Imaging

    the Department of Neurology (J.-C.B.), Cambridge University, Cambridge, UK
    the National Institute of Neurological Disorders and Stroke (S.W.), National Institutes of Health, Bethesda, Md.

    Key Words: Advances in Stroke  diffusion magnetic resonance imaging  magnetic resonance imaging  positron-emission tomography

    Acute Stroke

    The Melbourne group reported further application of the positron-emission tomography (PET) hypoxia marker 18F-labeled fluoromisonidazole (F-MISO).1–3 In one article, they further developed and validated their novel imaging methodology to map the penumbra using this tracer.1 Applying this method, they elegantly showed that hypoxia affects white matter to a similar degree and extent as gray matter, suggesting the former has at least as high a resistance to ischemia than the latter and that its salvage should help to maximize benefit of treatment.2 In a third article,3 they report that the impact of hypoxic tissue escaping infarction on subsequent clinical recovery is similar whether the tissue is identified within 12 hours of, or in the 12- and 48-hour interval after stroke onset, documenting that F-MISO identifies true penumbral tissue, and that, consistent with earlier evidence, appropriate interventions should improve outcome even beyond 24 hours.

    The year 2004 has seen the first, long-awaited, articles reporting direct PET and diffusion-weighted imaging (DWI)/perfusion-weighted imaging (PWI) comparisons.4–6 Using state-of-the-art diffusion tensor imaging (DTI) and fully quantitative PET as gold standard, Guadagno et al4 documented that the acute DWI lesion not only contains irreversibly damaged, but also penumbral tissue, in agreement with studies showing potential reversibility of the DWI lesion, while even severe apparent diffusion coefficient decreases can be found in either tissue category. One therapeutic implication is that a matched DWI/PWI lesion may still represent, at least in part, salvageable tissue. Comparing the predictive value of DWI and 11C-Flumazenil (FMZ) for final infarction, Heiss et al5 found that although both have similar overall predictive power (around 84% of the final infarct), false-positives occurred with DWI but not with FMZ, consistent with the Guadagno et al findings.4 Assessing the validity of PWI to assess the at-risk tissue by means of PET, Sobesky et al6 concluded that overall the simple DWI-PWI mismatch overestimates the penumbra, but the use of time-to-peak (TTP) delay maps helps toward solving this problem, with TTP delays >4 s being best suited. These results apply specifically to the TTP method of deriving magnetic resonance imaging (MRI) perfusion maps; other methods, such as mean transit time (MTT) maps, may be less prone to overestimate the region of symptomatic ischemia.7 Thijs et al8 found large variations in hypoperfusion lesion size with different arterial input function (AIF) locations used to derive MRI perfusion maps. They found that the AIF derived from the contralateral middle cerebral artery (MCA) gave ischemic volumes that most accurately predicted follow-up lesion volume.

    The sensitivity of MRI relative to computed tomography (CT) has now been established for acute hemorrhage diagnosis in patients with focal stroke symptoms of less than 6 hours duration. Susceptibility-weighted MRI, most commonly the gradient-recalled echo (GRE) sequence, is used for that purpose. Fiebach et al9 found near perfect discrimination of hemorrhagic from ischemic stroke on MRI in a sample containing 62 cases of each, obtained in <6 hours: 100% sensitivity among experts; 95% sensitivity among medical students after a brief tutorial. Kidwell et al10 prospectively investigated a broad sample of 200 stroke patients, in which MRI followed by CT was obtained in <6 hours. The consensus of 4 experts’ independent, blinded reads found MRI superior for detecting any hemorrhage (because of MRI sensitivity to micro- and other chronic bleeds) and equivalent for acute hemorrhage, which was diagnosed by both modalities in 25 patients. There were 8 discrepant reads, 4 in either direction, for acute hemorrhage. Three of the discrepant cases of acute hemorrhage on CT were also diagnosed by MRI but classified incorrectly as chronic hemorrhage. However, 4 cases of acute hemorrhagic transformation on MRI were missed on CT. Smaller retrospective series have also reported cases of hemorrhagic transformation evident on susceptibility-weighted MRI but not CT following thrombolytic therapy,11,12 including cases where CT findings were equivocal because of residual angiography contrast.11

