Imaging the Ischaemic Penumbra using BOLD MRI with oxygen challenge as a metabolic biotracer
Lead Research Organisation:
University of Glasgow
Department Name: Institute of Neuroscience & Psychology
Abstract
Stroke is a major killer, and has a greater disability impact than any other chronic disease. Patients occupy one of the largest numbers of acute hospital bed days of any patient group (2.6 million per year), and the disease consumes between 4-6% of NHS expenditure (approx £2.8 billion) with costs projected to rise 30% by 2010 as life expectancy and survive rates increase.
Treatment options are limited (clot busting drugs like rt-PA or aspirin) with less than 2% of stroke patients receiving rt-PA since it must be given within 3 hours of stroke for safety reasons, and patients must have a brain scan first to rule out brain haemorrhage.
rt-PA is very effective in patients where brain damage has not fully evolved. In the first few hours after stroke, injured but potentially salvageable tissue (penumbra) can be saved by rt-PA. Penumbral tissue can be identified by magnetic resonance imaging (MRI), but current techniques underestimate penumbra size. If a rapid, more accurate MRI technique was available, more patients could be treated and recruitment into clinical trials to study new therapies, improved. This proposal describes development and validation of such a technique and provides preliminary MRI data from animal models and man.
Treatment options are limited (clot busting drugs like rt-PA or aspirin) with less than 2% of stroke patients receiving rt-PA since it must be given within 3 hours of stroke for safety reasons, and patients must have a brain scan first to rule out brain haemorrhage.
rt-PA is very effective in patients where brain damage has not fully evolved. In the first few hours after stroke, injured but potentially salvageable tissue (penumbra) can be saved by rt-PA. Penumbral tissue can be identified by magnetic resonance imaging (MRI), but current techniques underestimate penumbra size. If a rapid, more accurate MRI technique was available, more patients could be treated and recruitment into clinical trials to study new therapies, improved. This proposal describes development and validation of such a technique and provides preliminary MRI data from animal models and man.
Technical Summary
Further development of acute stroke imaging is required to determine whether potentially salvageable tissue (penumbra) is still present, to improve treatment decisions for individual patients, and to enhance patient selection for clinical trials. An MRI-based technique which could disriminate between metabolically active and inactive tissue would represent a significant advance in physiological brain imaging and provide a means to study penumbral tissue and factors which influence its survival. This proposal describes such a technique, based on BOLD contrast and signal changes in brain associated with ventilating with 100% oxygen versus air which we believe will discriminate between ischaemic core and penumbra. BOLD contrast is sensitive to changes in oxy:deoxyhaemoglobin ratios during this ?oxygen challenge?. The planned studies will determine whether it can be developed to produce an improved technique for defining the ischaemic penumbra. Pilot experiments in animals and man provide novel and convincing data to support our hypothesis that oxygen can be used as a biotracer to identify metabolically active tissue within the ischaemic brain.
The BOLD oxygen challenge technique (BOC) will be developed and validated using permanent middle cerebral artery occlusion (MCAO) in rats (Studies 1-3) and the consequences of reperfusion on identified penumbral tissue studied with transient MCAO (Study 4). Study 1: defining diffusion and perfusion thresholds for ischaemic damage and characterising tissue response to oxygen challenge over time. The response of ischaemic brain to BOC will be studied 1,2,3 & 4 hours post-MCAO to differentiate ischaemic core from penumbra and results compared with tissue injury assessed by diffusion-weighted imaging (DWI) and perfusion deficit assessed with arterial spin labelling (ASL). Study 2: Technique validation. Cerebral blood flow (CBF) and tissue oxygen levels will be recorded simultaneously within penumbral cortex during oxygen challenge to confirm that BOLD signal changes are related to oxygen utilisation by tissue and not to a change in CBF associated with changes in PaO2. Study 3: Confirming tissue viability within the defined penumbra. [14C] 2-deoxyglucose autoradiography will be used to confirm that tissue identified as penumbra by BOC, shows evidence of metabolic activity. Study 5: Consequences of reperfusion on penumbra. BOC, DWI and ASL conducted during ischaemia and following reperfusion to assess the consequences of reperfusion on tissue viability. In a separate group, BOC combined with assessment of perfusion deficit will define penumbral tissue, reperfusion will be induced and final infarct size determined (from T2) at day 7.
The BOLD oxygen challenge technique (BOC) will be developed and validated using permanent middle cerebral artery occlusion (MCAO) in rats (Studies 1-3) and the consequences of reperfusion on identified penumbral tissue studied with transient MCAO (Study 4). Study 1: defining diffusion and perfusion thresholds for ischaemic damage and characterising tissue response to oxygen challenge over time. The response of ischaemic brain to BOC will be studied 1,2,3 & 4 hours post-MCAO to differentiate ischaemic core from penumbra and results compared with tissue injury assessed by diffusion-weighted imaging (DWI) and perfusion deficit assessed with arterial spin labelling (ASL). Study 2: Technique validation. Cerebral blood flow (CBF) and tissue oxygen levels will be recorded simultaneously within penumbral cortex during oxygen challenge to confirm that BOLD signal changes are related to oxygen utilisation by tissue and not to a change in CBF associated with changes in PaO2. Study 3: Confirming tissue viability within the defined penumbra. [14C] 2-deoxyglucose autoradiography will be used to confirm that tissue identified as penumbra by BOC, shows evidence of metabolic activity. Study 5: Consequences of reperfusion on penumbra. BOC, DWI and ASL conducted during ischaemia and following reperfusion to assess the consequences of reperfusion on tissue viability. In a separate group, BOC combined with assessment of perfusion deficit will define penumbral tissue, reperfusion will be induced and final infarct size determined (from T2) at day 7.
