The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: A serial diffusion MRI study

Several magnetic resonance (MR) techniques have proved to be sensitive enough to detect the subtle pathological changes that post-mortem studies showed to occur in the normal-appearing white matter (NAWM) from patients with multiple sclerosis (MS). Although these abnormalities can be detected in other neurological conditions, they seem to be more frequent and diffuse in MS. However, the contribution of NAWM changes to the diagnosis is still unclear. Their nature is also unknown and perhaps differs in different phases and clinical manifestations of the disease. Nevertheless, the extent and severity of NAWM damage seems to be relevant in causing disability and influencing the clinical evolution in MS patients. This review will summarize the present knowledge about MR-detected NAWM changes in MS and their relevance to the diagnosis and the understanding of disease evolution.

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Serial Clinical and MRI Study of Diffuse Cerebral White Matter Changes in Multiple Sclerosis

Imaging of Brain Metabolism Spine and Cord Interventional Neuroradiology Free Communications ◽

10.1007/978-3-642-74337-5_119 ◽

1989 ◽

pp. 419-423 ◽

Cited By ~ 1

Author(s):

M. Brainin ◽

Th. Reisner ◽

E. Maida ◽

A. Neuhold ◽

L. Wicke ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Cerebral White Matter ◽

White Matter Changes ◽

Mri Study

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White matter changes in multiple sclerosis: correlation of q-space diffusion MRI and 1H MRS

Magnetic Resonance Imaging ◽

10.1016/j.mri.2005.04.008 ◽

2005 ◽

Vol 23 (6) ◽

pp. 703-710 ◽

Cited By ~ 53

Author(s):

Yaniv Assaf ◽

Joab Chapman ◽

Dafna Ben-Bashat ◽

Talma Hendler ◽

Yoram Segev ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Diffusion Mri ◽

1H Mrs ◽

White Matter Changes

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Normal-Appearing White Matter Changes in Multiple Sclerosis: Magnetization Transfer

Normal-appearing White and Grey Matter Damage in Multiple Sclerosis ◽

10.1007/978-88-470-2127-3_4 ◽

2004 ◽

pp. 37-45

Author(s):

F. Fazekas ◽

C. Enzinger ◽

S. Ropele

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Magnetization Transfer ◽

White Matter Changes ◽

Normal Appearing White Matter

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Modern Technology in Multi-Shell Diffusion MRI Reveals Diffuse White Matter Changes in Young Adults With Relapsing-Remitting Multiple Sclerosis

Frontiers in Neuroscience ◽

10.3389/fnins.2021.665017 ◽

2021 ◽

Vol 15 ◽

Author(s):

Ann-Marie Beaudoin ◽

François Rheault ◽

Guillaume Theaud ◽

Frédéric Laberge ◽

Kevin Whittingstall ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Diffusion Mri ◽

Free Water ◽

Cerebral White Matter ◽

Fiber Density ◽

White Matter Changes ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

ObjectiveTo characterize microstructural white matter changes related to relapsing-remitting multiple sclerosis using advanced diffusion MRI modeling and tractography. The association between imaging data and patient’s cognitive performance, fatigue severity and depressive symptoms is also explored.MethodsIn this cross-sectional study, 24 relapsing-remitting multiple sclerosis patients and 11 healthy controls were compared using high angular resolution diffusion imaging (HARDI). The imaging method includes a multi-shell scheme, free water correction to obtain tissue-specific measurements, probabilistic tracking algorithm robust to crossing fibers and white matter lesions, automatic streamlines and bundle dissection and tract-profiling with tractometry. The neuropsychological evaluation included the Symbol Digit Modalities Test, Paced Auditory Serial Addition Test, Modified Fatigue Impact Scale and Beck Depression Inventory-II.ResultsBundle-wise analysis by tractometry revealed a difference between patients and controls for 11 of the 14 preselected white matter bundles. In patients, free water corrected fractional anisotropy was significantly reduced while radial and mean diffusivities were increased, consistent with diffuse demyelination. The fornix and left inferior fronto-occipital fasciculus exhibited a higher free water fraction. Eight bundles showed an increase in total apparent fiber density and four bundles had a higher number of fiber orientations, suggesting axonal swelling and increased organization complexity, respectively. In the association study, depressive symptoms were associated with diffusion abnormalities in the right superior longitudinal fasciculus.ConclusionTissue-specific diffusion measures showed abnormalities along multiple cerebral white matter bundles in patients with relapsing-remitting multiple sclerosis. The proposed methodology combines free-water imaging, advanced bundle dissection and tractometry, which is a novel approach to investigate cerebral pathology in multiple sclerosis. It opens a new window of use for HARDI-derived measures and free water corrected diffusion measures. Advanced diffusion MRI provides a better insight into cerebral white matter changes in relapsing-remitting multiple sclerosis, namely diffuse demyelination, edema and increased fiber density and complexity.

