Areas Of Normal-appearing White Matter Research Articles

Comparison of diffusion tensor imaging (DTI) tissue characterization parameters in white matter tracts of patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD).

To investigate the microstructural properties of T2 lesion and normal-appearing white matter (NAWM) in 20 white matter tracts between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) and correlations between the tissue damage and clinical variables. The white matter (WM) compartment of the brain was segmented for 56 healthy controls (HC), 48 patients with MS, and 38 patients with NMOSD, and for the patients further subdivided into T2 lesion and NAWM. Subsequently, the diffusion tensor imaging (DTI) tissue characterization parameters of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were compared for 20 principal white matter tracts. The correlation between tissue damage and clinical variables was also investigated. The higher T2 lesion volumes of 14 fibers were shown in MS compared to NMOSD. MS showed more microstructure damage in 13 fibers of T2 lesion, but similar microstructure in seven fibers compared to NMOSD. MS and NMOSD had microstructure damage of NAWM in 20 fibers compared to WM in HC, with more damage in 20 fibers in MS compared to NMOSD. MS patients showed higher correlation between the microstructure of T2 lesion areas and NAWM. The T2 lesion microstructure damage was correlated with duration and impaired cognition in MS. Patients with MS and NMOSD show different patterns of microstructural damage in T2 lesion and NAWM areas. The prolonged disease course of MS may aggravate the microstructural damage, and the degree of microstructural damage is further related to cognitive impairment. Microstructure differences between T2 lesion areas and normal-appearing white matter help distinguish multiple sclerosis and neuromyelitis optica spectrum disorder. In multiple sclerosis, lesions rather than normal-appearing white matter should be a concern, because the degree of lesion severity correlated both with normal-appearing white matter damage and cognitive impairment. • Multiple sclerosis and neuromyelitis optica spectrum disorder have different damage patterns in T2 lesion and normal-appearing white matter areas. • The microstructure damage of normal-appearing white matter is correlated with the microstructure of T2 lesion in multiple sclerosis and neuromyelitis optica spectrum disorder. • The microstructure damage of T2 lesion in multiple sclerosis is correlated with duration and cognitive impairment.

Impact of White Matter Hyperintensity Changes on Cognition One Year After Mild Ischemic Stroke

AbstractBackgroundWhite matter hyperintensities (WMH) are a main MRI feature of cerebral small vessel disease, and are associated with increased risk of stroke and dementia. Progression can lead to cognitive decline, but some evidence suggests that WMH can also regress. Regression might relate to better clinical outcomes, but this is not well examined yet. We explored if net WMH volume change accounts for changes in cognition 1‐year after mild ischemic stroke. We also explore tissue signatures in areas of white matter change using brain diffusion imaging.MethodIn a prospective study, we assessed vascular risk factors (VRF), structural and diffusion‐tensor brain MRI and cognition (Montreal Cognitive Assessment; MoCA) at baseline (≤3 months post‐stroke) and at 1‐year. We assessed change in cognition over 1‐year using a linear mixed model. Predictors were age, sex, stroke severity (National Institutes of Health Stroke Scale; NIHSS), combined VRFs, disability (modified Rankin Score), occurrence of incidental infarct in‐between visits and WMH volume (%intracranial volume). We studied tissue areas of stable normal‐appearing white matter (NAWM), stable WMH, regressing and progressing WMH (Figure1) and measured diffusion‐tensor fractional anisotropy (FA) and mean diffusivity (MD), to assess microstructure in each areaResultAt baseline, mean age = 67.5 (SD = 11.1), 66% male (N = 229), mean MoCA score = 25.0 (SD = 3.5). Between baseline and 1‐year post‐stroke, MoCA score decreased with older age (standardized B[95%CI]: ‐0.271[‐0.383; ‐0.159]) and increasing NIHSS (‐0.193[‐0.287; ‐0.099]). Areas of NAWM that progress to WMH already have lower FA and higher MD at baseline than NAWM that stays NAWM (N = 191; Figure2). WMH that regress to NAWM have higher FA and lower MD than stable WMH. At 1‐year, MD values seem higher and FA values seem lower in progressing WMH than at baseline.ConclusionCognition deteriorates 1 year post‐stroke with older age and higher stroke severity, but not with WMH changes, when considering net WMH volume. Areas of WMH changes exist within individuals, these areas show different underlying tissue structures before becoming apparent on conventional MRI, indicating that WMH regression is real. Separate areas of WMH progression and regression might be more sensitive to cognitive changes and potentially be intervention targets.

Evaluation of normal-appearing white matter with perfusion and diffusion MRI in patients with treated glioblastoma.

