Quantitative Imaging in Multiple Sclerosis
Cornelia Laule1
1University of British Columbia, Vancouver, BC, Canada

Synopsis

Keywords: Neuro: Brain, Neuro: White matter, Neuro: Spinal Cord

This lecture will provide an overview of quantitative MRI findings in multiple sclerosis (MS) brain and spinal cord. MS clinical features, tissue changes and the need for advanced MRI biomarkers will be reviewed. Results from magnetization transfer, diffusion MRI, quantitative T1, quantitative susceptibility mapping, myelin water imaging, magnetic resonance spectroscopy, and non-proton MRI (23Na, 31P) in MS lesions and normal appearing white/grey matter will be summarized. Clinical translation of advanced MRI techniques through normative atlases will be discussed, as well as challenges such as standardization, reproducibility, and integration with other clinical and biological markers for personalized medicine approaches in MS.

Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is characterized by demyelination, axonal loss, gliosis, and neurodegeneration in the brain and spinal cord.1. MS is a leading cause of non-traumatic disability in young adults, with people most commonly being diagnosed between ages 20-40 years.2 Approximately 2.8 million people worldwide are affected by MS, with women being affected about 2-3 times more often than men and higher rates in North America and Europe.3, 4 Environmental and genetic risk factors contribute to the development of MS, but the exact causes remain unknown.5

The clinical manifestations of MS vary widely, depending on the location and extent of the tissue damage, and include motor, sensory, cognitive, and visual symptoms, and the clinical course is highly variable. The disease course is highly variable, with relapsing-remitting MS (RRMS) being the most common subtype, characterized by acute attacks (relapses) followed by periods of remission. Secondary progressive MS (SPMS) often follows RRMS, with gradual worsening of disability independent of relapses and primary progressive MS (PPMS) involves gradual progression from disease onset without distinct relapses.6 A variety of tissue changes characterize MS.7 Inflammation occurs through immune cell infiltration and release of cytokines and other inflammatory mediators. Demyelination arises through an autoimmune attack on the myelin sheaths surrounding axons, leading to disrupted signal transmission. Axonal injury and neuronal loss drives neurodegeneration which contributes to irreversible disability. Tissue changes in MS involve both white and gray matter pathology. White matter lesions are the hallmark of MS, appearing as areas focal abnormality on conventional MRI. Normal-appearing white matter (NAWM) also exhibits diffuse microscopic injury, including demyelination and axonal degeneration. Gray matter pathology, such as cortical demyelination and neuronal loss, is increasingly recognized as a significant contributor to disability.8

MS diagnosis is based on clinical criteria, supported by magnetic resonance imaging (MRI) findings. Clinical MRI scans are very sensitive to damage within the CNS, however, conventional MRI measures, such as lesion volume and brain atrophy, do not fully capture the complexity and heterogeneity of MS pathology. For example, MS lesions appear bright on proton density and T2-weighted images, but the underlying pathology can include edema, inflammation, demyelination, axonal loss and gliosis. In addition to conventional MRI’s limited specificity for the underlying tissue changes, poor sensitivity for non-lesional pathology, and generally poor correlation with clinical outcomes have created a clinico—radiological paradox in MS.9 Therefore, there is a need for more advanced MRI techniques that can provide additional information on the metabolic and microstructural aspects of MS tissue pathology, clinical progression and response to therapy.

