Deficient MWF mapping in multiple sclerosis using 3D whole-brain multi-component relaxation MRI

Recent multiple sclerosis (MS) MRI research has highlighted the need to move beyond the lesion-centric view and to develop and validate new MR imaging strategies that quantify the invisible burden of disease in the brain and establish much more sensitive and specific surrogate markers of clinical disability. One of the most promising of such measures is myelin-selective MRI that allows the acquisition of myelin water fraction (MWF) maps, a parameter that is correlated to brain white matter (WM) myelination. The aim of our study was to apply the newest myelin-selective MRI method, multi-component Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) in a controlled clinical MS pilot trial. This study was designed to assess the capabilities of this new method to explain differences in disease course and degree of disability in subjects spanning a broad spectrum of MS disease severity. The whole-brain isotropically-resolved 3D acquisition capability of mcDESPOT allowed for the first time the registration of 3D MWF maps to standard space, and consequently a formalized voxel-based analysis of the data. This approach combined with image segmentation further allowed the derivation of new measures of MWF deficiency: total deficient MWF volume (DV) in WM, in WM lesions, in diffusely abnormal white matter and in normal appearing white matter (NAWM). Deficient MWF volume fraction (DVF) was derived from each of these by dividing by the corresponding region volume. Our results confirm that lesion burden does not correlate well with clinical disease activity measured with the extended disability status scale (EDSS) in MS patients. In contrast, our measurements of DVF in NAWM correlated significantly with the EDSS score (R² = 0.37; p < 0.001). The same quantity discriminated clinically isolated syndrome patients from a normal control population (p < 0.001) and discriminated relapsing-remitting from secondary-progressive patients (p < 0.05); hence this new technique may sense early disease-related myelin loss and transitions to progressive disease. Multivariate analysis revealed that global atrophy, mean whole-brain myelin water fraction and white matter atrophy were the three most important image-derived parameters for predicting clinical disability (EDSS). Overall, our results demonstrate that mcDESPOT-defined measurements in NAWM show great promise as imaging markers of global clinical disease activity in MS. Further investigation will determine if this measure can serve as a risk factor for the conversion into definite MS and for the secondary transition into irreversible disease progression.     

Prognostic value of high-field proton magnetic resonance spectroscopy in patients presenting with clinically isolated syndromes suggestive of multiple sclerosis

Introduction The aim of this study was to determine the prognostic value of metabolic alterations in the normal-appearing white matter (NAWM) of patients presenting with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) with special regard to the prediction of conversion to definite MS. Methods Using a 3T whole-body MR system, a multisequence conventional MRI protocol and single-voxel proton MR spectroscopy (PRESS, repetition time 2000 ms, echo times 38 ms and 140 ms) of the parietal NAWM were performed in 25 patients presenting with CIS at baseline and in 20 controls. Absolute concentrations of N-acetyl-aspartate (tNAA), myo-inositol (Ins), choline (Cho) and creatine (tCr) as well as metabolite ratios were determined. Follow-up including neurological assessment and conventional MRI was performed 3–4 and 6–7 months after the initial event. Results Nine patients converted to definite MS during the follow-up period. Compared to controls, those patients who converted to MS also showed significantly lower tNAA concentrations in the NAWM (−13.4%, P = 0.002) whereas nonconverters (−6.5%, P = 0.052) did not. The Ins concentration was 20.2% higher in the converter group and 1.9% higher in the nonconverter group, but these differences did not reach significance. No significant differences could be observed for tCr and Cho in either patient group. Conclusion Axonal damage at baseline in patients presenting with CIS was more prominent in those who subsequently converted to definite MS in the short term follow-up, indicating that tNAA might be a sufficient prognostic marker for patients with a higher risk of conversion to early definite MS.     