We tried to reveal how the normal appearing white matter (NAWM) was affected in patients with glioblastoma treated with chemo-radiotherapy (CRT) in the period following the treatment, by multiparametric MRI. 43 multiparametric MRI examinations of 17 patients with glioblastoma treated with CRT were examined. A total of six different series or maps were analyzed in the examinations: Apparent Diffusion Coefficient (ADC) and Fractional Anisotropy (FA) maps, Gradient Echo (GRE) sequence, Dynamic susceptibility contrast (DSC) and Arterial spin labeling (ASL) perfusion sequences. Each sequence in each examination was examined in detail with 14 Region of Interest (ROI) measurements. The obtained values were proportioned to the contralateral NAWM values and the results were recorded as normalized values. Time dependent changes of normalized values were statistically analyzed. The most prominent changes in follow-up imaging occurred in the perilesional region. In perilesional NAWM, we found a decrease in normalized FA (nFA), rCBV (nrCBV), rCBF (nrCBF), ASL (nASL)values (p < 0.005) in the first 3 months after treatment, followed by a plateau and an increase approaching pretreatment values, although it did not reach. Similar but milder findings were present in other NAWM areas. In perilesional NAWM, nrCBV values were found to be positively high correlated with nrCBF and nASL, and negatively high correlated with nADC values (r: 0.963, 0.736, - 0.973, respectively). We also found high correlations between the mean values of nrCBV, nrCBF, nASL in other NAWM areas (r: 0.891, 0.864, respectively). We showed that both DSC and ASL perfusion values decreased correlatively in the first 3 months and showed a plateau after 1 year in patients with glioblastoma treated with CRT, unlike the literature. Although it was not as evident as perfusion MRI, it was observed that the ADC values also showed a plateau pattern following the increase in the first 3 months. Further studies are needed to explain late pathophysiological changes. Because of the high correlation, our results support ASL perfusion instead of contrast enhanced perfusion methods.

Myelin content changes in Clinically Isolated Syndrome and Relapsing- Remitting Multiple Sclerosis: Associations with lesion type and severity of visuomotor impairment

BackgroundCognitive disturbances occur in patients with Relapsing Remitting Multiple Sclerosis (RR-MS) and Clinically Isolated Syndrome (CIS). The Multi-Echo-Spin-Echo (MESE) T2-weighted sequence quantifies demyelination, the pathological hallmark of MS, but has not been used for the documentation of the potential relationship between anatomically specific demyelinating changes and cognitive impairment in MS. PurposeTo identify markers of regional demyelination in patients with RR-MS and CIS in relation to clinical variables and severity of cognitive impairment. Methods and materials37 RR-MS patients, 39 CIS patients and 52 healthy controls (HC) were examined using the MESE sequence. Long T2 and myelin water fraction (MWF) values were measured, serving as indices of intra/extracellular water content and myelin content, respectively, in focal white matter lesions and 12 normal appearing white matter (NAWM) areas of the patients and HC. A comprehensive neuropsychological assessment was administered to all patients. ResultsRR-MS patients showed widespread long T2 increases and MWF reductions in NAWM, compared to the respective values of HC (p < 0.001), which correlated with total lesion volume. Among RR-MS patients illness duration correlated negatively with MWF in right hemisphere frontal and periventricular NAWM areas (and positively with corresponding long T2 values). MWF values were lower in the CIS, as compared to the HC group, in the temporal, frontal and periventricular NAWM areas. Focal demyelinating lesions displayed variable higher T2 and lower MWF values, compared to NAWM, closely corresponding to their intensity on T1 sequences. Reduced MWF values and increased long T2 values in right periventricular NAWM were significantly associated with poor visuomotor performance. ConclusionThe MESE sequence affords accurate estimation of myelin and water content in NAWM and focal lesions in RR-MS and CIS patients, by means of the MWF and long T2 values, respectively, providing a sensitive index of demyelination associated with visuomotor deficits.

The Distribution of GPR17-Expressing Cells Correlates with White Matter Inflammation Status in Brain Tissues of Multiple Sclerosis Patients

In multiple sclerosis (MS), oligodendrocyte precursor cells (OPCs) are recruited to the site of injury to remyelinate damaged axons; however, in patients this process is often ineffective due to defects in OPC maturation. The membrane receptor GPR17 timely regulates the early stages of OPC differentiation; however, after reaching its highest levels in immature oligodendrocytes, it has to be downregulated to allow terminal maturation. Since, in several animal models of disease GPR17 is upregulated, the aim of this work was to characterize GPR17 alterations in MS patients. We developed immunohistochemistry and immunofluorescence procedures for the detection of GPR17 in human tissues and stained post-mortem MS brain lesions from patients with secondary progressive MS and control subjects. The inflammatory activity in each lesion was evaluated by immunohistochemistry for the myelin protein MOG and the HLA antigen to classify them as active, chronic inactive or chronic active. Hence, we assessed the distribution of GPR17-positive cells in these lesions compared to normal appearing white matter (NAWM) and white matter (WM) of control subjects. Our data have shown a marked increase of GPR17-expressing oligodendroglial cells accumulating at NAWM, in which moderate inflammation was also found. Furthermore, we identified two distinct subpopulations of GPR17-expressing oligodendroglial cells, characterized by either ramified or rounded morphology, that differently populate the WM of healthy controls and MS patients. We concluded that the coordinated presence of GPR17 in OPCs at the lesion sites and inflamed NAWM areas suggests that GPR17 could be exploited to support endogenous remyelination through advanced pharmacological approaches.

