Brain Advance Access originally published online on October 25, 2008
Brain 2009 132(1):239-249; doi:10.1093/brain/awn275
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Disconnection as a mechanism for cognitive dysfunction in multiple sclerosis
1 Department of Academic Radiology, University of Nottingham, Nottingham, UK 2 Department of Clinical Neurology, University of Nottingham, Nottingham, UK 3 Department of Psychiatry, University of Nottingham, Nottingham, UK
Correspondence to: Dr R. A. Dineen, BMBS, MRCP, FRCR, Department of Academic Radiology, University of Nottingham, Queen's Medical Centre, Derby Road, Nottingham NG7 2UH, UK E-mail: robert.dineen{at}nhs.net
Disconnection of cognitively important processing regions by injury to the interconnecting white matter provides a potential mechanism for cognitive dysfunction in multiple sclerosis. The contribution of tract-specific white matter injury to dysfunction in different cognitive domains in patients with multiple sclerosis has not previously been studied. We apply tract-based spatial statistics (TBSS) to diffusion tensor imaging (DTI) in a cohort of multiple sclerosis patients to identify loci where reduced white matter tract fractional anisotropy (FA) predicts impaired performance in cognitive testing. Thirty-seven multiple sclerosis patients in remission (median age 43.5 years; Expanded Disability Status Scale range 1.5–6.5; 35 relapsing remitting, two secondary-progressive) underwent 3 T MRI including high-resolution DTI. Multiple sclerosis patients underwent formal testing of performance in multiple cognitive domains. Normalized cognitive scores were used for voxel-wise statistical analysis using TBSS, while treating age as a covariate of no interest. Permutation-based inference on cluster size (t > 2, P <0.05 corrected) was used to correct for multiple comparisons. Statistical mapping revealed differential patterns of FA reduction for tests of sustained attention, working memory and processing speed, visual working memory and verbal learning and recall. FA was not associated with frontal lobe function or visuospatial perception. Cognitively relevant tract localizations only partially overlapped with areas of high FLAIR lesion probability, confirming the contribution of normal-appearing white matter abnormality to cognitive dysfunction. Of note, tract localizations showing significant associations with cognitive impairment were found to interconnect cortical regions thought to be involved in processing in these cognitive domains, or involve possible compensatory processing pathways. This suggests that TBSS reveals functionally relevant tract injury underlying cognitive dysfunction in patients with multiple sclerosis.
Key Words: multiple sclerosis; cognitive impairment; magnetic resonance imaging; diffusion tensor imaging; disconnection
Abbreviations: BA, Brodmann area; CIS, clinically isolated syndrome; COWAT, Controlled Oral Word Association Test; DTI, diffusion tensor imaging; FA, fractional anisotropy; MRS, magnetic resonance spectroscopy; MTI, magnetization transfer imaging; NAWM, normal-appearing white matter; PASAT, Paced Auditory Serial Addition Test; ROI, region of interest; TBSS, tract-based spatial statistics
Received April 6, 2008. Revised September 4, 2008. Accepted October 1, 2008.
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