Lesion Load May Predict Long-Term Cognitive Dysfunction in Multiple Sclerosis Patients

March Lesion Load May Predict Long-Term Cognitive Dysfunction in Multiple Sclerosis Patients Data Availability Statement: All relevant data are within the paper. 0 1 Funding: These authors have no support or funding to report. 0 1 Francesco Patti 0 1 Manuela De Stefano 0 1 Luigi Lavorgna 0 1 Silvia Messina 0 1 Clara Grazia Chisari 0 1 Domenico Ippolito 0 1 Roberta Lanzillo 0 1 Veria Vacchiano 0 1 Sabrina Realmuto 0 1 Paola Valentino 0 1 Gabriella Coniglio 0 1 Maria Buccafusca 0 1 Damiano Paolicelli 0 1 Alessandro D'Ambrosio 0 1 Patrizia Montella 0 1 Vincenzo Brescia Morra 0 1 Giovanni Savettieri 0 1 Bruno Alfano 0 1 Antonio Gallo 0 1 Isabella Simone 0 1 Rosa Viterbo 0 1 Mario Zappia 0 1 Simona Bonavita 0 1 Gioacchino Tedeschi 0 1 0 1 Department G.F. Ingrassia, Section of Neurosciences, University of Catania , Catania , Italy , 2 Department of Medical , Surgical, Neurological , Metabolic and Aging Sciences, Second University of Naples , Naples , Italy , 3 Department of Neurological Sciences, University 'Federico II , ' Naples , Italy , 4 Department of Experimental Biomedicine and Clinical Neurosciences-University of Palermo , Palermo , Italy , 5 Department of Medical Sciences, Institute of Neurology, University Magna Graecia , Catanzaro , Italy , 6 Department of Neurology, Madonna delle Grazie Hospital , Matera , Italy , 7 Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina , Messina , Italy , 8 Department Scienze Mediche di Base, Neuroscienze e Organi di Senso, University of Bari , Bari , Italy , 9 Biostructure and Bioimaging Institute, National Research Council , Naples , Italy , 10 Neurological Institute for Diagnosis and Care Hermitage Capodimonte , Naples , Italy 1 Academic Editor: Glenn Wylie, Kessler Foundation Research Center , UNITED STATES - Competing Interests: The authors of this manuscript have the following competing interests: Dr. Patti has received honoraria for scientific lectures from Biogen Idec; Dr. De Stefano report no disclosure; Dr. Lavorgna has received travel payment from MerckSerono, Novartis and Biogen Idec; Dr. Messina has received travel payment from Novartis, Biogen Idec, Bayer Schering, Merck Serono; report no disclosure; Background Magnetic Resonance Imaging (MRI) techniques provided evidences into the understanding of cognitive impairment (CIm) in Multiple Sclerosis (MS). Objectives CIm in a cohort of MS patients. To investigate the role of white matter (WM) and gray matter (GM) in predicting long-term 303 out of 597 patients participating in a previous multicenter clinical-MRI study were enrolled (49.4% were lost at follow-up). The following MRI parameters, expressed as fraction (f) of intracranial volume, were evaluated: cerebrospinal fluid (CSF-f), WM-f, GM-f and abnormal WM (AWM-f), a measure of lesion load. Nine years later, cognitive status was assessed in 241 patients using the Symbol Digit Modalities Test (SDMT), the Semantically Related Word List Test (SRWL), the Modified Card Sorting Test (MCST), and the Paced Auditory Serial Addition Test (PASAT). In particular, being SRWL a memory test, both immediate recall and delayed recall were evaluated. MCST scoring was calculated based on the number of categories, number of perseverative and non-perseverative errors. Drs Chisari, Ippolito, Vacchiano, Valentino, Buccafusca, Paolicelli, DAmbrosio, Montella, Viterbo, Realmuto and Prof. Alfano report no disclosure; Dr Lanzillo has received travel payment from MerckSerono, Novartis, Biogen Idec, Schering-Plough and Teva; Dr Coniglio has received funding for a trip from Novartis; Dr. Bresciamorra has received travel payment from Novartis, Biogen Idec, ScheringPlough and Teva. Prof. Savettieri has received travel payment from Teva and honoraria for scientific lectures from Biogen Idec; Dr. Gallo has received travel payment from Biogen Idec and ScheringPlough and honoraria for scientific lectures from Biogen Idec; Prof. Simone has received honoraria for educational lectures from Biogen Idec, Bayer, Sanofi Aventis-Genzyme and Teva; Prof. Zappia has received funding for a trip from Schering-Plough; Prof. Bonavita has received travel payment from Merck-Serono, Novartis, Biogen Idec and Teva and honoraria for scientific lectures from Novartis; Prof. Tedeschi has received travel payment from MerckSerono, Novartis, Biogen Idec and Teva and honoraria for scientific lectures from Novartis, Teva and Biogen Idec. Francesco Patti declares, on behalf of all authors, all potential competing interests do not alter their adherence to PLOS ONE policies on sharing data and materials. AWM-f was predictive of an impaired performance 9 years ahead in SDMT (OR 1.49, CI 1.121.97 p = 0.006), PASAT (OR 1.43, CI 1.141.80 p = 0.002), SRWL-immediate recall (OR 1.72 CI 1.352.20 p<0.001), SRWL-delayed recall (OR 1.61 CI 1.282.03 p<0.001), MCST-category (OR 1.52, CI 1.21.9 p<0.001), MCST-perseverative error(OR 1.51 CI 1.21.9 p = 0.001), MCST-non perseverative error (OR 1.26 CI 1.021.55 p = 0.032). In our large MS cohort, focal WM damage appeared to be the most relevant predictor of the long-term cognitive outcome. Cognitive Impairment (CIm) has been recognized as an important feature of Multiple Sclerosis (MS), affecting up to 65% patients. CIm, such as memory impairment, reduced information processing speed, attention deficit, impaired executive function, can occur from the early stage of the disease and tends to worsen over time. The prevailing pattern of CIm in MS is represented by attention, processing speed, memory, executive function and visuo-spatial deficits, while language abilities are typically unaffected [1]. In the last years, novel Magnetic Resonance Imaging (MRI) techniques have provided further evidences into the understanding of CIm in MS, highlighting the involvement of both white matter (WM) and gray matter (GM) damage in the development of disability [2, 3].T1-, T2-lesion load (LL) and brain atrophy measures may predict the onset of CIm after several years [4, 5]. Conversely, other studies showed a clear discrepancy between LL and severity of CIm in MS [6].WM abnormalities were weakly correlated with CIm, suggesting that WM abnormalities alone cannot fully explain the extent of clinical symptoms and CIm in MS [7, 8].In the present study, WM, and GM atrophy and WM LL were obtained through a fully automated, operator-independent, multiparametric segmentation method from a large MS population [9, 10]. By using this approach, we recently showed that baseline (BL) GM atrophy and EDSS were the best long-term (9 years follow-up) predictors of clinical disease progression in relapsing remitting (RR) MS patients[11].Considering these findings, the aim of the present study was to investigate the role of WM and GM damage in predicting long term (9 years follow-up) CIm in a large multicenter cohort of MS patients. Materials and Methods Ethics statement The study was previously approved by the Ethics Committee (EC) of the (...truncated)