Quantitative MR Imaging of Acute Stroke Risto Kauppinen

Acute Stoke: Advances since 1990 Unambiguous diagnosis of acute ischemia by MRI (1990) Monitoring expansion of ischaemic damage by MRI (1991) rtPA introduced as a therapeutic agent (1996) Availability of CT scans for stroke A & E (since mid 90s) [Shift to 3T MR scanners in Clinical Radiology (since 2005)] [Computing power has increased and become cheaper]

MRI: translation to clinic DWI (45 min) T2w (65 min)

MRI: translation to clinic DWI (45 min) T2w (65 min) Kuharchyck et al. 1991 Warach et al. 1992

Quantitative MRI (qMRI) Each pixel in an image is represented by a physically meaningful number - Relaxation times (T1, T2, T1r), ADC, haemodynamics etc. Normative values - Requires acquisition of multiple data points Griffin JL et al. Cancer Res 63:3195, 2003

qMRI in clinical settings Griffin JL et al. Cancer Res 63:3195, 2003

qMRI in clinical settings Griffin JL et al. Cancer Res 63:3195, 2003

Expectations from imaging in clinics Griffin JL et al. Cancer Res 63:3195, 2003 Radiol Clin N Am 49:1-26 (2011)

Goals in acute stroke management Rescue the penumbra by maximising use of available treatment strategies Patient –specific management Guide patient triaging for investigational therapies

qMRI: Diffusion MRI in acute ischaemia DWI ADC image -Catastrophic drop in CBF -Energy failure -Depolarisation -Disturbance in water homeostasis Change in temperature and changes in relaxation times might also influence the estimation of pH from ΔPTR.

ADC and Blood Flow Ischaemia compromised normal blood flow Grohn et al. J Cereb Blood Flow Metab 20: 316, 2000

ADC and Blood Flow ADC/Trace decrease in acute ischaemia Ischaemia penumbra normal blood flow ADC/Trace decrease in acute ischaemia is not an ON-OFF event motivation for qMRI Grohn et al. J Cereb Blood Flow Metab 20: 316, 2000

qMRI: pixelwise histogram of ADCs ADC map Normal Ischaemic + compromised V O L U M E

qMRI: pixelwise histogram of ADCs ADC map Normal Ischaemic + compromised V O L U M E

qMRI: Potentials of (q)ADC State of tissue beyond perfusion-diffusion mismatch as assessed by volume (mis)match Degree of ischaemia in parenchyma Guide patient selection for reperfusion therapy

qMRI: Potentials of (q)ADC State of tissue beyond perfusion-diffusion mismatch as assessed by volume (mis)match Degree of ischaemia in parenchyma Guide patient selection for reperfusion therapy

MR relaxometry Image pixels are either absolute T1 or T2 relaxation times Absolute T1/T2 are much more sensitive to parenchymal alterations than either T1w or T2w images Change in temperature and changes in relaxation times might also influence the estimation of pH from ΔPTR.

T1 and T2 in acute stroke

Multiparametric qMRI in acute ischaemia 24 h after ischaemia Dav T1r T2 25 min of reperfusion 40 60 80 100 120 T1r (ms) 20 T2 (ms) 0.5 0.6 0.7 0.8 0.9 Dav ( 10-3 mm2/s) 50 70 90 45 55 65 75 35 min of hypoperfusion 45 min of This slide summarises results from both hypoperfusion and MCA occlusion models. It becomes clear that misery perfusion without energy failure, et with negative BOLD response in T2 MRI, does not affect T1rho. I will explain why this happens little later. In the transient MCA occlusion model we have an interesting dissociation between diffusion and T1rho MRI. In the cortical brain after occlusion diffusion recovers, however, T1rho shows elevated values in this tissue type. During the course of insult the entire MCA territory develops infarction. This is very interesting suggesting that elevated T1rho in a sign of irreversible ischaemia. Gröhn O.H.J. et al. MRM 42: 268, 1999

Acute ischaemia DDav (10-3 mm2/s) DT2 (ms) Time post-ischaemia (min) Transition to irreversible 4 0.2 0.1 2 20 40 60 80 * 20 40 60 80 DT2 (ms) DDav (10-3 mm2/s) -0.1 * -0.2 -2 * * * * ** * * * -0.3 * -4 * ** -0.4 ** -6 -0.5 Time post-ischaemia (min) Time post-ischaemia (min) In fact, one can find brain areas with differing time course for T2, for instance striatal ROI displays negative BOLD in the early moments of MCA occlusion and low diffusion. T2 returns to the normal or even above it as a result of transition to irreversible ischaemia. In contrast, cortex 1 on the periphery of ischaemia remain BOLD negative for much longer time, suggesting that there is collateral flow and oxygen uptake in this tissue and perhaps this tissue type would be salvageable by therapy. Cortex1 Cortex2 Putamen Areas analysed: Gröhn O et al. JCBFM 18:911 (1998)

Time of Stroke Onset by MRI Vertebral artery occlusions Remote control graded occlusion 2 days later remote controlled gradual occluder We have used several animal models to test our simulations, one of them being a variant of Pulsinelli model for 4-vessel occlusion. In this model vertebral arteries are permanemtly occluded 2 day prior to controlled restriction of flow in both carotid arteries. By doing so we can get a global control decline in blood flow. We have also used permanent hypoperfusion model in which a distal branch of MCA is occluded as well as standard thread occlusion of MCA through internal carotid aretry. Jokivarsi et al. Stroke 41; 2335-40, 2010

