Technical Note Correlation of Cognitive Dysfunction and Diffusion Tensor MRI Measures in Patients With Mild and Moderate Multiple Sclerosis Wim Van Hecke, PhD, 1,2 * Guy Nagels, MD, PhD, 3 Alexander Leemans, PhD, 4 Evert Vandervliet, MD, 2 Jan Sijbers, PhD, 1 and Paul M. Parizel, MD, PhD 2 Purpose: To compare the diffusion tensor imaging (DTI) measures of multiple sclerosis (MS) patients and healthy subjects in every brain voxel and to correlate them with Paced Auditory Serial Addition Test (PASAT) scores. Materials and Methods: Fractional anisotropy (FA), and mean, longitudinal, and transverse diffusivity are com- pared between control subjects and MS patients, which were subdivided as mildly and moderately impaired. In addition, PASAT scores are correlated for both MS groups with the diffusion measures. An optimized voxel based analysis (VBA) method, in terms of coregistration, atlas construction, and image smoothing, was thereby used. Results:: Diffusion differences between the control sub- jects and the patients with MS were found in the corpus callosum, inferior longitudinal fasciculus, cortico spinal tracts, forceps major, superior longitudinal fasciculus, and cingulum. In addition, we observed significant corre- lations of the FA and PASAT scores in the left inferior lon- gitudinal fasciculus, the forceps minor, the capsula interna and externa, the genu of the corpus callosum, the left cingulum, the superior longitudinal fasciculus, and the corona radiata. Conclusion:: Diffusion differences were observed between the mildly impaired MS patients and control subjects. In addition, different diffusion measures correlated with PASAT scores for cognitive decline in parietal, frontal, as well as temporal white matter (WM) regions. Key Words: diffusion tensor imaging; multiple sclerosis; voxel based analysis; cognitive decline; paced auditory serial addition test J. Magn. Reson. Imaging 2010;31:1492–1498. V C 2010 Wiley-Liss, Inc. ALTHOUGH IT HAS BEEN demonstrated that conven- tional magnetic resonance (MR) images are sensitive for detecting multiple sclerosis (MS) plaques, the T2 lesions reflect the clinical outcome only to a limited extent (1). One of the major drawbacks of conven- tional T2 lesion imaging in MS is the lack of patho- physiological specificity if this technique. T1 hypoin- tense lesions are more specific, and correlate with axonal density in MS. Newer MRI techniques, such as diffusion tensor imaging (DTI), may show more subtle pathological changes in brain tissue that is normal- appearing on conventional images, which do show white matter (WM) lesions and atrophy (1). DTI pro- vides in vivo and non-invasive information about the orientation and integrity of WM fiber bundles. Diffu- sion measures that are often used to quantify WM damage include the fractional anisotropy (FA), which is a normalized measure of the diffusion anisotropy, the mean diffusivity (MD), which is the average diffu- sion in a voxel and the longitudinal and the trans- verse diffusivities L1 and L23, which measure the dif- fusion along and perpendicular to the WM bundle (2). It has been reported in other studies that cognitive dysfunction in MS patients might be related to WM lesions, normal appearing brain tissue on conven- tional MRI, and cortical as well as deep gray matter (3). Rao et al (3) suggested that cognitive impairment is induced by a disruption of the cortico-subcortical circuits, connecting the frontal cortices to thalamus and basal ganglia. However, other studies reported that posterior brain regions and the corpus callosum might also play a role in the cognitive malfunctioning (4). In addition, it has been suggested that a slowing of information processing speed might be related to sensory-motor damage. Since DTI provides measures of WM integrity, it is a relevant technique to investi- gate the correlation of WM microstructural properties 1 Visionlab, Department of Physics, University of Antwerp, Antwerp, Belgium. 2 Department of Radiology, University Hospital Antwerp, University of Antwerp, Antwerp, Belgium. 3 Department of Neurology, National Multiple Sclerosis Centre, Melsbroek, Belgium. 4 Department of Radiology Image Sciences Institute, University Medical Center Utrecht, Utrecht, the Netherlands. *Address reprint requests to: W.V.H., Vision Lab, Dept. of Physics, University of Antwerp, Universiteitsplein 1, N 1.18, B-2610 Ant- werpen, Belgium. E-mail: wim.vanhecke@ua.ac.be Received November 16, 2009; Accepted March 9, 2010. DOI 10.1002/jmri.22198 Published online in Wiley InterScience (www.interscience.wiley.com). JOURNAL OF MAGNETIC RESONANCE IMAGING 31:1492–1498 (2010) V C 2010 Wiley-Liss, Inc. 1492