Synopsis
Quantitative susceptibility mapping (QSM) is the most sensitive technique available for studying tissue iron in vivo. In this work, we applied QSM to more than 1000 patients with multiple sclerosis (MS) and almost 250 patients with clinically isolated syndrome (CIS). Our results provide strong support for changed deep gray matter iron concentrations in MS and CIS. Introduction
A variety of MRI-based imaging studies indicated increased iron levels in deep gray matter (DGM) regions of patients with multiple sclerosis1 (MS) and clinically isolated syndrome2 (CIS). However, most studies employed techniques that provide only qualitative results (e.g. "weighted" imaging), rely on a rather indirect measure of iron (e.g. phase imaging), or have a rather limited sensitivity for iron (e.g. R2*), hampering the detection of subtle concentration changes and complicating the interpretation of findings. In addition, many studies relied on rather small cohorts.
In this work, we applied quantitative susceptibility mapping (QSM) to a relatively large population. QSM is the most sensitive technique available for studying tissue iron in vivo.
Methods
Subjects: 1018 MS patients and 69 CIS patients were recruited for the present study. Two groups of healthy controls (HCs) were age- and sex-matched to the MS group (HC1, N=228) and to the CIS group (HC2, N=246), respectively. Table 1 lists demographic and clinical characteristics of the study groups.
Data acquisition: Participants were scanned on a 3T GE Signa Excite HD 12.0 with a multi-channel
head-neck coil using a 3D flow-compensated gradient-echo sequence (matrix 512x192x64,
256x192x128mm3, TE/TR=22ms/40ms, BW=13.9kHz, flip=12°). Magnetic susceptibility maps
were reconstructed from raw k-space data using scalar-phase-matching3, gradient
unwarping4, best-path unwrapping5, V-SHARP6,7, and HEIDI8.
Analysis: DGM regions were automatically segmented using FSL FIRST based on an additional magnetization-prepared spoiled gradient-echo scan with 1mm isotropic resolution. Group differences were compared using analysis of variance (ANOVA). Associations with clinical and MRI measures were explored using Pearson’s and Spearman’s correlation coefficient, where appropriate. A p-value below 0.05 was considered as statistically significant.
Results
The average susceptibility values of HCs were strongly correlated with putative iron concentrations reported by Hallgren and Sourander12 (Fig. 2). Figure 3 presents the average susceptibility values of anatomical regions in the different groups.
MS group: Susceptibility was significantly higher in MS patients compared to HC1 in caudate, globus pallidus, and putamen. Increased susceptibility was associated with higher EDSS (R between 0.133 and 0.269, p<0.001), disease duration (R between 0.063 and 0.323, p<0.05), T2 lesion load (R between 0.127 and 0.405, p<0.001) and lower volumes (R between -0.161 and -0.459, p<0.001). Thalamic susceptibility was significantly lower in MS patients than in HCs and showed inverse correlations with EDSS, disease duration, T2 lesion load, and lower volume.
CIS group: In CIS, only the caudate had a significantly higher susceptibility compared to HCs. Thalamic susceptibility and volume were positively correlated (R=0.431, p<0.001).
Discussion and Conclusion
This is the first time that QSM has been applied in a study involving more than 1000 MS and almost 250 CIS patients.
Our findings of increased DGM susceptibility in MS patients are in line with recent smaller QSM-based studies by Rudko et al.9 and Langkammer et al.10 in cohorts of 25 MS and 42 patients, respectively. However, while Langkammer et al. did not see a significant difference, Rudko et al. reported significantly increased susceptibility in the Thalamus of MS patients. An explanation for this deviation to our results may be the substantially lower mean age of (37±6)y and (34±9)y, respectively, in these studies. However, this would imply that changes toward lower susceptibility in the thalamus occur later in the disease course.
Using QSM in CIS patients with a similar mean age as in our study, Langkammer et al.10 and Al-Radaideh et al.11 found increased susceptibility in all studied DGM regions (excluding thalamus) in 26 and 19 CIS patients, respectively. Al-Radaideh et al. also reported significantly increased susceptibility in the pulvinar (but no significant results in the global Thalamus).
Due to the high sensitivity of QSM to iron and the relatively low myelin content in the DGM, it is reasonable to assume that our findings are due to changes in tissue iron concentration. Due to the size of the population studied, our work provides strong support for changed DGM iron concentrations in MS and CIS. However, further research is needed to elucidate the effect of age and disease duration on iron concentrations in the DGM, and ultimately provide deeper insights into pathological processes.
Acknowledgements
No acknowledgement found.References
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