Refl ection and Reaction

http://neurology.thelancet.com Vol 5 August 2006 639

Aβ is produced by many cell types in the body, including platelets, and to what extent plasma Aβ concentrations refl ect Aβ metabolism in the brain is uncertain. The study by van Oijen and co-workers lends support to a notion of a derangement of Aβ metabolism early in the patho-genesis of sporadic Alzheimer’s disease. However, whether plasma concentration of Aβ1–42, the central molecule in the disorder, is up or down still needs to be resolved.

Henrik Zetterberg, Kaj BlennowClinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, University of Göteborg, Sahlgren’s University Hospital, Mölndal, S-431 80 Mölndal, Swedenkaj.blennow@neuro.gu.se

KB has, on one occasion, received a consulting fee for an advisory board meeting from Innogenetics, but has no other confl icts of interest. HZ has no confl icts of interest.

1 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297: 353–56.

Brain imaging for thrombolysis Clinical suspicion of stroke needs to be confi rmed by brain imaging. CT, fi rst introduced in 1971,1 has now become the most widely available test for urgent assessment of patients with acute stroke. Development of diff usion-weighted imaging (DWI) to identify acute cerebral ischaemia2 has revolutionised MRI applications in stroke and more and more centres use MRI at the front line. However, questions remain. Which test is best suited for the decision whether to give thrombolysis? Which test can identify responders to reperfusion treatments beyond the strict 3 h time window?

Köhrmann and colleagues3 present a sizeable dataset from one of the leading centres that pioneered systemic thrombolysis. Although the study was not a randomised trial, their conclusions that MRI is as eff ective as CT accord with observations from controlled studies that showed low variability in detection of acute ischaemic changes with DWI,4 equal ability of MRI and CT to detect acute haemorrhages, and potentially better identifi cation of chronic brain haemorrhages with MRI than with CT.5 On the contrary, experienced CT users argue that structured reading of non-contrast CT in acute stroke using the Alberta Stroke Program Early CT Score (ASPECTS)6 can yield results comparable to DWI.7

Selection of patients with MRI by Köhrmann and colleagues3 resulted in fewer symptomatic intracerebral

haemorrhages than did selection with CT. If overlapping confi dence intervals are put to one side, a major confounding factor is that an uncooperative, restless, or unstable patient will be more likely to undergo CT than MRI. This possibility might not be accounted

CT imaging of ischaemic stroke

2 Blennow K, deLeon MJ, Zetterberg H. Alzheimer’s disease. Lancet 2006 (in press).

3 Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2003; 2: 605–13.

4 Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B. Ann Neurol 2004; 55: 306–19.

5 Irizarry MC. Biomarkers for Alzheimer disease in plasma. NeuroRx 2004; 1: 226–34.

6 Peskind ER, Riekse R, Quinn JF, et al. Safetey and acceptability of research lumbar puncture. Alzheimer Dis Assoc Disord 2005; 19: 220–25.

7 Van Oijen M, Hofman A, Soares HD, Koudstaal PJ, Breteler MM. Plasma Aβ1–40 and Aβ1–42 and risk of dementia. Lancet Neurol 2006; 5: 655–60.

8 Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006; 5: 228–34.

9 Mayeux R, Honig LS, Tang MX, et al. Plasma Aβ40 and Aβ42 and Alzheimer’s disease: relation to age, mortality and risk. Neurology 2003; 61: 1185–90.

10 Pomara N, Willoughby LM, Sidtis JJ, Mehta PD. Selective reductions in plasma Abeta 1-42 in healthy elderly subjects during longitudinal follow-up: a preliminary report. Am J Geriatr Psychiatry 2005; 13: 914–17.

11 Kuo YM, Emmerling MR, Lampert HC, et al. High levels of circulating Aβ42 are sequestered by plasma proteins in Alzheimer’s disease. Biochem Biophys Res Comm 1999; 257: 787–91.

See Articles page 661

Zeph

yr/S

cienc

e Ph

oto

Libr

ary

Refl ection and Reaction

640 http://neurology.thelancet.com Vol 5 August 2006

for by pretreatment stroke severity scores. In their multivariate analysis, age and stroke severity, but not the time to treatment nor the method of scanning, were independent predictors of worse outcomes. Why are the time window and the method of scanning not the most important issues? Any one factor might be predictive, but multiple factors will provide more predictive power. According to Warach,8 brain-tissue viability depends on four factors: time, haemodynamics, tissue itself, and an intervention. There is no absolute viability threshold that is independent of time, but there is also no absolute time window of tissue viability. Both CT and MRI can give clues to tissue viability. Time from clinical symptom onset is usually associated with the duration of haemodynamic changes, but not necessarily with ischaemia itself. Ischaemia of suffi cient duration and severity can be seen by both CT and MRI, whereas reperfusion must occur early enough to rescue brain tissue. Time window therefore should not be equated with time to actual treatment (which was an independent predictor of good outcomes in large randomised trials). We do not have the luxury of time to wait till the end of any window or for any images to be acquired slowly. In this multifactorial and rapidly evolving environment, the person and his or her skills to make diagnostic and treatment decisions are more important than actual imaging tools. Both CT and MRI off er enough clues—one must learn how to obtain and use this information quickly.

