Normal-appearing White Matter Of Multiple Sclerosis Patients Research Articles

Quantitative myelin water assessment for multiple sclerosis using multi-inversion magnetic resonance fingerprinting.

Multiple sclerosis (MS) is a demyelination disease. Myelin water is a biomarker of myelin and thus myelin water imaging is a vital tool to provide insight into the demyelination process. This study aimed to characterize the multiple compartments including myelin water fraction (MWF), gray matter (GM) cellular water, white matter (WM) cellular water, and cerebrospinal fluid (CSF) using multiple inversion recovery (mIR) magnetic resonance fingerprinting (MRF) on a clinical MS cohort. The Phantom experiment was conducted with tubes containing different WM and GM concentrations extracted from pig brains. For the in-vivo experiment, 23 healthy control (HC) volunteers and 18 MS patients were recruited for this study. The experiments were performed using a clinical 3T MRI. A multi-slice, fast imaging with a steady-state precession (FISP) based mIR MRF protocol was used to obtain the MWF measurements, with 6min of scan time for each volunteer. The quantification was based on the iterative non-negative least squares (NNLS) with reweighting. The brain compartments quantified were myelin water, WM cellular water, GM cellular water, and CSF. A radiologist with 6 years of experience labeled the MS lesions on FLAIR, MPRAGE, and MWF. Statistical analysis was performed by applying unpaired and paired student's t-tests to compare the MWF results in different groups and in normal-appearing white matter (NAWM) and MS lesions. The phantom result demonstrated the ability to detect MWF with various myelin concentrations. The maps derived from mIR MRF, including MWF, WM cellular water, GM cellular water, and CSF were consistent with the anatomical structures observed in FLAIR and MPRAGE. The MWF values in the NAWM of MS patients were significantly different from those in HC, with values of 0.32±0.025 and 0.25±0.036, respectively. Additionally, the MWF values in WM lesions were significantly smaller than in NAWM at 0.034±0.036. The mIR-MRF technique, using multi-compartment analysis, can simultaneously generate maps of MWF, WM cellular water, GM cellular water, and CSF with sufficient brain coverage and in a reasonably short scan time. The MWF map might provide insights into the demyelination associated with MS.

Changes of brain parenchyma free water fraction reflect tissue damage and impaired processing speed in multiple sclerosis.

Free water fraction (FWF) represents the amount of water per unit volume of brain parenchyma, which is not bound to macromolecules. Its excess in multiple sclerosis (MS) is related to increased tissue loss. The use of mcDESPOT (multicomponent driven single pulse observation of T1 and T2), a 3D imaging method which exploits both the T1 and T2 contrasts, allows FWF to be derived in clinically feasible times. However, this method has not been used to quantify changes of FWF and their potential clinical impact in MS. The aim of this study is to investigate the changes in FWF in MS patients and their relationship with tissue damage and cognition, under the hypothesis that FWF is a proxy of clinically meaningful tissue loss. To this aim, we tested the relationship between FWF, MS lesion burden and information processing speed, evaluated via the Symbol Digit Modalities Test (SDMT). In addition to standard sequences, used for T1- and T2-weighted lesion delineation, the mcDESPOT sequence with 1.7 mm isotropic resolution and a diffusion weighted imaging protocol (b = 0, 1200 s/mm2, 40 diffusion directions) were employed at 3 T. The fractional anisotropy map derived from diffusion data was used to define a subject-specific white matter (WM) atlas. Brain parenchyma segmentation returned masks of gray matter (GM) and WM, and normal-appearing WM (NAWM), in addition to the T1 and T2 lesion masks (T1L and T2L, respectively). Ninety-nine relapsing-remitting MS patients (age = 43.3 ± 9.9 years, disease duration 12.3 ± 7.7 years) were studied, together with twenty-five healthy controls (HC, age = 38.8 ± 11.0 years). FWF was higher in GM and NAWM of MS patients, compared to GM and WM of HC (both p < .001). In MS patients, FWF was the highest in the T1L and GM, followed by T2L and NAWM, respectively. FWF increased significantly with T1L and T2L volume (ρ ranging from 0.40 to 0.58, p < .001). FWF in T2L was strongly related to both T1L volume and the volume ratio T1L/T2L (ρ = 0.73, p < .001). MS patients performed worse than HC in the processing speed test (mean ± SD: 54.1 ± 10.3 for MS, 63.8 ± 10.8 for HC). FWF in GM, T2L, perilesional tissue and NAWM increased with SDMT score reduction (ρ = -0.30, -0.29, -0.33 respectively and r = -.30 for T2L, all with p < .005). A regional analysis, conducted to determine which NAWM regions were of particular importance to explain the relationship between FWF and cognitive impairment, revealed that FWF spatial variance was negatively related to SDMT score in the corpus callosum and the superior longitudinal fasciculus, WM structures known to be associated with cognitive impairment, in addition to the left corticospinal tract, the sagittal stratum, the right anterior limb of internal capsule. In conclusion, we found excess free water in brain parenchyma of MS patients, an alteration that involved not only MS lesions, but also the GM and NAWM, impinging on brain function and negatively associated with cognitive processing speed. We suggest that the FWF metric, derived from noninvasive, rapid MRI acquisitions and bearing good biological interpretability, may prove valuable as an MRI biomarker of tissue damage and associated cognitive impairment in MS.

