Serum neurofilament light chain correlates with myelin and axonal magnetic resonance imaging markers in multiple sclerosis.

BACKGROUND: Neurofilaments are cytoskeletal proteins that are detectable in the blood after neuroaxonal injury. Multiple sclerosis (MS) disease progression, greater lesion volume, and brain atrophy are associated with higher levels of serum neurofilament light chain (NfL), but few studies have examined the relationship between NfL and advanced magnetic resonance imaging (MRI) measures related to myelin and axons. We assessed the relationship between serum NfL and brain MRI measures in a diverse group of MS participants. METHODS AND MATERIALS: 103 participants (20 clinically isolated syndrome, 33 relapsing-remitting, 30 secondary progressive, 20 primary progressive) underwent 3T MRI to obtain myelin water fraction (MWF), geometric mean T2 (GMT2), water content, T1; high angular resolution diffusion imaging (HARDI)-derived axial diffusivity (AD), radial diffusivity (RD), fractional anisotropy (FA); diffusion basis spectrum imaging (DBSI)-derived AD, RD, FA; restricted, hindered, water and fiber fractions; and volume measurements of normalized brain, lesion, thalamic, deep gray matter (GM), and cortical thickness. Multiple linear regressions assessed the strength of association between serum NfL (dependent variable) and each MRI measure in whole brain (WB), normal appearing white matter (NAWM) and T2 lesions (independent variables), while controlling for age, expanded disability status scale, and disease duration. RESULTS: Serum NfL levels were significantly associated with metrics of axonal damage (FA: R2WB-HARDI = 0.29, R2NAWM-HARDI = 0.31, R2NAWM-DBSI = 0.30, R2Lesion-DBSI = 0.31; AD: R2WB-HARDI=0.31), myelin damage (MWF: R2WB = 0.29, R2NAWM = 0.30, RD: R2WB-HARDI = 0.32, R2NAWM-HARDI = 0.34, R2Lesion-DBSI = 0.30), edema and inflammation (T1: R2Lesion = 0.32; GMT2: R2WB = 0.31, R2Lesion = 0.31), and cellularity (restricted fraction R2WB = 0.30, R2NAWM = 0.32) across the entire MS cohort. Higher serum NfL levels were associated with significantly higher T2 lesion volume (R2 = 0.35), lower brain structure volumes (thalamus R2 = 0.31; deep GM R2 = 0.33; normalized brain R2 = 0.31), and smaller cortical thickness R2 = 0.31). CONCLUSION: The association between NfL and myelin MRI markers suggest that elevated serum NfL is a useful biomarker that reflects not only acute axonal damage, but also damage to myelin and inflammation, likely due to the known synergistic myelin-axon coupling relationship.

Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging.

BACKGROUND: Advanced magnetic resonance imaging (MRI) methods can provide more specific information about various microstructural tissue changes in multiple sclerosis (MS) brain. Quantitative measurement of T1 and T2 relaxation, and diffusion basis spectrum imaging (DBSI) yield metrics related to the pathology of neuroinflammation and neurodegeneration that occurs across the spectrum of MS. OBJECTIVE: To use relaxation and DBSI MRI metrics to describe measures of neuroinflammation, myelin and axons in different MS subtypes. METHODS: 103 participants (20 clinically isolated syndrome (CIS), 33 relapsing-remitting MS (RRMS), 30 secondary progressive MS and 20 primary progressive MS) underwent quantitative T1, T2, DBSI and conventional 3T MRI. Whole brain, normal-appearing white matter, lesion and corpus callosum MRI metrics were compared across MS subtypes. RESULTS: A gradation of MRI metric values was seen from CIS to RRMS to progressive MS. RRMS demonstrated large oedema-related differences, while progressive MS had the most extensive abnormalities in myelin and axonal measures. CONCLUSION: Relaxation and DBSI-derived MRI measures show differences between MS subtypes related to the severity and composition of underlying tissue damage. RRMS showed oedema, demyelination and axonal loss compared with CIS. Progressive MS had even more evidence of increased oedema, demyelination and axonal loss compared with CIS and RRMS.

Myelin Water Fraction and Intra/Extracellular Water Geometric Mean T2 Normative Atlases for the Cervical Spinal Cord from 3T MRI.

BACKGROUND AND PURPOSE: Acquiring and interpreting quantitative myelin-specific MRI data at an individual level is challenging because of technical difficulties and natural myelin variation in the population. To overcome these challenges, we used multiecho T2 myelin water imaging (MWI) to create T2 metric healthy population atlases that depict the mean and variation of myelin water fraction (MWF), and intra- and extracellular water mobility as described by geometric mean T2 (IEGMT2 ). METHODS: Cervical cord MWI was performed at 3T on 20 healthy individuals (10M/10F, mean age: 36 years) and 3 relapsing remitting multiple sclerosis (RRMS) participants (1M/2F, age: 39/42/37 years). Anatomical data were collected for the purpose of image segmentation and registration. Atlases were created by coregistering and averaging T2 metrics from all controls. Voxel-wise z-score maps from 3 RRMS participants were produced to demonstrate the preliminary utility of the MWF and IEGMT2 atlases. RESULTS: The average MWF atlas provides a representation of myelin in the spinal cord consistent with well-known spinal cord anatomical characteristics. The IEGMT2 atlas also depicted structural variations in the spinal cord. Z-score analysis illustrated distinct abnormalities in MWF and IEGMT2 in the 3 RRMS cases. CONCLUSIONS: Our findings highlight the potential for using a quantitative T2 relaxation metric atlas to visualize and detect pathology in spinal cord. Our MWF and IEGMT2 atlases (URL: https://sourceforge.net/projects/mwi-spinal-cord-atlases/) can serve as normative references in the cervical spinal cord for other studies.