    As evidence continues to confirm that prethrombolysis severity of clinical or MRI parameters predict outcome with recanalization, so does evidence that resolution of perfusion deficits is predictive of clinical recovery. Singer et al13 reported that greater amounts of at-risk tissue did not progress to infarct among patients who had recanalized relative to those who had not in a sample of 17; 80% of the MTT defect and 78% of the TTP 2 s delayed region did not progress to infarct on follow-up imaging. Chalela et al14 reported in a sample of 42 patients that resolution of at least 30% of the volume of MTT defect by 2 hours after standard IV tissue plasminogen activator treatment was associated with excellent clinical outcome (modified Rankin score of 0 or 1). This degree of early reperfusion was a stronger predictor of outcome than pretreatment clinical severity or the volume of pretreatment diffusion or hypoperfusion lesion. This 30% early reperfusion criterion associated with 90-day clinical recovery in thrombolytic therapy was confirmed in the Desmoteplase In Acute Stroke (DIAS) Trial,15 a randomized placebo controlled trial that found a similar dose positive response on both early reperfusion (using 30% or greater resolution of MTT volume) and excellent 90-day clinical outcome. Significant clinical benefits at the highest dose were observed when this thrombolytic therapy was initiated 3 to 9 hours from onset. The DIAS trial also illustrated that the simple diffusion-perfusion mismatch, although an overestimate of true penumbra, may effectively select the target population for intravenous thrombolytic trials beyond the 3-hour time window.

    There is growing interest in understanding the potential role of tissue inflammation after stroke. Using single photon emission computed tomography (SPECT) and 111In-troponolate-labeled neutrophils, Price et al16 longitudinally studied cerebral neutrophil recruitment after MCA stroke. Significant neutrophil recruitment was demonstrated within 24 hours of onset and shown to attenuate over time. Neutrophil accumulation appeared to correlate significantly with infarct expansion. PET studies using the activated microglia-specific ligand 11C-PK11 195 are now awaited.

    Three novel applications of MRI contrast material show promise for clinical application. Invasion of macrophages into the evolving infarction has been demonstrated in patients with T1-weighted MRI by Saleh and colleagues following injection of ultrasmall superparamagnetic iron oxide (USPIO) particles, which are taken up by macrophages 1 week after ischemic stroke.17 Increasing contrast, distinct from the pattern of parenchymal gadolinium enhancement, was found from 24 to 48 hours after injection, indicative of increasing accumulation of labeled macrophages.

    Latour and colleagues18 identified gadolinium enhancement on fluid-attenuated inversion recovery MRI of the intrasulcal and other hemispheric CSF spaces indicative of blood brain barrier disruption <12 hours after onset of ischemia in acute stroke patients. This enhancement pattern was associated with reperfusion, risk of hemorrhagic transformation and worse clinical outcome and was exacerbated by treatment with thrombolytics, suggesting this marker may have utility in evaluating strategies to decrease hemorrhagic risk of thrombolytics.

    Barber and colleagues19 demonstrated binding of a novel MRI contrast agent, gadolinium-DTPA-sLe(x) A, to activated endothelium in a mouse ischemic stroke model. Such targeted contrast agents might one day find clinical application in developing therapeutic strategies addressing inflammatory response to ischemia/reperfusion.

    Carotid Disease

    It is well established that in patients with symptomatic internal carotid artery (ICA) occlusion the presence of misery perfusion or severely impaired vasodilatory reserve considerably increases the risk of subsequent ipsilateral stroke, justifying ongoing trials of extracranial/intracranial bypass on selected patients. Yamauchi et al20 found evidence that by resetting the oxygen needs of the tissue the occurrence of cortical metabolic depression (secondary to diaschisis or selective neuronal damage in patients with striatocapsular infarction) might "mask" misery perfusion in ICA disease, a confounder that will be important to consider in future studies. In the same vein, Kuroda et al21 found that patients with ICA disease and reduced cerebral blood flow but normal vasodilatory reserve had cortical metabolic depression and proportionally reduced cortical FMZ binding, suggesting selective neuronal damage. Thus, cortical metabolic depression may afford protection from further ischemic events distal to ICA disease.