Quantitative myelin water imaging using short TR adiabatic inversion recovery prepared echo-planar imaging (STAIR-EPI) sequence.

Numerous techniques for myelin water imaging (MWI) have been devised to specifically assess alterations in myelin. The biomarker employed to measure changes in myelin content is known as the myelin water fraction (MWF). The short TR adiabatic inversion recovery (STAIR) sequence has recently been identified as a highly effective method for calculating MWF. The purpose of this study is to develop a new clinical transitional myelin water imaging (MWI) technique that combines STAIR preparation and echo-planar imaging (EPI) (STAIR-EPI) sequence for data acquisition. Myelin water (MW) in the brain has shorter T1 and T2 relaxation times than intracellular and extracellular water. In the proposed STAIR-EPI sequence, a short TR (e.g., ≤300 ms) together with an optimized inversion time enable robust long T1 water suppression with a wide range of T1 values [i.e., (600, 2,000) ms]. The EPI allows fast data acquisition of the remaining MW signals. Seven healthy volunteers and seven patients with multiple sclerosis (MS) were recruited and scanned in this study. The apparent myelin water fraction (aMWF), defined as the signal ratio of MW to total water, was measured in the lesions and normal-appearing white matter (NAWM) in MS patients and compared with those measured in the normal white matter (NWM) in healthy volunteers. As seen in the STAIR-EPI images acquired from MS patients, the MS lesions show lower signal intensities than NAWM do. The aMWF measurements for both MS lesions (3.6 ± 1.3%) and NAWM (8.6 ± 1.2%) in MS patients are significantly lower than NWM (10 ± 1.3%) in healthy volunteers (P < 0.001). The proposed STAIR-EPI technique, which can be implemented in MRI scanners from all vendors, is able to detect myelin loss in both MS lesions and NAWM in MS patients.

Diffusely appearing white matter in multiple sclerosis: Insights from sodium (23Na) MRI

BackgroundIn multiple sclerosis (MS), magnetic resonance imaging (MRI) frequently shows ill-defined areas with intermediate signal intensity between the normal appearing white matter (NAWM) and focal T2-hyperintense lesions, termed “diffusely appearing white matter” (DAWM). Even though several advanced MRI techniques have shown the potential to detect and quantify subtle commonly not visible microscopic tissue changes, to date only a few advanced MRI studies investigated DAWM changes in a quantitative manner. The aim of this study was to detect and quantify tissue abnormalities in the DAWM in comparison to focal lesions and the NAWM in MS patients by sodium (23Na) MRI. Methods23Na and conventional MRI were performed in 25 MS patients with DAWM (DAWM+) and in 25 sex- and age matched MS patients without DAWM (DAWM−), as well as in ten healthy controls (HC). Mean total sodium concentrations (TSC) were quantified in the DAWM, NAWM, normal appearing grey matter (NAGM) and in focal MS lesions. ResultsIn MS DAWM+and DAWM−, TSC values were increased in the NAGM (DAWM+: 44.61 ± 4.09 mM; DAWM–: 45.37 ± 3.8 mM) and in the NAWM (DAWM+: 39.85 ± 3.89 mM; DAWM–: 39.82 ± 4.25 mM) compared to normal grey and white matter in HC (GM 40.87 ± 3.25 mM, WM 35.9 ± 1.81 mM; p < 0.05 for all comparisons). Interestingly, the DAWM showed similar sodium concentrations (39.32 ± 4.59 mM) to the NAWM (39.85 ± 3.89 mM), whereas TSC values in T1 hypointense (46.53 ± 7.87 mM) and T1 isointense (41.99 ± 6.10 mM) lesions were significantly higher than in the DAWM (p < 0.001 and 0.017 respectively). Conclusion23Na MRI is confirmed as a sensitive marker of even subtle tissue abnormalities. DAWM sodium levels are increased and comparable to the abnormalities in NAWM, suggesting pathological changes less severe than in focal lesions comparable to what is expected in the NAWM.

Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis

Inter-individual differences in cortisol production by the hypothalamus–pituitary–adrenal (HPA) axis are thought to contribute to clinical and pathological heterogeneity of multiple sclerosis (MS). At the same time, accumulating evidence indicates that MS pathogenesis may originate in the normal-appearing white matter (NAWM). Therefore, we performed a genome-wide transcriptional analysis, by Agilent microarray, of post-mortem NAWM of 9 control subjects and 18 MS patients to investigate to what extent gene expression reflects disease heterogeneity and HPA-axis activity. Activity of the HPA axis was determined by cortisol levels in cerebrospinal fluid and by numbers of corticotropin-releasing neurons in the hypothalamus, while duration of MS and time to EDSS6 served as indicator of disease severity. Applying weighted gene co-expression network analysis led to the identification of a range of gene modules with highly similar co-expression patterns that strongly correlated with various indicators of HPA-axis activity and/or severity of MS. Interestingly, molecular profiles associated with relatively mild MS and high HPA-axis activity were characterized by increased expression of genes that actively regulate inflammation and by molecules involved in myelination, anti-oxidative mechanism, and neuroprotection. Additionally, group-wise comparisons of gene expression in white matter from control subjects and NAWM from (subpopulations of) MS patients uncovered disease-associated gene expression as well as strongly up- or downregulated genes in patients with relatively benign MS and/or high HPA-axis activity, with many differentially expressed genes being previously undescribed in the context of MS. Overall, the data suggest that HPA-axis activity strongly impacts on molecular mechanisms in NAWM of MS patients, but partly also independently of disease severity.

Quantification of normal-appearing white matter tract integrity in multiple sclerosis: a diffusion kurtosis imaging study.

Our aim was to characterize the nature and extent of pathological changes in the normal-appearing white matter (NAWM) of patients with multiple sclerosis (MS) using novel diffusion kurtosis imaging-derived white matter tract integrity (WMTI) metrics and to investigate the association between these WMTI metrics and clinical parameters. Thirty-two patients with relapsing-remitting MS and 19 age- and gender-matched healthy controls underwent MRI and neurological examination. Maps of mean diffusivity, fractional anisotropy and WMTI metrics (intra-axonal diffusivity, axonal water fraction, tortuosity and axial and radial extra-axonal diffusivity) were created. Tract-based spatial statistics analysis was performed to assess for differences in the NAWM between patients and controls. A region of interest analysis of the corpus callosum was also performed to assess for group differences and to evaluate correlations between WMTI metrics and measures of disease severity. Mean diffusivity and radial extra-axonal diffusivity were significantly increased while fractional anisotropy, axonal water fraction, intra-axonal diffusivity and tortuosity were decreased in MS patients compared with controls (p values ranging from <0.001 to <0.05). Axonal water fraction in the corpus callosum was significantly associated with the expanded disability status scale score (ρ=-0.39, p=0.035). With the exception of the axial extra-axonal diffusivity, all metrics were correlated with the symbol digits modality test score (p values ranging from 0.001 to <0.05). WMTI metrics are thus sensitive to changes in the NAWM of MS patients and might provide a more pathologically specific, clinically meaningful and practical complement to standard diffusion tensor imaging-derived metrics.

MRI Directional Diffusivity Values of Cervical Cord White Matter: Multiple Sclerosis Patients Vs. Healthy Controls

