Health Inequity and Time From Pediatric Stroke Onset to Arrival.

BACKGROUND: Time from stroke onset to hospital arrival determines treatment and impacts outcome. Structural, socioeconomic, and environmental factors are associated with health inequity and onset-to-arrival in adult stroke. We aimed to assess the association between health inequity and onset-to-arrival in a pediatric comprehensive stroke center. METHODS: A retrospective observational study was conducted on a consecutive cohort of children (>28 days-18 years) diagnosed with acute arterial ischemic stroke (AIS) between 2004 and 2019. Neighborhood-level material deprivation was derived from residential postal codes and used as a proxy measure for health inequity. Patients were stratified by level of neighborhood-level material deprivation, and onset-to-arrival was categorized into 3 groups: <6, 6 to 24, and >24 hours. Association between neighborhood-level material deprivation and onset-to-arrival was assessed in multivariable ordinal logistic regression analyses adjusting for sociodemographic and clinical factors. RESULTS: Two hundred and twenty-nine children were included (61% male; median age [interquartile range] at stroke diagnosis 5.8-years [1.1-11.3]). Over the 16-year study period, there was an increase in proportion of children diagnosed with AIS living in the most deprived neighborhoods and arriving at the emergency room within 6 hours (P=0.01). Among Asian patients, a higher proportion lived in the most deprived neighborhoods (P=0.02) and level of material deprivation was associated with AIS risk factors (P=0.001). CONCLUSIONS: Our study suggests an increase in pediatric stroke in deprived neighborhoods and certain communities, and earlier arrival times to the emergency room over time. However, whether these changes are due to an increase in incidence of childhood AIS or increased awareness and diagnosis is yet to be determined. The association between AIS risk factors and material deprivation highlights the intersectionality of clinical factors and social determinants of health. Finally, whether material deprivation impacts onset-to-arrival is likely complex and requires further examination.

Assessment of MR blood-oxygen-level-dependent (BOLD) cerebrovascular reactivity under general anesthesia in children with moyamoya.

BACKGROUND: Moyamoya is a progressive, non-atherosclerotic cerebral arteriopathy that may present in childhood and currently has no cure. Early diagnosis is critical to prevent a lifelong risk of neurological morbidity. Blood-oxygen-level-dependent (BOLD) MRI cerebrovascular reactivity (CVR) imaging provides a non-invasive, in vivo measure of autoregulatory capacity and cerebrovascular reserve. However, non-compliant or younger children require general anesthesia to achieve BOLD-CVR imaging. OBJECTIVE: To determine the same-day repeatability of BOLD-CVR imaging under general anesthesia in children with moyamoya. MATERIALS AND METHODS: Twenty-eight examination pairs were included (mean patient age = 7.3 ± 4.0 years). Positive and negatively reacting voxels were averaged over signals and counted over brain tissue and vascular territory. The intraclass correlation coefficient (ICC), Wilcoxon signed-rank test, and Bland-Altman plots were used to assess the variability between the scans. RESULTS: There was excellent-to-good (≥ 0.59) within-day repeatability in 18 out of 28 paired studies (64.3%). Wilcoxon signed-rank tests demonstrated no significant difference in the grey and white matter CVR estimates, between repeat scans (all p-values > 0.05). Bland-Altman plots of differences in mean magnitude of positive and negative and fractional positive and negative CVR estimates illustrated a reasonable degree of agreement between repeat scans and no systematic bias. CONCLUSION: BOLD-CVR imaging provides repeatable assessment of cerebrovascular reserve in children with moyamoya imaged under general anesthesia.

Hyperpolarized 129 Xe MRI of the rat brain with chemical shift saturation recovery and spiral-IDEAL readout.

