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.

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.

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.

Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease.

OBJECTIVE: To determine mechanisms underlying regional vulnerability to infarction in sickle cell disease (SCD) by measuring voxel-wise cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen utilization (CMRO2) in children with SCD. METHODS: Participants underwent brain MRIs to measure voxel-based CBF, OEF, and CMRO2. An infarct heat map was created from an independent pediatric SCD cohort with silent infarcts and compared to prospectively obtained OEF maps. RESULTS: Fifty-six participants, 36 children with SCD and 20 controls, completed the study evaluation. Whole-brain CBF (99.2 vs 66.3 mL/100 g/min, p < 0.001), OEF (42.7% vs 28.8%, p < 0.001), and CMRO2 (3.7 vs 2.5 mL/100 g/min, p < 0.001) were higher in the SCD cohort compared to controls. A region of peak OEF was identified in the deep white matter in the SCD cohort, delineated by a ratio map of average SCD to control OEF voxels. CMRO2 in this region, which encompassed the CBF nadir, was low relative to all white matter (p < 0.001). Furthermore, this peak OEF region colocalized with regions of greatest infarct density derived from an independent SCD cohort. CONCLUSIONS: Elevated OEF in the deep white matter identifies a signature of metabolically stressed brain tissue at increased stroke risk in pediatric patients with SCD. We propose that border zone physiology, exacerbated by chronic anemic hypoxia, explains the high risk in this region.

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.

Large-Vessel Vasculopathy in Children With Sickle Cell Disease: A Magnetic Resonance Imaging Study of Infarct Topography and Focal Atrophy.

BACKGROUND: Large-vessel vasculopathy (LVV) increases stroke risk in pediatric sickle cell disease beyond the baseline elevated stroke risk in this vulnerable population. The mechanisms underlying this added risk and its unique impact on the developing brain are not established. METHODS: We analyzed magnetic resonance imaging and angiography scans of 66 children with sickle cell disease and infarcts by infarct density heatmaps and Jacobian determinants, a metric utilized to delineate focal volume change, to investigate if infarct location, volume, frequency, and cerebral atrophy differed among hemispheres with and without LVV. RESULTS: Infarct density heatmaps demonstrated infarct "hot spots" within the deep white matter internal border zone region in both LVV and non-LVV hemispheres, but with greater infarct density and larger infarct volumes in LVV hemispheres (2.2 mL versus 0.25 mL, P < 0.001). Additional scattered cortical infarcts in the internal carotid artery territory occurred in LVV hemispheres, but were rare in non-LVV hemispheres. Jacobian determinants revealed greater atrophy in gray and white matter of the parietal lobes of LVV compared with non-LVV hemispheres. CONCLUSION: Large-vessel vasculopathy in sickle cell disease appears to increase ischemic vulnerability in the borderzone region, as demonstrated by the increased frequency and extent of infarction within deep white matter, and increased risk of focal atrophy. Scattered infarctions across the LVV-affected hemispheres suggest additional stroke etiologies of vasculopathy (i.e., thromboembolism) in addition to chronic hypoxia-ischemia.

Periventricular hyperintensity in children with hydrocephalus.

BACKGROUND: Magnetic resonance images of children with hydrocephalus often include a rim of hyperintensity in the periventricular white matter (halo). OBJECTIVE: The purpose of this study was to decide between the hypothesis that the halo is caused by cerebrospinal fluid (CSF) flow during the cardiac cycle, and the alternate hypothesis that the halo is caused by anatomical changes (stretching and compression of white matter). MATERIALS AND METHODS: Participants were selected from a multicenter imaging study of pediatric hydrocephalus. We compared 19 children with hydrocephalus to a group of 52 controls. We quantified ventricle enlargement using the frontal-occipital horn ratio. We conducted qualitative and quantitative analysis of diffusion tensor imaging in the corpus callosum and posterior limb of the internal capsule. Parameters included the fractional anisotropy (FA), mean diffusivity, axial diffusivity and radial diffusivity. RESULTS: The halo was seen in 16 of the 19 children with hydrocephalus but not in the controls. The corpus callosum of the hydrocephalus group demonstrated FA values that were significantly decreased from those in the control group (P = 4 · 10(-6)), and highly significant increases were seen in the mean diffusivity and radial diffusivity in the hydrocephalus group. In the posterior limb of the internal capsule the FA values of the hydrocephalus group were higher than those for the control group (P = 0.002), and higher values in the hydrocephalus group were also noted in the axial diffusivity. We noted correlations between the diffusion parameters and the frontal-occipital horn ratio. CONCLUSION: Our results strongly support the hypothesis that the halo finding in hydrocephalus is caused by structural changes rather than pulsatile CSF flow.