Time of Stroke Onset 2 days later remote controlled gradual occluder Vertebral artery occlusions Remote control graded occlusion 2 days later remote controlled gradual occluder We have used several animal models to test our simulations, one of them being a variant of Pulsinelli model for 4-vessel occlusion. In this model vertebral arteries are permanemtly occluded 2 day prior to controlled restriction of flow in both carotid arteries. By doing so we can get a global control decline in blood flow. We have also used permanent hypoperfusion model in which a distal branch of MCA is occluded as well as standard thread occlusion of MCA through internal carotid aretry. a) Controllable forebrain ischaemia b) Cortical hypoperfusion (’misery perfusion’) c) Middle cerebral artery (MCA) occlusion Jokivarsi et al. Stroke 41; 2335-40, 2010

Time of Stroke Onset 2 days later remote controlled gradual occluder Vertebral artery occlusions Remote control graded occlusion 2 days later remote controlled gradual occluder We have used several animal models to test our simulations, one of them being a variant of Pulsinelli model for 4-vessel occlusion. In this model vertebral arteries are permanemtly occluded 2 day prior to controlled restriction of flow in both carotid arteries. By doing so we can get a global control decline in blood flow. We have also used permanent hypoperfusion model in which a distal branch of MCA is occluded as well as standard thread occlusion of MCA through internal carotid aretry. a) Controllable forebrain ischaemia b) Cortical hypoperfusion (’misery perfusion’) c) Middle cerebral artery (MCA) occlusion Jokivarsi et al. Stroke 41; 2335-40, 2010

Time of Stroke Onset 2 days later remote controlled gradual occluder Vertebral artery occlusions Remote control graded occlusion 2 days later remote controlled gradual occluder Calibration for human brain parenchyma not trivial We have used several animal models to test our simulations, one of them being a variant of Pulsinelli model for 4-vessel occlusion. In this model vertebral arteries are permanemtly occluded 2 day prior to controlled restriction of flow in both carotid arteries. By doing so we can get a global control decline in blood flow. We have also used permanent hypoperfusion model in which a distal branch of MCA is occluded as well as standard thread occlusion of MCA through internal carotid aretry. a) Controllable forebrain ischaemia b) Cortical hypoperfusion (’misery perfusion’) c) Middle cerebral artery (MCA) occlusion Jokivarsi et al. Stroke 41; 2335-40, 2010

Absolute T2 in Acute Stroke <3 hours of stroke: qT2 @1.5T Cut-off 7.5ms Sensitivity 0.824 Accuracy 0.794 ROC 0.757 (ROC(ADC) 0.635) Siemonsen et al. Stroke 40: 1612, 2009

T1 in Acute Stroke Very early increase in T1 in Str by 63±16ms (+6%) 30 min 2.5 h 24 Very early increase in T1 in Str by 63±16ms (+6%) Able to discriminate lesion expansion and non-damaging cortex, despite similar CBF values in early stroke Change in temperature and changes in relaxation times might also influence the estimation of pH from ΔPTR.

Multi-parametric MRI of Acute Stroke T1rho increases upon ischaemia at the ischaemic blood flow threshold, i.e. at the threshold where ATP is exhausted, lactate accumulates and diffusion failure develops. Jokivarsi et al. MRM under revision

Multi-parametric MRI of Acute Stroke 30 min of ischaemia 24 hours of ischaemia S1 S2 C1 C2 C3 T1rho increases upon ischaemia at the ischaemic blood flow threshold, i.e. at the threshold where ATP is exhausted, lactate accumulates and diffusion failure develops. Jokivarsi et al. MRM under revision

qMR spectroscopy (qMRS) Focus on endogenous metabolites Change in temperature and changes in relaxation times might also influence the estimation of pH from ΔPTR.

State-of-the-art 1H MRS NAA Cr (lac) ‘1H MRS neurochemical profile at 3T’ Wilson et al. Magn Reson Med 65: 1 (2011)

1H MRS Metabolites in Stroke Cr NAA Lac Van der Toorn et al. MRM 32: 865 (1994)

1H MRS in Acute Stroke Saunders et al. JMRI 7: 1116 (1997)

Reduced NAA: clinical stroke syndrome, more extensive infarction, severe drop in blood flow, presence of lactate Increased lactate: large infarcts and reduced NAA

Reduced NAA: clinical stroke syndrome, more extensive infarction, severe drop in blood flow, presence of lactate Increased lactate: large infarcts and reduced NAA

Low NAA and high lactate predicted expansion of DWI lesion

qMR in acute stroke: Conclusions Potentials to provide clinically important data from a single exam Objective assessment of tissue status (early on) Potentially guides clinical management of patients Aids to maximise use of available therapies Allows patient –specific treatment protocols

qMRI/S in clinical setting Standard clinical hardware Requires expertise and commitment Standardised MR protocols Regular QA according to appropriate procedures Automated on-line data processing Computer-assisted decision making tools

Stroke Management in the 21st Century Active prevention Thrombolysis Minocyclin Hematopoetic growth factors Hypothermia Remote preconditioning

MR in Evaluation of Acute Stroke Patients in 2020s Application specific scanners Lower capital costs Lower running costs Increased availability at A&E Faster through-put Improved data quality Tissue status assignment for therapeutic procedures Improving overall outcome of stroke patients Change in temperature and changes in relaxation times might also influence the estimation of pH from ΔPTR.