title: In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy.
abstract: There is a need for accurate quantitative non-invasive biomarkers to monitor myelin pathology in vivo and distinguish myelin changes from other pathological features including inflammation and axonal loss. Conventional MRI metrics such as T2, magnetization transfer ratio and radial diffusivity have proven sensitivity but not specificity. In highly coherent white matter bundles, compartment-specific white matter tract integrity (WMTI) metrics can be directly derived from the diffusion and kurtosis tensors: axonal water fraction, intra-axonal diffusivity, and extra-axonal radial and axial diffusivities. We evaluate the potential of WMTI to quantify demyelination by monitoring the effects of both acute (6weeks) and chronic (12weeks) cuprizone intoxication and subsequent recovery in the mouse corpus callosum, and compare its performance with that of conventional metrics (T2, magnetization transfer, and DTI parameters). The changes observed in vivo correlated with those obtained from quantitative electron microscopy image analysis. A 6-week intoxication produced a significant decrease in axonal water fraction (p<0.001), with only mild changes in extra-axonal radial diffusivity, consistent with patchy demyelination, while a 12-week intoxication caused a more marked decrease in extra-axonal radial diffusivity (p=0.0135), consistent with more severe demyelination and clearance of the extra-axonal space. Results thus revealed increased specificity of the axonal water fraction and extra-axonal radial diffusivity parameters to different degrees and patterns of demyelination. The specificities of these parameters were corroborated by their respective correlations with microstructural features: the axonal water fraction correlated significantly with the electron microscopy derived total axonal water fraction (ρ=0.66; p=0.0014) but not with the g-ratio, while the extra-axonal radial diffusivity correlated with the g-ratio (ρ=0.48; p=0.0342) but not with the electron microscopy derived axonal water fraction. These parameters represent promising candidates as clinically feasible biomarkers of demyelination and remyelination in the white matter.
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA. Electronic address: ijelescu@gmail.com.
authors.forename: Ileana O
authors.initials: IO
authors.lastname: Jelescu
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zurek
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Kerryanne V
authors.initials: KV
authors.lastname: Winters
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Jelle
authors.initials: J
authors.lastname: Veraart
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Rajaratnam
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Kim
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Babb
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Shepherd
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Novikov
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Sungheon G
authors.initials: SG
authors.lastname: Kim
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Els
authors.initials: E
authors.lastname: Fieremans
mesh_terms: D000818:Animals; D001931:Brain Mapping / Q000379:methods*; D003337:Corpus Callosum / Q000000981:diagnostic imaging / Q000473:pathology* / Q000648:ultrastructure*; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000473:pathology*; D004058:Diffusion; D038524:Diffusion Magnetic Resonance Imaging; D056324:Diffusion Tensor Imaging; D005260:Female; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000473:pathology / Q000648:ultrastructure; D000074586:Remyelination
chemical_list: D003471:Cuprizone
keywords: Biomarker; Cuprizone; Demyelination; Diffusion MRI; White matter tract integrity