Imaging stroke risk in children

Background:
This project will establish a link between UCL GOSH ICH and Hospital for Sick Children (Sickkids), Toronto to study pathophysiology of first and recurrent arterial ischaemic stroke (AIS) in children, in which there is reduced blood flow secondary to arteriopathy.1 Paediatric AIS is associated with diverse risk factors different to that of adults, including anaemias of genetic origin, such as sickle cell disease (SCD),1 as well as iron deficiency. With anaemia and hypoxia, cerebral blood flow (CBF) is maintained by dilatation of vessels, which is exacerbated after a stroke. When that compensatory mechanism is exhausted and CBF can no longer increase, the oxygen extraction fraction (OEF) increases up to a point where there is insufficient delivery of oxygen to meet the metabolic demand and tissue is at risk of permanent damage;2 this may also be examined using the cerebrovascular response to carbon dioxide (CVR).3 Recurrence occurs in up to a quarter of children with a first stroke. Prevention of first stroke by screening in SCD, and of recurrent stroke in all children with first stroke, are immediate goals. Quantitative magnetic resonance imaging (MRI) techniques,4,5 including CBF, OEF and CVR, as endpoints in randomised controlled trials (RCTs) will enable this soon.

Aims/Objectives:
In children with SCD and those convalescing from acute stroke:
1. To examine the effect of intracranial vasculopathy on quantitative MRI
2. To compare methods of assessing cerebral haemodynamic reserve
3. To compare quantitative MRI of CBF and functional connectivity

Methods:
In year 1, the student will address objectives 1 and 3 in the data available for the SCD cohorts (n>150) from ICH. For objective 1 the majority of the vasculopathy data have been graded.1 The student will be taught how to analyse diffusion tensor4 and arterial spin labelling (ASL)5 data by Prof Clark and his team for comparison with the vasculopathy grading. For objective 3, resting state and ASL data have been acquired in at least 43 patients with SCD but require processing. The student may acquire quantitative MRI data at ICH from young children with SCD undergoing MRI as part of the Montelukast RCT.
At the beginning of year 2, the student will spend 6 months in Toronto comparing the ICH SCD data with the Sickkids AIS data for aims 1 and 3. In addition, s/he will learn more about the practicalities of acquiring CVR data using the breath hold technique. In the 2nd half of year 2, s/he will conduct a pilot study in consenting children with SCD in the Montelukast trial to compare CVR using a breath hold3 with TRUST and QSM OEF data.2

Collaboration with University of Toronto:
Prof Kirkham is a clinical academic with an international reputation in studying the pathophysiology of stroke in childhood, particularly SCD. She has collaborated for several years with Prof Clark (including supervision of Dr Dlamini’s PhD) and Dr Shmueli, who have equally strong international reputations in quantitative MRI. Dr Dlamini in Toronto, has unique experience in the conduct of MR CVR studies in young children.

Timeline:
Year 1 at GOSH ICH, first 6 months of Year 2 in Toronto, remainder at GOSH ICH.

References:
1.   Dlamini, N., et al (2017) Neurology, 89(24), 2406–2412.
2.   Stotesbury, HA, et al  (2020a) ISMRM August 2020.
3.   Dlamini, N., et al. AJNR. American journal of neuroradiology, 39(9), 1717–1723.
4.   Jacob, M. et al (2020). Stroke, 51(4), 1166–1173.
5.   Kawadler, J.M., NMR Biomed. 2018;31(6):e3915.