Multiple Sclerosis Journal 0(0) 1–7 © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458513475490 msj.sagepub.com MULTIPLE SCLEROSIS MSJ JOURNAL Introduction Multiple sclerosis (MS) was for a long time considered a dis- ease affecting mainly the white matter. However, in recent years neuropathological and imaging studies have drawn attention to the involvement of grey matter in MS in terms of focal lesions and atrophy. 1–10 This is especially so since the application of more sensitive magnetic resonance imaging (MRI) sequences, such as double inversion recovery (DIR), have enabled cortical lesions (CLs) to be described in vivo in the majority of patients with MS as well as in one-third of patients with clinically isolated syndrome (CIS). 3,11–13 In Contribution of cortical and white matter lesions to cognitive impairment in multiple sclerosis Athina Papadopoulou 1,2 , Nicole Müller-Lenke 2 , Yvonne Naegelin¹, Gabriela Kalt 2 , Kerstin Bendfeldt 2 , Pascal Kuster 2 , Markus Stoecklin 5 , Achim Gass 1,3 , Till Sprenger 1,4 , Ernst Wilhelm Radue 2 , Ludwig Kappos¹ and Iris-Katharina Penner 1,5 Abstract Background: Cortical lesions (CLs) have been reported to be a better predictor for cognitive impairment than white matter (WM) lesions in relapsing–remitting multiple sclerosis (RRMS). Objectives: The objectives of this article are to investigate the contribution of CLs and WM lesions to cognitive impairment in 91 patients with MS and clinically isolated syndrome, and to test potential associations of CLs and WM lesions with fatigue and depression. Methods: Lesions were scored and segmented on 3D double inversion recovery sequences, according to their location (cortical, WM). Normalised grey matter volume was also determined. Cognitive performance was assessed with the SDMT and PASAT-3, fatigue with the FSMC and depression with the German version of the CES-D. Results: CL volume did not correlate with fatigue or depression, but correlated significantly with both neuropsychological outcome measures: PASAT-3 (r = -0.275, p = 0.009) and SDMT (r = -0.377, p < 0.001). Multiple regression analyses with age, WM lesions, CLs and GM volume as independent variables, however, did not reveal CL volume as a significant predictor of neuropsychological outcomes, whereas WM lesion volume significantly predicted SDMT and by trend PASAT performance. Conclusions: These findings suggest a role of WM lesions in the development of cognitive deficits, especially information- processing speed, which may be higher than previously assumed. Abbreviations: CES-D: Center for Epidemiologic Studies Depression scale (ADS-L: Allgemeine Depressions Skala-L, German version of CES-D), CIS: clinically isolated syndrome, CL: cortical lesion, DIR: double inversion recovery, EDSS: Expanded Disability Status Scale, FSMC: fatigue scale for motor and cognitive functions, GM: grey matter, MRI: magnetic resonance imaging, MS: multiple sclerosis, PASAT-3: paced auditory serial addition test 3s, PPMS: primary progressive multiple sclerosis, RRMS: relapsing–remitting multiple sclerosis, SDMT: symbol digit modalities test, SPM: statistical parametric mapping, SPMS: secondary progressive multiple sclerosis, WM: white matter Keywords Cortical lesions, white matter lesions, cognition, multiple sclerosis Date received: 23rd August 2012; revised: 4th November 2012; accepted: 24th December 2012 1 Department of Neurology, University Hospital Basel, Switzerland. 2 Medical Image Analysis Center (MIAC), University Hospital Basel, Switzerland. 3 Department of Neurology, University Hospital Mannheim, Germany. 4 Department of Radiology, Division of Diagnostic and Interventional Neuroradiology, University Hospital Basel, Switzerland. 5 Department of Cognitive Psychology and Methodology, University of Basel, Switzerland. Corresponding author: Iris-Katharina Penner, University of Basel, Department of Cognitive Psychology and methodology, Missionsstrasse 60/62, CH-4055 Basel, Switzerland. Email: Ik.Penner@unibas.ch 475490MSJ 0 0 10.1177/1352458513475490Multiple Sclerosis JournalPapadopoulou et al. 2013 Research Paper