Search

Introduction Sickle cell disease (SCD) is associated with silent cerebral infarcts (SCI) which are related to neurocognitive damage. One of the major causes of SCI is the impaired cerebral oxygenation, which makes cerebral blood flow (CBF) an essential parameter to measure. Previous hemodynamic studies have shown elevated CBF and reduced cerebrovascular reserve (CVR) in patients with SCD (Helton 2015; Václavů 2018). CVR is known as the increase of CBF in response to vasoactive stimulus, relative to the baseline. The reduced CVR renders SCD patients susceptible to cerebral ischemia, especially under hypotensive or hypoxic conditions. Possible factors contributing to microvascular damage and thus reduced CVR include hemoglobin S polymerization, neutrophil activation and endothelial activation and adhesion. Previous studies examined the role of these factors in patients with SCD (Sins 2017; Al Najjar 2017). However, the association between the endothelial biomarkers and hemodynamic parameters is unknown in adult patients with SCD. In this study, we investigated the correlation between CBF and CVR and the adhesion molecules including sVCAM-1, sP-selectin, VWF-Ag and ADAMTS13. Additionally, we studied the association of these endothelial biomarkers with standard laboratory parameters. Methods This study was performed in accordance with the Declaration of Helsinki and was approved by the Review Board of Amsterdam UMC. For this study, 33 steady state patients with SCD (mean age 32.1 ± 10.7, 64% male, 29 HbSS, 4 HbSß) and 10 healthy volunteers (mean age 36,4 ± 15.9, 60% male, 2 HbAS, 8 HbAA) were included. Hematologic laboratory parameters were assessed using standard laboratory procedures. Plasma levels of sVCAM-1 and sP-selectin were determined using ELISA (R&D Systems, USA) and ADAMTS13 and VWF-Ag were measured with the INNOVANCE assay (Siemens Healthcare Diagnostics). For the CBF measurements, pseudo-continuous arterial spin labelling (pCASL) was acquired at 3T MRI (Philips Healthcare, The Netherlands). CBF was measured before and after acetazolamide (vasoactive stimulus) administration and subsequently CVR was calculated using the following equation: CVR = (CBFafter - CBFbefore) / CBFbefore x 100% Plasma levels of endothelial biomarkers were compared between groups using ANOVA test. Correlation between the parameters were measured using single regression model where p Results sVCAM-1 levels and VWF-Ag were significantly higher in SCD patients compared to healthy controls (p < 0.01 and p = 0.01). ADAMTS13 and sP-selectin were not significantly different between the two groups (p = 0.06 and p = 0.33). sVCAM-1 was significantly associated with CBF, and parameters of hemolysis LDH and bilirubin in SCD patients (Fig. 1A and 2C). Negative correlation was observed between sVCAM-1 and hemoglobin (Fig. 1B). The relationship between sVCAM-1 and hemodynamic and laboratory parameters are shown in Table 1. No significant correlation was found between sVCAM-1, hemodynamic and standard laboratory parameters in healthy controls. VWF-Ag, ADAMTS13 and sP-selectin were not significantly associated with hemodynamic MRI parameters. Discussion Our results show elevated sVCAM-1 levels in sickle cell patients, strongly related to CBF. sVCAM-1 is an adhesion molecule and elevated plasma levels are found in patients with endothelial activation due to inflammation or atherosclerosis (Cook-Mills 2013; Cybulsky 2001). Previous studies showed elevated levels in sickle cell disease but no correlation with parameters of cerebral perfusion have been demonstrated yet (Antwi-Boasiako 2018; Kato 2005). The strong correlation with CBF is mostly related to the chronic hemolysis given the association found with hemoglobin levels and markers of hemolysis like LDH and bilirubin. In contrast to sVCAM-1, no such relation was found with other markers of endothelial activation such as VWF activity and sP-selectin levels. No correlation between endothelial markers and the CVR was demonstrated, suggesting that endothelial damage itself may not related to the impaired cerebral vasodilatation in response to a vasoactive stimulus. Conclusion Endothelial adhesion molecule sVCAM-1 showed a strong correlation with CBF and parameters of hemolysis, suggesting a relation between the hemolytic damage of endothelial cells and impaired cerebral perfusion. Disclosures Nur: Novartis Pharmaceuticals: Consultancy.

