ALBERT

Description: Introduction: Sickle cell disease (SCD) is the leading cause of overt stroke in children, resulting in increased morbidity and mortality (Prengler et al. 2002). Neurologic injury in SCD is caused by a cascade of complex physiological processes that may manifest as abnormal cerebral blood flow (CBF), abnormal oxygen extraction fraction (OEF), and ultimately lead to oxygen deprivation of the brain tissue (Adams et al. 2007., Cheung et al. 2002), however, the underlying pathophysiology is not well understood. While much research has focused on the role of vasculopathy in neurologic injury in SCD, over one third of children with sickle cell disease who suffer an overt ischemic event do not present with arterial stenosis (Hulbert et al. 2011). Extending the work of Nur et al. (2009), we have recently shown in children without stenosis in SCD that elevated cerebral blood flow and diminished cerebrovascular reserve is associated with the severity of anemia (Kosinski et al. 2015). However, to date, little is known about the relative contributions of non-vasculopathic hemodynamic compromise that may occur in children with SCD. Therefore, a comprehensive model of pathophysiology in this population will help stratify stroke risk and guide therapeutic strategies. Aim: To noninvasively quantify both CBF and OEF in children with SCD using magnetic resonance imaging. Methods: 11 patients (7M/4F; age 14 ± 2.7 years (mean ± SD)) with SCD and no history of stroke nor arterial stenosis were imaged on a 3T MRI system. 9 patients were on hydroxyurea (average dose: 19.7 ± 3 mg/kg/day). Hematological parameters were acquired at a clinic visit no more than one month prior to the MRI scan (Table 1). Pulsed arterial spin labelling MRI was used to noninvasively assess grey matter cerebral blood flow according to a standard kinetic model. A T2*-weighted flow-compensated image provided phase information, with the phase signal difference between the sagittal sinus and surrounding tissue used to quantify venous oxygenation (SvO2) (Driver et al. 2014). Arterial oxygen saturation (SaO2) was measured via peripheral pulse oximetry and OEF was determined by (SaO2 - SvO2/SaO2) according to Fick's principle of arteriovenous difference. Results: A significant positive association was observed between CBF and OEF (p = 0.82, p = 0.02, pearson product moment correlation coefficient), as shown in Figure 1. Mean values (± SD) were 0.75 ± 0.08, 0.23 ± 0.08 and 54.1 ± 11 ml/min/100g for SvO2, OEF and CBF respectively. Discussion: The observed correlation between CBF and OEF suggests that children with SCD who do not present with vasculopathy, utilize both the perfusion and metabolic reserve in order to meet the cerebral demand for O2. This allows CBF and OEF to increase simultaneously rather than sequentially as proposed by Powers et al. (1991). This non-sequential hemodynamic compromise is in agreement with previous literature in cerebrovascular disease (Kanno et al. 1988) and may serve to minimise increases in cardiac output (Varat et al. 1972). This data suggests that elevated OEF may serve as an early risk marker for overt stroke in addition to elevated blood flow velocity and thus may help better screen for those who will most benefit from transfusion therapy. Table 1. SCD Patients Sample Size (N) 11 Gender (M/F) 7/4 Age (y) 13.7 ± 2.7 BMI (Kg/m2) 18.8 ± 3.0 Hematocrit 0.282 ± 0.03 Hemoglobin (g/L) 100 ± 10.3 SaO2 0.99 ± 0.02 SvO2 0.75 ± 0.08 Absolute Reticulocyte (K/uL) 205 ± 72 Neutrophil Count (K/uL) 5.3 ± 3.7 Clinical parameters acquired within 30 days of the MRI session Figure 1. A significant positive association was observed between grey matter cerebral blood flow and oxygen extraction fraction (r = 0.76, p = 0.002) in children with sickle cell disease Figure 1. A significant positive association was observed between grey matter cerebral blood flow and oxygen extraction fraction (r = 0.76, p = 0.002) in children with sickle cell disease Disclosures No relevant conflicts of interest to declare.