PURPOSE: To demonstrate the feasibility of 129 Xe chemical shift saturation recovery (CSSR) combined with spiral-IDEAL imaging for simultaneous measurement of the time-course of red blood cell (RBC) and brain tissue signals in the rat brain. METHODS: Images of both the RBC and brain tissue 129 Xe signals from the brains of five rats were obtained using interleaved spiral-IDEAL imaging following chemical shift saturation pulses applied at multiple CSSR delay times, τ. A linear fit of the signals to τ was used to calculate the slope of the signal for both RBC and brain tissue compartments on a voxel-by-voxel basis. Gas transfer was evaluated by measuring the ratio of the whole brain tissue-to-RBC signal intensities as a function of τ. To investigate the relationship between the CSSR images and gas transfer in the brain, the experiments were repeated during hypercapnic ventilation. RESULTS: Hypercapnia, affected the ratio of the tissue-to-RBC signal intensity (p = 0.026), consistent with an increase in gas transfer. CONCLUSION: CSSR with spiral-IDEAL imaging is feasible for acquisition of 129 Xe RBC and brain tissue time-course images in the rat brain. Differences in the time-course of the signal intensity ratios are consistent with gas transfer changes expected under hypercapnic conditions.

Effect of inhaled oxygen concentration on 129 Xe chemical shift of red blood cells in rat lungs.

PURPOSE: To investigate the dependence of dissolved 129 Xe chemical shift on the fraction of inhaled oxygen, Fi O2 , in the lungs of healthy rats. METHODS: The chemical shifts of 129 Xe dissolved in red blood cells, δRBC , and blood plasma and/or tissue, δPlasma , were measured using MRS in 12 Sprague Dawley rats mechanically ventilated at Fi O2 values of 0.14, 0.19, and 0.22. Regional effects on the chemical shifts were controlled using a chemical shift saturation recovery sequence with a fixed delay time. MRS was also performed at an Fi CO2 value of 0.085 to investigate the potential effect of the vascular response on δRBC and δPlasma . RESULTS: δRBC increased with decreasing Fi O2 (P = .0002), and δPlasma showed no dependence on Fi O2 (P = .23). δRBC at Fi CO2 = 0 (210.7 ppm ± 0.1) and at Fi CO2 = 0.085 (210.6 ppm ± 0.2) were not significantly different (P = .67). δPlasma at Fi CO2 = 0 (196.9 ppm ± 0.3) and at Fi CO2 = 0.085 (197.0 ppm ± 0.1) were also not significantly different (P = .81). CONCLUSION: Rat lung δRBC showed an inverse relationship to Fi O2 , opposite to the relationship previously demonstrated for in vitro human blood. Rat lung δRBC did not depend on Fi CO2 .

Chemical shift of 129 Xe dissolved in red blood cells: Application to a rat model of bronchopulmonary dysplasia.

PURPOSE: To measure the chemical shift of hyperpolarized 129 Xe dissolved in the red blood cells(δRBC ) of a cohort of rats exposed to hyperoxia and intermittent hypoxia (IH) to mimic human bronchopulmonary dysplasia, and to investigate the effect of xenon-blood distribution time on δRBC . METHODS: δRBC was measured from spectra acquired using a chemical shift saturation recovery sequence from 15 Sprague-Dawley rats exposed to hyperoxia-IH and 10 age-matched control rats. Sensitization to the xenon-blood distribution time was achieved by varying the time between saturation pulses, τ. δRBC was compared with blood fraction measured by histology of the cohort and blood oxygenation measured directly using pulse oximetry following a hypoxic challenge in an identically exposed cohort. RESULTS: The mean δRBC in the hyperoxia-IH exposed rats was 0.55 ± 0.04 ppm lower than that of the healthy cohort (P = .0038), and this difference did not depend on τ (P = .996). The blood fraction of the exposed cohort was lower than that of the healthy cohort (P = .0397). Oximetry measurements showed that the baseline arterial oxygen saturation (Sa O2 ) of each cohort was not different (P = .72), but after a hypoxic challenge, the Sa O2 of the exposed cohort was lower than that of the healthy cohort (P = .003). CONCLUSION: δRBC is reduced in rats exposed to hyperoxia-IH compared with control rats. The change in δRBC is consistent with enhanced blood oxygen desaturation of the exposed cohort measured by pulse oximetry during a hypoxic challenge. This suggests that the observed change in δRBC reflects enhanced desaturation in the hyperoxia-IH exposed cohort compared with the healthy cohort.