What if only 15 min remain in the 3 h time window to complete scanning? In most hospitals alteplase (recombinant tissue plasminogen activator) would not be given because there is not enough time to complete tests. However, scanning can be completed quickly with either CT or MRI. Helical CT scan can be completed within 2 min of acquisition time and read directly off the console. MRI imaging can start with DWI and gradient echo sequences that can also be completed within 2 min each. Scanning can be interrupted and alteplase bolus can be given in the scanner. Alteplase infusion can continue with use of an MRI-compatible infusion pump while the rest of the sequences are being acquired. In reality, many factors can interfere with this plan. I take patients to scanners myself to make it happen.

Can CT and MRI identify safe responders to reperfusion after the fi rst 3 h? The answer emerging from multiple studies is yes. Reanalysis of a randomised trial of intra-arterial thrombolysis showed that

patients with few or no changes on ASPECTS were three times more likely to benefi t from treatment with recombinant prourokinase.9 In the European Cooperative Stroke Study II, patients with low ASPECTS scores had more bleeding events.10 A multicentre study of MRI in the 3–6 h window showed that large (≥100 cm³) DWI or perfusion lesions can identify those likely to have symptomatic haemorrhages, whereas target diff usion–perfusion mismatch of 20% or more identifi ed those with the highest probability of recovery after early recanalisation.11 The report by Köhrmann and colleagues3 points in the same direction.

This commentary cannot solve the issue whether CT or MRI is the way to go in the future. Check which selection protocol fi ts best at your hospital. If you use CT fi rst, most stroke survivors will need a multiparameter MRI within 48 h of hospital stay. If multiparameter MRI works best but is contraindicated in a few patients, have access to CT and know how to read it. Also, know how to use other CT modalities such as CT-angiography and CT-perfusion to aid selection of patients. The story does not end here, it is just the beginning.

Andrei V AlexandrovBarrow Neurological Institute, Phoenix, AZ 85013, USAavalexandrov@att.net

I have no confl icts of interest.

1 Hounsfi eld GN. Historical notes on computerized axial tomography. J Can Assoc Radiol 1976; 27: 135–42.

2 Moseley ME, Mintorovitch J, Cohen Y, et al. Early detection of ischemic injury: comparison of spectroscopy, diff usion-, T2-, and magnetic susceptibility-weighted MRI in cats. Acta Neurochir Suppl (Wien)1990; 51: 207–09.

3 KöhrmannM, Jüttler E, Fiebach JB, et al. MRI-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study. Lancet Neurol 2006; 5: 661–67.

4 Fiebach JB, Schellinger PD, Jansen O, et al. CT and diff usion-weighted MR imaging in randomized order: diff usion-weighted imaging results in higher accuracy and lower interrater variability in the diagnosis of hyperacute ischemic stroke. Stroke 2002; 33: 2206–10.

5 Kidwell CS, Chalela JA, Saver JL, et al. Comparison of MRI and CT for detection of acute intracerebral hemorrhage. JAMA 2004; 292: 1823–30.

6 Barber PA, Demchuk AM, Zhang J, Buchan AM, ASPECTS Study Group. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Lancet 2000; 355: 1670–74.

7 Barber PA, Hill MD, Eliasziw M, et al. Imaging of the brain in acute ischaemic stroke: comparison of computed tomography and magnetic resonance diff usion-weighted imaging. J Neurol Neurosurg Psychiatry 2005; 76: 1528–33.

8 Warach S. Tissue viability thresholds in acute stroke: the 4-factor model.Stroke 2001; 32: 2460–61.

9 Hill MD, Rowley HA, Adler F, et al. Selection of acute ischemic stroke patients for intra-arterial thrombolysis with pro-urokinase by using ASPECTS. Stroke 2003; 34: 1925–31.

10 Dzialowski I, Hill MD, Coutts SB, et al. Extent of early ischemic changes on computed tomography (CT) before thrombolysis: prognostic value of the Alberta Stroke Program Early CT Score in ECASS II. Stroke 2006; 37: 973–78.

11 Albers GW, Thijs VN, Wechsler L, et al. Results of diff usion-weighted evaluation for understanding stroke (DEFUSE) study. Stroke 2006; 37: 635–36.