    In 2002, 18F-2-fluorodeoxyglucose–PET was shown to be able to detect inflammation within carotid plaques in vivo. This year, a novel tracer to detect plaque inflammation was reported in a preliminary form. Kietselaer et al22 used SPECT and 99mTc-annexin A5 to label apoptotic cells. They report increased uptake in symptomatic carotid bifurcations subsequently shown to exhibit evidence of plaque instability at histology, whereas stable plaques did not show increased uptake before endarterectomy. This type of approach may allow in the future the detection of patients most at risk of ischemic event –perhaps independently of degree of stenosis. Using USPIO-enhanced MRI with histological correlation, Trivedi et al23 found areas of signal intensity reduction within the plaque in 7 of 8 symptomatic patients, corresponding to USPIO particles accumulation in macrophages, with imaging being optimal 24 to 36 hours after contrast infusion.

    Plasticity

    A substantial number of functional MRI (fMRI) studies have addressed the neural processes underlying motor recovery after stroke.24–33 Although difficult to achieve, several longitudinal studies assessed both clinical recovery and fMRI patterns over time.24–29 Expanding on earlier studies, Ward et al25 showed that as recovery proceeds, there is correlated decrease in the amount of activation in widespread motor areas bilaterally, indicating less neural recruitment needed to perform the same task over time. Across patients, the amount of activation in these areas correlated with the severity of motor deficit at each time point, but a few cortical areas showed a significant change in this relationship,29 suggesting different rehabilitation strategies might be required as recovery proceeds. Excessive contralesional M1 activation is present during hand movement from the early stages after stroke,26,30 but does not appear to contribute directly (ie, via the uncrossed corticospinal tract) to recovery of affected hand as shown by single-pulse transcranial magnetic stimulation applied in the same patients;30 it might be part of a widespread top-down recruitment in an effort by the stroked brain to perform the task. In parallel with recovery under regular physiotherapy however, the activation pattern tends to return toward a more ipsilesional, ie, physiological, pattern.26 Consistent with this, intensive gait training is associated with shifts of activation toward the ipsilesional hemisphere, which correlate with the amount of gait recovery.31 In a randomized controlled trial, Luft et al32 found that relative to regular physiotherapy, additional bilateral arm training was associated with increased activation of bilateral motor areas, more so contralesionally, during affected elbow flexion-extension movements. This suggests that contralesional M1 activation may be useful for enhanced motor function after stroke, which may however relate to the proximal limb movement or the bilateral training used, or more likely to the fact that the patients were all severely affected. Studying patients with sensorimotor cortex infarcts during tactile exploration, Binkofski and Seitz26 found foci of activation in the cortex adjacent to the infarcted area as early as a few days from stroke, consistent with earlier studies indicating that survival of the peri-infarct penumbra offers opportunities for cortical map reorganization.

    In addition to fMRI, more studies using DTI in stroke are beginning to appear.34,35 Fractional anisotropy mapping was used to assess the presence and severity of corticospinal tract disruption, be it by direct damage33 or secondary Wallerian degeneration.34 Combining fractional anisotropy mapping or full DTI-derived tractography with fMRI should help to better understand the mechanisms underlying recovery. New methods to map progressive focal or extensive atrophy following stroke36 may also find similar applications.

    References

    Markus R, Donnan G, Kazui S, Read S, Reutens D. Penumbral topography in human stroke: methodology and validation of the ‘Penumbragram’. Neuroimage. 2004; 21: 1252–1259.

    Falcao AL, Reutens DC, Markus R, Koga M, Read SJ, Tochon-Danguy H, Sachinidis J, Howells DW, Donnan GA. The resistance to ischemia of white and gray matter after stroke. Ann Neurol. 2004; 56: 695–701.

    Markus R, Reutens DC, Kazui S, Read S, Wright P, Pearce DC, Tochon-Danguy HJ, Sachinidis JI, Donnan GA. Hypoxic tissue in ischaemic stroke: persistence and clinical consequences of spontaneous survival. Brain. 2004; 127: 1427–1436.

    Guadagno JV, Warburton EA, Aigbirhio FI, Smielewski P, Fryer TD, Harding S, Price CJ, Gillard JH, Carpenter TA, Baron JC. Does the acute diffusion-weighted imaging lesion represent penumbra as well as core A combined quantitative PET/MRI voxel-based study. J Cereb Blood Flow Metab. 2004; 24: 1249–1254.

    Heiss WD, Sobesky J, Smekal U, Kracht LW, Lehnhardt FG, Thiel A, Jacobs AH, Lackner K. Probability of cortical infarction predicted by flumazenil binding and diffusion-weighted imaging signal intensity: a comparative positron emission tomography/magnetic resonance imaging study in early ischemic stroke. Stroke. 2004; 35: 1892–1898.

