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 CO 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.

Key pointsr Cerebrovascular reactivity (CVR) reflects the vasodilatory reserve of cerebral resistance vessels. r 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.r The study acquired magnetic resonance imaging measures of CVR and CBF in healthy children and young adults to trace their changes with age.r 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.r 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 CO 2 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.

Breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging is a repeatable technique for the assessment of cerebrovascular reactivity in children with Moyamoya disease and is reliably interpretable for use in clinical practice. Standardization of such protocols will allow further research into its application for the assessment of ischemic risk in childhood cerebrovascular disease.

Acute ischemic stroke (AIS) often results in degeneration of the blood-brain barrier (BBB), which can lead to vasogenic edema and an increased risk of intracerebral hemorrhage. Imatinib is an agent that may be able to protect the BBB and reduce the risk of the harmful consequences of BBB degeneration. We sought to measure the effect of Imatinib on the BBB after experimental stroke longitudinally in vivo with permeability dynamic contrast-enhanced MRI. Ischemia/reperfusion injury was induced with a transient middle cerebral artery occlusion surgery. Rats were given Imatinib at 2 and 20 h after stroke onset. Post-assessment included neurologic functioning, MR imaging, Evans Blue extravasation, Western blot, and immunohistology assay. Imatinib protected the BBB by 24 h but failed to decrease BBB permeability at an earlier time-point. Imatinib also reduced infarct volume, edema, and improved neurologic functioning by 24 h. Rats treated with Imatinib also had a higher expression of the BBB structural protein Zona ocludens-1 and a reduction in nuclear factor-kappa beta (NF-κβ) activation. Imatinib is a promising agent to protect the BBB after AIS, but its effect on the BBB may not become prominent until 24 h after the onset of ischemia. This finding may help elucidate Imatinib's role in the clinical management of AIS and influence future study designs.

ObjectivesCerebrovascular reactivity (CVR) measures the ability of cerebral blood vessels to change their diameter and, hence, their capacity to regulate regional blood flow in the brain. High resolution quantitative maps of CVR can be produced using blood-oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in combination with a carbon dioxide stimulus, and these maps have become a useful tool in the clinical evaluation of cerebrovascular disorders. However, conventional CVR analysis does not fully characterize the BOLD response to a stimulus as certain regions of the brain are slower to react to the stimulus than others, especially in disease. Transfer function analysis (TFA) is an alternative technique that can account for dynamic temporal relations between signals and has recently been adapted for CVR computation. We investigated the application of TFA in data on children with sickle cell disease (SCD) and healthy controls, and compared them to results derived from conventional CVR analysis.Materials and methodsData from 62 pediatric patients with SCD and 34 age-matched healthy controls were processed using conventional CVR analysis and TFA. BOLD data were acquired on a 3 Tesla MRI scanner while a carbon dioxide stimulus was quantified by sampling the end-tidal partial pressures of each exhaled breath. In addition, T1 weighted structural imaging was performed to identify grey and white matter regions for analysis. The TFA method generated maps representing both the relative magnitude change of the BOLD signal in response to the stimulus (Gain), as well as the BOLD signal speed of response (Phase) for each subject. These were compared to CVR maps calculated from conventional analysis. The effect of applying TFA on data from SCD patients versus controls was also examined.ResultsThe Gain measures derived from TFA were significantly higher than CVR values based on conventional analysis in both SCD patients and healthy controls, but the difference was greater in the SCD data. Moreover, while these differences were uniform across the grey and white matter regions of controls, they were greater in white matter than grey matter in the SCD group. Phase was also shown to be significantly correlated with the amount that TFA increases CVR estimates in both the grey and white matter.ConclusionsWe demonstrated that conventional CVR analysis underestimates vessel reactivity and this effect is more prominent in patients with SCD. By using TFA, the resulting Gain and Phase measures more accurately characterize the BOLD response as it accounts for the temporal dynamics responsible for the CVR underestimation. We suggest that the additional information offered through TFA can provide insight into the mechanisms underlying CVR compromise in cerebrovascular diseases.