Associations Between Findings From Myelin Water Imaging and Cognitive Performance Among Individuals With Multiple Sclerosis

Abstract

Importance: Cognitive impairment is a debilitating symptom of multiple sclerosis (MS) that affects up to 70% of patients. An improved understanding of the underlying pathology of MS-related cognitive impairment would provide considerable benefit to patients and clinicians.

Objective: To determine whether there is an association between myelin damage in tissue that appears completely normal on standard clinical imaging, but can be detected by myelin water imaging (MWI), with cognitive performance in MS.

Design, setting, and participants: In this cross-sectional study, participants with MS and controls underwent cognitive testing and magnetic resonance imaging (MRI) from August 23, 2017, to February 20, 2019. Participants were recruited through the University of British Columbia Hospital MS clinic and via online recruitment advertisements on local health authority websites. Cognitive testing was performed in the MS clinic, and MRI was performed at the adjacent academic research neuroimaging center. Seventy-three participants with clinically definite MS fulfilling the 2017 revised McDonald criteria for diagnosis and 22 age-, sex-, and education-matched healthy volunteers without neurological disease were included in the study. Data analysis was performed from March to November 2019.

Exposures: MWI was performed at 3 T with a 48-echo, 3-dimensional, gradient and spin-echo (GRASE) sequence. Cognitive testing was performed with assessments drawn from cognitive batteries validated for use in MS.

Main outcomes and measures: The association between myelin water measures, a measurement of the T2 relaxation signal from water in the myelin bilayers providing a specific marker for myelin, and cognitive test scores was assessed using Pearson correlation. Three white matter regions of interest-the cingulum, superior longitudinal fasciculus (SLF), and corpus callosum-were selected a priori according to their known involvement in MS-related cognitive impairment.

Results: For the 95 total participants, the mean (SD) age was 49.33 (11.44) years. The mean (SD) age was 50.2 (10.7) years for the 73 participants with MS and 46.4 (13.5) for the 22 controls. Forty-eight participants with MS (66%) and 14 controls (64%) were women. The mean (SD) years of education were 14.7 (2.2) for patients and 15.8 (2.5) years for controls. In MS, significant associations were observed between myelin water measures and scores on the Symbol Digit Modalities Test (SLF, r = -0.490; 95% CI, -0.697 to -0.284; P < .001; corpus callosum, r = -0.471; 95% CI, -0.680 to -0.262; P < .001; and cingulum, r = -0.419; 95% CI, -0.634 to -0.205; P < .001), Selective Reminding Test (SLF, r = -0.444; 95% CI, -0.660 to -0.217; P < .001; corpus callosum, r = -0.411; 95% CI, -0.630 to -0.181; P = .001; and cingulum, r = -0.361; 95% CI, -0.602 to -0.130; P = .003), and Controlled Oral Word Association Test (SLF, r = -0.317; 95% CI, -0.549 to -0.078; P = .01; and cingulum, r = -0.335; 95% CI, -0.658 to -0.113; P = .006). No significant associations were found in controls.

Conclusions and relevance: This study used MWI to demonstrate that otherwise normal-appearing brain tissue is diffusely damaged in MS, and the findings suggest that myelin water measures are associated with cognitive performance. MWI offers an in vivo biomarker feasible for use in clinical trials investigating cognition, providing a means for monitoring changes in myelination and its association with symptom worsening or improvement.

Figure 1.. Correlations Between Symbol Digit Modalities Test (SDMT) Performance and Myelin Heterogeneity Index

Correlations between the myelin heterogeneity index in normal-appearing white matter and SDMT scores are shown for participants with multiple sclerosis (MS) and controls in 3 regions of interest. Lines denote lines of best fit.

Figure 2.. Correlations Between Selective Reminding Test (SRT) Performance and Myelin Heterogeneity Index

Correlations between the myelin heterogeneity index in normal-appearing white matter and SRT scores are shown for participants with multiple sclerosis (MS) and controls in 3 regions of interest. Lines denote lines of best fit.

Figure 3.. Correlations Between Controlled Oral Word Association Test (COWAT) Performance and Myelin Heterogeneity Index

Correlations between the myelin heterogeneity index in normal-appearing white matter and COWAT scores are shown for participants with multiple sclerosis (MS) and controls in 3 regions of interest. Lines denote lines of best fit.

Figure 4.. Axial Map of Myelin Water Fraction (MWF) Values, MWF Distributions in Superior Longitudinal Fasciculus (SLF), Myelin Heterogeneity Index (MHI) in SLF, and Cognitive z Scores in 3 Participants with Multiple Sclerosis

Axial maps of MWF values (top), normalized histograms of MWF values in the SLF (middle), MHI in the SLF and cognitive z scores (bottom) of 3 participants with multiple sclerosis. Patient A had a high MHI in the SLF (0.59), matching their low cognitive scores compared with controls (range of z scores, −5.1 to −3.6). Patient B had both moderate MHI in the SLF (0.28) and cognitive test scores (range of z scores, −1.6 to −0.9). Patient C had a low MHI in the SLF (0.22) and performed at and above the level of controls on the cognitive tests range of z scores (−0.08 to 0.9). The z scores were calculated using the mean and SD for each cognitive test from the control sample. ROI indicates region of interest.