The accuracy of linear indices of ventricular volume in pediatric hydrocephalus: technical note.

Assessment of ventricular size is essential in clinical management of hydrocephalus and other neurological disorders. At present, ventricular size is assessed using indices derived from the dimensions of the ventricles rather than the actual volumes. In a population of 22 children with congenital hydrocephalus and 22 controls, the authors evaluated the relationship between ventricular volume and linear indices in common use, such as the frontooccipital horn ratio, Evans' index, and the bicaudate index. Ventricular volume was measured on high-resolution anatomical MR images. The frontooccipital horn ratio was found to have a stronger correlation with both absolute and relative ventricular volume than other indices. Further analysis of the brain volumes found that congenital hydrocephalus produced a negligible decrease in the volume of the brain parenchyma.

Visualizing the prostate gland by MR imaging in young and old mice.

PURPOSE: Prostate imaging requires optimization in young and old mouse models. We tested which MR sequences and field strengths best depict the prostate gland in young and old mice; and, whether prostate MR signal, size, and architecture change with age. TECHNIQUE: Magnetic resonance imaging (MRI) of the prostate of young (2 months) and old (18 months) male nude mice (n = 6) was performed at 4.7 and 7 T and SCID mice (n = 6) at 7 T field strengths, using T1, fat suppressed T1, DWI, T2, fat suppressed T2, as well as T2-based- and proton density-based Dixon "water only" sequences. Images were ranked for best overall sequence for prostate visualization, prostate delineation, and quality of fat suppression. Prostate volume and signal characteristics were compared and histology was performed. RESULTS: T2-based-Dixon "water only" images ranked best overall for prostate visualization and delineation as well as fat suppression (n = 6, P<0.001) at both 4.7 T and 7 T in nude and 7T in SCID mice. Evaluated in nude mice, T2-based Dixon "water only" had greater prostate CNR and lower fat SNR at 7 T than 4.7 T (P<0.001). Prostate volume was less in older than younger mice (n = 6, P<0.02 nude mice; n = 6, P<0.002 SCID mice). Prostate T2 FSE as well as proton density-based and T2-based-Dixon "water only" signal intensity was higher in younger than older mice (P<0.001 nude mice; P<0.01 SCID mice) both at 4.7 and 7 T. This corresponded to an increase in glandular hyperplasia in older mice by histology (P<0.01, n = 6). CONCLUSION: T2-based Dixon "water only" images best depict the mouse prostate in young and old nude mice at 4.7 and 7 T. The mouse prostate decreases in size with age. The decrease in T2 and T2-based Dixon "water only" signal with age corresponds with glandular hyperplasia. Findings suggest age should be an important determinant when choosing models of prostate biology and disease.

Alterations in cerebral oxygen metabolism after traumatic brain injury in children.

Traumatic brain injury (TBI) is the most common cause of acquired disability in children. Metabolic defects, and in particular mitochondrial dysfunction, are important contributors to brain injury after TBI. Studies of metabolic dysfunction are limited, but magnetic resonance methods suitable for use in children are overcoming this limitation. We performed noninvasive measurements of cerebral blood flow and oxygen metabolic index (OMI) to assess metabolic dysfunction in children with severe TBI. Cerebral blood flow is variable after TBI but hypoperfusion and low OMI are predominant, supporting metabolic dysfunction. This finding is consistent with preclinical and adult clinical studies of brain metabolism and mitochondrial dysfunction after TBI.

Depression of whole-brain oxygen extraction fraction is associated with poor outcome in pediatric traumatic brain injury.

INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Metabolic failure is an integral component of the pathological aftermath of TBI. The oxygen extraction fraction (OEF) is a valuable parameter for characterization and description of metabolic abnormalities; however, OEF measurement has required either invasive procedures or the use of ionizing radiation, which significantly limits its use in pediatric research. RESULTS: Patients with TBI had depressed OEF levels that correlated with the severity of injury. In addition, the OEF measured within 2 weeks of injury was predictive of patient outcome at 3 mo after injury. In pediatric TBI patients, low OEF-a marker of metabolic dysfunction-correlates with the severity of injury and outcome. DISCUSSION: Our findings support previous literature on the role of metabolic dysfunction after TBI. METHODS: Using a recently developed magnetic resonance (MR) technique for the measurement of oxygen saturation, we determined the whole-brain OEF in both pediatric TBI patients and in healthy controls. Injury and outcome were classified using pediatric versions of the Glasgow Coma Scale (GCS) and Glasgow Outcome Scale-Extended (GOS-E), respectively.