Background: Early diagnosis of multiple sclerosis (MS) can lead to preventive treatment and a favorable prognosis. Cervical spinal cord matter that appears normal on conventional MR images may be detected as abnormal using advanced MRI techniques. Objective: To pinpoint values and cervical spine locations in Diffusion Tensor Imaging (DTI) which best differentiate relapsing-remitting MS from healthy cases. Methods: 10 relapsing-remitting MS and 8 healthy control patients underwent DTI of the cervical spine. DTI values were measured in anterior, lateral and posterior cord locations. Results: Differences in values per location show statistical significance among all areas of the cord in both Normal Appearing White Matter (NAWM) and control groups. We derived an ADC cut-off value of 0.8 mm2/sec and λ2 value of 0.8 mm2/sec for optimal differentiation between NAWM and control. Using these cut-off metrics, values above 0.8 for Receiver Operating Characteristics (ROC) (area under curve) may be considered ‘good’ tests for pathology. ROC analysis showed that the optimal differentiation between NAWM of MS patients versus healthy controls was seen in the anterior area of the cervical cord. Sensitivity and specificity for λ2 and ADC are 85.7 & 75.0 and 85.7 & 75.0 respectively. Conclusion: DTI can detect early changes in relapsing-remitting MS with the anterior area of the cervical spine being the most representative of disease processes. Diagnostic cut-off values should be considered.

A quantitative evaluation of damage in normal appearing white matter in patients with multiple sclerosis using diffusion tensor MR imaging at 3 T.

The white matter (WM) of the brain is damaged in multiple sclerosis (MS), even in areas that appear normal on standard MR imaging. The purpose of our study is to evaluate the damage of normal appearing white matter (NAWM) in patients with MS. In our study, 84 MS patients and 42 healthy adults underwent a routine brain MRI, including also diffusion tensor imaging (DTI). All studies were performed on a 3 T MRI scanner. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained. The DTI parameters of NAWM were correlated with expanded disability status scales (EDSS) scores. Our results showed statistically significant differences in FA and ADC values between MS plaques and the symmetrical NAWM, as also between NAWM and the respective white matter in controls. The ADC values of the NAWM correlated with the EDSS scores. The present study demonstrated damage of the NAWM in MS patients, using DTI in 3.0 T. DTI may be used in the detection of subtle damage of the white matter.

Iron and neurodegeneration in the multiple sclerosis brain

ObjectiveIron may contribute to the pathogenesis and progression of multiple sclerosis (MS) due to its accumulation in the human brain with age. Our study focused on nonheme iron distribution and the expression of the iron-related proteins ferritin, hephaestin, and ceruloplasmin in relation to oxidative damage in the brain tissue of 33 MS and 30 control cases.MethodsWe performed (1) whole-genome microarrays including 4 MS and 3 control cases to analyze the expression of iron-related genes, (2) nonheme iron histochemistry, (3) immunohistochemistry for proteins of iron metabolism, and (4) quantitative analysis by digital densitometry and cell counting in regions representing different stages of lesion maturation.ResultsWe found an age-related increase of iron in the white matter of controls as well as in patients with short disease duration. In chronic MS, however, there was a significant decrease of iron in the normal-appearing white matter (NAWM) corresponding with disease duration, when corrected for age. This decrease of iron in oligodendrocytes and myelin was associated with an upregulation of iron-exporting ferroxidases. In active MS lesions, iron was apparently released from dying oligodendrocytes, resulting in extracellular accumulation of iron and uptake into microglia and macrophages. Iron-containing microglia showed signs of cell degeneration. At lesion edges and within centers of lesions, iron accumulated in astrocytes and axons.InterpretationIron decreases in the NAWM of MS patients with increasing disease duration. Cellular degeneration in MS lesions leads to waves of iron liberation, which may propagate neurodegeneration together with inflammatory oxidative burst.

Microglia in normal appearing white matter of multiple sclerosis are alerted but immunosuppressed

Little is known about the functional phenotype of microglia in normal appearing white matter (NAWM) of multiple sclerosis (MS), although it may hold valuable clues about mechanisms for lesion development. Therefore, we studied microglia from NAWM obtained post-mortem from controls (n = 25) and MS patients (n = 21) for their phenotype ex vivo and their immune responsiveness in vitro, using a microglia isolation method that omits culture and adherence. By flow cytometry, microglia in MS NAWM displayed elevated CD45 levels and increased size and granularity but were distinct from autologous choroid plexus macrophages by absent or low expression of additional markers, in particular CD206. Flow cytometric analysis of microglia from NAWM of three controls and four MS patients showed alterations in levels of Fc-gamma receptors in MS. In primary microglia from a bigger sample of subjects, analysis of Fc-gamma receptors by quantitative PCR indicated a significant increase in mRNA levels of the inhibitory CD32b isoform in MS NAWM. Despite their changed activation status, microglia from MS NAWM were unresponsive to lipopolysaccharide in vitro. Notably, culture with dexamethasone led to an impaired induction of the inflammation-limiting cytokine CCL18 in microglia from MS NAWM compared with those from control NAWM. Together, these data demonstrate that microglia in MS NAWM are in an alerted state, but display features of immunosuppression. Thus, the activation status of microglia in NAWM of MS patients likely reflects a response to ongoing neuroinflammation, which coincides with upregulation of immunoregulatory molecules to prevent full activation and damage to the vulnerable milieu.