Hydroxycarbamide treatment in children with Sickle Cell Anaemia is associated with more intact white matter integrity: a quantitative MRI study.

Sickle cell anaemia (SCA) is a devastating genetic blood disorder leading to chronic anaemia, impaired cerebrovascular dilatory capacity and cerebral infarctions. Our aim was to assess the relationship between microstructural properties of the white matter (WM) and both cerebrovascular reactivity (CVR) and cerebral blood flow, as well as the effects of hydroxycarbamide on these relationships. Our results demonstrate that mean CVR was increased in hydroxycarbamide-treated patients compared to untreated patients. Moreover, untreated SCA patients had increased skew and kurtosis of mean diffusivity histograms in the WM compared to hydroxycarbamide-treated patients and healthy age-matched controls, indicating disruption of WM integrity. Regression analysis of CVR and WM mean diffusivity (MD) revealed a significant linear relationship between CVR and MD histogram skew and kurtosis in healthy controls, but not in either of the two SCA groups. These findings suggest that patients treated with hydroxycarbamide possess white matter MD histogram parameters which more closely resemble those of healthy controls.

The severity of anaemia depletes cerebrovascular dilatory reserve in children with sickle cell disease: a quantitative magnetic resonance imaging study.

Overt ischaemic stroke is one of the most devastating complications in children with sickle cell disease (SCD). The compensatory response to anaemia in SCD includes an increase in cerebral blood flow (CBF) by accessing cerebrovascular dilatory reserve. Exhaustion of dilatory reserve secondary to anaemic stress may lead to cerebral ischaemia. The purpose of this study was to investigate CBF and cerebrovascular reactivity (CVR) using magnetic resonance imaging (MRI) in children with SCD and to correlate these with haematological markers of anaemia. Baseline CBF was measured using arterial spin labelling. Blood-oxygen level-dependent MRI in response to a CO2 stimulus was used to acquire CVR. In total, 28 children with SCD (23 not on any disease-modifying treatment, 5 on chronic transfusion) and 22 healthy controls were imaged using MRI. Transfusion patients were imaged at two time points to assess the effect of changes in haematocrit after a transfusion cycle. In children with SCD, CBF was significantly elevated compared to healthy controls, while CVR was significantly reduced. Both measures were significantly correlated with haematocrit. For transfusion patients, CBF decreased and CVR increased following a transfusion cycle. Lastly, a significant correlation was observed between CBF and CVR in both children with SCD and healthy controls.

Normal appearing white matter permeability: a marker of inflammation and information processing speed deficit among relapsing remitting multiple sclerosis patients.

PURPOSE: Blood-brain barrier breakdown (BBBB) occurs in relapsing remitting multiple sclerosis (RRMS). Relative recirculation (rR), a BBBB surrogate, may show inflammation undetectable by gadolinium. We compared normal appearing white matter (NAWM) rR in patients with and without disability measured with Symbol Digit Modalities Test and the Expanded Disability Status Scale (EDSS). METHODS: Thirty-nine RRMS patients were prospectively recruited and classified as impaired or non-impaired based on the SDMT and EDSS threshold ≥3. Significant demographic, MRI structural and regional rR characteristics were advanced into multivariate analysis to assess the association with impairment of cognition and EDSS. Bonferroni corrected p < 0.025 was applied to demographic and rR group comparisons; p < 0.05 was used in the final multivariate logistic regression. RESULTS: rR was higher in NAWM (p = 0.012), NAGM (p = 0.004), and basal ganglia (p = 0.007) in cognitively impaired versus non-impaired patients. The difference between NAWM and T2HL rR was significant in cognitively non-impaired patients and approximated that of T2HL in impairment (0.084 vs. 0.075, p = 0.008; 0.118 vs. 0.101, p = 0.091, respectively). After adjusting for confounders, rR elevation for NAWM (OR 1.777; 95% CI 1.068-2.956; p = 0.026), NAGM (OR 2.138; 1.100-4.157; p = 0.025), and basal ganglia (OR 2.192; 1.120-4.289; p = 0.022) remained significantly predictive of cognitive impairment. NAWM area under the curve (AUC) for cognitive impairment was 0.783. No significant group differences or associations were seen for rR and EDSS impairment. No NAGM and cortical lesion rR difference was present within any of the impaired or non-impaired groups. CONCLUSION: rR elevation in NAWM, NAGM, and basal ganglia appears sensitive to cognitive impairment but not EDSS.