Introduction: Cerebral blood flow (CBF) is increased in sickle cell disease (SCD) to compensate for chronic hemolytic anemia. Since the brain is strongly dependent on adequate oxygen levels, severe anemia may result in ischemia and silent cerebral infarctions (SCIs), which are present in the majority of patients with SCD. Besides CBF, the cerebral metabolic rate of oxygen (CMRO2), representing the cerebral oxygen consumption, can be measured using specialized MRI techniques. CMRO2 is dependent on CBF, OEF oxygen extraction fraction (OEF) and the hematocrit in the cerebral circulation. In order to maintain stable CMRO2 the OEF changes to compensate for fluctuations in CBF. Previous studies found either elevated or reduced rather than stable CMRO2 in SCD. To further explore the regulation of cerebral oxygenation in SCD, we measured CMRO2, OEF and CBF using MRI at rest and upon administration of acetazolamide (ACZ), a non-metabolic vasodilator. In addition, we related the CMRO2 to the prevalence and location of SCIs and to laboratory parameters of hemolysis. Methods: Adult SCD patients (HbSS/HbSβ0) without a history of stroke, and healthy age-, sex, and race-matched controls were recruited for this IRB-approved MRI study with ACZ-induced vasodilation and venous blood sampling. MRI images were acquired at 3T (Philips Healthcare, Best, NL). Sequences included 3D FLAIR with 1mm isotropic resolution for lesion evaluation, longitudinal and transverse relaxation times of blood (T1b and T2b) in the cerebral sagittal sinus using a T2 prepared tissue relaxation with inversion recovery sequence (T2-TRIR), and pseudo-continuous arterial spin labeling (ASL) for whole brain CBF measurements. T1b was used to correct ASL-based CBF values. T2b was converted to venous saturation (Yv) using a recently published SCD-specific model, which was calibrated in sickle blood rather than bovine blood. CBF was measured at baseline and 10 min post acetazolamide (ACZ) (16mg/kg intravenous infusion over 3min). Images were co-registered and quantified using the ExploreASL toolbox. CMRO2 was calculated as follows: CMRO2 = CBF * OEF * Ca, where CBF is the whole brain CBF map from ASL, OEF is the arteriovenous oxygen saturation (Y) difference (Ya-Yv/Ya) derived from T2 measurements, and Ca is the oxygen carrying capacity of blood calculated from hematocrit sampled immediately prior to MRI. Blood markers of hemolysis (reticulocyte count and bilirubin) were correlated to MRI hemodynamic markers using bivariate Spearman's rho (ρ). Group comparisons were tested using Student's t-tests. P values Results: As expected, CBF was significantly higher in patients with SCD (69 ± 16 mL/100g/min) compared to healthy controls (42 ± 4 mL/100g/min, P Conclusion: We observed reduced CMRO2 in patients with SCD compared to healthy controls due to low OEF. A reduced CMRO2 could pose a risk for ischemia, despite high flow rate delivering oxygen, because of low OEF. This is supported by the fact that the silent cerebral infarcts are located in regions with the lowest CMRO2. We postulate that patients with SCD have a reduced capacity to increase the OEF in regions with inadequate CBF resulting in local ischemia and local infarction. The pathogenesis of the reduced OEF remains unclear but could be related to arteriovenous shunting whereby there is insufficient time for oxygen to dissociate. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Introduction Approximately 40% of children with a severe form of sickle cell disease (SCD) will develop cerebral white matter hyperintensities (WMHs), visible on magnetic resonance imaging (MRI). This may be associated with impaired neurocognitive functioning. It is unknown whether the volume of these WHMs is associated with the degree of neurocognitive dysfunction. Our objective was to investigate the association between volume of WMHs and neurocognitive functioning. Methods We prospectively included children with HbSS or HbS-beta(0)thalassemia aged 8-16 years. Exclusion criteria were prior stroke and chronic blood transfusion therapy. Volume of WMHs was calculated on MRI and patients were ranked by size of WMHs. Neurocognitive function was evaluated by testing intelligence (IQ, intelligence quotient), memory, visuo-motor functioning and executive functioning. Fatigue was measured using a validated questionnaire (Pediatric Quality of Life Inventory Multidimensional Fatigue Scale, PedsQL Fatigue) in which lower scores indicate more symptoms of fatigue. For each neurocognitive outcome, univariate linear regression was used to identify which variables (age, sex and hemoglobin level) were confounders. The independent association of volume of WMHs on neurocognitive outcomes was analyzed