DTI takes the advantage of diffusion of water in brain tissue within three main directions, which is decreased perpendicularly to the myelin sheaths and cell membranes of white-matter axons [6].
In the present study, the RRMS group showed a significant reduction of NAWM FA in the spinal cord only with a significant increase of NAWM ADC in both brain and spinal cord. In SPMS, the FA reduction was significant in both brain and spinal cord but more significant in the spinal cord than in the brain and as regards the ADC increase, it was significant in the brain as well as the spinal cord.
Concerning the spinal cord, the present study agreed with previous DTI studies of the spinal cord in MS patients reported a statistically significant FA difference between the control group and the MS patient group [3, 7,8,9,10,11].
Chen et al. [7] stated that the decrease in the FA value of NAWM and the increase in MD value as compared to normal controls indicate the presence of occult damage to the NAWM.
Fatehi et al. [8] concluded that MD values in NAWM of the patients were higher than NAWM of healthy individuals. The FA values also were lower in NAWM of the patients compared to NAWM of the healthy individuals.
Gratsias et al. [9] showed that NAWM is indeed affected in the patients with MS, regardless of its identification on conventional MR images. The FA and ADC values of NAWM were decreased and increased respectively in comparison with the FA and ADC values of the symmetrical white matter (WM) of the control group.
The present study results also suggest that the spinal cord is not preserved in MS even if lesions are only detected in the brain and MS cord pathology seems to be independent of concomitant brain changes as well as to develop at different rates according to disease subtype.
Bergers et al. [12] confirmed extensive axonal loss in postmortem analysis of the spinal cords of patients with MS, largely independent of local lesion load seen at T2-weighted MR imaging.
Moreover, the present results showed that RRMS patients have milder structural affection of NAWM (especially in the brain) than SPMS patients as indicated by the discrepancy of FA reduction in the brain being significant in SPMS patients only.
Cercignani et al. [13] and Nusbaum et al. [14] stated that DTI changes are significantly more severe in patients with SPMS than in those with RRMS supporting a role for DTI in monitoring advanced stages of the disease.
In addition, FA affection of the NAWM of the spinal cord of both groups with only brain affection in SPMS group, could be explained by the fact that spinal cord has a small surface area compared to the brain, so RRMS patients with milder structural white matter changes among large surface area of the brain could escape detection by DTI at the time that similar changes in small surface area of spinal cord are easily detectable by DTI. Hence, DTI sensitivity is affected by the surface area of the studied tissues and the smaller the surface area, the more sensitive the DTI measures.
The present study showed that ADC affection appears to occur in an earlier stage than FA values do, as indicated by significant ADC increase in RRMS patients’ brain with still no significant FA changes. This coincides with considering ADC as an indicator of demyelination and FA for axonal degeneration.
Werring and colleagues also found that a steady and moderate elevation of ADC values can precede the development of new plaques. Such finding suggests that new lesions are preceded by progressive, albeit subtle, tissue abnormalities beyond the resolution of conventional MRI [15].
We could explain these results as follows: MD parameter is primarily influenced by free space hence its increase with vasogenic edema, inflammation as well as myelin loss which occurs first in the disease process while FA is more sensitive to the detection of the integrity of WM which is affected later on.
However, Agosta et al. [16] stated that astrocytic proliferation, cell debris, fibrillary gliosis, and inflammatory infiltrates can result in a (pseudo) normalization of the MD values and can, therefore, prevent the MD differences to be statistically significant. This can explain the presence of some normal or even low ADC values in our study.
Considering DTI affection of brain tracts, the present study revealed significant ADC changes; in RRMS, there was a significant ADC increase in corpus callosum only, while in SPMS the ADC values increased significantly in the corpus callosum and both cortico-spinal tracts. The FA results were insignificant.
Temel et al. [11] showed that mean fiber ADC value was statistically significantly higher than that in the control group.
In the present study, the regions that showed the most significant decrease in FA and increase in ADC in NAWM of the brain and spinal cord in both study disease groups compared to the normal control group were as follows:
In RRMS group, left frontal, right frontal, pons, and dorsal cord at D7–8 level. So we can say that in spite of the insignificant decrease of global average FA in NAWM of the brain in the relapsing-remitting group, there were certain regions within the brain that showed significant FA decrease namely both frontal regions and pons.
Meanwhile, in SPMS group, the most significant FA and ADC changes were noted at the following regions: left frontal, right frontal, pons, dorsal cord at D7–8 level, corpus callosum splenium, right occipital, and cervical cord at C2–3 level.
Once again, this confirms that white matter affection in SPMS patients is more advanced than in those with RRMS.
