Modeling of Cognitive Impairment by Disease Duration in Multiple Sclerosis: A Cross-Sectional Study Anat Achiron 1,2,3 *, Joab Chapman 1,2,3 , David Magalashvili 1 , Mark Dolev 1 , Mor Lavie 1 , Eran Bercovich 1 , Michael Polliack 1,3 , Glen M. Doniger 4 , Yael Stern 1 , Olga Khilkevich 1 , Shay Menascu 1,3 , Gil Hararai 1,5 , Micharel Gurevich 1 , Yoram Barak 1,3,6 1 Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel, 2 Neurology Department, Sheba Medical Center, Tel-Hashomer, Israel, 3 Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel, 4 NeuroTrax Corporation, Ono Academic College, Kiryat Ono, Israel, 5 MediStat Ltd., Ramat Hachayal, Tel-Aviv, Israel, 6 Abarbanel Mental Health Center, Bat-Yam, Israel Abstract Background/Aims: Large-scale population studies measuring rates and dynamics of cognitive decline in multiple sclerosis (MS) are lacking. In the current cross-sectional study we evaluated the patterns of cognitive impairment in MS patients with disease duration of up to 30 years. Methods: 1,500 patients with MS were assessed by a computerized cognitive battery measuring verbal and non-verbal memory, executive function, visual spatial perception, verbal function, attention, information processing speed and motor skills. Cognitive impairment was defined as below one standard deviation (SD) and severe cognitive impairment as below 2SD for age and education matched healthy population norms. Results: Cognitive performance in our cohort was poorer than healthy population norms. The most frequently impaired domains were information processing speed and executive function. MS patients with secondary-progressive disease course performed poorly compared with clinically isolated syndrome, relapsing-remitting and primary progressive MS patients. By the fifth year from disease onset, 20.9% of patients performed below the 1SD cutoff for impairment, p = 0.005, and 6.0% performed below the 2SD cutoff for severe cognitive impairment, p = 0.002. By 10 years from onset 29.3% and 9.0% of patients performed below the 1SD and 2SD cutoffs, respectively, p = 0.0001. Regression modeling suggested that cognitive impairment may precede MS onset by 1.2 years. Conclusions: The rates of cognitive impairment in this large sample of MS patients were lower than previously reported and severe cognitive impairment was evident only in a relatively small group of patients. Cognitive impairment differed significantly from expected normal distribution only at five years from onset, suggesting the existence of a therapeutic window during which patients may benefit from interventions to maintain cognitive health. Citation: Achiron A, Chapman J, Magalashvili D, Dolev M, Lavie M, et al. (2013) Modeling of Cognitive Impairment by Disease Duration in Multiple Sclerosis: A Cross-Sectional Study. PLoS ONE 8(8): e71058. doi:10.1371/journal.pone.0071058 Editor: Orhan Aktas, University of Du¨ sseldorf, Germany Received February 28, 2013; Accepted June 26, 2013; Published August 1, 2013 Copyright: ß 2013 Achiron et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The study was funded by Sheba Medical Center research grant for excellency in medicine. The funders as well as NeuroTrax Corp. had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Doniger M. Glen, PhD, and Hararai Gil, MSc Eng, are employed by a commercial company (NeuroTrax Corporation and MediStat Ltd). This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: Anat.Achiron@sheba.health.gov.il; achiron@post.tau.ac.il Introduction Cognitive impairment is a major predicament in multiple sclerosis (MS) and adversely affects patients’ quality of life. Cognitive decline may appear early in the disease process and has been reported even at disease onset [1]. Prevalence of cognitive impairment in MS has been estimated to occur in 20% to 65% of patients [2,3]. This wide range is probably related to variation in the disease subtypes, disease duration and level of disability of the MS population studied, as well as to differences in the cognitive assessment scales, procedures and tools used. Moreover, variation in the tests’ cutoff adopted as indicative of cognitive impairment and criteria for inclusion of patients with significant cognitive decline or motor disability may also account for the wide range of prevalence estimates across studies [4]. The influence of disease duration on cognitive functioning in MS remains controversial. While some studies report no correlation between disease duration and cognition [5,6], a trend for higher frequency of poor cognitive performance was reported in patients with longer disease duration [7]. Investigations of the natural history of cognitive function along the disease course are frequently confounded by small sample sizes, inadequate control for practice effects, high drop-out rates and brief retest intervals [8–11]. The cognitive functions most commonly impaired in MS patients are verbal and visual memory, including difficulties in learning and forgetfulness, especially recall of recently learned information; memory impairment has been reported in 22% to 31% of patients [12]. Impairment in the information processing PLOS ONE | www.plosone.org 1 August 2013 | Volume 8 | Issue 8 | e71058