Myelin heterogeneity for assessing normal appearing white matter myelin damage in multiple sclerosis.

BACKGROUND AND PURPOSE: Conventional MRI measures of multiple sclerosis (MS) disease severity, such as lesion volume and brain atrophy, do not provide information about microstructural tissue changes, which may be driving physical and cognitive progression. Myelin damage in normal-appearing white matter (NAWM) is likely an important contributor to MS disability. Myelin water fraction (MWF) provides quantitative measurements of myelin. Mean MWF reflects average myelin content, while MWF standard deviation (SD) describes variation in myelin within regions. The myelin heterogeneity index (MHI = SD/mean MWF) is a composite metric of myelin content and myelin variability. We investigated how mean MWF, SD, and MHI compare in differentiating MS from controls and their associations with physical and cognitive disability. METHODS: Myelin water imaging data were acquired from 91 MS participants and 31 healthy controls (HC). Segmented whole-brain NAWM and corpus callosum (CC) NAWM, mean MWF, SD, and MHI were compared between groups. Associations of mean MWF, SD, and MHI with Expanded Disability Status Scale and Symbol Digit Modalities Test were assessed. RESULTS: NAWM and CC MHI had the highest area under the curve: .78 (95% confidence interval [CI]: .69, .86) and .84 (95% CI: .76, .91), respectively, distinguishing MS from HC. CONCLUSIONS: Mean MWF, SD, and MHI provide complementary information when assessing regional and global NAWM abnormalities in MS and associations with clinical outcome measures. Examining all three metrics (mean MWF, SD, and MHI) enables a more detailed interpretation of results, depending on whether regions of interest include areas that are more heterogeneous, earlier in the demyelination process, or uniformly injured.

Myelin water imaging in relapsing multiple sclerosis treated with ocrelizumab and interferon beta-1a.

BACKGROUND: Myelin water imaging is a magnetic resonance imaging (MRI) technique that quantifies myelin damage and repair in multiple sclerosis (MS) via the myelin water fraction (MWF). OBJECTIVE: In this substudy of a phase 3 therapeutic trial, OPERA II, MWF was assessed in relapsing MS participants assigned to interferon beta-1a (IFNb-1a) or ocrelizumab (OCR) during a two-year double-blind period (DBP) followed by a two-year open label extension (OLE) with ocrelizumab treatment. METHODS: MWF in normal appearing white matter (NAWM), including both whole brain NAWM and 5 white matter structures, and chronic lesions, was assessed in 29 OCR and 26 IFNb-1a treated participants at weeks 0, 24, 48 and 96 (DBP), and weeks 144 and 192 (OLE), and in white matter for 23 healthy control participants at weeks 0, 48 and 96. RESULTS: Linear mixed-effects models of data from baseline to week 96 showed a difference in the change in MWF over time favouring ocrelizumab in all NAWM regions. At week 192, lesion MWF was lower for participants originally randomised to IFNb-1a compared to those originally randomised to OCR. Controls showed no change in MWF over 96 weeks in any region. CONCLUSION: Ocrelizumab appears to protect against demyelination in MS NAWM and chronic lesions and may allow for a more permissive micro environment for remyelination to occur in focal and diffusely damaged tissue.

Cervical Spinal Cord Atrophy can be Accurately Quantified Using Head Images.

BACKGROUND: Spinal cord atrophy provides a clinically relevant metric for monitoring MS. However, the spinal cord is imaged far less frequently than brain due to artefacts and acquisition time, whereas MRI of the brain is routinely performed. OBJECTIVE: To validate spinal cord cross-sectional area measurements from routine 3DT1 whole-brain MRI versus those from dedicated cord MRI in healthy controls and people with MS. METHODS: We calculated cross-sectional area at C1 and C2/3 using T2*-weighted spinal cord images and 3DT1 brain images, for 28 healthy controls and 73 people with MS. Correlations for both groups were assessed between: (1) C1 and C2/3 using cord images; (2) C1 from brain and C1 from cord; and (3) C1 from brain and C2/3 from cord. RESULTS AND CONCLUSION: C1 and C2/3 from cord were strongly correlated in controls (r = 0.94, p<0.0001) and MS (r = 0.85, p<0.0001). There was strong agreement between C1 from brain and C2/3 from cord in controls (r = 0.84, p<0.0001) and MS (r = 0.81, p<0.0001). This supports the use of C1 cross-sectional area calculated from brain imaging as a surrogate for the traditional C2/3 cross-sectional area measure for spinal cord atrophy.

Cortical morphology predicts placebo response in multiple sclerosis.

Despite significant insights into the neural mechanisms of acute placebo responses, less is known about longer-term placebo responses, such as those seen in clinical trials, or their interactions with brain disease. We examined brain correlates of placebo responses in a randomized trial of a then controversial and now disproved endovascular treatment for multiple sclerosis. Patients received either balloon or sham extracranial venoplasty and were followed for 48 weeks. Venoplasty had no therapeutic effect, but a subset of both venoplasty- and sham-treated patients reported a transient improvement in health-related quality of life, suggesting a placebo response. Placebo responders did not differ from non-responders in total MRI T2 lesion load, count or location, nor were there differences in normalized brain volume, regional grey or white matter volume or cortical thickness (CT). However, responders had higher lesion activity. Graph theoretical analysis of CT covariance showed that non-responders had a more small-world-like CT architecture. In non-responders, lesion load was inversely associated with CT in somatosensory, motor and association areas, precuneus, and insula, primarily in the right hemisphere. In responders, lesion load was unrelated to CT. The neuropathological process in MS may produce in some a cortical configuration less capable of generating sustained placebo responses.