Early axonal damage and progressive myelin pathology define the kinetics of CNS histopathology in a mouse model of multiple sclerosis

Studies of MS histopathology are largely dependent on suitable animal models. While light microscopic analysis gives an overview of tissue pathology, it falls short in evaluating detailed changes in nerve fiber morphology. The ultrastructural data presented here and obtained from studies of myelin oligodendrocyte glycoprotein (MOG):35–55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice delineate that axonal damage and myelin pathology follow different kinetics in the disease course. While myelin pathology accumulated with disease progression, axonal damage coincided with the initial clinical disease symptoms and remained stable over time. This pattern applied both to irreversible axolysis and early axonal pathology. Notably, these histopathological patterns were reflected by the normal-appearing white matter (NAWM), suggesting that the NAWM is also in an active neurodegenerative state. The data underline the need for neuroprotection in MS and suggest the MOG model as a highly valuable tool for the assessment of different therapeutic strategies.     

Multiple white matter tract abnormalities underlie cognitive impairment in RRMS

Diffusion tensor imaging (DTI) is a sensitive tool for detecting microstructural tissue damage in vivo. In this study, we investigated DTI abnormalities in individuals with relapsing remitting multiple sclerosis (RRMS) and examined the relations between imaging-based measures of white matter injury and cognitive impairment. DTI-derived metrics using tract-based spatial statistics (TBSS) were compared between 37 individuals with RRMS and 20 healthy controls. Cognitive impairment was assessed with three standard tests: the Symbol Digit Modalities Test (SDMT), which measures cognitive processing speed and visual working memory, the Rey Auditory Verbal Learning Test (RAVLT), which examines verbal memory, and the Paced Auditory Serial Addition Test (PASAT), which assesses sustained attention and working memory. Correlations between DTI-metrics and cognition were explored in regions demonstrating significant differences between the RRMS patients and the control group. Lower fractional anisotropy (FA) was found in RRMS participants compared to controls across the tract skeleton (0.40 ± 0.03 vs. 0.43 ± 0.01, p < 0.01). In areas of reduced FA, mean diffusivity was increased and was dominated by increased radial diffusivity with no significant change in axial diffusivity, an indication of the role of damage to CNS myelin in MS pathology. In the RRMS group, voxelwise correlations were found between FA reduction and cognitive impairment in cognitively-relevant tracts, predominantly in the posterior thalamic radiation, the sagittal stratum, and the corpus callosum; the strongest correlations were with SDMT measures, with contributions to these associations from both lesion and normal-appearing white matter. Moreover, results using threshold-free cluster enhancement (TFCE) showed more widespread white matter involvement compared to cluster-based thresholding. These findings indicate the important role for DTI in delineating mechanisms underlying MS-associated cognitive impairment and suggest that DTI could play a critical role in monitoring the clinical and cognitive effects of the disease.     

The effects Of Interferon Beta-1a on Proton MR Spectroscopic Imaging in Patients With Multiple Sclerosis,A Controlled Study,Preliminary Results

To evaluate the effects of interferon beta-1a(INFβ-1a) on brain metabolites in patients with multiple sclerosis (MS), we performed Magnetic Resonance Spectroscopy Imaging (MRSI) on five patients treated with INFβ-1a (Rebif 44 μg), and on five untreated patients. Six healthy volunteers were used as controls. Patients were evaluated at the beginning, in the first, third, sixth, and twelfth month. There were no significant differences in normal appearing white matter (NAWM) metabolite peaks of the control group and patients with MS. However, in white matter lesions (WML) and NAWM there was significant differences between the basal and the other months’ metabolic peaks (p < 0.05) in the treatment group although no differences emerged in the untreated group. These data suggest that INFβ-1a has a favorable effect on restoration of metabolites in MS lesions.     

Use of ultrasmall superparamagnetic particles of iron oxide (USPIO)‐enhanced MRI to demonstrate diffuse inflammation in the normal‐appearing white matter (NAWM) of multiple sclerosis (MS) patients: An exploratory study

Purpose

To explore ultrasmall superparamagnetic particles of iron oxide (USPIO) as a marker for diffuse inflammation in multiple sclerosis (MS) normal‐appearing white matter (NAWM), using quantitative MRI. Disease activity in the NAWM of MS patients partly explains why MRI lesion burden correlates only moderately with disability. USPIO have been shown to visualize the cellular component of inflammation in focal MS lesions. In this study, we aimed to explore USPIO as a marker for the more diffuse inflammation in MS NAWM, using quantitative MRI.

