Longitudinal MR imaging to characterize tissue damage patterns in acute ischemic stroke (ESCAPE-CORE)

Research summary

Acute ischemic stroke (AIS) is a major cause of disability and mortality worldwide. It is caused by an abrupt blockage of an arterial vessel to the brain that results in focal ischemia. The primary therapeutic goal is rapid blood flow restoration using established treatment strategies such as intravenous thrombolysis (IVT) or endovascular therapy (mechanical retraction of blood clots,[EVT]). Despite major advances in reperfusion therapies since EVT became the standard of care in 2015,up to 40% of patients treated with EVT remain disabled or die. Until reperfusion is achieved (and possibly in the initial time after macroscopic reperfusion) ischemic tissue progressively becomes irreversibly damaged,due to a series of deleterious cell-signalling pathways that are dependent on tissue type,cell-type,susceptibility,and severity (depth) and duration of ischemia. Numerous biochemical pathways have been uncovered that contribute to ischemic cell death,each with a varying role,and each with varying timing. The macroscopic categories in which we see and interpret ischemic damage include cytotoxic edema,vasogenic edema,blood-brain barrier disruption,hemorrhage,cystic necrosis resulting in encephalomalacia and more selective neuronal knock out resulting in late atrophy and distal Wallerian-type degeneration. Ultimately,the progressive nature of these biochemical mechanisms results in infarction and then re-modelling of the brain. Depending on the patient,type of brain tissue and pre-existing co-morbidities (susceptibility),the extent and severity of ischemia different imaging manifestations may emerge at varying time points after ischemic stroke onset. Our hypothesis is that we can identify unique imaging features of ischemic tissue damage obtained by sequential imaging beginning shortly after reperfusion and these features would reflect the underlying biochemical mechanisms of ischemic tissue damage. This understanding will provide a starting point to advance stroke therapies,including specific targets for cerebro-protection. Study objectives: ESCAPE-CORE is prospective serial magnetic resonance imaging (MRI) cohort study aimed at developing an advanced serial MRI toolbox to characterize distinct imaging signatures of ischemic tissue damage. It is intended to serve as the groundwork to inform the design of future adjunctive stroke treatment trials and the development of adjunct stroke therapies. Research plan: For this multicenter,prospective observational study,all patients with acute ischemic stroke due to an anterior circulation large vessel occlusion (LVO) at participating centers without contraindications for MRI who are intended to receive EVT will be enrolled. Study consent will be obtained according to local regulations,allowing for data collection from baseline up to 1 year follow-up. Those enrolled will undergo a pre-specified serial MRI protocol. Patient characteristics and treatment variables will be collected at baseline/after EVT. Clinical and imaging outcomes will be obtained at 90 (60-120) days. We will then assess a) the association of individual patient and treatment characteristics with tissue damage mechanisms,and b) their association with long-term cognitive,functional,and imaging outcomes. Inclusion criteria: • Large vessel occlusion in the anterior circulation (terminal internal carotid artery,M1 segment or proximal M2 segment middle cerebral artery occlusion) • Intention to treat with EVT • No contraindications to MRI • Adult patients (age 18 years or older) Exclusion criteria: • Contraindications to MRI (eg,incompatible pacemaker or other implants,sever renal failure) • Inability to complete 90-day follow up (eg,institutionalized in a nursing home) • Expected life expectancy <90 days (patient unlikely to survive until 90 day follow up) • Known pregnancy (in women of childbearing potential,a negative blood or urine beta-HCG pregnancy test is required prior to enrolment) Consent Process: Written,informed consent in our center will be obtained prior to enrolment according to a protocol approved by our local Research Ethics Board. Similarly,consent at the participating sites prior to enrolment will be obtained according to the local Research Ethics Board approvals. Participants who initially gave their consent to be enrolled in ESCAPE-CORE can withdraw their consent at any time during the study. Each potential participant will be assessed by the on-call stroke team who will ask the patients or the family for consent to contact the study team for possible study enrolment. If the patient is unable to consent or if the family is not immediately available,two physician consent process will be used to recruit the patients. If the subject or legally authorized representative withdraws consent,subject data will be included in the analysis up to the date of the consent withdrawal and withdrawal will be documented in the electronic RedCap CRF. Besides traditional,feature-based analysis,we will assess additionally collected imaging information that are not part of MRI tissue damage signatures but nevertheless collected (e.g.,diffusion tensor imaging),and use machine learning approaches that have been developed at the University of Calgary in collaboration with the department of Biomedical Engineering to predict patient outcomes based on serial MRI. Impact: At the time being,it is uncertain whether and to which extent the various tissue damage mechanisms contribute to the overall ischemic damage,their individual impact on clinical outcome,and whether certain tissue damage pathways predominate in certain AIS patient subgroups. ESCAPE-CORE will allow us to identify distinct MRI signatures of ischemic tissue damage mechanisms,and ideally,will set reference standards for specific ischemic tissue damage patterns. This will enable optimized patient selection and mechanism-specific outcome measures for stroke treatment,including cerebro-protective strategies. By doing so,ESCAPE core will provide an excellent starting point for future adjunctive EVT and cerebro-protection trials,paving the way for the transition of adjunctive EVT therapies into clinical routine. Ultimately,this will contribute to improve outcomes of AIS patients undergoing EVT.

Principal Investigator

Dr James Kennedy

Contact us

Email: Rachel.teal@ouh.nhs.uk

IRAS number

344577