Suppression of vascular enhancement artifacts through the use of a multiband, selectively spoiled radiofrequency excitation pulse.

PURPOSE: To test the ability of a multi-band RF pulse to reduce flow enhancement artifacts for steady state imaging without compromising temporal resolution or spatial coverage. MATERIALS AND METHODS: Selectively spoiled composite RF pulses that provide simultaneous excitation and flow preparation were designed and tested by means of simulation, phantom, and in vivo measurements under varying conditions of flow. RESULTS: Suppression of flow enhancement was found to depend on flow velocity and spatial extent of spoiled regions. By determining necessary pulse characteristics for a given experimental geometry, flow enhancement was reduced and sensitivity to T(1)-reducing contrast agent was dramatically increased. CONCLUSION: These pulses provide an effective means of suppressing flow enhancement without sacrificing temporal resolution or spatial coverage.

Fast, reproducible measurement of the vascular input function in mice using constrained reconstruction and cardiac sampling.

Dynamic contrast-enhanced MRI is often used to assess the response to therapy in small animal models of cancer. Rigorous quantification of dynamic contrast-enhanced MRI data using common pharmacokinetic models requires dynamic determination of the concentration of contrast in tumor tissue and in blood. Measurement of the blood concentration, or vascular input function (VIF), requires high temporal resolution and is prone to distortion as a result of flow and partial volume artifacts when measured in local blood vessels. We have developed a strategy for the robust measurement of VIF in mice that uses a constrained reconstruction algorithm to enable sampling from the left ventricle of the heart. The feasibility of the algorithm and its resistance to cardiac motion are demonstrated in vivo and through numerical simulations. VIF sampling is interleaved with slices dedicated to tumor coverage to yield a fast VIF sampling period (81 ms) that is decoupled from the temporal resolution of tumor data (3.9 s). The algorithm provides results that agree with fully encoded measurements in the slowly varying component of VIF to within a 4% root-mean-square signal difference. Analysis of a parametric representation of VIFs measured in a population of mice showed a significant reduction in variations observed within subjects (5%-58% over four parameters; p < 0.05) and a reduction in variations between subjects (19%-62%) when using this technique. Preliminary dynamic measurements in an orthotopic xenograft model of anaplastic thyroid cancer revealed a decrease in the variation of pharmacokinetic parameters between mice by a factor of two.

Two-point Dixon technique provides robust fat suppression for multi-mouse imaging.

PURPOSE: To determine whether Dixon-based fat separation techniques can provide more robust removal of lipid signals from multiple-mouse magnetic resonance imaging (MRI)-acquired images than conventional frequency selective chemical saturation techniques. MATERIALS AND METHODS: A two-point Dixon technique was implemented using a RARE-based pulse sequence and techniques for multivolume fat suppression were evaluated using a 4-element array of volume resonators at 4.7 T. Images were acquired of both phantoms and mice. RESULTS: Fat saturation was achieved on all four channels of the multiple mouse acquisition with the Dixon technique, while failures of fat saturation were found with chemical saturation techniques. CONCLUSION: This proof of concept study found that Dixon fat separation provided more reliable and homogenous fat suppression than chemical saturation in phantoms and in vivo.

Feasibility of multiple-mouse dynamic contrast-enhanced MRI.

Dynamic contrast-enhanced (DCE-) MRI is often used to evaluate the response to experimental antiangiogenic therapies in small animal models of cancer. Unfortunately, DCE-MRI studies often require a substantial investment of both time and money to achieve the desired level of statistical significance. Multiple-mouse MRI has previously been used to improve imaging efficiency, but its feasibility for DCE-MRI has not been investigated. The purpose of this work was to determine if multiple-mouse DCE-MRI is feasible when using gadolinium-based contrast agents with a low molecular weight. A population of tumor-bearing mice was scanned using two four-element arrays and a single-coil configuration on a 4.7T, 40 cm bore Bruker Biospec MRI scanner. Pharmacokinetic parameters were calculated and compared to determine if a significant difference between methodologies existed. With both four-animal imaging configurations, animal throughput accelerations of just less than three were achieved and quantitative data were not significantly different than from single-animal acquisitions.