    Sobesky J, Weber OZ, Lehnhardt FG, Hesselmann V, Thiel A, Dohmen C, Jacobs A, Neveling M, Heiss WD. Which time-to-peak threshold best identifies penumbral flow A comparison of perfusion-weighted magnetic resonance imaging and positron emission tomography in acute ischemic stroke. Stroke. 2004; 35: 2843–2847.

    Rose SE, Janke AL, Griffin M, Finnigan S, Chalk JB. Improved prediction of final infarct volume using bolus delay-corrected perfusion-weighted MRI: implications for the ischemic penumbra. Stroke. 2004; 35: 2466–2471.

    Thijs VN, Somford DM, Bammer R, Robberecht W, Moseley ME, Albers GW. Influence of arterial input function on hypoperfusion volumes measured with perfusion-weighted imaging. Stroke. 2004; 35: 94–98.

    Fiebach JB, Schellinger PD, Gass A, Kucinski T, Siebler M, Villringer A, Olkers P, Hirsch JG, Heiland S, Wilde P, Jansen O, Rother J, Hacke W, Sartor K. Kompetenznetzwerk Schlaganfall B5. Stroke magnetic resonance imaging is accurate in hyperacute intracerebral hemorrhage: a multicenter study on the validity of stroke imaging. Stroke. 2004; 35: 502–506.

    Kidwell CS, Chalela JA, Saver JL, Starkman S, Hill MD, Demchuk AM, Butman JA, Patronas N, Alger JR, Latour LL, Luby ML, Baird AE, Leary MC, Tremwel M, Ovbiagele B, Fredieu A, Suzuki S, Villablanca JP, Davis S, Dunn B, Todd JW, Ezzeddine MA, Haymore J, Lynch JK, Davis L, Warach S. Comparison of MRI and CT for detection of acute intracerebral hemorrhage. JAMA. 2004; 292: 1823–1830.

    Arnould MC, Grandin CB, Peeters A, Cosnard G, Duprez TP. Comparison of CT and three MR sequences for detecting and categorizing early (48 hours) hemorrhagic transformation in hyperacute ischemic stroke. AJNR Am J Neuroradiol. 2004; 25: 939–944.

    Greer DM, Koroshetz WJ, Cullen S, Gonzalez RG, Lev MH. Magnetic resonance imaging improves detection of intracerebral hemorrhage over computed tomography after intra-arterial thrombolysis. Stroke. 2004; 35: 491–495.

    Singer OC, Du Mesnil De Rochemont R, Foerch C, Stengel A, Sitzer M, Lanfermann H, Neumann-Haefelin T. Early functional recovery and the fate of the diffusion/perfusion mismatch in patients with proximal middle cerebral artery occlusion. Cerebrovascular Diseases. 2004; 17: 13–20.

    Chalela JA, Kang DW, Luby M, Ezzeddine M, Latour LL, Todd JW, Dunn B, Warach S. Early magnetic resonance imaging findings in patients receiving tissue plasminogen activator predict outcome: Insights into the pathophysiology of acute stroke in the thrombolysis era. Annals of Neurology. 2004; 55: 105–112.

    Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, Fischer M, Furlan A, Kaste M, Lees KR, Soehngen M, Warach S. The Desmoteplase In Acute Ischemic Stroke Trial (DIAS). A phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005; 36: 66–73.

    Price CJ, Menon DK, Peters AM, Ballinger JR, Barber RW, Balan KK, Lynch A, Xuereb JH, Fryer T, Guadagno JV, Warburton EA. Cerebral neutrophil recruitment, histology, and outcome in acute ischemic stroke: an imaging-based study. Stroke. 2004; 35: 1659–1664.

    Saleh A, Schroeter M, Jonkmanns C, Hartung H, Mdder U, Jander S. In vivo MRI of brain inflammation in human ischaemic stroke. Brain. 2004; 127: 1670–1677.

    Latour LL, Kang DW, Ezzeddine MA, Chalela JA, Warach S. Early blood-brain barrier disruption in human focal brain ischemia. Annals of Neurology. 2004; 56: 468–477.

    Barber PA, Foniok T, Kirk D, Buchan AM, Laurent S, Boutry S, Muller RN, Hoyte L, Tomanek B, Tuor UI. MR molecular imaging of early endothelial activation in focal ischemia. Annals of Neurology. 2004; 56: 116–120.

