Characterization of Axonal Disease in Patients with Multiple Sclerosis Using High-Gradient-Diffusion MR Imaging

Huang, Susie Y.; Tobyne, Sean M.; Nummenmaa, Aapo; Witzel, Thomas; Wald, Lawrence L.; McNab, Jennifer A.; Klawiter, Eric C.

doi:10.1148/radiol.2016151582

Cited by 39 publications

(47 citation statements)

References 27 publications

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“…The spherically averaged form of the signal model was fitted using Markov chain Monte Carlo sampling to yield orientation-independent estimates of restricted volume fraction (f r ), hindered diffusion coefficient, and CSF volume fraction (f csf ). 28 The longitudinal diffusion coefficient was assumed to be 1.7 Â 10 À3 mm 2 /s within axons, and the free diffusivity coefficient was assumed to be 3 mm 2 /s (diffusivity of free water at 37°C).…”

Section: Data Processing and Analysismentioning

confidence: 99%

“…Advanced diffusion MRI methods such as diffusional kurtosis imaging, 4 neurite orientation dispersion and density imaging (NODDI), 5 and AxCaliber, 6 provide metrics such as the axonal volume fraction (AVF) that may be more specific to axonal microstructure than DTI metrics in white matter disease 7 and neurodegeneration. 8 The availability of higher gradient strengths on clinical and research MRI scanners also offers improved sensitivity to intra-axonal water diffusion compared with measurements at conventional gradient strengths.…”

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confidence: 99%

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Imaging G-Ratio in Multiple Sclerosis Using High-Gradient Diffusion MRI and Macromolecular Tissue Volume

Fan

Tian

et al. 2019

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE: Remyelination represents an area of great therapeutic interest in multiple sclerosis but currently lacks a robust imaging marker. The purpose of this study was to use high-gradient diffusion MRI and macromolecular tissue volume imaging to obtain estimates of axonal volume fraction, myelin volume fraction, and the imaging g-ratio in patients with MS and healthy controls and to explore their relationship to neurologic disability in MS. MATERIALS AND METHODS:Thirty individuals with MS (23 relapsing-remitting MS, 7 progressive MS) and 19 age-matched healthy controls were scanned on a 3T MRI scanner equipped with 300 mT/m maximum gradient strength using a comprehensive multishell diffusion MRI protocol. Macromolecular tissue volume imaging was performed to quantify the myelin volume fraction. Diffusion data were fitted to a 3-compartment model of white matter using a spheric mean approach to yield estimates of axonal volume fraction. The imaging g-ratio was calculated from the ratio of myelin volume fraction and axonal volume fraction. Imaging metrics were compared between groups using 2-sided t tests with a Bonferroni correction. RESULTS:The mean g-ratio was significantly elevated in lesions compared with normal-appearing WM (0.74 vs 0.67, P , .001). Axonal volume fraction (0.17 vs 0.23, P , .001) and myelin volume fraction (0.17 vs 0.25, P , .001) were significantly lower in lesions than normal-appearing WM. Myelin volume fraction was lower in normal-appearing WM compared with that in healthy controls (0.25 vs 0.27, P = .009). Disability, as measured by the Expanded Disability Status Scale, was significantly associated with myelin volume fraction (b = -40.5, P = .001) and axonal volume fraction (b = -41.0, P = .016) in normal-appearing WM. CONCLUSIONS:The imaging g-ratio may serve as a biomarker for the relative degree of axonal and myelin loss in MS.ABBREVIATIONS: AVF 4 axonal volume fraction; EDSS 4 Expanded Disability Status Scale; HC 4 healthy controls; MSFC 4 multiple sclerosis functional composite; MTV 4 macromolecular tissue volume; MVF 4 myelin volume fraction; NAWM 4 normal-appearing white matter; NODDI 4 neurite orientation dispersion and density imaging; PMS 4 progressive MS; qMT 4 quantitative magnetization transfer; RRMS 4 relapsing-remitting MS M ultiple sclerosis is a disease of the CNS characterized by inflammatory demyelination and axonal loss. Demyelination predisposes axons to immune-mediated injury, resulting in axonal loss that is thought to be the substrate of permanent disability. 1 Myelin repair occurs to a variable extent, and promoting remyelination represents an area of great therapeutic interest. 2,3 Unfortunately, conventional MRI is unable to distinguish remyelination from myelin loss and axonal damage. This lack of sensitivity and specificity highlights the need for more specific imaging approaches.

