Reversibility of Cognitive Deficits and Functional Connectivity With Transfusion in Children With Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: People with sickle cell disease (SCD) are at risk of cognitive dysfunction independent of stroke. Diminished functional connectivity in select large-scale networks and white matter integrity reflect the neurologic consequences of SCD. Because chronic transfusion therapy is neuroprotective in preventing stroke and strengthening executive function abilities in people with SCD, we hypothesized that red blood cell (RBC) transfusion facilitates the acute reversal of disruptions in functional connectivity while white matter integrity remains unaffected. METHODS: Children with SCD receiving chronic transfusion therapy underwent a brain MRI measuring white matter integrity with diffusion tensor imaging and resting-state functional connectivity within 3 days before and after transfusion of RBCs. Cognitive assessments with the NIH Toolbox were acquired after transfusion and then immediately before the following transfusion cycle. RESULTS: Sixteen children with a median age of 12.5 years were included. Global assessments of functional connectivity using homotopy (p = 0.234) or modularity (p = 0.796) did not differ with transfusion. Functional connectivity within the frontoparietal network significantly strengthened after transfusion (median intranetwork Z-score 0.21 [0.17-0.30] before transfusion, 0.29 [0.20-0.36] after transfusion, p < 0.001), while there was not a significant change seen within the sensory motor, visual, auditory, default mode, dorsal attention, or cingulo-opercular networks. Corresponding to the change within the frontoparietal network, there was a significant improvement in executive function abilities after transfusion (median executive function composite score 87.7 [81.3-90.7] before transfusion, 90.3 [84.3-93.7] after transfusion, p = 0.021). Participants with stronger connectivity in the frontoparietal network before transfusion had a significantly greater improvement in the executive function composite score with transfusion (r = 0.565, 95% CI 0.020-0.851, p = 0.044). While functional connectivity and executive abilities strengthened with transfusion, there was not a significant change in white matter integrity as assessed by fractional anisotropy and mean diffusivity within 16 white matter tracts or globally with tract-based spatial statistics. DISCUSSION: Strengthening of functional connectivity with concomitant improvement in executive function abilities with transfusion suggests that functional connectivity MRI could be used as a biomarker for acutely reversible neurocognitive injury as novel therapeutics are developed for people with SCD.

Comparison of cerebral oxygen extraction fraction using ASE and TRUST methods in patients with sickle cell disease and healthy controls.

Abnormal oxygen extraction fraction (OEF), a putative biomarker of cerebral metabolic stress, may indicate compromised oxygen delivery and ischemic vulnerability in patients with sickle cell disease (SCD). Elevated OEF was observed at the tissue level across the brain using an asymmetric spin echo (ASE) MR method, while variable global OEFs were found from the superior sagittal sinus (SSS) using a T2-relaxation-under-spin-tagging (TRUST) MRI method with different calibration models. In this study, we aimed to compare the average ASE-OEF in the SSS drainage territory and TRUST-OEF in the SSS from the same SCD patients and healthy controls. 74 participants (SCD: N = 49; controls: N = 25) underwent brain MRI. TRUST-OEF was quantified using the Lu-bovine, Bush-HbA and Li-Bush-HbS models. ASE-OEF and TRUST-OEF were significantly associated in healthy controls after controlling for hematocrit using the Lu-bovine or the Bush-HbA model. However, no association was found between ASE-OEF and TRUST-OEF in patients with SCD using either the Bush-HbA or the Li-Bush-HbS model. Plausible explanations include a discordance between spatially volume-averaged oxygenation brain tissue and flow-weighted volume-averaged oxygenation in SSS or sub-optimal calibration in SCD. Further work is needed to refine and validate non-invasive MR OEF measurements in SCD.

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.

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.

The Development of Neuroimaging Biomarkers for Cognitive Decline in Sickle Cell Disease.