Developmental trajectories of cerebrovascular reactivity in healthy children and young adults assessed with magnetic resonance imaging.

KEY POINTS: Cerebrovascular reactivity (CVR) reflects the vasodilatory reserve of cerebral resistance vessels. Normal development in children is associated with significant changes in blood pressure, cerebral blood flow (CBF) and cerebral oxygen metabolism. Therefore, it stands to reason that CVR will also undergo changes during this period. The study acquired magnetic resonance imaging measures of CVR and CBF in healthy children and young adults to trace their changes with age. We found that CVR changes in two phases, increasing with age until the mid-teens, followed by a decrease. Baseline CBF declined steadily with age. We conclude that CVR varies with age during childhood, which prompts future CVR studies involving children to take into account the effect of development. ABSTRACT: Cerebrovascular reactivity (CVR) reflects the vasculature's ability to accommodate changes in blood flow demand thereby serving as a critical imaging tool for mapping vascular reserve. Normal development is associated with extensive physiological changes in blood pressure, cerebral blood flow and cerebral metabolic rate of oxygen, all of which can affect CVR. Moreover, the evolution of these physiological parameters is most prominent during childhood. Therefore, the aim of this study was to use non-invasive magnetic resonance imaging (MRI) to characterize the developmental trajectories of CVR in healthy children and young adults, and relate them to changes in cerebral blood flow (CBF). Thirty-four healthy subjects (17 males, 17 females; age 9-30 years) underwent CVR assessment using blood oxygen level-dependent MRI in combination with a computer controlled CO2 stimulus. In addition, baseline CBF was measured with a pulsed arterial spin labelling sequence. CVR exhibited a gradual increase with age in both grey and white matter up to 14.7 years. After this break point, a negative correlation with age was detected. Baseline CBF maintained a consistent negative linear correlation across the entire age range. The significant age-dependent changes in CVR and CBF demonstrate the evolution of cerebral haemodynamics in children and should be taken into consideration. The shift in developmental trajectory of CVR from increasing to decreasing suggests that physiological factors beyond baseline CBF also influence CVR.

Reproducibility of cerebrovascular reactivity measures in children using BOLD MRI.

PURPOSE: To evaluate the reproducibility of cerebrovascular reactivity (CVR) measurements acquired in children using magnetic resonance imaging (MRI) in combination with a computer-controlled carbon dioxide (CO2 ) stimulus. MATERIALS AND METHODS: Ten healthy children (age 16.1 ± 1.6 years) underwent CVR imaging on a 3T scanner using a blood-oxygen level-dependent (BOLD) MRI sequence. Targeted hypercapnia was induced during imaging with a CO2 gas challenge delivered using a specialized gas sequencer (RespirAct). A total of four BOLD scans were performed over 2 separate days to test within-day and between-day consistency of the data. CVR values were computed by correlating the relative change in BOLD signal in response to the CO2 stimulus delivered to the each subject. RESULTS: Intraclass correlation coefficients (ICCs) of within-day values show highly reproducible measures in both the gray matter (ICC = 0.857, P < 0.001) and white matter (ICC = 0.895, P < 0.001). Relatively lower between-day reproducibility was observed in both the gray matter (ICC = 0.776, P = 0.001) and white matter (ICC = 0.719, P = 0.004). CONCLUSION: Using a computer-controlled CO2 stimulus, we have demonstrated the reliability of BOLD-CVR measurements in pediatric subjects. Within-day and between-day metrics of reproducibility were comparable to adult data.

