ECMO initiation. Primary outcomes included mortality, electroencephalography abnormalities, and head imaging findings. The secondary outcomes included brain MRI abnormalities and Functional Status Score (FSS) at discharge. SETTING:Pediatric ECMO center in North America. PATIENTS:We included infants younger than 1 year old who were supported on ECMO between 2013 and 2017. We excluded cases with congenital diaphragmatic hernia or postcardiac surgery ECMO. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We identified 47 infants meeting the inclusion criteria. Median (interquartile range [IQR]) age and weight at ECMO initiation were 16 days (IQR, 6-112 d) and 3.3 kg (IQR, 2.8-4.8 kg). The overall mortality was 26 of 47 (55% [95% CI, 41-69%]). Nonsurvival compared with survival was associated with a greater proportion of patients with congenital heart disease ( p = 0.03) and pre-ECMO cardiac arrest ( p = 0.006). Time spent above iD o2 thresholds of 25%, 50%, and 75% increased closer to ECMO initiation. Higher iD o2 dose correlated with adverse neurologic outcomes, including electroencephalography abnormalities and abnormal imaging. Last, a logistic regression model for poor outcome (composite of death and FSS), including the time spent above the three iD o2 thresholds at the three time intervals pre-ECMO, showed classification model performance with an area under the receiver operating characteristic curve 0.81 (95% CI, 0.7-0.92; p = 0.0002). CONCLUSIONS:Markers of impaired oxygen delivery, such as iD o2 in the 6 hours before ECMO are associated with subsequent outcome. Incorporation of these metrics into clinical decision-support systems need to be prospectively tested and evaluated.

Abstract Background Recent AHA guidelines recommend the use of IV Tenecteplase (TNK) in adult stroke patients, but there is minimal safety and dosing data on TNK in pediatric patients. We performed a safety surveillance study aiming to evaluate risk of symptomatic intracranial hemorrhage (ICH) in children who received TNK for suspected acute ischemic stroke (AIS). Methods This was a prospective observational cohort surveillance study analyzing responses from a monthly email survey sent to members of two large international pediatric stroke and neurocritical care research consortia querying recent use of TNK in children. Limited demographic, clinical, and outcome data were collected. A Bayesian beta-binomial model for risk of symptomatic ICH with IV TNK was fit using a prior distribution based on the risk level in adults. Results Between February 2023-June 2026, 44 children received TNK for suspected AIS. Most patients (n=37, 84.1%) were adolescents; no children under 5 received TNK. Twelve patients (27.3%) were ultimately diagnosed with a stroke mimic. Symptomatic ICH was not reported in any children who received IV TNK; 3 had asymptomatic ICH on follow-up imaging. One patient received intra-arterial TNK and experienced symptomatic ICH. No other major bleeding events were reported. Conclusions IV TNK is being administered to pediatric patients with suspected stroke in clinical practice, and may be safe in older children with AIS. Rigorous prospective studies are needed to better assess risk and outcomes in this unique population.

Extracorporeal membrane oxygenation (ECMO) provides life support for severe, reversible cardiac or respiratory failure but carries substantial risk of neurological complications. Pediatric ECMO patients are particularly vulnerable, with over half of survivors exhibiting abnormal neuroimaging findings following discharge. Currently available clinical neuroimaging tools are limited, offering either static anatomical snapshots (ultrasound, computed tomography) or sparse functional monitoring (electroencephalography, functional near infrared spectroscopy) with limited spatial specificity. High-density diffuse optical tomography (HD-DOT) addresses these limitations to provide noninvasive, longitudinal, wide-field measurements of changes in cortical oxygenation at the beside. Here, we investigate safety and feasibility for bedside longitudinal HD-DOT monitoring of cerebral oxygenation focusing on data collected over 20 days in seven pediatric ECMO patients. Results confirm the reliable acquisition of high-quality HD-DOT data without adverse events, establishing HD-DOT as a promising tool for continuous, and safe bedside neuroimaging in this population. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by funding from the Childrens Discovery Institute at St. Louis Childrens Hospital (CDI-II-2021-953-2) and the American Heart Association (AHA 25PRE1194156 AHA 25CSA1421325) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Human Research Protections Office Institutional Review Board of Washington University School of Medicine gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