Interferon Beta-1b May Reverse Axonal Dysfunction in Multiple Sclerosis

Progression of the disability of multiple sclerosis (MS) is thought to be related to axonal damage that is seen even in normal appearing white matter (NAWM) of patients' brains. Interferon beta (IFNβ) treatment for MS reduces the frequency of clinical exacerbations and the appearance of new inflammatory demyelinating lesions on magnetic resonance imaging (MRI). However, the effect of IFNβ treatment on axonal damage in MS is not known. The present study aimed to assess the effect of IFNβ on axonal function by comparing the data from localised single voxel proton MR spectroscopy (MRS) performed on eight MS patients given IFNβ-1b treatment and 11 untreated patients. Brain MRI and MRS were performed before the initiation of IFNβ-1b treatment and 24 months after treatment initiation. Levels of N-acetylaspartate (NAA), choline-containing compounds (Cho) and creatine (Cr) were calculated as the areas under their peaks shown on MRS and the ratios of NAA/Cr and Cho/Cr were calculated. In the patients treated with IFNβ-1b there was a significant increase in the ratio of NAA/Cr in NAWM (p=0.028) at 24 months after the initiation of treatment. In contrast, there was no significant change in the NAA/Cr ratio in the untreated patients. These results suggest that IFNβ-1b treatment might recover axonal function in NAWM of MS patients.

Low choline concentrations in normal-appearing white matter of patients with multiple sclerosis and normal MR imaging brain scans.

Spectroscopic studies (1H-MR spectroscopy) of normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS) with MR imaging brain lesions have already been performed, but our intention was to investigate NAWM in MS patients who lack brain lesions to elucidate whether the same pathologic changes could be identified. We checked 350 medical files of patients with MS who are registered in our institution. Fourteen patients (11 women and 3 men; mean age, 48.6 years; handicap score, Expanded Disability Status Scale [EDSS] 2.9; range, 1-6.5) with clinically definite MS and a normal MR imaging of the brain were included. 1H-MR spectroscopy was performed in 4 voxels (size approximately 17x17x17 mm3) using absolute quantification of metabolite concentrations. Fourteen healthy control subjects (11 women and 3 men; mean age, 43.3 years) were analyzed in the same way. Significant differences in absolute metabolite concentrations were observed, with the patients with MS showing a lower total concentration of N-acetyl compounds (tNA), including N-acetylaspartate and N-acetyl aspartylglutamate (13.5 mmol/L versus 14.6 mmol/L; P=.002) compared with the healthy control subjects. Unexpectedly, patients with MS presented significantly lower choline-containing compounds (Cho) compared with healthy control subjects (2.2 mmol/L versus 2.4 mmol/L; P<.001). The EDSS showed a positive correlation to myo-inositol concentrations (0.14 mmol/L per EDSS; r2=0.06) and a negative correlation to tNA concentrations (-0.41 mmol/L per EDSS; r2=0.22). The unexpected finding of lower Cho concentrations has not been reported previously. We suggest that patients with MS who lack lesions in the brain constitute a separate entity and may have increased protective or healing abilities.

Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated

In previous studies, we documented increased citrullinated myelin basic protein (MBP) was present in MBP isolated from multiple sclerosis (MS) normal appearing white matter (NAWM). This increase was due to the myelin enzyme peptidyl argininedeiminase 2 (PAD2). In this study, we show that methylation of cytosine of the PAD2 promoter in DNA from MS NAWM was decreased to one-third of the level of that in DNA from normal white matter. The PAD2 promoter in DNA from thymus obtained from the same MS patients and white matter DNA from Alzheimer's, Huntington's, and Parkinson's was not hypomethylated. DNA demethylase activity in supernatants prepared from NAWM of MS patients was 2-fold higher than the DNA demethylase from normal, Alzheimer's, Huntington's and Parkinson's disease white matter. The amount of PAD2 enzyme and citrullinated MBP was increased in MS NAWM. The decreased methylation of cytosines in the PAD2 promoter may explain the increased synthesis of PAD2 protein that is responsible for the increased amount of citrullinated MBP, which in turn results in loss of myelin stability in MS brain.