    Yamauchi H, Kudoh T, Sugimoto K, Takahashi M, Kishibe Y, Okazawa H. Pattern of collaterals, type of infarcts, and haemodynamic impairment in carotid artery occlusion. J Neurol Neurosurg Psychiatry. 2004; 75: 1697–1701.

    Kuroda S, Shiga T, Ishikawa T, Houkin K, Narita T, Katoh C, Tamaki N, Iwasaki Y. Reduced blood flow and preserved vasoreactivity characterize oxygen hypometabolism due to incomplete infarction in occlusive carotid artery diseases. J Nucl Med. 2004; 45: 943–949.

    Kietselaer BL, Reutelingsperger CP, Heidendal GA, Daemen MJ, Mess WH, Hofstra L, Narula J. Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N Engl J Med. 2004; 350: 1472–1473.

    Trivedi RA, U-King-Im JM, Graves MJ, Cross JJ, Horsley J, Goddard MJ, Skepper JN, Quartey G, Warburton E, Joubert I, Wang L, Kirkpatrick PJ, Brown J, Gillard JH. In vivo detection of macrophages in human carotid atheroma: temporal dependence of ultrasmall superparamagnetic particles of iron oxide-enhanced MRI. Stroke. 2004; 35: 1631–1635.

    Loubinoux I, Carel C, Pariente J, Dechaumont S, Albucher JF, Marque P, Manelfe C, Chollet F. Correlation between cerebral reorganization and motor recovery after subcortical infarcts. Neuroimage. 2003; 20: 2166–2180.

    Ward NS, Brown MM, Thompson AJ, Frackowiak RS. Neural correlates of motor recovery after stroke: a longitudinal fMRI study. Brain. 2003; 126: 2476–2496.

    Binkofski F, Seitz RJ. Modulation of the BOLD-response in early recovery from sensorimotor stroke. Neurology. 2004; 63: 1223–1229.

    Nhan H, Barquist K, Bell K, Esselman P, Odderson IR, Cramer SC. Brain function early after stroke in relation to subsequent recovery. J Cereb Blood Flow Metab. 2004; 24: 756–763.

    Calautti C, Leroy F, Guincestre JY, Baron JC. Displacement of primary sensorimotor cortex activation after subcortical stroke: a longitudinal PET study with clinical correlation. Neuroimage. 2003; 19: 1650–1654.

    Ward NS, Brown MM, Thompson AJ, Frackowiak RS. The influence of time after stroke on brain activations during a motor task. Ann Neurol. 2004; 55: 829–834.

    Foltys H, Krings T, Meister IG, Sparing R, Boroojerdi B, Thron A, Topper R. Motor representation in patients rapidly recovering after stroke: a functional magnetic resonance imaging and transcranial magnetic stimulation study. Clin Neurophysiol. 2003; 114: 2404–2415.

    Miyai I, Yagura H, Hatakenaka M, Oda I, Konishi I, Kubota K. Longitudinal optical imaging study for locomotor recovery after stroke Stroke. 2003; 34: 2866–2870.

    Luft AR, McCombe-Waller S, Whitall J, Forrester LW, Macko R, Sorkin JD, Schulz JB, Goldberg AP, Hanley DF. Repetitive bilateral arm training and motor cortex activation in chronic stroke: a randomized controlled trial. JAMA. 2004; 292: 1853–1861.

    Feydy A, Krainik A, Bussel B, Maier MA. Cortical reorganization allows for motor recovery after crossed cerebrocerebellar atrophy. J Neuroimaging. 2004; 14: 49–53.

    Thomalla G, Glauche V, Koch MA, Beaulieu C, Weiller C, Rother J. Diffusion tensor imaging detects early Wallerian degeneration of the pyramidal tract after ischemic stroke. Neuroimage. 2004; 22: 1767–1774.

    Lie C, Hirsch JG, Rossmanith C, Hennerici MG, Gass A. Clinicotopographical correlation of corticospinal tract stroke: a color-coded diffusion tensor imaging study. Stroke. 2004; 35: 86–92.

    Kraemer M, Schormann T, Hagemann G, Qi B, Witte OW, Seitz RJ. Delayed shrinkage of the brain after ischemic stroke: preliminary observations with voxel-guided morphometry. Journal of Neuroimaging. 2004; 14: 265–272.