Physiologic characterization of inflammatory arthritis in a rabbit model with BOLD and DCE MRI at 1.5 Tesla.

OBJECTIVE: Our aim was to test the feasibility of blood oxygen level dependent magnetic resonance imaging (BOLD MRI) and dynamic contrast-enhanced (DCE) MRI to monitor periarticular hypoxic/inflammatory changes over time in a juvenile rabbit model of arthritis. METHODS: We examined arthritic and contralateral nonarthritic knees of 21 juvenile rabbits at baseline and days 1,14, and 28 after induction of arthritis by unilateral intra-articular injection of carrageenin with BOLD and DCE MRI at 1.5 Tesla (T). Nine noninjected rabbits served as controls. Associations between BOLD and DCE-MRI and corresponding intra-articular oxygen pressure (PO2) and blood flow [blood perfusion units (BPU)] (polarographic probes, reference standards) or clinical-histological data were measured by correlation coefficients. RESULTS: Percentage BOLD MRI change obtained in contralateral knees correlated moderately with BPU on day 0 (r = -0.51, p = 0.02) and excellently on day 28 (r = -0.84, p = 0.03). A moderate correlation was observed between peak enhancement DCE MRI (day 1) and BPU measurements in arthritic knees (r = 0.49, p = 0.04). In acute arthritis, BOLD and DCE MRI highly correlated (r = 0.89, p = 0.04; r = 1.0, p < 0.0001) with histological scores in arthritic knees. CONCLUSION: The proposed techniques are feasible to perform at 1.5 T, and they hold potential as surrogate measures to monitor hypoxic and inflammatory changes over time in arthritis at higher-strength MRI fields. KEY POINTS: • BOLD and DCE MRI detect interval perisynovial changes in a rabbit knee • BOLD and DCE MRI act as surrogate markers of physiologic changes in arthritis • BOLD MRI signal represents oxygen extraction compared with intra-articular PO 2 • DCE MRI measurements estimate physiologic periarticular vascular properties • In rabbit knees with acute arthritis, BOLD/DCE MRI highly correlated with histological scores.

Assessment of intracranial blood flow velocities using a computer controlled vasoactive stimulus: a comparison between phase contrast magnetic resonance angiography and transcranial Doppler ultrasonography.

PURPOSE: To compare measurements of blood flow velocity (BFV) and BFV changes in the middle cerebral arteries (MCA) acquired from phase contrast magnetic resonance angiography (PCMRA) and transcranial Doppler ultrasound (TCD) during controlled manipulation of end-tidal partial pressure of carbon dioxide (PetCO2 ). MATERIALS AND METHODS: In vivo TCD and PCMRA velocity data from the M1 segment in the MCA of nine healthy adult volunteers were acquired during precise targeting of PetCO2 induced by a computer-controlled gas delivery system. Doppler spectra and phase contrast data were processed into time-averaged peak-velocity (TAPV) values for comparison. Changes in velocity between baseline and hypercapnia were analyzed in terms of velocity-based cerebrovascular reactivity (CVR). RESULTS: Good correlation between the pairs of velocity measurements acquired from the two modalities were found (ρ = 0.81), but Bland-Altman analysis indicates a significant bias error. There was relatively weak agreement between the pairs of computed CVR values (ρ = -0.26). CONCLUSION: Under precise PetCO2 control, PCMRA proves to be more consistent than TCD. Despite issues with variability, TCD is qualitatively comparable to PCMRA measures of velocity in the MCA. However, PCMRA velocity results are better suited for analyses that require quantitative values, such as CVR.

Non-invasive accurate measurement of arterial PCO2 in a pediatric animal model.