Sickle cell disease (SCD) is complicated by neurologic complications including vasculopathy, hemorrhagic or ischemic overt stroke, silent cerebral infarcts and cognitive dysfunction. Patients with SCD, even in the absence of vasculopathy or stroke, have experience cognitive dysfunction that progresses with age. Transcranial Doppler ultrasound and structural brain MRI are currently used for primary and secondary stroke prevention, but laboratory or imaging biomarkers do not currently exist that are specific to the risk of cognitive dysfunction in patients with SCD. Recent investigations have used advanced MR sequences assessing cerebral hemodynamics, white matter microstructure and functional connectivity to better understand the pathophysiology of cognitive decline in SCD, with the long-term goal of developing neuroimaging biomarkers to be used in risk prediction algorithms and to assess the efficacy of treatment options for patients with SCD.

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.

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.

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.

Neurologic and Cognitive Outcomes in Sickle Cell Disease from Infancy through Adolescence.

Children with sickle cell disease (SCD) are at risk for neurologic and cognitive complications beginning in early childhood. Current treatment for SCD focuses on primary prevention of complications, such as hydroxyurea for prevention of pain and acute chest syndrome, and chronic transfusion therapy for children who are at high risk for strokes. In this article, the prevalence, pathophysiology, and available interventions to prevent and treat neurologic and cognitive complications of SCD will be reviewed.

Cerebral Oxygen Metabolic Stress, Microstructural Injury, and Infarction in Adults With Sickle Cell Disease.

OBJECTIVE: To determine the patient- and tissue-based relationships between cerebral hemodynamic and oxygen metabolic stress, microstructural injury, and infarct location in adults with sickle cell disease (SCD). METHODS: Control participants and patients with SCD underwent brain MRI to quantify cerebral blood flow (CBF), oxygen extraction fraction (OEF), mean diffusivity (MD), and fractional anisotropy (FA) within normal-appearing white matter (NAWM) and infarcts on fluid-attenuated inversion recovery. Multivariable linear regression examined the patient- and voxel-based associations between hemodynamic and metabolic stress (defined as elevated CBF and OEF, respectively), white matter microstructure, and infarct location. RESULTS: Of 83 control participants and patients with SCD, adults with SCD demonstrated increased CBF (50.9 vs 38.8 mL/min/100 g, p < 0.001), increased OEF (0.35 vs 0.25, p < 0.001), increased MD (0.76 vs 0.72 × 10-3 mm2s-1, p = 0.005), and decreased FA (0.40 vs 0.42, p = 0.021) within NAWM compared to controls. In multivariable analysis, increased OEF (ß = 0.19, p = 0.035), but not CBF (ß = 0.00, p = 0.340), independently predicted increased MD in the SCD cohort; neither were predictors in controls. On voxel-wise regression, the SCD cohort demonstrated widespread OEF elevation, encompassing deep white matter regions of elevated MD and reduced FA, which spatially extended beyond high-density infarct locations from the SCD cohort. CONCLUSION: Elevated OEF, a putative index of cerebral oxygen metabolic stress, may provide a metric of ischemic vulnerability that could enable individualization of therapeutic strategies in SCD. The patient- and tissue-based relationships between elevated OEF, elevated MD, and cerebral infarcts suggest that oxygen metabolic stress may underlie microstructural injury prior to the development of cerebral infarcts in SCD.

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.

Higher executive abilities following a blood transfusion in children and young adults with sickle cell disease.

Individuals with sickle cell disease (SCD) experience cognitive deficits; however, it remains unclear whether medical treatments for SCD improve cognition. Given that executive abilities are typically impaired in individuals with SCD, they were the focus of the current study. Our primary hypothesis was that executive abilities would be higher acutely soon after a blood transfusion in children and young adults with SCD. We used tests from the NIH Toolbox to assess executive abilities in 27 participants with SCD receiving chronic transfusion in comparison to 34 participants with SCD receiving hydroxyurea (HU) and 41 non-SCD demographically matched controls, all of whom were tested at two time points. Participants in the transfusion group completed cognitive testing within 3 days after a transfusion (soon after transfusion) and then within 3 days before their next transfusion (long after transfusion) over an interval of 3-7 weeks. We found that executive abilities were significantly poorer for the transfusion and HU groups than for the control group. In support of our primary hypothesis, executive abilities for the transfusion group were significantly better soon after a transfusion compared to long after a transfusion, χ2 (1) = 17.8, P < .0001. Our results demonstrate that executive abilities were higher acutely following a blood transfusion. These findings have implications for daily functioning, medical decision making, and academic achievement in children and young adults with SCD.

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.