Objective. To characterize MR signal changes associated with tissue damage in the fornix and cingulum in multiple sclerosis (MS) using quantitative MRI measures and to determine associations with cognitive dysfunction. Background. The fornix and cingulum are white-matter bundles that carry information related to cognition. While cognitive dysfunction is reported in 40–60% of MS patients, the neuroanatomical correlates of cognitive impairment remain incompletely understood. Methods. The cingulum, pillars of the fornix, and corticospinal tract were segmented by fiber tracking via diffusion tensor imaging. Average tract-specific fractional anisotropy (FA), mean diffusivity (MD), and magnetization transfer ratio (MTR) were compared in MS cases and healthy volunteers. Associations with clinical measures and neuropsychological tests were derived by multivariate linear regression. Results. Fornix FA ( ) and MTR ( ) were decreased, and fornix MD ( ) and cingulum MD ( ) increased, in MS cases ( ) relative to healthy volunteers ( ) after adjustment for age and sex. Lower fornix FA and MTR, and higher fornix MD and , were correlated with lower PASAT-3 scores, but not with slower 25FTW times. Lower PASAT-3 scores were associated with lower cingulum FA and higher MD and . Conclusions. Cognitive dysfunction in MS may involve damage to a widespread network of brain structures, including white-matter pathways within the limbic system. 1. Introduction Cognitive dysfunction is reported in 40–60% of MS cases, can be present at both early and late stages of the disease, and can occur even in the presence of low overall physical disability [1–3]. MS-related cognitive dysfunction is most commonly characterized by relative decline of neuropsychological tasks assessing processing speed, short-term memory, attention, visuospatial abilities, and executive functioning [4, 5]. These deficits can negatively impact quality of life, as people with cognitive impairments are less likely to be employed, run a household, or participate in social and vocational activities [6]. Cognitive deficits may be subtle and unreliably detected in clinical evaluation of MS [7], and their neuroanatomic basis is incompletely understood. Many studies have used MRI to investigate the relationship between structural damage and cognitive impairment. Cognitive impairment has been associated with frontal and temporal lobe T2-weighted lesion load, T1 “black holes” (indicative of more severe tissue damage within lesions), and brain atrophy [8–13]. The corpus callosum, the major white-matter structure
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