Objective: Cognitive impairment (CI) is an important component of multiple sclerosis (MS) disability. A complex biological interplay between white matter (WM) and gray matter (GM) disease likely sustains CI. This study aims to address this issue by exploring the association between the extent of normal WM and GM disease and CI.

Methods: Cognitive function of 24 MS patients and 24 healthy volunteers (HVs) was studied using the Automated Neuropsychological Assessment Metrics (ANAM) battery. WM focal lesions and normal appearing WM (NAWM) volume in patients, cortical thickness (CTh) and deep GM structure volumes in both patients and HVs were measured by high field strength (3.0-Tesla; 3T) imaging.

Results: An analysis of covariance showed that patients performed worse than HVs on Code Substitution Delayed Memory (P = .04) and Procedural Reaction Time (P = .05) indicative of reduced performance in memory, cognitive flexibility, and processing speed. A summary score (Index of Cognitive Efficiency) indicating global test battery performance was also lower for the patient group (P = .04). Significant associations, as determined by the Spearman rank correlation tests, were noted between each of these 3 cognitive scores and measures of NAWM volume [CDD-TP1(r = .609; P = .0035), PRO-TP1 (r = .456; P = .029) and ICE (r = .489; P = .0129)], CTh (r = .5; P ≤ .05) and volume of subcortical normal appearing GM (NAGM) structures (r = .4; P≤ .04), but not WM lesions.

Conclusions: Both NAWM and NAGM volumes are related to CI in MS. The results highlight once again the urgent need to develop pharmacological strategies protecting patients from widespread neurodegeneration as possible preventive strategies of CI development.