RATIONALE: Increased respiratory drive to eliminate carbon dioxide (CO2) manifests as elevated tidal volume (Vt), respiratory rate (RR), and minute ventilation (V̇). The sequence and magnitude of this response remains poorly characterized in children. We investigated differences in RR and Vt responses to rapid versus slow CO₂ challenges in healthy children and young adults (8.4-19.3 years old) as part of a study evaluating cerebral vascular reactivity to CO2. METHODS: Baseline demographics were collected. The RespirActⓇ device delivered controlled partial pressures of inhaled O2 and CO2 while continuously monitoring the RR (breaths per minute, BPM) and Vt per breath. Participants underwent two separate CO2 challenges: a rapid increase in inhaled CO₂ to +8 mmHg, maintained for 60 seconds (the “Step” challenge), and then a gradual 150-second linear increase in CO₂ to +10 mmHg (the “Ramp” challenge), each followed by a return to baseline (Figure 1a). We evaluated the relative changes in RR and Vt from the average of the last three breaths of each challenge. Subjects were split into two groups (A<13yr; B≥13yr), to approximate pre- and post-puberty. Data were processed using a vendor-provided algorithm, manually reviewed to exclude outliers, and statistically analyzed with a Kruskal-Wallis test using Python libraries. RESULTS: For the whole cohort (n=26), which was 65% female, the median age was 14.4 years (IQR 11.9-15.5) and the median BMI was 21.33 (IQR 17.17-26.31). Comparing ‘Step’ vs ‘Ramp’ across the entire cohort, the median RR increased 9.3% (IQR 2.5-29.3%) vs 10.8% (IQR -1.4-17.5%) (p = 0.70), and Vt increased 42.7% (IQR 33.2-67.5%) vs 66.8% (IQR 50.0-102.5%) (p=0.004). In the ‘Step’ challenge, RR increased by 27.3% (IQR 8.2-34.7%) in group A and 8.9% (IQR -0.3-14.4%) in group B (p = 0.13), while Vt increased by 48.0% (IQR 27.8-62.5%) in A and 41.3% (IQR 34.7-67.5%) in B (p = 0.78). During the ‘Ramp’, RR increased by 21.0% (IQR 8.3-47.0%) in group A and 8.3% (IQR -9.8-15.4%) in B (p = 0.07), and Vt increased by 59.8% (IQR 49.9-76.5%) in A and 79.3% (IQR 50.8-105.7%) in B (p = 0.32) (Example subjects seen in Figures 1b and 1c). CONCLUSIONS: Vt responses differed significantly between rapid and slow CO₂ challenges, whereas RR responses did not. Although not statistically significant, children below the age of 13 demonstrated higher increases in RR compared to the older group. These findings together suggest that Vt changes differentially to rapidity of CO2 challenge while RR responses are age dependent.

Introduction: Previous single-center studies have found a higher prevalence of mental health disorders in parents of children with pediatric stroke compared to general population prevalences of 5% with depression and 6% with anxiety. Social determinants of health may influence mental health outcomes. We aimed to measure associations between social determinants of health and parental report of mental health symptoms following their child’s diagnosis of ischemic stroke. Methods: We performed a multicenter, international prospective study through the International Pediatric Stroke Study (IPSS). From 2016 to 2021, parents of children within 3.5 years after arterial ischemic stroke enrolled and completed validated and standardized surveys on anxiety (Beck’s Anxiety Inventory II), depression (Beck’s Depression Inventory), post-traumatic stress disorder (PTSD) (Post-Traumatic Stress Disorder Checklist for DSM-5), severity of their child’s stroke deficits (Recovery and Recurrence Questionnaire), and social determinants of health. For our statistical analysis we employed a linear mixed-effects model, both unadjusted and adjusted. Results: Fifty-two parents (13 fathers, 39 mothers) of 39 children enrolled. Of the 39 children 21 (54%) had perinatal stroke and 18 (46%) had childhood stroke. Median time from stroke diagnosis to parental survey completion was 1.3 years (interquartile range [IQR] 1.0-2.0). On parental surveys, parents scored in the clinical range for: depression in 35% of mothers and 23% of fathers; anxiety in 2% of mothers and 0% of fathers; PTSD in 26% of mothers and 8% of fathers. Lower parental education was significantly associated with higher levels of depression both in our unadjusted (0.02) and adjusted (0.03) models. Interestingly, the child’s functional outcome and parental income were not significantly associated with any parental mental health outcomes. Conclusion: Among social determinants of health, parental education level may be associated with depression in parents of children with pediatric arterial ischemic stroke and needs further exploration. Parents of children with pediatric arterial ischemic stroke had higher rates of depression and PTSD compared to general population estimates. Further research in this area will help facilitate understanding and development of interventions to prevent these mental health outcomes.