by multivariate linear regression, adjusted for these confounders when appropriate. The explained variance (R2) refers to the independently explained variance of volume of WMHs on the neurocognitive outcome and the presented p-value corresponds to the unique contribution of volume of WMHs on the outcome, both adjusted for confounders when appropriate. Results We included 38 children; mean age was 12.5 ± 2.7 years, WMHs were present in 50%. Mean full-scale, verbal IQ, performal IQ and Processing Speed Index were all between 85 and 90; this is significantly lower compared to the mean norm scores of 100. Our patients had significantly more symptoms of fatigue compared to Dutch reference values. A higher volume of WMHs was significantly associated with lower scores on full-scale IQ, verbal IQ and Processing Speed Index (see table). In addition, higher volume of WMHs was associated with higher scores of total and cognitive fatigue. Standardized beta coefficients ranged from -0.350 to -0.461, indicating a substantial negative effect of an increasing volume of WMHs on neurocognitive outcome. The volume of WMHs could explain between 12.1% and 21.2% of the variance of these outcomes. Conclusion Our findings suggest that the volume of WMHs is an independent predictor of full-scale IQ, verbal IQ, Processing Speed Index and fatigue in children with SCD. As WMHs are mostly found in the frontal lobe, this could explain the association with processing speed, which is an executive function and thought to be located in the frontal lobe. The association between WMHs and measures of fatigue has not been investigated before. Our results suggest the PedsQL Fatigue could be a promising screening tool for larger studies as it is easy and quick to administer and has a high validity. We suggest that future studies should consider taking the total volume of WMHs into account as an independent predictor of neurocognitive outcome, instead of only the presence or absence of WMHs. Taking the volume of WMHs into account is an important approach for individualized diagnostic and treatment strategies that could be further explored in a clinical setting. | Prediction model of neurocognitive outcome by volume of white matter hyperintensities | | -------------------------------------------------------------------------------------------------------------- | ------ | | | s | R2 | p | | Full-scale IQ | -0.382 | 0.146 | 0.018 | | Verbal IQ | -0.460 | 0.212 | 0.004 | | Performal IQ | -0.170 | 0.029 | 0.314 | | Processing Speed Index | -0.461 | 0.212 | 0.005 | | PedsQL Fatigue, Total Score | -0.350 | 0.121 | 0.025 | | PedsQL Fatigue, General Fatigue | -0.289 | 0.083 | 0.071 | | PedsQL Fatigue, Cognitive Fatigue | -0.352 | 0.123 | 0.026 | | IQ, Intelligence Quotient; PedsQL Fatigue, Pediatric Quality of Life Inventory Multidimensional Fatigue Scale. | Table Disclosures No relevant conflicts of interest to declare.

Introduction Almost 40% of patients with a severe form of sickle cell disease (SCD) develop small silent cerebral infarctions (SCIs), often located in the deep white matter, that may be associated with cognitive impairment. In patients with cardiovascular disease or risk factors, occurrence of these SCIs is a well known phenomenon, and considered as part of ‘cerebral small vessel disease’. Currently, it is unknown whether small vessel disease is the underlying cause of SCIs in sickle cell disease. If we can identify imaging features supporting the hypothesis that cerebral small vessel disease occurs in patients with SCD, this may provide new targets for therapeutic interventions. The aim of the present study is to investigate the brain imaging features of neurologically asymptomatic young SCD patients with ultra-high field 7T MRI. Methods Ten consecutive, neurological asymptomatic patients with SCD (homozygous hemoglobin S) without other cardiovascular risk factors were included (mean age 23 years, range 19-25). Brain lesions were scored using a 3D magnetization prepared fluid attenuated inversion recovery scan (MP-FLAIR) and a dual-echo T2*-weighted scan for the visualization of small arteries and veins. Results With the exception of two patients, all displayed round and circumscript infarcts in the deep white matter of the frontal or parietal lobe (Table). Most lesions (82%) were Conclusion In our series of young and neurological asymptomatic SCD patients, we found the typical imaging features of SCIs in 8 out of 10 patients. Our findings suggest that patients with SCD may have manifestations of cerebral small vessel disease before the occurrence of symptoms, even at a young age and without other cardiovascular risk factors. Disclosures: No relevant conflicts of interest to declare.