The PCO2 in arterial blood (PaCO2) is a good parameter for monitoring ventilation and acid-base changes in ventilated patients, but its measurement is invasive and difficult to obtain in small children. Attempts have been made to use the partial pressure of CO2 in end-tidal gas (PETCO2), as a noninvasive surrogate for PaCO2. Studies have revealed that, unfortunately, the differences between PETCO2 and PaCO2 are too variable to be clinically useful. We hypothesized that end-inspiratory rebreathing, previously shown to equalize PETCO2 and PaCO2 in spontaneously breathing humans, would also be effective with positive pressure ventilation. Eight newborn Yorkshire pigs were mechanically ventilated via a partial rebreathing circuit to implement end-inspiratory rebreathing. Arterial blood was sampled and tested for PaCO2. A variety of alveolar ventilations resulting in different combinations of end-tidal PCO2 (30-50 mmHg) and PO2 (35-500 mmHg) were tested for differences between PETCO2 and PaCO2 (PET-aCO2). The PET-aCO2 of all samples was (mean ± 1.96 SD) 0.4 ± 2.7 mmHg. Our study demonstrates that, in ventilated juvenile animals, end-inspiratory rebreathing maintains PET-aCO2 to what would be a clinically useful range. If verified clinically, this approach could open the way for non-invasive monitoring of arterial PCO2 in critically ill patients.

The development of the pediatric stroke neuroimaging platform (PEDSNIP).

Childhood stroke occurs from birth to 18 years of age, ranks among the top ten childhood causes of death, and leaves lifelong neurological impairments. Arterial ischemic stroke in infancy and childhood occurs due to arterial occlusion in the brain, resulting in a focal lesion. Our understanding of mechanisms of injury and repair associated with focal injury in the developing brain remains rudimentary. Neuroimaging can reveal important insights into these mechanisms. In adult stroke population, multi-center neuroimaging studies are common and have accelerated the translation process leading to improvements in treatment and outcome. These studies are centered on the growing evidence that neuroimaging measures and other biomarkers (e.g., from blood and cerebrospinal fluid) can enhance our understanding of mechanisms of risk and injury and be used as complementary outcome markers. These factors have yet to be studied in pediatric stroke because most neuroimaging studies in this population have been conducted in single-centred, small cohorts. By pooling neuroimaging data across multiple sites, larger cohorts of patients can significantly boost study feasibility and power in elucidating mechanisms of brain injury, repair and outcomes. These aims are particularly relevant in pediatric stroke because of the decreased incidence rates and the lack of mechanism-targeted trials. Toward these aims, we developed the Pediatric Stroke Neuroimaging Platform (PEDSNIP) in 2015, funded by The Brain Canada Platform Support Grant, to focus on three identified neuroimaging priorities. These were: developing and harmonizing multisite clinical protocols, creating the infrastructure and methods to import, store and organize the large clinical neuroimaging dataset from multiple sites through the International Pediatric Stroke Study (IPSS), and enabling central searchability. To do this, developed a two-pronged approach that included building 1) A Clinical-MRI Data Repository (standard of care imaging) linked to clinical data and longitudinal outcomes and 2) A Research-MRI neuroimaging data set acquired through our extensive collaborative, multi-center, multidisciplinary network. This dataset was collected prospectively in eight North American centers to test the feasibility and implementation of harmonized advanced Research-MRI, with the addition of clinical information, genetic and proteomic studies, in a cohort of children presenting with acute ischemic stroke. Here we describe the process that enabled the development of PEDSNIP built to provide the infrastructure to support neuroimaging research priorities in pediatric stroke. Having built this Platform, we are now able to utilize the largest neuroimaging and clinical data pool on pediatric stroke data worldwide to conduct hypothesis-driven research. We are actively working on a bioinformatics approach to develop predictive models of risk, injury and repair and accelerate breakthrough discoveries leading to mechanism-targeted treatments that improve outcomes and minimize the burden following childhood stroke. This unique transformational resource for scientists and researchers has the potential to result in a paradigm shift in the management, outcomes and quality of life in children with stroke and their families, with far-reaching benefits for other brain conditions of people across the lifespan.