Materials and Methods

In this prospective MRI study, 16 MS patients (eight relapsing‐remitting MS [RRMS] and eight primary‐progressive MS [PPMS] cases) and five healthy control (HC) subjects were included. Using a flip‐angle (FA) array, B1‐corrected T1 maps were generated before and 24 hours after USPIO (SHU555C) injection. White‐matter (WM) T1 histogram and region‐of‐interest (ROI) characteristics were compared between both time points using Wilcoxon signed‐rank test.

Results

Both NAWM ROI and histogram analyses showed T1 shortening after USPIO injection in MS patients (P < 0.01), but not in HCs (P = 0.68).

Conclusion

This exploratory study suggests that USPIO‐enhanced MRI may be a new potential marker for subtle inflammatory activity in MS NAWM. Further studies should focus on relating diffuse inflammation to clinical disease activity and treatment efficacy. J. Magn. Reson. Imaging 2009;29:774–779. © 2009 Wiley‐Liss, Inc.     

Elevated protein carbonylation in the brain white matter and gray matter of patients with multiple sclerosis

Oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS). Increased levels of reactive oxygen species (ROS) derived from infiltrating macrophages and microglial cells have been shown to reduce the levels of endogenous antioxidants and to cause the oxidation of various substrates within the MS plaque. To determine whether oxidative damage takes place beyond visible MS plaques, the occurrence of total carbonyls (TCOs) and protein carbonyls (PCOs) in the normal-appearing white matter (NAWM) and gray matter (NAGM) of eight MS brains was assessed and compared with those of four control brains. The data show that most (7/8) of the MS-WM samples contain increased amounts of PCOs as determined by reaction with 2,4-dinitrophenylhydrazine and Western blot analysis. These samples also have high levels of glial fibrilary acidic protein (GFAP), suggesting that oxidative damage is related to the presence of small lesions. In contrast, we detected no evidence of protein thiolation (glutathionylation and cysteinylation) in the diseased tissue. To our surprise, MS-NAGM specimens with high GFAP content also showed three times the concentration of TCOs and PCOs as the controls. The increase in PCOs is likely to be a consequence of reduced levels of antioxidants, in that the concentration of nonprotein thiols in both MS-WM and -GM decreased by 30%. Overall, our data support the current view that both NAWM and -GM from MS brains contain considerable biochemical alterations. The involvement of GM in MS was also supported by the decrease in the levels of neurofilament light protein in all the specimens analyzed. To the best of our knowledge, this is the first study demonstrating the presence of increased protein carbonylation in post-mortem WM and GM tissue of MS patients.     

Pathological abnormalities in the normal-appearing white matter in multiple sclerosis

In established cases of multiple sclerosis (MS), the normal-appearing white matter (NAWM), as defined for magnetic resonance imaging (MRI), is abnormal in the majority of cases. The clinical significance of these NAWM abnormalities is the subject of debate, but there is strong correlation with degree and progression of disability. New lesions form in NAWM before blood-brain barrier breakdown, as evidenced by gadolinium enhancement. The pathological basis of these neuroimaging abnormalities is largely unknown. Definitive pathological studies on the NAWM are few and are often based on small numbers of samples and of cases. Despite a variety of MS NAWM pathological studies, major research questions, of importance to our understanding of basic pathogenetic mechanisms and consequent rational therapies, remain unanswered. These relate to the frequency and extent of oligodendrocyte/myelin and axonal abnormalities in MS NAWM, and to the cellular basis of very early MS lesions detected by neuroimaging. In a pilot study of MS NAWM, microglial activation was demonstrated in 9 of 10 MS cases. We are currently testing the hypothesis that microglial activation, as defined by altered phenotype and HLA-DR positivity, will act as a marker for oligodendrocyte/myelin and axonal pathology in MS NAWM.