ImportanceBoth sickle cell anemia (SCA) and socioeconomic status have been associated with altered brain structure and cognitive disability, yet precise mechanisms underlying these associations are unclear.ObjectiveTo determine whether brains of individuals with and without SCA appear older than chronological age and if brain age modeling using brain age gap (BAG) can estimate cognitive outcomes and mediate the association of socioeconomic status and disease with these outcomes.Design, Setting, and ParticipantsIn this cross-sectional study of 230 adults with and without SCA, individuals underwent brain magnetic resonance imaging (MRI) and cognitive assessment. Brain age was estimated using DeepBrainNet, a model trained to estimate chronological age from 14 468 structural MRIs from healthy individuals across the lifespan. BAG was defined as estimated brain age minus chronological age. Linear regression examined clinical factors associated with BAG and the ability of BAG to estimate cognitive performance compared to neuroimaging metrics of brain health and ischemic brain injury, such as normalized whole brain volume, white matter mean diffusivity (MD), and infarct volume. BAG and white matter MD were tested further as mediators of the association of socioeconomic status and SCA with cognitive performance. Data were analyzed from October 15, 2023, to July 1, 2024.ExposuresSCA disease status and economic deprivation as measured using the area deprivation index (ADI).Main Outcome and MeasuresExecutive function, crystallized function, processing speed, and full-scale intelligence quotient (FSIQ) were derived from the National Institutes of Health (NIH) Toolbox and Wechsler Abbreviated Scale of Intelligence, Second Edition.ResultsAmong 230 included adults, 123 individuals had SCA (median [IQR] age, 26.4 [21.8-34.3] years; 77 female [63%]) and 107 individuals did not (control cohort; median [IQR] age, 30.1 [26.3-34.8] years; 77 female [72%]). Participants with SCA had a larger median (IQR) BAG compared to individuals in the control cohort (14.2 [8.0-19.2] vs 7.3 [3.2-11.1] years; median difference, 6.13 years; 95% CI, 4.29-8.05 years; P < .001). Individuals in the control cohort demonstrated a larger BAG relative to the reference population (mean difference, 7.52 years; 95% CI, 6.32-8.72 years; P < .001). Higher economic deprivation was associated with BAG in the control cohort (β [SE] per 1% ADI increase, 0.079 [0.028]; 95% CI, 0.023 to 0.135; P = .006), while intracranial vasculopathy (β [SE], 6.562 [1.883]; 95% CI, 2.828 to 10.296; P < .001) and hemoglobin S percentage (β [SE] per 1% increase, 0.089 [0.032]; 95% CI, 0.026 to 0.151; P = .006) were associated with BAG in participants with SCA. Across neuroimaging metrics of brain health, BAG demonstrated the largest effect size for cognitive outcomes in the control cohort (eg, executive function: r = −0.430; P = .001), while white matter MD demonstrated the largest effect size for cognitive outcomes (eg, executive function: r = −0.365; P = .001) in the SCA cohort. Across the study population, BAG mediated the association of ADI with cognitive performance (eg, executive function: β [SE] per 1-unit decrease in ADI, −0.031 [0.014]; 95% CI, −0.061 to −0.006), while BAG (eg, FSIQ: β [SE], −3.79 [1.42]; 95% CI, −6.87 to −1.40) and white matter MD (eg, FSIQ: β [SE], −4.55 [1.82]; 95% CI, −8.14 to −0.94) mediated the association of SCA with cognitive performance.Conclusions and RelevanceAdults with SCA and a healthy control cohort with greater economic deprivation demonstrated older brain age, suggestive of insufficient brain development, premature brain aging, or both. Brain estimates of chronological age may inform mechanisms of the association between chronic disease and socioeconomic status with cognitive outcomes in healthy and SCA populations, yet will require confirmation in larger and longitudinal studies.

Purpose:Cerebral blood flow (CBF) is commonly measured by pseudo-continuous arterial spin labeling (PCASL) in human research, but recent advancements in methodology have limited data reuse. The object of this work is to harmonize two distinct PCASL techniques within a cohort with a wide range of CBF values. Methods:Participants had two PCASL sequences collected within a single session: a single post-label delay sequence with a 2D echo-planar imaging (EPI) readout, " CBF 2 D , 1 PLD ", and a five post-label delay sequence with gradient and spin echo (GRASE) 3D readout, " CBF 3 D , 5 PLD ". Linear regression modeling to impute CBF 3 D , 5 PLD from CBF 2 D , 1 PLD , hemoglobin, and age were assessed within gray matter (GM) and white matter (WM) using leave-one-out cross-validation for prediction errors and confidence intervals. Within-subject coefficient of variation (wsCV) and inter-class correlation coefficient (ICC) were calculated using CBF 3 D , 5 PLD imputed vs. measured as pseudo test-retest pairs. Results:Fifty participants, ages 8-45 (median 25) years, had usable CBF 3 D , 5 PLD and CBF 2 D , 1 PLD , including 17 participants with sickle cell disease (SCD), who were matched by age ( p = 0.90 ) and sex ( p = 0.16 ) to those without SCD. A multiple linear regression model including hemoglobin and age fit GM CBF ( R 2 adj. = 0.82 ; for WM CBF R 2 adj. = 0.78 ). The wsCV for CBF 3 D , 5 PLD was 9.1% for GM, 11.3% for WM. ICC was 0.89 for GM and 0.87 for WM. Models without age or hemoglobin fit slightly worse. Conclusion:Our study demonstrates feasibility to impute 3D-GRASE multi-PLD CBF from a 2D-EPI single-PLD technique, which promotes data sharing and harmonization.