Fronto-Parietal and White Matter Haemodynamics Predict Cognitive Outcome in Children with Moyamoya Independent of Stroke.

Moyamoya disease is a major arteriopathy characterised by progressive steno-occlusion of the arteries of the circle of Willis. Studies in adults with moyamoya suggest an association between abnormal fronto-parietal and white matter regional haemodynamics and cognitive impairments, even in the absence of focal infarction. However, these associations have not been investigated in children with moyamoya. We examined the relationship between regional haemodynamics and ratings of intellectual ability and executive function, using hypercapnic challenge blood oxygen level-dependent magnetic resonance imaging of cerebrovascular reactivity in a consecutive cohort of children with confirmed moyamoya. Thirty children were included in the final analysis (mean age: 12.55 ± 3.03 years, 17 females, 15 idiopathic moyamoya and 15 syndromic moyamoya). Frontal haemodynamics were abnormal in all regardless of stroke history and comorbidity, but occipital lobe haemodynamics were also abnormal in children with syndromic moyamoya. Executive function deficits were noted in both idiopathic and syndromic moyamoya, whereas intellectual ability was impaired in syndromic moyamoya, even in the absence of stroke. Analysis of the relative effect of regional abnormal haemodynamics on cognitive outcomes demonstrated that executive dysfunction was predominantly explained by right parietal and white matter haemodynamics independent of stroke and comorbidity, while posterior circulation haemodynamics predicted intellectual ability. These results suggest that parietal and posterior haemodynamics play a compensatory role in overcoming frontal vulnerability and cognitive impairment.

Measurement of cerebrovascular reactivity in pediatric patients with cerebral vasculopathy using blood oxygen level-dependent MRI.

BACKGROUND AND PURPOSE: Cerebrovascular reactivity (CVR) is an indicator of cerebral hemodynamics. In adults with cerebrovascular disease, impaired CVR has been shown to be associated with an increased risk of stroke. In children, however, CVR studies are not common. This may be due to the difficulties and risks associated with current CVR study methodologies. We have previously described the application of precise control of end-tidal carbon dioxide partial pressure for CVR studies in adults. Our aim is to report initial observations of CVR studies that were performed as part of a larger observational study regarding investigations in pediatric patients with cerebral vascular disease. METHODS: Thirteen patients between the ages of 10 and 16 years (10 with a diagnosis of Moyamoya vasculopathy and 3 with confirmed, or suspected, intracranial vascular stenosis) underwent angiography, MRI, and functional blood oxygen level-dependent MRI mapping of CVR to hypercapnia. The results of the CVR study were then related to both the structural imaging and clinical status. RESULTS: Sixteen blood oxygen level-dependent MRI CVR studies were performed successfully in 13 consecutive patients. Twelve of the 13 patients with angiographic abnormalities also had CVR deficits in the corresponding downstream vascular territories. CVR deficits were also seen in 8 of 9 symptomatic patients and 2 of the asymptomatic patients. Notably, in patients with abnormalities on angiography, the reductions in CVR extended beyond the ischemic lesions identified with MR structural imaging into normal-appearing brain parenchyma. CONCLUSIONS: This is the first case series reporting blood oxygen level-dependent MRI CVR in children with cerebrovascular disease. CVR studies performed so far provide information regarding hemodynamic compromise, which complements traditional clinical assessment and structural imaging.

Noninvasive MRI measures of microstructural and cerebrovascular changes during normal swine brain development.

The swine brain is emerging as a potentially valuable translational animal model of neurodevelopment and offers the ability to assess the impact of experimentally induced neurological disorders. The goal for this study was to characterize swine brain development using noninvasive MRI measures of microstructural and cerebrovascular changes. Thirteen pigs at various postnatal ages (2.3-43.5 kg) were imaged on a 1.5-Tesla MRI system. Microstructural changes were assessed using diffusion tensor imaging measures of mean diffusivity and fractional anisotropy. Cerebrovascular changes were assessed using arterial spin labeling measures of baseline cerebral blood flow (CBF) and the cerebrovascular reactivity (CVR) of the blood-oxygen level dependent (BOLD) MRI signal to CO2. We found a positive logarithmic relationship for regional tissue volumes and fractional anisotropy with body weight, which is similar to the pattern reported in the developing human brain. Unlike in the maturing human brain, no consistent changes in mean diffusivity or baseline CBF with development were observed. Changes in BOLD CVR exhibited a positive logarithmic relationship with body weight, which may impact the interpretation of functional MRI results at different stages of development. This animal model can be validated by applying the same noninvasive measures in humans.