Multislice Brain Myelin Water Fractions at 3T in Multiple Sclerosis

To evaluate a multislice nonlinearly-spaced 12-echo imaging sequence at 3T covering the supratentorial brain for the quantification of myelin water fraction (MWF) in multiple sclerosis (MS) patients. Eighty-nine patients with, or at risk of, MS (69 relapsing remitting MS [RRMS], 7 secondary progressive MS [SPMS], 13 clinically isolated syndrome [CIS]) and 28 controls were studied. Twelve-echo datasets were acquired using a multislice T2 prep spiral imaging sequence and were fitted using a nonnegative least squares algorithm. The mean MWF within normal appearing white matter (NAWM), contrast-enhancing (CE), and nonenhancing T2 lesions were calculated. Mean MWF in white matter for controls was 11.3%. Mean MWF was significantly reduced in NAWM of MS patients (10.6%, P= .004) relative to controls. SPMS/RRMS patients with disease duration >5 years (10.3%) had lower MWF compared to CIS/RRMS with disease duration <or=5 years (10.8%, P= .03). Mean MWF was reduced by 26% and 29% within both CE (P < .0001) and nonenhancing T2 lesions (P < .0001) relative to controls. Using a multicomponent T2 sequence at 3T, a significant decrease in the supratentorial MWF was observed in MS NAWM and lesions relative to controls. The method was sensitive to detect white matter changes early in the disease process.

White matter changes in multiple sclerosis: correlation of q-space diffusion MRI and 1H MRS

To explore the diagnostic usefulness of high b-value diffusion magnetic resonance brain imaging ("q-space" imaging) in multiple sclerosis (MS). More specifically, we aimed at evaluating the ability of this methodology to identify tissue damage in the so-called normal-appearing white matter (NAWM). In this study we examined the correlation between q-space diffusion imaging and magnetic resonance spectroscopy (MRS)-based two-dimensional 1H chemical shift imaging. Eight MS patients with different degree of disease severity and seven healthy subjects were scanned in a 1.5-T magnetic resonance imaging (MRI) scanner. The MRI protocol included diffusion tensor imaging (DTI) (with bmax of 1000 s/mm2), high b-value diffusion-weighted imaging (with bmax of 14,000 s/mm2) and 2D chemical shift imaging. The high b-value data set was analyzed using the q-space methodology to produce apparent displacement and probability maps. We found that the q-space diffusion displacement and probability image intensities correlated well with N-acetylaspartate levels (r=.61 and .54, respectively). Furthermore, NAWM that was abnormal on MRS was also found to be abnormal using q-space diffusion imaging. In these areas, the q-space displacement values increased from 3.8+/-0.2 to 4.6+/-0.6 microm (P<.02), the q-space probability values decreased from 7.4+/-0.3 to 6.8+/-0.3 (P<.002), while DTI revealed only a small, but still significant, reduction in fractional anisotropy values from 0.40+/-0.02 to 0.37+/-0.02 (P<.05). High b-value diffusion imaging can detect tissue damage in the NAWM of MS patients. Despite the theoretical limitation of this method, in practice it provides additional information which is clinically relevant for detection of tissue damage not seen in conventional imaging techniques.

A magnetization transfer imaging study of normal-appearing white matter in multiple sclerosis.

We attempted to define the role of subtle changes in the normal-appearing white matter (NAWM) in the development of disability in multiple sclerosis (MS). Twenty-seven clinically definite MS patients with either relapsing-remitting or chronic-progressive courses and 10 sex- and age-matched controls entered the study. For each patient and control, we studied two NAWM areas in the frontal lobe with magnetization transfer imaging (MTI). For patients, we also calculated the MT ratios (MTRs) for three contiguous areas of NAWM progressively further from "isolated" lesions visible on conventional MRI. Frontal NAWM in MS patients had lower mean MTRs than the frontal white matter of the controls (p = 0.02). MTRs in the NAWM adjacent to isolated lesions increased with distance from them to the cortical gray matter (p = 0.04). This pattern was typical for patients with chronic-progressive MS whose MTRs in the first two regions of NAWM adjacent to lesions were lower than those of the same regions of patients with relapsing-remitting MS. This study confirms that there are alterations in the NAWM of MS patients and suggests that such changes might be relevant to the disability in MS.