Consequently, in the present study, the left frontal, right frontal, pons, and dorsal cord at D7–8 level regions were the most significantly affected areas of the NAWM in the brain and spinal cord respectively (in both RRMS and SPMS groups) regarding the changes in DTI parametric FA and ADC indices.
Karami et al. [17] demonstrated that the values in the bilateral frontal peri-ventricular WM of the brain were much higher than the other parts.
The present study yielded no significant correlation between FA and ADC indices and the clinical score (EDSS) in RRMS group. This may be attributed to the short disease duration, less severity, and mild white matter affection in those patients together with the fact that most of them suffer from mild motor disability with low EDSS scores.
Patients of SPMS group experienced longer disease duration, more aggressive and extensive white matter affection with higher EDSS scores. This was the cause of the strong highly significant negative correlation found in our study between the EDSS score and global (brain, spinal cord, and white matter tracts) average FA values. This means that the more FA reduction the more EDSS score increase.
Filippi et al. [18] found a mild negative and positive correlation between NAWM mean FA and mean ADC values, respectively, and the EDSS score of patients with SPMS, whereas no correlation was noted with EDSS score in RRMS patients.
Karami et al. [17] have found that there is a significant correlation between DTI indices and EDSS scores in MS patients. One of the reasons was the higher EDSS scores of this study (EDSS = 2.6) compared with other studies EDSS scores (EDSS < 2.6). Fatehi et al. [8] also found similar results.
The present study disagreed with Yu et al. [19], Temel et al. [11], and Rovira and Leon [20] where they found no significant correlation between diffusion parameters and EDSS scores. This may be attributed to different statistical software in DTI analysis, small sample size, or presence of mild clinical disability in their patients.
Based on that, if a multiple sclerosis patient with high EDSS score and the conventional MRI findings do not match with this score, as well as his heavy motor disability cannot be explained by conventional imaging, we can subject this patient for further assessment by DTI MR so his symptoms can be explained; in addition, we can expect that this patient is classified as having secondary progressive phenotype or at least is going to progress to the secondary progressive MS eventually. These DTI results can be a justification to give this patient some medication that is used for treatment or prevention from progression to SPMS.
Considering the previously mentioned regions that displayed the most significant FA and ADC changes (both frontal, pons, and dorsal cord at D7–8 level), our study results revealed that in RRMS the only significant correlation was a positive one between the ADC of the right frontal region and the EDSS score. The same was noted in the SPMS group as well.
In RRMS group, the FA/region did not show any significant correlation with EDSS score at any of the above-mentioned regions, this was in line with our result regarding the non-significant FA reduction in NAWM of the brain in those patients and the fact that axonal degeneration is not widely seen among those patients.
On the other hand, in SPMS the FA/region, values were significant negatively correlated with the EDSS score in two regions namely the right frontal region and pons.
Based on the present study results, it seems that the right frontal region is the most significantly affected region by the disease process in both groups as confirmed by the changes in the non-conventional magnetic resonance DTI indices and moreover the changes in this region were most significantly correlated with the patient’s clinical status and motor disability in both RRMS and SPMS groups.
Considering the present study results regarding the corpus callosum tract (being the most morphologically affected tract), these supported the forementioned results that showed more ADC increase in RRMS patients due to demyelination and more FA reduction in SPMS group due to axonal degeneration. This also reflects that affection of the corpus callosum in MS patient is intimately related to the clinical status of patients (Fig. 5).
Sigal et al. [21] focusing on the corpus callosum, concluded that changes in ADC and specifically in transverse diffusivity represent microstructural damage in RRMS and positively correlated with clinical activity and progression of the disease.
Rimkus et al. [22] results showed a correlation between mean diffusion and radial diffusivity, and extended disability status scale (EDSS), suggesting a possible relationship between demyelination of corpus callosum and the motor/sensory dysfunction.
Caligiuri et al. [23] conducted a study which revealed that EDSS score correlated with regions of the corpus callosum bundle crossed by motor and pre-motor fibers.
In both studied MS subgroups, DTI provides insight on the pathology of NAWM that can help to differentiate relapsing-remitting from secondary progressive MS subtypes, better understand the clinical correlates, and help in monitoring the evolution of the disease process.
DTI can be also performed in cases with clinically suspected spinal cord plaques where conventional MRI lacks sensitivity.
Future modifications of dissemination in time (DIT) and dissemination in space (DIS) McDonald criteria taking DT-MRI changes into considerations is also a matter of time and further studies for longitudinal follow-up is highly indicated for fully establishing the role of DTI examination of the NAWM in diagnosis and management of patients with multiple sclerosis.