One of the most devastating complications of SCD is cerebral infarction. Cerebral infarcts are present on MRI scans in one third of SCD patients at the age of 18 years, although most of them are not accompanied by overt, focal neurological deficits. These so-called silent infarcts appear to be associated with diminished neurocognitive functioning and an increased risk of new infarcts. The risk of infarction is commonly attributed to the hyperemia that is associated with anemia and reduces the cerebral vascular reserve. In patients with anemia, adequate oxygenation of the brain tissue is presumably preserved by vasodilatation of the cerebral vasculature. In this hyperemic state there is limited reserve for further vasodilatation to assure adequate oxygen supply to the brain if the arterial pressure falls or metabolic demands increase. The lack of reserve capacity and ensuing ischemia is thought to predispose to cerebral infarction. The regional cerebral blood flow (rCBF) can be measured non-invasively by continuous arterial spin labeling (CASL) MRI. Proximal to entry in the brain, protons in the arterial blood are labeled using a radiofrequency pulse and quantified in terms of tissue perfusion on distal images in the brain. We performed a study to evaluate whether CASL MRI could detect differences in rCBF when these regions appear unaffected on conventional 3T MRI. The purpose of this study was to examine rCBF in children with SCD and compare it to rCBF in healthy children. Neurologically normal patients with sickle cell disease (HbSS or HbS-β-thalassemia) and normal flow on Transcranial Doppler Ultrasonography (TCD) and healthy children (HbAA, matched for ethnicity and age) underwent 3T MRI examination in a stable clinical situation between August 2006 and June 2007. Conventional MRI and MRA images were assessed by a standardized evaluation protocol by two independent observers (MW and CM), blinded to the clinical data. Cerebral infarcts, leukoareosis and vasculopathy were scored. From CASL MRI the rCBF was calculated for 6 vascular territories (left and right anterior, middle and posterior cerebral artery, respectively ACA, MCA and PCA). Left-right asymmetry in rCBF for the vascular territories within each patient was evaluated by calculating differences in flow between both hemispheres. Asymmetry was defined as > 11.7 ml/100g/min between the two hemispheres. Mean differences between patients and controls and 95% confidence intervals were calculated. The Chi-square test was performed to test the hypothesis that left-right asymmetry was equally distributed among the patients and controls. We enrolled 24 SCD patients (mean age 13.4 yr, SD 3.0) and 12 controls (mean age 13.4 yr, SD 3.5). The rCBF was of similar magnitude in SCD patients and controls in the frontal, middle and posterior territories (Table 1). A left-right asymmetry of rCBF in one or more vascular territories was present in the majority of SCD patients (58%), whereas this was absent in all controls. The difference in proportions of patients and controls with left-right asymmetry was statistically significant for the MCA and PCA territory (Chi-square test respectively p=0.005 and p=0.037). In contrast to previous studies we found no difference in CBF between patients and controls. We did observe an asymmetry in rCBF in the majority of patients with SCD that was not present in healthy controls. Table 1. rCBF (ml/100g/min) values of patients and healthy controls. | | Patients n=24 | Healthy controls n=12 | Mean difference | 95% CI | |:----------------:| ------------- | --------------------- | --------------- | ------ | ---- | | Territories | Mean | SD | Mean | SD | | | | ACA | 73.2 | 17.4 | 71.5 | 14.4 | −1.7 | (−13.6–10.1) | | MCA | 77.1 | 19.9 | 76.1 | 16.4 | −1.0 | (−14.5–12.5) | | PCA | 89.6 | 16.4 | 84.5 | 16.6 | −5.1 | (−17.0–6.7) | | Right hemisphere | 77.6 | 19.2 | 76.3 | 15.3 | −1.3 | (−14.3–11.5) | | Left hemisphere | 77.5 | 17.7 | 76.6 | 16.1 | −0.9 | (−13.3–11.4) | | Total | 77.6 | 17.4 | 76.4 | 15.6 | −1.2 | (−13.4–11.0)