Cervical cord myelin abnormality is associated with clinical disability in multiple sclerosis.

BACKGROUND: Myelin water imaging (MWI) was recently optimized to provide quantitative in vivo measurement of spinal cord myelin, which is critically involved in multiple sclerosis (MS) disability. OBJECTIVE: To assess cervical cord myelin measurements in relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis (ProgMS) participants and evaluate the correlation between myelin measures and clinical disability. METHODS: We used MWI data from 35 RRMS, 30 ProgMS, and 28 healthy control (HC) participants collected at cord level C2/C3 on a 3 T magnetic resonance imaging (MRI) scanner. Myelin heterogeneity index (MHI), a measurement of myelin variability, was calculated for whole cervical cord, global white matter, dorsal column, lateral and ventral funiculi. Correlations were assessed between MHI and Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), timed 25-foot walk, and disease duration. RESULTS: In various regions of the cervical cord, ProgMS MHI was higher compared to HC (between 9.5% and 31%, p ⩽ 0.04) and RRMS (between 13% and 26%, p ⩽ 0.02), and ProgMS MHI was associated with EDSS (r = 0.42-0.52) and 9HPT (r = 0.45-0.52). CONCLUSION: Myelin abnormalities within clinically eloquent areas are related to clinical disability. MWI metrics have a potential role for monitoring subclinical disease progression and adjudicating treatment efficacy for new therapies targeting ProgMS.

Comparison of multi echo T2 relaxation and steady state approaches for myelin imaging in the central nervous system.

The traditional approach for measuring myelin-associated water with quantitative magnetic resonance imaging (MRI) uses multi-echo T2 relaxation data to calculate the myelin water fraction (MWF). A fundamentally different approach, abbreviated "mcDESPOT", uses a more efficient steady-state acquisition to generate an equivalent metric (fM). Although previous studies have demonstrated inherent instability and bias in the complex mcDESPOT analysis procedure, fM has often been used as a surrogate for MWF. We produced and compared multivariate atlases of MWF and fM in healthy human brain and cervical spinal cord (available online) and compared their ability to detect multiple sclerosis pathology. A significant bias was found in all regions (p < 10-5), albeit reversed for spinal cord (fM-MWF = - 3.4%) compared to brain (+ 6.2%). MWF and fM followed an approximately linear relationship for regions with MWF < ~ 10%. For MWF > ~ 10%, the relationship broke down and fM no longer increased in tandem with MWF. For multiple sclerosis patients, MWF and fM Z score maps showed overlapping areas of low Z score and similar trends between patients and brain regions, although those of fM generally had greater spatial extent and magnitude of severity. These results will guide future choice of myelin-sensitive quantitative MRI and improve interpretation of studies using either myelin imaging approach.

An atlas for human brain myelin content throughout the adult life span.

Myelin water imaging is a quantitative neuroimaging technique that provides the myelin water fraction (MWF), a metric highly specific to myelin content, and the intra-/extra-cellular T2 (IET2), which is related to water and iron content. We coupled high-resolution data from 100 adults with gold-standard methodology to create an optimized anatomical brain template and accompanying MWF and IET2 atlases. We then used the MWF atlas to characterize how myelin content relates to demographic factors. In most brain regions, myelin content followed a quadratic pattern of increase during the third decade of life, plateau at a maximum around the fifth decade, then decrease during later decades. The ranking of mean myelin content between brain regions remained consistent across age groups. These openly available normative atlases can facilitate evaluation of myelin imaging results on an individual basis and elucidate the distribution of myelin content between brain regions and in the context of aging.

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

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.

Myelin Damage in Normal Appearing White Matter Contributes to Impaired Cognitive Processing Speed in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment is a core symptom in multiple sclerosis (MS). Damage to normal appearing white matter (NAWM) is likely involved. We sought to determine if greater myelin heterogeneity in NAWM is associated with decreased cognitive performance in MS. METHODS: A total of 27 participants with MS and 13 controls matched for age, sex, and education underwent myelin water imaging (MWI) from which the myelin water fraction (MWF) was calculated. Corpus callosum, superior longitudinal fasciculus, and cingulum were chosen as regions of interest (ROIs) a priori based on their involvement in MS-related cognitive impairment. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT). Pearson ́s product moment correlations were performed to assess relationships between cognitive performance and myelin heterogeneity (variance of MWF within an ROI). RESULTS: In MS, myelin heterogeneity in all three ROIs was significantly associated with performance on the SDMT. These correlations ranged from moderate (r = -.561) to moderately strong (r = -.654) and were highly significant (P values ranged from .001 to .0002). Conversely, myelin heterogeneity was not associated with SDMT performance in controls in any ROI (P > .108). CONCLUSION: Increased myelin heterogeneity in NAWM is associated with decreased cognitive processing speed performance in MS.