In the present study, we tested the strength of the MRDSS against individual MRI measures for sensitivity to longitudinal change in a relatively small group of patients with MS. The major finding of our study was that MRDSS showed improved sensitivity to longitudinal change vs. individual MRI measures of lesions and atrophy. MRDSS was better able to differentiate RR and SP patients than individual MRI components longitudinally and was the only variable that significantly changed in SP patients over time. Our data further support the potential utility of our neuroimaging-based composite scale to comprehensively evaluate disease severity in MS.
Our study directly compared the longitudinal performance of the MRDSS with two brain MRI measures of lesions (T1 hypointense, T2 hyperintense) and whole brain atrophy. While the individual MRI measures also showed some degree of longitudinal change, the MRDSS showed significant change in the entire patient cohort and within the patient subgroups to a better extent than the individual MRI measures, suggesting its sensitivity in both the inflammatory and neurodegenerative stages of the disease. Unlike the individual MRI measures, MRDSS was the only variable that significantly worsened in both RR and SP groups. While BPF and T1 hypointense lesions also showed a statistically significant change over time, there was no significant difference in the amount of change between the RR and SP phenotypes. Furthermore, T2 lesions did not significantly change over time in the entire patient cohort nor within the patient subgroups. Similar results regarding lesions (T1 hypointense, T2 hyperintense) and whole brain atrophy have been reported in prior studies [17
With regard to the relationship between baseline data (both clinical and MRI measures) and subsequent on-study change in MRDSS, there was a tendency towards larger worsening on MRDSS with a lower baseline MRDSS, lower baseline T2LV, and lower T1/T2. This result was driven in part by the upper limit imposed by the scale; however, even when the zMRDSS was used rather than the 0-10 scale, a similar correlation was observed. The patients with the largest changes in the MRDSS were patients with no T1 lesion volume at baseline. To address this limitation, we adjusted the z-score for these patients compared to our original paper, but the impact of these patients remained. When the alternative transformation for the T1/T2 (arc-sine square root) was investigated, the correlation between baseline MRDSS and change in MRDSS was reduced, but it remained statistically significant. Future work should involve considering other statistical transformations of the T1 lesion volume that may further reduce the impact of patients who change from no T1 lesion volume.
We also evaluated the relationship between clinical and MRI data. The pattern of MRDSS-clinical relationships at exit in the current study is consistent with our previously reported baseline data suggesting that MRDSS has good internal consistency and concurrent validity [7
]. On the other hand, we found some unexpected results in terms of its predictive validity for disability progression. Our previous study found that baseline MRDSS was associated with the risk of developing sustained progression of physical disability three years later [7
]. However, this association was not statistically significant in our reduced sample. In addition, the on-study change in MRDSS was also not related to clinical progression. Thus, it seems that our scale has an unreliable strength for predicting clinical change in terms of disability in the current form and needs further refinements. Similar to MRDSS, individual MRI measures also showed unreliable strength for predicting clinical change. This is in agreement with prior studies demonstrating that these measures show relatively weak correlations with clinical progression [1
]. Of note, we found an inverse correlation between baseline T2LV and a higher risk of progressing on EDSS, driven largely by the SPMS/PPMS patients. One potential explanation for this observation is that SPMS/PPMS patients with low T2 lesion volume in our sample may have lesions in clinical eloquent areas such that even though the total volume is low, the impact on clinical features may be high. Of note, there is a well known dissociation between T2 lesion volume and clinical findings [1
], which is not entirely surprising given that T2 lesion volume is not completely representative of all features of disease progression, such as neurodegeneration. Nonetheless, given the lack of association with change in T2 lesion volume, our results must be considered preliminary and require validation in larger samples. The tendency for SP and PP patients with lower MRI disease burden to progress was also seen with the MRDSS and T1/T2 measures.
Several other limitations were also evident in our study. A more even balance of primary and secondary progressive patients with a larger sample size would afford the opportunity to continue to evaluate the MRDSS across a wide spectrum of disease states. This would strengthen any conclusions reached regarding its utility in the general MS population as well as enabling it to be used as a potential marker in clinical trials with smaller sample sizes. Additional measurements detailing diffuse damage in the normal appearing brain tissue (such as magnetization transfer, diffusion imaging, or MR spectroscopy) [18
], would help refine the scale and potentially allow for greater predictability even earlier in the disease course prior to accumulation of atrophy. The inclusion of gray matter atrophy and spinal cord damage may also be a very informative addition to our scale, given that involvement of these areas of the CNS are common and clinically relevant in MS [22
]. Furthermore, the use of 3T MRI [19
] may also increase the sensitivity of structural changes detected and may strengthen the validity of the composite scale. We are currently collecting data to refine the MRDSS scale along these lines, which we will present in future publications.
In further considering directions for future studies, investigating correlation of the MRDSS with other disability and quality of life variables, which are not heavily represented in the EDSS score, such as cognition and fatigue, would help to better understand the validity of the scale. Unfortunately, quality of life measures, including cognitive and fatigue scores, were not available for these cases. Assessment of the MRDSS over shorter (less than 2 years) and longer (greater than 6 years) periods of time would be useful to determine the dynamic longitudinal range of the scale. It would be particularly interesting to test if the MRDSS can predict the conversion from RR to SP MS in individual cases.
In conclusion, after defining the MRDSS scale in our original work and obtaining some information on its validity [7
], we now have shown the longitudinal characteristics of the scale, including the sensitivity to change over time. Our study suggests that the composite MRDSS scale may be able to capture the destructive aspects of the disease with more longitudinal sensitivity than derived from conventional MRI lesion and whole brain atrophy measurements. Further studies are warranted to confirm and extend our findings regarding the potential utility of the MRDSS.