MRI Evidence of Acute Inflammation in Cortical Gray Matter of Early Multiple Sclerosis Patients: Gadolinium Enhancing Cortical Lesions Josefina Maranzano, MD1, David A. Rudko, PhD1, Kunio Nakamura, PhD1,2, Stuart Cook, MD3, Diego Cadavid, MD3, Leo Wolansky, MD4 , Douglas L. Arnold, MD1, and Sridar Narayanan, PhD1. 1 Montreal Neurological Hospital and Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec Canada, H3A 2B4 2 Cleveland Clinic, Cleveland, Ohio, USA 3 Rutgers-New Jersey Medical School, Newark, New Jersey, USA 4 University of Connecticut School of Medicine, Farmington, CT, USA Results: 36% of patients showed gadolinium-enhancing lesions affecting the cortex. Background: Cortical lesions (CL) in multiple sclerosis (MS) have generally been described as having little inflammation, based on post mortem pathology studies1-2. However, biopsy studies have shown that CLs can exhibit acute inflammation, including gadolinium enhancement on MRI scans3. Very few MRI studies have assessed gadolinium enhancement of CL, and their reported incidence has been variable4-5. Gadolinium-enhancing lesions Number Percentage White and Grey matter 2044 100 Cortical GM 120 6 Cortical GM at baseline 25/120 21 New Cortical GM 49/120 41 Persistent Cortical GM 46/120 38 Type I (Figure1) 114/120 95 Type II (Figures 2-3) 6/120 5 Length of enhancement in 52 lesions followed in consecutive scans < 30 days >30 <60 days >60 <90 >90 <120 >120 <180 Number 27 17 6 1 Frequency 52% 33% 11% 2% Figure 1 Objective: To identify gadolinium enhancing lesions affecting the cortex of early MS patients, and to describe the frequency and evolution of these lesions. Signal Evolution T2w-FLAIR of 69 lesions followed to m24 Complete Resolution (Figure 3) Partial Resolution (Figure 2) Persistent Bright Signal (Figure 1) Number 20 12 37 Frequency 29% 17% 54% Methods: Retrospective, observational, longitudinal analysis of MRI scans from the BECOME study: Betaseron vs Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints6-7. 75 early stage MS patients: 61RRMS and CIS; 52 women, 23 men; 18 to 55 years of age; median EDSS 2 (range 0-5.5). Monthly scans, over 12 to 24 months; 3T MRI and triple-dose gadolinium with prolonged delay. Pulse sequences: T1-weighted spin-echo (TE 8ms, TR 700ms, voxel size 0.7x0.7x3mm); turbo dual spin-echo: proton density and T2-weighted (TE 10/100ms, TR 4800ms, turbo factor 5 , voxel size 0.7x0.7x3mm); FLAIR scan (TE 80ms, TR 8530ms, TI 2500ms, voxel size 0.7x0.7x3mm). 1188 scans were included in the analysis, showing 2044 gadolinium-enhancing lesions. 139 candidate cortical lesions were selected using an image pipeline integrating information from cortical grey matter masks and gadolinium-enhancing lesion masks. Lesion identification protocol: manual segmentation using all available MRI contrasts on the interactive software package Display (McConnell Brain Imaging Centre, Montreal Neurological Institute). Conclusion: Our study indicates that at least some newly formed leukocortical lesions in early MS exhibit gadolinium-enhancement similar to that of WM lesions. This demonstration of transient blood-brain barrier impairment in CL formation suggests that there may be an acute, peripherally-driven, inflammatory phase in the development of leukocortical lesions in MS. Figure 2   Bo L, Vedeler CA, Nyland H, Trapp BD, Mork SJ. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 2003;9:323-331. Wegner C, Esiri MM, Chance SA, Palace J, Matthews PM. Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 2006;67:960-967. Popescu BF, Bunyan RF, Parisi JE, Ransohoff RM, Lucchinetti CF. A case of multiple sclerosis presenting with inflammatory cortical demyelination. Neurology 2011;76:1705-1710. Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T. Cortical lesions in multiple sclerosis. Brain 1999;122 ( Pt 1):17-26. Calabrese M, Poretto V, Favaretto A, et al. Cortical lesion load associates with progression of disability in multiple sclerosis. Brain 2012;135:2952-2961 Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology 2009;72:1976-1983. Wolansky LJ, Finden SG, Chang R, et al. Gadoteridol in multiple sclerosis patients. A comparison of single and triple dose with immediate vs. delayed imaging. Clinical imaging 1998;22:385-392. Figure 3 Disclosures: Josefina Maranzano, MD: reports no disclosures; David A. Rudko, PhD: reports no disclosures; Kunio Nakamura, PhD: received personal compensation from NeuroRx Research for consulting services; Stuart Cook, MD: participated in the original BECOME study; Diego Cadavid, MD: presently is a full time employee of Fulcrum Therapeutics, to which the work on the BECOME study is not related, and participated in the original BECOME study; Leo Wolansky, MD: participated in the original BECOME study and received salary support from Bayer; Douglas L. Arnold, MD: president and CEO of NeuroRx Research; Sridar Narayanan, PhD: received personal compensation from NeuroRx Research for consulting services unrelated to the current work. Contact information: Josefina Maranzano, MD jmaranzano@mrs.mni.mcgill.ca