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Early axonal damage in normal appearing white matter in multiple sclerosis: Novel insights from multi-shell diffusion MRI

2017 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) ◽

10.1109/embc.2017.8037494 ◽

2017 ◽

Cited By ~ 4

Author(s):

Silvia De Santis ◽

Tobias Granberg ◽

Russell Ouellette ◽

Constantina A. Treaba ◽

Qiuyun Fan ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Diffusion Mri ◽

Axonal Damage ◽

Normal Appearing White Matter

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Disentangling white-matter damage from physiological fibre orientation dispersion in multiple sclerosis

Brain Communications ◽

10.1093/braincomms/fcaa077 ◽

2020 ◽

Vol 2 (2) ◽

Cited By ~ 6

Author(s):

Kasper Winther Andersen ◽

Samo Lasič ◽

Henrik Lundell ◽

Markus Nilsson ◽

Daniel Topgaard ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Fractional Anisotropy ◽

Diffusion Mri ◽

Fibre Orientation ◽

Cerebral White Matter ◽

Healthy Controls ◽

Lesion Load ◽

Normal Appearing White Matter ◽

Relapsing Remitting

Abstract Multiple sclerosis leads to diffuse damage of the central nervous system, affecting also the normal-appearing white matter. Demyelination and axonal degeneration reduce regional fractional anisotropy in normal-appearing white matter, which can be routinely mapped with diffusion tensor imaging. However, the standard fractional anisotropy metric is also sensitive to physiological variations in orientation dispersion of white matter fibres. This complicates the detection of disease-related damage in large parts of cerebral white matter where microstructure physiologically displays a high degree of fibre dispersion. To resolve this ambiguity, we employed a novel tensor-valued encoding method for diffusion MRI, which yields a microscopic fractional anisotropy metric that is unaffected by regional variations in orientation dispersion. In 26 patients with relapsing-remitting multiple sclerosis, 14 patients with primary-progressive multiple sclerosis and 27 age-matched healthy controls, we compared standard fractional anisotropy mapping with the novel microscopic fractional anisotropy mapping method, focusing on normal-appearing white matter. Mean microscopic fractional anisotropy and standard fractional anisotropy of normal-appearing white matter were significantly reduced in both patient groups relative to healthy controls, but microscopic fractional anisotropy yielded a better reflection of disease-related white-matter alterations. The reduction in mean microscopic fractional anisotropy showed a significant positive linear relationship with physical disability, as reflected by the expanded disability status scale. Mean reduction of microscopic fractional anisotropy in normal-appearing white matter also scaled positively with individual cognitive dysfunction, as measured with the symbol digit modality test. Mean microscopic fractional anisotropy reduction in normal-appearing white matter also showed a positive relationship with total white-matter lesion load as well as lesion load in specific tract systems. None of these relationships between normal-appearing white-matter microstructure and clinical, cognitive or structural measures emerged when using mean fractional anisotropy. Together, the results provide converging evidence that microscopic fractional anisotropy mapping substantially advances the assessment of cerebral white matter in multiple sclerosis by disentangling microstructure damage from variations in physiological fibre orientation dispersion at the stage of data acquisition. Since tensor-valued encoding can be implemented in routine diffusion MRI, microscopic fractional anisotropy mapping bears considerable potential for the future assessment of disease progression in normal-appearing white matter in both relapsing-remitting and progressive forms of multiple sclerosis as well as other white-matter-related brain diseases.

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