Distinct Clinical and Radiographic Phenotypes in Pediatric Patients With Moyamoya.

BACKGROUND: Given the expanding evidence of clinico-radiological differences between moyamoya disease (MMD) and moyamoya syndrome (MMS), we compared the clinical and radiographic features of childhood MMD and MMS to identify predictors of ischemic event recurrence. METHODS: We reviewed a pediatric moyamoya cohort followed between 2003 and 2019. Clinical and radiographic characteristics at diagnosis and follow-up were abstracted. Comparisons between MMD and MMS as well as between MMD and two MMS subgroups (neurofibromatosis [MMS-NF1] and sickle cell disease [MMS-SCD]) were performed. RESULTS: A total of 111 patients were identified. Patients with MMD presented commonly with transient ischemic attacks (TIAs) (35 % MMD versus 13% MMS-NF1 versus 9.5% MMS-SCD; P = 0.047). Symptomatic stroke presentation (MMD 37% versus MMS-NF1 4% versus 33%; P = 0.0147) and bilateral disease at diagnosis (MMD 73% versus MMS-NF1 22 % versus MMS-SCD 67%; P = 0.0002) were uncommon in MMS-NF1. TIA recurrence was common in MMD (hazard ratio 2.86; P = 0.001). The ivy sign was absent on neuroimaging in a majority of patients with MMS-SCD (MMD 67% versus MMS-NF1 52% versus MMS-SCD 9.5%; P = 0.0002). Predictors of poor motor outcome included early age at diagnosis (odds ratio [OR] 8.45; P = 0.0014), symptomatic stroke presentation (OR 6.6; P = 0.019), and advanced Suzuki stage (OR 3.59; P = 0.019). CONCLUSIONS: Moyamoya exhibits different phenotypes based on underlying etiologies. Frequent TIAs is a common phenotype of MMD and symptomatic stroke presentation a common feature of MMD and MMS-SCD, whereas unilateral disease and low infarct burden are common in MMS-NF1. In addition, absence of ivy sign is a common phenotype in MMS-SCD.

Blood-oxygen level dependent MRI measures of cerebrovascular reactivity using a controlled respiratory challenge: reproducibility and gender differences.

PURPOSE: To evaluate the reproducibility and gender differences in cerebrovascular reactivity (CVR) measurements obtained using the blood-oxygen level dependent (BOLD) response to controlled changes in end-tidal partial pressure of carbon dioxide (PETCO(2)). MATERIALS AND METHODS: We obtained ethical approval to image 19 healthy volunteers (10 men, 9 women) on a 1.5 Tesla (T) MRI scanner twice on two separate days using identical procedures. CVR images were generated by collecting BOLD MRI data during controlled changes in PETCO(2) induced by a sequential gas delivery system. RESULTS: Using the intraclass correlation coefficient (ICC), we demonstrated excellent within-day CVR measures in gray matter (GM) (ICC = 0.92) and white matter (WM) (ICC = 0.88) regions, excellent between-day reproducibility in GM (ICC = 0.81), and good between-day reproducibility in the WM (ICC = 0.66). CVR values between men and women were significantly different in the GM and WM. Men exhibited a 22 +/- 2% greater CVR in GM and a 17 +/- 2% greater CVR in WM compared with females. CONCLUSION: Our results demonstrate the reliability of BOLD MRI CVR measurements obtained using a controlled cerebrovascular challenge. Using this technique, we also revealed significantly increased BOLD response to CO(2) in males compared with females.