Description: Introduction: The pathophysiology of overt stroke in children with sickle cell anemia (SCA) is not well understood. However, a compromised cerebral hemodynamic environment, marked by elevated cerebral blood flow (CBF) and impaired cerebrovascular reserve are thought to play a critical role. Currently, stroke prevention is based on chronic transfusion therapy (Tx). However, Tx suffers from several complications including; iron overload, risk of infection, and hyperhemolysis reactions. Hydroxyurea (HU) is a well-tolerated myelosupressive agent, which increases fetal hemoglobin (HbF) and is being tested as an alternative to Tx for primary stroke prevention in children with SCA. However, it is currently not clear how either Tx or HU treatment compare with respect to their effects on the precarious hemodynamic environment in children with SCA. Therefore, we assessed cerebrovascular reserve by obtaining MR-based measures of cerebrovascular reactivity (CVR), defined as the change in blood flow in response to a vasoactive stimulus. Considering that HU and Tx both act to dilute HbS and increase oxygen carrying capacity, we hypothesized that SCA children treated with HU and Tx will exhibit increased CVR and decreased CBF compared to age-matched, non-treated, SCA children. Methods: 21 SCA (HbSS) untreated SCA children (5M/16F; avg age 14.1 ± 2.42), 16 SCA children treated with HU (10M/6F; avg age 14.0 ± 2.49) and 7 patients on Tx (3M/4F ; avg age 13.0 ± 1.81) were recruited from the Haematology Department at The Hospital for Sick Children. Exclusion criteria were; history of overt stroke, vasoocclusive crises, and febrile illness within 30 days of the scan. CVR was obtained using a blood-oxygen level-dependent (BOLD) MRI sequence in combination with a CO2 breathing challenge. CO2 was administered via a re-breathing mask in 4 alternating cycles of 40 mmHg PETCO2 for 60 seconds and 45 mmHg PETCO2 for 45 seconds. BOLD MRI signal changes were aligned and regressed against the CO2 waveform on a voxel-wise bases using FSLv4.1 to yield the raw CVR maps. The CVR maps were then co-registered to anatomical images. CBF measurements were obtained using a pulsed arterial spin labeling (pASL) sequence and were quantified from the mean signal difference between the ASL tag and control images using a single compartment kinetic model. The Student's t-test was used to test for significant differences between CVR, CBF, and blood parameters between the HU, Tx, and No Treatment groups. Blood parameters were obtained from complete blood counts. Results: Blood parameters are shown in Table 1.HU-treated SCA children exhibited significantly higher Hct and CVR in both the gray and white matter compared to the No Treatment group, with no significant differences in CBF. The Tx-treated SCA group exhibited higher Hct, CVR in the gray matter, and decreased CBF in both the grey and white matter compared to the No Treatment group (see Figure 1). Conclusions: Both the HU and Tx-treated SCA groups demonstrated significantly improved cerebrovascular reserve compared to the No Treatment group. The increase vascular reserve may be a result of HU and Tx decreasing the severity of anemia thereby reducing the baseline vessel tone necessary to sufficiently perfuse the cerebral tissue. CBF was significantly reduced in the Tx-treated group compared to the No Treatment group, which may be due to the higher oxygen content provided by Tx. Interestingly, CBF was not significantly different between the HU-treated and No Treatment group despite the HU-treated group having significantly greater hematocrit. This was surprising as a previous study using Doppler ultrasound (TCD) demonstrated that HU significantly reduces blood velocities (TCDv). However, unlike TCDv which are velocity measurements obtained at the large feeding arteries, pASL CBF values reflect perfusion at the tissue level. Further studies are required to fully compare TCDv and pASL measures of CBF as a means to monitor treatment effects in SCA patients. Table 1. SCA: No Treatment SCA: Hydroxyurea SCA: Transfusion Sample Size (N) 21 16 7 Gender (M/F) 5/16 10/6* 3/4 Age (mean ± SD) 14.1 ± 2.42 14.0 ± 2.49 13.0 ±1.81 Hematocrit 0.253 ± 0.037 0.289 ± 0.034* 0.308 ± 0.034¥ Hemoglobin (g/L) 86.4 ± 10.9 101 ± 12.1* 105 ± 11.2¥ Hemoglobin F (%) - 15.8 ± 8.07 3.01 ± 32.2 Reticulocyte (%) 9.4 ± 6.1 7.2 ± 3.6 - MCV (fL) 80.3 ± 10.8 94.9 ± 12.3* - SaO2 0.97 ± 0.03 0.99 ± 0.01 - Neutrophils (K/uL) 6.1 ± 3.1 4.2 ± 1.6* - Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Sickle Cell Disease (SCD) is an inherited blood disorder, afflicting 1 in 400 African Americans, clinically characterized by hemolytic anemia, painful vaso-occlusive crises and endothelial dysfunction resulting in chronic organ damage.1 Hydroxyurea (HU) is a myelosuppressive agent that has been shown to reduce the number of vaso-occlusive crises, acute chest syndromes, blood transfusions and hospital admissions and is currently being investigated as an alternative to transfusion therapy for primary stroke prevention.2,3 HU's protective properties are primarily thought to be a result of its ability to increase HbF levels, which reduces sickle hemoglobin polymerization.4 However, HU requires a minimum of 3-6 months for sufficient HbF induction and previous studies have shown improved clinical performance well before a detectable rise in HbF.3,4 The HbF-independent clinical improvement is hypothesized to be a result of HU acting as a nitric oxide (NO) donor, a potent vasodilator, whose bioavailability is reduced in SCD.5,6 Reduced NO has a direct effect on the dilation of cerebral vessels, which warrants investigation into the impact of HU treatment length on cerebral hemodynamics. To assess cerebral hemodynamics we obtained dynamic MR measurements of cerebrovascular reactivity (CVR), which reflect the capacity of vascular endothelia to dilate in the presence of a vasoactive stimulus. In addition, we also obtained CBF data using arterial-spin labelling (ASL) to assess its relationship to CVR. We hypothesized that CVR will be higher in long-term HU-treated patients compared to short-term HU-treated patients. Furthermore, we hypothesized that CBF will be inversely correlated with CVR and will be lower in patients on long-term HU compared to short-term HU-treated patients. Methods: 21 Patients (11M/10F; avg age 14±2.45) with no history of stroke, were imaged on a 3T MRI system. 15 patients were on HU for more than 1 year (long-term) and 6 were on HU less than 5 months (short-term). The hematocrit of both groups was similar. CVR data of the entire brain was obtained using a standard blood-oxygen-level-dependent (BOLD) MRI sequence in combination with a CO2 breathing challenge. CO2 was delivered via a re-breathing mask in 4 alternating cycles of 40 mmHg PETCO2 for 60 seconds and 45mmHg PETCO2 for 45 seconds. Correlations of voxel-based BOLD changes to end-tidal CO2 waveforms were analyzed using FSL v4.1 and yielded CVR maps that were co-registered to anatomical images. CBF was obtained with a standard pulsed ASL protocol and was quantified from the mean signal difference between ASL tag and control images using a kinetic model. The Student's t-test was used to assess whether the mean global CVR and CBF were significantly different (p

Description: The Pacific Islander population in the U.S. continues to grow, with the Portland-Salem, Oregon area serving as one of the largest communities, notably among those from the Micronesian region. Migrants emigrate for a variety of reasons including educational and employment opportunities, improved healthcare, and assisting family members. The purpose of this study is to better understand the transition of Micronesians – specifically Chuukese, Marshallese, and Palauans – to Oregon and to identify factors that help or hinder that transition. The study utilizes a Migration with Dignity framework, assessing reasons for emigration to the U.S., experienced quality of life, especially livelihoods, potential reasons for (not) returning to one’s home country, and barriers and facilitating factors for an improved quality of life in Oregon.