Quantitative diffusion weighted imaging measures in patients with multiple sclerosis Eleonora Tavazzi, a,b Michael G. Dwyer, a Bianca Weinstock-Guttman, c Jordan Lema, a Stefano Bastianello, b Roberto Bergamaschi, b Vittorio Cosi, b Ralph H.B. Benedict, a,c Frederick E. Munschauer III, c and Robert Zivadinov a,c, ⁎ a Buffalo Neuroimaging Analysis Center, Department of Neurology, University at Buffalo, State University of New York, Buffalo, NY, USA b Department of Neurology, IRCCS, C. Mondino, University of Pavia, Pavia, Italy c The Jacobs Neurological Institute, Department of Neurology, University at Buffalo, State University of New York, Buffalo, NY, USA Received 12 November 2006; revised 15 March 2007; accepted 16 March 2007 Available online 10 April 2007 Diffusion-weighted imaging (DWI) has been proposed as a sensitive measure of disease severity capable of detecting subtle changes in gray matter and white matter brain compartments in patients with multiple sclerosis (MS). However, DWI has been applied to the study of MS clinical subtypes in only a few studies. The objective of this study was to demonstrate the validity of a novel, fully automated method for the calculation of quantitative DWI measures. We also wanted to assess the correlation between whole brain (WB)-DWI variables and clinical and MRI measures of disease severity in a large cohort of MS patients. For this purpose we studied 432 consecutive MS patients (mean age 44.4 ± 10.2 years), 16 patients with clinically isolated syndrome (CIS) and 38 normal controls (NC) using 1.5 T brain MRI. Clinical disease subtypes were as follows: 294 relapsing–remitting (RR), 123 secondary-progressive (SP) and 15 primary-progressive (PP). Mean disease duration was 12 ± 10 years. Mean Expanded Disability Status Scale (EDSS) was 3.3 ± 2.1. Brain parenchymal fraction (BPF), gray matter fraction (GMF) and white matter fraction (WMF) were calculated using a fully automated method. Mean parenchymal diffusivity (MPD) maps were created. DWI indices of peak position (PP), peak height (PH), MPD and entropy (ENT) were obtained. T2- and T1-lesion volumes (LV), EDSS, ambulation index (AI) and nine- hole peg test (9-HPT) were also assessed. MS patients had significantly lower BPF (d = 1.26; p < 0.001) and GMF (d = 0.61; p = 0.003), and higher ENT (d = 1.2; p < 0.0001), MPD (d = 1.04; p < 0.0001) and PH (d = 0.47; p = 0.045) than NC subjects. A GLM analysis, adjusted for age and multiple comparisons, revealed significant differences between different clinical subtypes for BPF, GMF, ENT, PH, PP, T2-LV and T1-LV (p < 0.0001), WMF (p = 0.001) and MPD (p = 0.023). In RR and SP MS patients, ENT showed a more robust correlation with other MRI (r = 0.54 to 0.67, p < 0.0001) and clinical (r = 0.31 to 0.36, p < 0.0001) variables than MPD (r = 0.23 to 0.41, p < 0.001 for MRI and r = 0.13 to 0.18; p = 0.006 to p < 0.001 for clinical variables). The GMF and BPF showed a slightly stronger relationship with all clinical variables (r = 0.33 to 0.48; p < 0.0001), when compared to both lesion and DWI measures. ENT (R 2 = 0.28; p < 0.0001) and GMF (R 2 = 0.26; p < 0.001) were best related with SP disease course. This study highlights the validity of DWI in discerning differences between NC and MS patients, as well as between different MS subtypes. ENT is a sensitive marker of overall brain damage that is strongly related to clinical impairment in patients with SP MS. © 2007 Elsevier Inc. All rights reserved. Keywords: Multiple sclerosis; MRI; Diffusion imaging; Mean diffusivity; Entropy; Brain atrophy; Lesion volume; Clinical disability Introduction Diffusion weighted imaging (DWI) is a magnetic resonance imaging (MRI) technique that measures tissue water diffusional motion and, as a consequence, provides information about orientation, size and geometry of the tissue. The mobility of water molecules is reduced in highly organized tissue-like white matter (WM) and gray matter (GM) because of interactions with cellular and tissue structures, so the apparent diffusion coefficient (ADC) is lower in those tissues than in pure water. Conventionally, the average ADC is calculated from three orthogonal directions that provide information about the overall diffusivity in the tissue. Pathological processes that modify tissue organization can cause abnormal water motion, with the consequence of altered ADC values. In multiple sclerosis (MS), the two main pathological processes affecting the brain are demyelination and neurodegen- eration; they can alter the ability of tissues to restrict water motion, resulting in an increase of water diffusivity measurable with different DWI indices. www.elsevier.com/locate/ynimg NeuroImage 36 (2007) 746 – 754 ⁎ Corresponding author. Department of Neurology, School of Medicine and Biomedical Sciences, The Jacobs Neurological Institute, 100 High St., Buffalo, NY 14203, USA. Fax: +1 716 859 7874. E-mail address: rzivadinov@thejni.org (R. Zivadinov). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2007.03.056