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Section: Data Processing and Analysismentioning

confidence: 99%

mentioning

confidence: 99%

Imaging G-Ratio in Multiple Sclerosis Using High-Gradient Diffusion MRI and Macromolecular Tissue Volume

Fan

Tian

et al. 2019

AJNR Am J Neuroradiol

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“…Dispersion of fiber orientations further limits the interpretation as does the relatively low diffusion resolution (16 directions in our protocol) [33, 46]. Future research could address this limitation through the addition of more specific myelin (i.e., quantitative magnetization transfer ratio and macromolecular tissue volume) and axonal imaging markers (AxCaliber, neurite orientation dispersion and density imaging [NODDI]) [46–48]. …”

Section: Limitationsmentioning

confidence: 99%

Characterization of normal-appearing white matter in multiple sclerosis using quantitative susceptibility mapping in conjunction with diffusion tensor imaging

Chiang

Stephens

et al. 2018

Neuroradiology

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Purpose Quantitative susceptibility mapping (QSM) is influenced by iron as well as myelin, which makes interpretation of pathologic changes challenging. Concurrent acquisition of MR sequences that are sensitive to axonal/myelin integrity, such as diffusion tensor imaging (DTI), may provide context for interpreting quantitative susceptibility (QS) signal. The purpose of our study was to investigate alterations in normal-appearing white matter (NAWM) in multiple sclerosis (MS) using QSM in conjunction with DTI. Methods Twenty relapsing–remitting MS patients and 20 age-matched healthy controls (HC) were recruited for this prospective study. QS, radial diffusivity (RD), fractional anisotropy (FA), and R2* maps within the whole brain as well as individual tracts were generated for comparison between NAWM and HC white matter (HCWM). Results MS lesions demonstrated significant differences in QS, FA, RD, and R2* compared to HCWM (p < 0.03). These metrics did not show a significant difference between whole-brain NAWM and HCWM. Among NAWM tracts, the cingulate gyri demonstrated significantly decreased QS compared to HCWM (p = 0.004). The forceps major showed significant differences in FA and RD without corresponding changes in QS (p < 0.01). Conclusion We found discordant changes in QSM and DTI metrics within the cingulate gyri and forceps major. This may potentially reflect the influence of paramagnetic substrates such as iron, which could be decreased along these NAWM tracts. Our results point to the potential role of QSM as a unique biomarker, although additional validation studies are needed.

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“…e76 A number of more complex compartmentspecific models attempt to address this limitation by accounting for intra-axonal, extra-axonal, and free water diffusion. 45 Diffusion basis spectrum imaging aims to evaluate the anisotropic component of diffusion, to account for cellularity and extracellular space. e77 Other approaches such as AxCaliber and ActiveAx can additionally provide information on axon diameter but may require high gradient MR systems to provide robust data.…”

Section: Advanced Diffusion Imagingmentioning

confidence: 99%

Imaging outcome measures of neuroprotection and repair in MS

Ontaneda

Azevedo

et al. 2019

Neurology

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ObjectiveTo summarize current and emerging imaging techniques that can be used to assess neuroprotection and repair in multiple sclerosis (MS), and to provide a consensus opinion on the potential utility of each technique in clinical trial settings. MethodsClinicians and scientists with expertise in the use of MRI in MS convened in Toronto, Canada, in November 2016 at a North American Imaging in Multiple Sclerosis (NAIMS) Cooperative workshop meeting. The discussion was compiled into a manuscript and circulated to all NAIMS members in attendance. Edits and feedback were incorporated until all authors were in agreement. ResultsA wide spectrum of imaging techniques and analysis methods in the context of specific study designs were discussed, with a focus on the utility and limitations of applying each technique to assess neuroprotection and repair. Techniques were discussed under specific themes, and included conventional imaging, magnetization transfer ratio, diffusion tensor imaging, susceptibility-weighted imaging, imaging cortical lesions, magnetic resonance spectroscopy, PET, advanced diffusion imaging, sodium imaging, multimodal techniques, imaging of special regions, statistical considerations, and study design. ConclusionsImaging biomarkers of neuroprotection and repair are an unmet need in MS. There are a number of promising techniques with different strengths and limitations, and selection of a specific technique will depend on a number of factors, notably the question the trial seeks to answer. Ongoing collaborative efforts will enable further refinement and improved methods to image the effect of novel therapeutic agents that exert benefit in MS predominately through neuroprotective and reparative mechanisms.

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Characterization of Axonal Disease in Patients with Multiple Sclerosis Using High-Gradient-Diffusion MR Imaging

Cited by 39 publications

References 27 publications

Imaging G-Ratio in Multiple Sclerosis Using High-Gradient Diffusion MRI and Macromolecular Tissue Volume

Imaging G-Ratio in Multiple Sclerosis Using High-Gradient Diffusion MRI and Macromolecular Tissue Volume

Characterization of normal-appearing white matter in multiple sclerosis using quantitative susceptibility mapping in conjunction with diffusion tensor imaging

Imaging outcome measures of neuroprotection and repair in MS

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