Measures of Thalamic Integrity are Associated with Cognitive Functioning in Fingolimod-treated Multiple Sclerosis Patients

Abstract

Background: Cognitive impairment is common in relapsing-remitting multiple sclerosis (RRMS) and multiple domains are affected, including information processing speed, episodic memory, and executive function. Damage to the thalamus appears to be related to cognitive functioning in MS. Fingolimod is a disease-modifying therapy for RRMS, which has been shown to have a protective effect on thalamic volume. Objective: To determine the relationship between cognitive measures and the thalamus in fingolimod-treated RRMS patients and healthy controls using ultra high-field magnetic resonance imaging (MRI). Methods: Fingolimod-treated RRMS and healthy participants were recruited from a single center to undergo neuropsychological testing and 7 tesla MRI. These assessments were performed at baseline, 6 months, and 12 months. The neuropsychological testing included the Brief Visuospatial Memory Test-Revised (BVMTR), the Symbol Digit Modalities Test (SDMT), the Selective Reminding Test (SRT), and the Delis-Kaplan Executive Function System (DKEFS). MRI metrics included thalamic volume, thalamic myelin density, thalamic axon density, T2 lesion volume, brain parenchymal fraction, and cortical thickness. Mixed-effects linear regression was used to determine the relationship between MRI parameters and neuropsychological test performance over time. Rates of change in patients and controls were compared using two-sample t-tests. Results: We enrolled 15 RRMS patients and 5 healthy controls. Controls performed better than patients at baseline, but this difference was only significant for the letter fluency subtest of the DKEFS and for long-term storage as assessed by the SRT. Thalamic volume and thalamic myelin density were significantly associated with visuospatial (BVMTR) and verbal memory (SRT). Thalamic volume alone was also associated with inhibitory control (Color word interference subtest of the DKEFS) and cognitive flexibility (Number letter switching subtest of the DKEFS), whereas thalamic myelin density alone was associated with semantic knowledge (Verbal fluency subtest of the DKEFS). There were no significant changes in the rates of change in neurometric test performance or MRI metrics between patients and controls from baseline to 6 months and baseline to 12 months. Conclusions: Thalamic injury is associated with cognitive performance in several domains. Fingolimod-treated RRMS patients evolved similarly to healthy controls over one year with regards to neuropsychological test performance and changes on MRI.