CSC injuries detected on MRI have critical diagnostic and prognostic value for MS[23]. Routine MRI of CSC could detect lesions with only limited micropathological change. Ozturk showed that T2*-weighted gradient-echo scans in the spinal cord reveal MS lesions with greater regularity compared to routine T2-weighted spin-echo imaging[24]. Thus, we used T2*-weighted imaging to count and outline all T2-hyperintense lesions in MS patients, which is consistent with the sequence used by chuhutin et al[25].
In the current study, MS patients with normal-appearing GM and WM had damage likely due to CSC microscopic injuries that were not detected by routine MRI. The MS pathology of CSC included axonal loss, inflammation, demyelination, and gliosis; each of these features could be inferred with quantitative MR metrics of tissue structure[26–29]. Therefore, the micropathological changes of CSC for MS patients played a critical role in determining the therapeutic plans and evaluating prognosis. In line with previous DKI studies[12], our DKI metrics from T2-hyperintense lesions and normal-appearing GM and WM suggested extensive microscopic damage of CSC in MS patients compared to healthy subjects, suggesting that quantitative MR of CSC overcomes clinical-radiology paradox. Demyelination seems to play a part in the early phase, while other processes, such as axonal loss, are prominent in the later course of the disease[12]. Both axonal loss and demyelination decrease FA and AD, inflammation, and gliosis, increasing in MD[23, 30].
Accumulating evidence indicated that CSC injury in MS patients is not only limited to WM but also involves the GM[31–34]. High annualized spinal cord atrophy rates were correlated with reductions in gray matter volume. The study by Kearney et al[17]. and Schlaeger et al[16]. suggested that loss of GM is the main contributor to progressive disability. The current study showed that only the MK and RK values of normal-appearing GM were significantly reduced in MS patients compared to the healthy participants, indicating that GM injury persists below the resolution of routine T2-weighted imaging, MK and AK could serve as a more sensitive potential biomarker for evaluating the GM than DTI-metrics in the early diagnosis of the disease. Subsequently, MK and AK may provide more information that is different and complementary to that obtained with DTI on the evaluation of GM damage. Decreased MK is likely associated with neuronal shrinkage, pronounced gliosis, and demyelination of the spinal cord GM[16]. This phenomenon was consistent with muscular atrophy (especially in the intrinsic hand muscles) for the majority of MS patients assessed at autopsy.
Additionally, we found severe lesions than in normal-appearing GM and WM for MS patients. Lukas et al. implied that patients suffering from disease progression during the follow-up period had significantly higher rates of CSC atrophy than patients with a stable disease course[7]. One of the main features of progressive patients with MS was the severe and extensive spinal cord involvement. A large number of lesions of CSC were observed in progressive MS than in relapsing MS phenotypes[37, 38]. In 15 MS patients with T2-hyperintense lesion, 14 were progressive MS, including 10 SPMS and 4 PPMS, confirming a greater number of lesions in patients with SPMS and PPMS vs. RRMS patients[39, 40]. This might be correlated with a greater axonal loss in this PPMS phenotype.
In the initial MR studies, a converse association was found between MK from the lesions and normal-appearing GM and the EDSS score in MS patients, implying that potential biomarkers of MK monitor the disability in MS. Also, MK might help to improve the monitoring of disease progression and prediction of disease evolution.
The variability of axon and dendrite orientations—termed neurite orientation dispersion—is reduced in the spinal cords of patients with MS[41]. This finding could provide a novel biomarker for MS prognosis and therapeutic efficacy. Axonal loss in the CSC is a key source of monitoring disease progression in patients with MS. Although no increase was detected in the number of lesions after the treatment in the current study. FA and AD values originated from lesions and normal-appearing WM are significantly increased (all P < 0.001), which might indicate regeneration of neural axons. Similarly, MK is increased (all P < 0.001) at lesions and normal-appearing GM, indicating that MK may assess therapeutic efficacy[38].
Limitations
First, the number of MS patients was low and not selected according to MS phenotypes. Reportedly, FA and MD of CSC are differences among different subtypes of MS patients[38]. However, the differences in MK have not been reported among various subtypes of MS patients, necessitating in-depth research. Second, the FA and MD estimated inside DKI framework may be more accurate in Thaler's study, which is what we need to improve in the future[42]. Third, the resolution and SNR of the DKI acquisition are not sufficiently high to differentiate the gray/white matter, future research needs to use a high in-plane resolution of DWI acquisitions (e.g. 1 mm2). Fourth, transferring the ROIs does not correct for the distortion from the EPI readout, low SNR and resolution in DKI images. Fifth, this cross-sectional study could not demonstrate how DKI-metrics dynamically change as MS advances continually. Future longitudinal studies are warranted to examine whether the current approach could be used to monitor the disease progression of MS. Sixth, our study was limited to the cervical spinal cord. Regina et al. demonstrated that remarkable GM atrophy is present at lower thoracic levels, which might affect the EDSS[43].