Effect of Citicoline on Ischemic Lesions as Measured by Diffusion-Weighted Magnetic Resonance Imaging S. Warach, MD, PhD, L. Creed Pettigrew, MD, J. F. Dashe, MD, PhD, P. Pullicino, MD, David M. Lefkowitz, MD, L. Sabounjian, RN, K. Harnett, MS, U. Schwiderski, PhD, and R. Gammans, PhD, for the Citicoline 010 Investigators We examined the effect of the neuroprotective and neuroreparative agent citicoline on the growth of cerebral ischemic lesions in a double-blind placebo-controlled study involving patients with acute ischemic stroke using diffusion-weighted magnetic resonance imaging (DWI). Patients with acute ischemic stroke symptom onset 24 hours or less before the start of treatment, National Institutes of Health Stroke Scale (NIHSS) scores of 5 or higher, and lesions of 1 to 120 cc in cerebral gray matter by DWI were enrolled. DWI, T2-weighted magnetic resonance imaging (MRI), perfusion-weighted MRI, and magnetic resonance angiography were obtained at baseline, week 1, and week 12. Citicoline (500 mg/day) was administered orally for 6 weeks, and patients were followed for 12 weeks. The primary assessment was progression of ischemic lesion volume from baseline to 12 weeks as measured by MRI. A total of 100 patients entered the study. The primary MRI analysis included 40 placebo-treated patients and 41 citicoline-treated patients with both baseline and week 12 MRI data and failed to demonstrate a significant difference in lesion volume change from baseline to week 12. From baseline to week 12, ischemic lesion volume [all values mean (SE)] expanded by 180% (107) among placebo-treated patients compared with 34% (19) among citicoline-treated patients. In a secondary analysis, lesion volume decreased from week 1 to week 12 by 6.9 cc (2.8) on placebo versus 17.2 cc (2.6) on citicoline. Baseline variables that were predictors of change in lesion size over 12 weeks were the volume of hypoperfusion (strongest association), baseline NIHSS score, lesion volume on DWI, arterial lesion by magnetic resonance angiography, and categorized elapsed time (<12 or >12 hours) from stroke onset to first dose. A marked association between lesion volume reduction and im- provement of NIHSS score by seven or more points was observed. Significant correlations between lesion volumes and clinical measures were found, replicating values reported in the literature for smaller case series. We observed a reduction in lesion volume growth from baseline to week 12 with citicoline treatment, with a significantly greater reduction in volume from week 1 to week 12 with citicoline. We found a significant inverse relationship between lesion volume change over 12 weeks as measured by MRI and clinical outcome for ischemic stroke. This relationship supports the role of DWI as a surrogate marker of clinically meaningful lesion progression in stroke clinical trials. The hypothesis that citicoline reduces lesion growth and improves clinical outcome will be tested further. Warach S, Creed Pettigrew L, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian L, Harnett K, Schwiderski U, Gammans R, for the Citicoline 010 Investigators. Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Ann Neurol 2000;48:713–722 Citicoline is an exogenous form of cytidine-59- diphosphocholine (CDP-choline). Endogenous CDP- choline is a key intermediate in the biosynthesis of membrane phosphatidylcholine, which is of primary importance for the dynamic regulation of cellular membrane integrity. During ischemia, phosphatidyl- choline is broken down into free fatty acids, which, in turn, are used to generate free radicals that potentiate ischemic injury. 1–3 The administration of citicoline has been shown in animal models to reduce this cell mem- brane breakdown, leading to increased synthesis of phosphatidylcholine and decreased levels of free fatty acids. 4 –10 The use of citicoline treatment has been shown to be beneficial in reducing infarct volume in animal models of ischemia or hypoxia. 11–15 Citicoline has been studied in several clinical trials. In randomized stroke treatment trials outside the United States using a variety of times to initiate treat- From the National Institute of of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. See Appendix on pages 720 –721 for a list of the investigators. Received Feb 14, 2000, and in revised form May 5. Accepted for publication May 25, 2000. Address correspondence to Dr Steven Warach, National Institutes of Health, National Institute of Neurological and Communicative Dis- orders and Stroke, 36 Convent Drive, MSC 4129, Room 4A03, Bethesda, MD 20892– 4129. Copyright © 2000 by the American Neurological Association 713