The quantification of the extent of NAWM and NABT involvement in MS can be obtained using either a region-of-interest (ROI) analysis or an histogram-based approach. While the main advantage of ROI analysis is that it enables to obtain detailed information on the characteristics of clinically eloquent NAWM sites, using histogram analysis, the amount of operator intervention is reduced, thus limiting both the measurement variability in serial studies and the time needed for the analysis. In addition, the recent development of fully automated techniques to segment the various components of brain parenchyma has enabled us to obtain histograms of the NAWM in isolation, by preliminarily excluding from the analysis those pixels belonging to T2-visible lesions and GM.
Using ROI analysis, reduced MTR, FA, and NAA and increased ADC and MD values have been shown in the NAWM of MS patients with all the major MS pheno-types (99,126-129,138-140,143-150). Diffusely elevated Cho, Cr, and Ins concentrations have been described in the NAWM of RRMS (151,152) and PPMS (153) patients. Elevated levels of Ins have also been detected in the NAWM of patients with early RRMS (112) and in patients at presentation with CIS suggestive of MS (100). MTR changes, of a lower magnitude than those observed in T2-visible lesions, have been detected in the dirty-appearing white matter of MS patients (154).
The application of histogram analysis (93,94,110,142,146,147,155-157) to the study of the NABT and of the NAWM confirmed and extended previous findings obtained with ROI analysis, showing that these abnormalities can be detected even in patients with CIS suggestive of MS (93,94,98) and in those with early onset MS (158), are more pronounced in SPMS and PPMS patients than in patients with the other disease phenotypes (156), and are similar between patients with SPMS and those with PPMS (110). Consistent with this is the demonstration that NAA reduction is more pronounced in the NAWM of SPMS and PPMS patients than in those with RRMS (149,153). Nevertheless, reduced NAWM NAA can also be detected in patients with no overt clinical disability (150) and in those in the early phase of the disease (159). The recent development of an unlocalized 1H-MRS sequence for measuring NAA concentration in the whole brain (WBNAA) (160) has allowed to extend the previous findings by showing the presence of marked axonal pathology in CDMS (161-164) and in patients at the earliest clinical phase of MS (99).
On average, NABT changes tend to worsen over time in all MS phenotypes (93,149,165-167), including patients with PPMS (168), even if these changes seem to be more pronounced in SPMS patients (165). In patients with established MS, NAWM MTR reduction has been shown to predict the accumulation of clinical disability over the subsequent five years (166,167). In patients with RRMS, longitudinal decrease over time of NAA/Cr in the NAWM correlates strongly with EDSS worsening (149,169), suggesting that progressive axonal damage or loss may be responsible for functional impairment in MS. More recently, it has been demonstrated that brain axonal damage begins early in the course of MS, develops more rapidly in the earlier than in the later clinical stages of the disease and correlates more strongly with disability in patients with mild than in those with more severe disease (159).
NABT MTR, MD, and NAA values are only partially correlated with the extent of macroscopic lesions and the severity of intrinsic lesion damage (93,99,127,129,146,147,156,162,170-172), thus suggesting that NABT pathology does not only reflect Wallerian degeneration of axons traversing large focal abnormalities, but they may also represent small focal abnormalities beyond the resolution of conventional scanning and independent of larger lesions.
The quantification of the extent of NABT and NAWM involvement has allowed to increase the strength of the relationship between MRI metrics and the clinical manifestations of the disease. Moderate to strong correlations between various brain MTR and MD histogram-derived metrics and the severity of disability have been shown by several studies (147,155,157,173-177). These correlations have been found to be stronger in patients with RRMS and SPMS than in other disease phenotypes (155,174). Subtle MTR changes in the NABT (178,179) and in the cortical/subcortical (180) brain tissue are well correlated with the presence of neuropsychological impairment in MS patients. In addition, a multivariate analysis of several cMRI and MT MRI variables has demonstrated that average NABT-MTR is more strongly associated to cognitive impairment in MS patients than the extent of T2-visible lesions and their intrinsic tissue damage (181). The reduction of NAA/Cr ratio in the NAWM of MS patients has been found to correlate with the presence of fatigue (182).
MT MRI, DW MRI, and 1H-MRS metrics of specific brain structures, such as the cerebellum (148,173,183), the brainstem (173) or the pyramidal tracts (182-186) of MS patients are significantly associated with impairment of these functional systems. Recently, Gadea et al. (187) found a relationship between attentional dysfunction in early RRMS patients and NAA/Cr values in the locus coeruleus nuclei of the pontine ascending reticular activation system.
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