Quantitative MRI Findings in MS

Quantitative MRI techniques provide valuable insights into the underlying pathology of MS, enabling a more comprehensive characterization of tissue damage beyond conventional MRI.
Magnetization transfer imaging examines the magnetization exchange macromolecules and water, providing a marker of overall tissue integrity which can be quantified through the commonly used magnetization transfer ratio (MTR).10 MTR is influenced by myelin, but also inflammation, axonal loss and gliosis. Newer approaches such as inhomogeneous magnetization transfer may be more specific to myelin lipids. MS lesions typically exhibit a MTR, indicating alterations in tissue composition including inflammation, demyelination and/or axon loss, and reduced NAWM MTR reflects global abnormalities in tissue microstructure.11, 12
Diffusion Tensor Imaging measures diffusion of water molecules, providing markers of tissue microstructure. Measures are affected by myelin, but also axonal density, fibre orientation and membrane permeability. MS lesions make tractography and interpretation difficult. Newer modeling approaches such as Neurite Orientation Dispersion and Density Imaging (NODDI) and Diffusion Basis Spectrum Imaging (DBSI) may provide more specific information about tissue microstructure and inflammation/edema. MS lesions demonstrate increased mean diffusivity and decreased fractional anisotropy, abnormalities which are also observed in NAWM, but to a lesser extent.13 NODDI-derived neurite density is reduced in both lesions and NAWM, and correlations with clinical disability, indicating diffuse pathology.14, 15 DBSI findings in MS lesions suggest increased cellularity and inflammation markers, and abnormal diffusion measures in NAWM using DBSI point to pathological changes across the spectrum of MS.16
Quantitative T1 mapping measures the T1 relaxation time, which is sensitive to many factors including water content and myelin.17 MS lesions exhibit increased T1 times and elevated T1 values in NAWM suggest the presence of occult damage and demyelination.18, 19
Quantitative Susceptibility Mapping (QSM) measures the magnetic susceptibility related to iron and myelin content in tissues.20 In chronic MS lesions, increased susceptibility is observed, potentially reflecting iron deposition, and in NAWM susceptibility changes indicate demyelination and potential iron accumulation.21 The presence of white matter paramagnetic rim lesions is associated with more severe disability, and deep grey matter susceptibility and disability measures correlate.22
Myelin water imaging separates the signal from water trapped between myelin bilayers (termed myelin water) and water in other physical spaces. Myelin water imaging yields a myelin water fraction (MWF, a validated biomarker of myelin content) and mean T2 time of the intra/extra-cellular water.23 In MS lesions, MWF is heterogeneously reduced, reflecting varying degrees of demyelination.24 NAWM MWF is also decreased and correlates with clinical disability, suggesting occult demyelination throughout the CNS.25
Magnetic resonance spectroscopy (MRS) measures the concentrations of metabolites like N-acetylaspartate (axon-myelin coupling), choline (membrane turnover) and free lipid (active demyelination). NAA levels are reduced in MS lesions, NAWM, and normal appearing grey matter, and NAA reduction correlates with disability progression, cognitive impairment and brain atrophy.26-36 Other metabolites also show abnormalities in lesions and NAWM, some of which correlate with clinical measures.
Non-proton-based magnetic resonance studies in MS are limited relative to 1H studies and could be a promising area for research. Sodium-23 (23Na) gives the second strongest MR signal from biological tissue after 1H, and plays important roles in nerve signal transmission, axon integrity and cell function.37, 38 23Na studies in MS include demonstration of differences between controls and SPMS WM but not GM,39 and the finding that total sodium concentration and intracellular sodium volume fraction correlate with lesion volumes and MS disability.40 Phosphorus-31 (31P) MRS studies can quantify chemicals related to phospholipid membrane composition, intra and extra cellular pH, magnesium (Mg) and energy metabolism.41, 42 Limited 31P MRS studies in MS exist but recent work shows a relationship between fatigue severity and β-adenosine triphosphate, a marker of cerebral ATP.43


In summary, quantitative MRI techniques offer valuable insights into the diverse pathological processes underlying MS, including demyelination, neurodegeneration, inflammation, and metabolic alterations. Integration of multimodal MRI metrics has the potential to provide a comprehensive characterization of MS pathology, enabling a more complete understanding of the disease processes. Future directions include the clinical translation of these advanced MRI techniques through normative atlases, as well as addressing challenges such as standardization, reproducibility, and integration with other clinical and biological markers for personalized medicine approaches in MS.

Acknowledgements

The presenter and lab receives funding support from NSERC, Craig H. Neilsen Foundation, MS Canada, Michael Smith Foundation for Health Research, ICORD, UBC. The presenter and lab resides on the traditional, ancestral, and unceded territories of Coast Salish Peoples, including the territories of the xwməθkwəy̓əm (Musqueam), Skwxwú7mesh (Squamish), Stó:lō and Səl̓ílwətaʔ/Selilwitulh (Tsleil-Waututh) Nations. I acknowledge that these lands are still home to many diverse First Nations, Métis, and Inuit people. I acknowledge that my ability to live and work on these lands today is a direct benefit of policies of expulsion and assimilation of Indigenous peoples during the time of settlement and Confederation, and since.

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