Background: Cognitive decline after stroke is more common than stroke recurrence. Stroke doubles the risk of dementia and is a major contributor to vascular cognitive impairment and vascular dementia. Nonetheless, few pharmacological studies have addressed vascular cognitive impairment after stroke. We assessed the safety of long-term administration and its possible efficacy of citicoline in preventing poststroke cognitive decline in patients with first-ever ischemic stroke. Methods: Open-label, randomized, parallel study of citicoline vs. usual treatment. All subjects were selected 6 weeks after suffering a qualifying stroke and randomized by age, gender, education and stroke type into parallel arms of citicoline (1 g/day) for 12 months vs. no citicoline (control group). Medical management was similar otherwise. All patients underwent neuropsychological evaluation at 1 month, 6 months and 1 year after stroke. Tests results were combined to give indexes of 6 neurocognitive domains: attention and executive function, memory, language, spatial perception, motor speed and temporal orientation. Using adjusted logistic regression models we determined the association between citicoline treatment and cognitive decline for each neurocognitive domain at 6 and 12 months. Results: We recruited 347 subjects (mean age 67.2 years, 186 male (56.6%), mean education 5.7 years); 172 (49.6%) received citicoline for 12 months (no significant differences from controls n = 175). Demographic data, risk factors, initial stroke severity (NIHSS), clinical and etiological classification were similar in both groups. Only 37 subjects (10.7%) discontinued treatment (10.5% citicoline vs. 10.9% control) at 6 months; 30 (8.6%) due to death (16 (9.3%) citicoline vs. 14 (8.0%) control, p = 0.740), 7 lost to follow-up or incorrect treatment, and 4 (2.3%) had adverse events from citicoline without discontinuation. 199 patients underwent neuropsychological evaluation at 1 year. Cognitive functions improved 6 and 12 months after stroke in the entire group but in comparison with controls, citicoline-treated patients showed better outcome in attention-executive functions (OR 1.721, 95% CI 1.065–2.781, p = 0.027 at 6 months; OR 2.379, 95% CI 1.269–4.462, p = 0.007 at 12 months) and temporal orientation (OR 1.780, 95% CI 1.020–3.104, p = 0.042 at 6 months; OR 2.155, 95% CI 1.017–4.566, p = 0.045 at 12 months) during the follow-up. Moreover, citicoline group showed a better functional outcome (modified Rankin scale ≤2) at 12 months (57.3 vs. 48.7%) without statistically significant differences (p = 0.186). Conclusions: Citicoline treatment for 12 months in patients with first-ever ischemic stroke is safe and probably effective in improving poststroke cognitive decline. Citicoline appears to be a promising agent to improve recovery after stroke. Large clinical trials are needed to confirm the net benefit of this therapeutic approach.

Lees R, Fearon P, Harrison JK, Broomfield NM, Quinn TJ: Cognitive and mood assessment in stroke research: focused review of contemporary studies. Stroke 2012;43:1678–1680.
Jaillard A, Grand S, François Le Bas J, Hommel M: Predicting cognitive disfunctioning in nondemented patients early after stroke. Cerebrovasc Dis 2010;29:415–423.
Tham W, Auchus AP, Thong M, Chang HM, Wong MC, Chen CP: Progression of cognitive impairment after stroke: one year results from a longitudinal study of Singaporean stroke patients. J Neurol Sci 2002;203–204:49–52.
Madureira S, Guerreiro M, Ferro JM: Dementia and cognitive impairment three months after stroke. Eur J Neurol 2001;8:621–627.
Rasquin SMC, Verhey FRJ, van Oostenbrugge RJ, Lousberg R, Lodder J: Demographic and CT scan features related to cognitive impairment in the first year after stroke. J Neurol Neurosurg Psychiatry 2004;75:1562–1567.
Wentzel C, Rockwood K, MacKnight C, et al: Progression of impairment in patients with vascular cognitive impairment without dementia. Neurology 2001;57:714–716.
Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C, Medical Research Council Cognitive Function and Ageing Study: Age, neuropathology and dementia. N Engl J Med 2009;360:2302–2309.
Fotuhi M, Hachinski V, Whitehouse PJ: Changing perspectives regarding late-life dementia. Nat Rev Neurol 2009;5:649–658.
Reitz C, Bos MJ, Hofman A, Koudstaal PJ, Breteler MMB: Prestroke cognitive performance, incident stroke, and risk of dementia. The Rotterdam study. Stroke 2008;39:36–41.
Gutierrez M, Diez Tejedor E, Alonso de Leciñana M, Fuentes B, Carceller F, Roda JM: Thrombolysis and neuroprotection in cerebral ischemia. Cerebrovasc Dis 2006;21(suppl 2):118–126.
Secades JJ, Lorenzo JL: Citicoline: Pharmacological and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006;28:B1–B56.
Hurtado O, Lizasoain I, Moro MA: Neuroprotection and recovery. Recent data at the bench on citicoline. Stroke 2011;42(suppl 1): S33–S35.
Davalos A, Castillo J, Alvarez-Sabin J, Secades JJ, Mercadal J, López S, Cobo E, Warach S, Sherman D, Clark WM, Lozano R: Oral citicoline in acute ischemic stroke. Stroke 2002;33:2850–2857.
Davalos A, Alvarez-Sabín J, Castillo J, Díez-Tejedor E, Ferro J, Martínez-Vila E, Serena J, Segura T, Cruz VT, Masjuan J, Cobo E, Secades JJ, International Citicoline Trial on Acute Stroke (ICTUS) Trial Investigators: Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet 2012;380:349–357.
Cho HJ, Kim YJ: Efficacy and safety of oral citicoline in acute ischemic stroke: drug surveillance study in 4,191 cases. Methods Find Exp Clin Pharmacol 2009;3:171–176.
Fioravanti M, Yanagi M: Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database System Rev 2005:CD000269.
Lezak M, Howieson DB, Loring DW: Neuropsychological Assessment, ed 4. New York, Oxford University Press, 2004.
Mitrushina M, Boone KL, D’Elia L: Handbook of Normative Data for Neuropsychological Assesment, ed 2. New York, Oxford University Press, 2005.
Strauss E, Shermann EMS, Spreen O: A Compendium of Neuropsychological Tests, ed 3. New York, Oxford University Press, 2006.
Savva GM, Stephan BC, Alzheimer’s Society Vascular Dementia Systematic Review Group: Epidemiological studies of the effect of stroke on incident dementia: a systematic review. Stroke 2010;41:e41–e46.
Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O’Brien RJ: Effect of infarcts on dementia in the Baltimore Longitudinal Study of Aging. Ann Neurol 2008;64:168–176.
Barker-Collo S, Feigin VL, Parag V, Lawes CM, Senior H: Auckland Stroke Outcomes Study. 2. Cognition and functional outcomes 5 years poststroke. Neurology 2010;75:1608–1616.
Patel MD, Coshall C, Rudd AG, Wolfe CD: Cognitive impairment after stroke: clinical determinants and its associations with long-term stroke outcomes. J Am Geriatr Soc 2002;50:700–706.
Saczynski JS, Sigurdsson S, Jonsdottir MK, et al: Cerebral infarcts and cognitive performance. Importance of location and number of infarcts. Stroke 2009;40:677–682.
Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MMB: Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215–1222.
Cukierman T, Gerstein HC, Williamson JD: Cognitive decline and dementia in diabetes – systematic overview of prospective observational studies. Diabetologia 2005;48:2460–2469.
Rasquin SM, Lodder J, Ponds RW, Winkens I, Jolles J, Verhey FR: Cognitive functioning after stroke. A one-year follow-up study. Dementia Geriatr Cognitive Dis 2004;18:138–144.
Rohling ML, Faust ME, Beverly B, Demakis G: Effectiveness of cognitive rehabilitation following acquired brain injury: a meta-analytic re-examination of Cicerone et al.’s (2000, 2005) systematic reviews. Neuropsychology 2009;23:20–39.
