Original Research Altered Diffusion Tensor in Multiple Sclerosis Normal-Appearing Brain Tissue: Cortical Diffusion Changes Seem Related to Clinical Deterioration Hugo Vrenken, PhD, 1 * Petra J.W. Pouwels, PhD, 2 Jeroen J.G. Geurts, PhD, 1 Dirk L. Knol, PhD, 3 Chris H. Polman, MD PhD, 4 Frederik Barkhof, MD PhD, 1 and Jonas A. Castelijns, MD, PhD 1 Purpose: To investigate normal-appearing white (NAWM) and cortical gray (NAGM) matter separately in multiple sclerosis (MS) in vivo using diffusion tensor imaging (DTI). Materials and Methods: In 64 MS patients (12 primary progressive [PP], 38 relapsing remitting [RR], 14 secondary progressive [SP]) and 20 healthy controls, whole-brain ap- parent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were acquired. A stimulated echo acquisition mode (STEAM) DTI sequence was used with minimal geo- metrical distortion in comparison to echo-planar imaging (EPI). NAWM and NAGM were identified using conventional magnetic resonance (MR) images, allowing a cautious as- sessment of FA in cortex. Results: Histogram analyses showed significant global FA decreases and ADC increases in MS NAWM compared to control WM. MS cortical NAGM had no significant global ADC increase, but FA was decreased significantly. In re- gional analyses, nearly all NAWM regions-of-interest (ROIs) had significantly increased ADC compared to controls, but FA was not changed. In nearly all cortical NAGM ROIs, ADC was significantly increased and FA significantly reduced. In multiple linear regression analyses in RR/SPMS patients, NAGM-ADC histogram peak height was associated more strongly with clinical disability than T 2 lesion load. Conclusion: Tissue damage occurs in both NAWM and cortical NAGM. The cortical damage appears to have more clinical impact than T 2 lesions. Key words: diffusion; water; multiple sclerosis; normal- appearing brain tissue; axonal damage; myelin J. Magn. Reson. Imaging 2006;23:628 – 636. © 2006 Wiley-Liss, Inc. THE LACK OF A STRONG correlation between the vol- ume of lesions visible on magnetic resonance (MR) im- ages (or “lesion load”) and clinical disability in multiple sclerosis (MS) has prompted investigations of the so- called normal-appearing brain tissue outside the MR visible lesions. Disease-inflicted damage to the normal- appearing brain tissue has been demonstrated in vivo by several quantitative MR measures, including altered metabolite concentrations (MR spectroscopy), pro- longed T 1 and T 2 relaxation times, reduced magnetiza- tion transfer ratios (MTR) and less restricted, more iso- tropic diffusion (a review is provided in Ref. 1)). The latter measurements employ diffusion-weighted imag- ing (DWI) or diffusion tensor imaging (DTI) techniques with the aim of obtaining information on tissue struc- ture that complements information obtained with other quantitative MR techniques. The two most commonly determined diffusion properties are the apparent diffu- sion coefficient (ADC, obtainable from both DWI and DTI), reflecting the orientation-averaged apparent dif- fusivity, and the fractional anisotropy (FA, obtainable from DTI only), reflecting the degree to which the diffu- sion tensor deviates from isotropy (2). The ADC is de- fined in this work as one third of the trace of the diffu- sion tensor, a directionally independent measure that is effectively equivalent to the mean diffusivity, or trace of the diffusion tensor reported by some papers, and is thought to be sensitive to general tissue damage. The FA is supposed to be most sensitive to damage to axonal tracts. Global analyses of all (normal-appearing) brain tissue have shown shifts of ADC histograms to higher ADC values in MS compared to controls (3,4) but this was 1 Department of Radiology, MR Center for MS Research, VU University Medical Center, Amsterdam, The Netherlands. 2 Department of Physics and Medical Technology, MR Center for MS Research, VU University Medical Center, Amsterdam, The Netherlands. 3 Department of Clinical Epidemiology and Biostatistics, MR Center for MS Research, VU University Medical Center, Amsterdam, The Nether- lands. 4 Department of Neurology, MR Center for MS Research, VU University Medical Center, Amsterdam, The Netherlands. Contract grant sponsor: Dutch MS Research Foundation, Voorschoten, The Netherlands; Contract grant numbers: 98-371 MS, 00-427 MS. *Address reprint requests to: H.V., VU University Medical Center, Dept. of Radiology, De Boelelaan 1117, 1081 HV Amsterdam, The Nether- lands. E-mail: h.vrenken@vumc.nl Received May 19, 2005; Accepted January 27, 2006. DOI 10.1002/jmri.20564 Published online 24 March 2006 in Wiley InterScience (www.interscience. wiley.com). JOURNAL OF MAGNETIC RESONANCE IMAGING 23:628 – 636 (2006) © 2006 Wiley-Liss, Inc. 628