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Updated: Dec 8, 2025
Magnetic Resonance Imaging of Multiple Sclerosis at 7.0 Tesla
Published on: February 19, 2021
Pathologic correlates of the magnetization transfer ratio in multiple sclerosis
Marcello Moccia1, Steven van de Pavert1, Arman Eshaghi1
1From the Department of Neuroinflammation, Queen Square MS Centre, NMR Research Unit, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences (M.M., S.v.d.P., A.E., L.H., M.Y., Y.W., C.W.-K., A.T., F.B., O.C.), Centre for Medical Image Computing, Department of Medical Physics and Bioengineering (J.P., S.O.), and Translational Imaging Group, UCL Institute of Healthcare Engineering (F.B.), University College London, UK; Multiple Sclerosis Clinical Care and Research Centre, Department of Neurosciences (M.M.), Federico II University, Naples, Italy; Department of Radiology and Nuclear Medicine (F.B.), VU University Medical Center, Amsterdam, the Netherlands; and National Institute for Health Research University College London Hospitals Biomedical Research Centre (A.T., F.B., O.C.), UK.
Objective:
To identify pathologic correlates of magnetization transfer ratio (MTR) in multiple sclerosis (MS) in an MRI-pathology study.
Methods:
We acquired MTR maps at 3T from 16 fixed MS brains and 4 controls, and immunostained 100 tissue blocks for neuronal neurofilaments, myelin (SMI94), tissue macrophages (CD68), microglia (IBA1), B-lymphocytes, T-lymphocytes, cytotoxic T-lymphocytes, astrocytes (glial fibrillary acidic protein), and mitochondrial damage (COX4, VDAC). We defined regions of interest in lesions, normal-appearing white matter (NAWM), and cortical normal-appearing gray matter (NAGM). Associations between MTR and immunostaining intensities were explored using linear mixed-effects models (with cassettes nested within patients) and interaction terms (for differences between regions of interest and between cases and controls); a multivariate linear mixed-effects model identified the best pathologic correlates of MTR.
Results:
MTR was the lowest in white matter (WM) lesions (23.4 ± 9.4%) and the highest in NAWM (38.1 ± 8.7%). In MS brains, lower MTR was associated with lower immunostaining intensity for myelin (coefficient 0.31; 95% confidence interval [CI] 0.07-0.55), macrophages (coefficient 0.03; 95% CI 0.01-0.07), and astrocytes (coefficient 0.51; 95% CI 0.02-1.00), and with greater mitochondrial damage (coefficient 0.31; 95% CI 0.07-0.55). Based on interaction terms, MTR was more strongly associated with myelin in WM (coefficient 1.58; 95% CI 1.09-2.08) and gray matter (GM) lesions (coefficient 0.66; 95% CI 0.13-1.20), and with macrophages (coefficient 1.40; 95% CI 0.56-2.25), astrocytes (coefficient 2.66; 95% CI 1.31-4.01), and mitochondrial damage (coefficient -12.59; 95% CI -23.16 to -2.02) in MS brains than controls. In the multivariate model, myelin immunostaining intensity was the best correlate of MTR (coefficient 0.31; 95% CI 0.09-0.52; p = 0.004).
Conclusions:
Myelin was the strongest correlate of MTR, especially in WM and cortical GM lesions, but additional correlates should be kept in mind when designing and interpreting MTR observational and experimental studies in MS.
Insights
Magnetization transfer ratio (MTR) in multiple sclerosis (MS) brain lesions is most strongly associated with myelin. Understanding these pathologic correlates of MTR is crucial for interpreting MRI studies in MS.
Area of Science:
- Neuroimaging
- Neuropathology
- Multiple Sclerosis Research
Background:
- Magnetization transfer ratio (MTR) is an MRI technique sensitive to tissue microstructure.
- Understanding the pathologic basis of MTR changes in multiple sclerosis (MS) is essential for accurate interpretation of imaging findings.
- Previous studies have suggested links between MTR and demyelination, but comprehensive pathologic validation is needed.
Purpose of the Study:
- To identify the specific pathologic substrates that correlate with MTR values in MS lesions and normal-appearing brain tissue.
- To investigate the association between MTR and various cellular and molecular markers, including myelin, axonal damage, inflammation, and glial responses.
- To determine the primary pathologic correlate of MTR in the context of MS.
Main Methods:
- Acquisition of MTR maps at 3T from fixed MS and control brains.
- Immunohistochemical staining of 100 tissue blocks for myelin, neurons, macrophages, microglia, lymphocytes, astrocytes, and mitochondrial damage.
- Definition of regions of interest in lesions, normal-appearing white matter (NAWM), and normal-appearing gray matter (NAGM).
- Statistical analysis using linear mixed-effects models to explore associations between MTR and immunostaining intensities.
Main Results:
- MTR was significantly lower in white matter (WM) lesions compared to NAWM.
- In MS brains, lower MTR correlated with reduced myelin, macrophage, and astrocyte immunostaining, and increased mitochondrial damage.
- Myelin immunostaining intensity emerged as the strongest and most significant correlate of MTR across different MS lesion types and normal-appearing tissues.
Conclusions:
- Myelin integrity is the primary determinant of MTR values in multiple sclerosis brain lesions.
- While myelin is the strongest correlate, other factors like inflammation and mitochondrial damage also contribute to MTR changes.
- These findings are critical for the accurate interpretation of MTR in observational and experimental MS studies.