Cicerone KD, Dahlberg C, Kalmar K, Langenbahn DM, Malec JF, Bergquist TF, Felicetti T, Giacino JT, Harely JP, Harrington DE, Herzog J, Kneipp S, Laatsch L, Morse PA: Evidence-based cognitive rehabilitation: recommendations for clinical practice. Arch Phys Med Rehabil 2000;12:1596–1615.
Cicerone KD, Dahlberg C, Malec JF, Langenbahn DM, Felicetti T, Kneipp S, Ellmo W, Kalmar K, Giacino JT, Harley JP, Laatsch L, Morse PA, Catanese J: Evidence-based cognitive rehabilitation: updated review of the literature from 1998 through 2002. Arch Phys Med Rehabil 2005;86:1681–1692.
Wilson BA: The effectiveness rehabilitation of memory-related disabilities; in Halligan PW, Wade DT (eds): Effectiveness of Rehabilitation for Cognitive Deficits. New York, Oxford, 2005, pp 143–151.
Adibhatla RM, Hatcher JF, Dempsey RJ: Effect of citicoline on phospholipids and glutathione levels in transient cerebral ischemia. Stroke 2001;32:2376–2381.
Hurtado O, Moro MA, Cárdenas A, Sánchez V, Fernández-Tome P, Leza JC, et al: Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport. Neurobiol Dis 2005;18:336–345.
Tovarelli G, DeMedio G, Dorman R, Piccinin G, Horrocks L, Porcellati G: Effects of cytidine diphosphate choline (CDP-choline) on ischemia-induced alteration of brain lipid in the gerbil. Neurochem Res 1981;6:821–833.
Krupinski J, Ferrer I, Barrachina M, Secades JJ, Mercadal J, Lozano R: CDP-choline reduces pro-caspase and cleaved caspase-3 expression, nuclear DNA fragmentation, and specific PARP-cleaved products of caspase activation following middle cerebral artery occlusion in the rat. Neuropharmacology 2002;42:846–854.
Sahin S, Alkan T, Temel SG, Tureyen K, Tolunay S, Korfali E: Effects of citicoline used alone and in combination with mild hypothermia on apoptosis induced by focal cerebral ischemia in rats. J Clin Neurosci 2010;17:227–231.
Hurtado O, Cárdenas A, Pradillo JM, Morales JR, Ortego F, Sobrino T, Castillo J, Moro MA, Lizasoain I: A chronic treatment with CDP-choline improves functional recovery and increases neuronal plasticity after experimental stroke. Neurobiol Dis 2007;26:105–111.
Sun D, Bullock MR, McGinn MJ, Zhou Z, Altememi N, Hagood S, Hamm R, Colello RJ: Basic fibroblast growth factor-enhanced neurogenesis contributes to cognitive recovery in rats following traumatic brain injury. Exp Neurol 2009;216:56–65.
Diederich K, Frauenknecht K, Minnerup J, Schneider BK, Schmidt A, Altach E, Eggert V, Sommer CJ, Schäbitz WR: Citicoline enhances neuroregenerative process after experimental stroke in rats. Stroke 2012;43:1931–1940.
Sobrino T, Hurtado O, Moro MA, Rodriguez-Yáñez M, Castellanos M, Brea D, et al: The increase of circulating endothelial progenitor cells after acute ischemic stroke is associated with good outcome. Stroke 2007;38:2759–2764.
Sobrino T, Arias S, Rodriguez-Osorio X, Brea D, Rodriguez-Gonzalez R, Ramos P, Castillo J: CDP-choline treatment improves functional recovery by an increment of circulating endothelial progenitor cells in human acute ischemic stroke. J Neurochemistry 2007;101(suppl 1):43.
Baune BT: The puzzle of predicting the impact of brain infarcts on cognitive impairment in the aging brain. Stroke 2009;40:667–669.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.