Microstructural and functional brain abnormalities in multiple sclerosis predicted by osteopontin and neurofilament light

BackgroundOsteopontin (OPN) is a proinflammatory biomarker, and neurofilament light chain (NFL) levels reflect axonal damage. Resting-state functional MRI (rs-fMRI) defines brain networks during wakeful rest. ObjectiveTo examine, if levels of OPN and NFL are associated on the long term with (i) lesion evolution, (ii) changes in normal-appearing white matter (NAWM) microstructure and (iii) functional connectivity in multiple sclerosis (MS). MethodsConcentration of NFL and OPN in the blood and CSF were related to MRI findings 10.3 ± 2.8 years later in 53 patients with MS. NFL was examined by Simoa method, OPN by ELISA. Lesion volume in the brain and cervical spinal cord was examined by 3D FLAIR images. Voxel-wise images of fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) were examined by tract-based spatial statistics corrected for gender, age and lesion volume. Metabolites were examined by single-voxel MR-spectroscopy in the NAWM. Fifty-five default mode network connections were examined by rs-fMRI corrected for gender, age, MS subtype and current therapy as covariates. ResultsWhile NFL in paired serum and CSF positively correlated (p = 0.019), there was no correlation between serum and CSF OPN. Higher OPN levels in the CSF but not in the serum showed association with increased brain WM lesion volume (p = 0.009) in 10.3 ± 2.8 years. Higher OPN in the CSF was associated with reduced FA, increased MD, and reduced RD in different NAWM areas 10.3 ± 2.8 years later. Higher OPN in the serum and CSF were associated with increased connectivity strength between the medial prefrontal cortex (MPFC) and other regions except with inferior parietal lobule. NFL in the CSF and in the serum was associated with decreased connectivity strength except for ventral MPFC-hippocampal formation. Neither serum OPN nor NFL at the time of the MRI were associated with functional connectivity changes. ConclusionWhile serum NFL levels reflects CNS production, OPN in serum and CSF may have different cellular sources. OPN within the CSF but not in the serum may forecast development of lesions and microstructural abnormalities in 10 years, indicating the detrimental role of CNS inflammation on the long-term. Although both OPN and NFL in the CSF were associated with functional connectivity changes in 10 years, NFL was associated with decreased strength possibly indicating general axonal loss. In contrast, the positive association of OPN levels in the CSF with increased connectivity strength in 10 years may point to adaptive re-organization due to inflammatory WM lesions and microstructural changes.

Normal appearing brain white matter changes in relapsing multiple sclerosis: Texture image and classification analysis in serial MRI scans

ObjectiveThere is a clinical interest in identifying normal appearing white matter (NAWM) areas in brain T2-weighted (T2W) MRI scans in multiple sclerosis (MS) subjects. These areas are susceptible to disease development and areas need to be studied in order to find potential associations between texture feature changes and disease progression. MethodsThe subjects investigated had a first demyelinating event (Clinically Isolated Syndrome-CIS) at baseline (Time0), and the NAWM0 (i.e. NAWM at Time0) of the brain tissue was subsequently converted to demyelinating plaques (as evaluated in a follow up MRI at Time6–12). 38 untreated subjects that had developed a CIS, had brain MRI scans within an interval of 6–12 months (Time6–12 at follow-up). An experienced MS neurologist manually delineated the demyelinating lesions at Time0 (L0) and at Time6–12 (L6–12). Areas in the Time6–12 MRI scans, where new lesions had been developed, were mapped back to their corresponding NAWM areas on the Time0 MR scans (ROIS0). In addition, contralateral ROIs of similar size and shape were segmented on the same images at Time0 (ROISC0) to form an intra-subject control group. Following that, texture features were extracted from all prescribed areas and MS lesions. ResultsTexture features were used as input into Support Vector Machine (SVM) models to differentiate between the following: NAWM0 vs ROISC0, NAWM0 vs NAWM6–12, NAWM0 vs L0, NAWM6–12 vs L6–12, ROIS0 vs L0, ROIS0 vs L6–12 and ROIS0 vs ROISC0, where the corresponding % correct classifications scores were 89%, 95%, 98%, 92%, 85%, 90% and 65% respectively. ConclusionsTexture features may provide complementary information for following up the development and progression of MS disease. Future work will investigate the proposed method on more subjects.

Multiparametric qMTI Assessment and Monitoring of Normal Appearing White Matter and Classified T1 Hypointense Lesions in Relapsing-Remitting Multiple Sclerosis

BackgroundQuantitative magnetization transfer imaging (qMTI)1 is an efficient technique that is sensitive to the density of the macromolecular protons which are found mainly in white matter myelin. ObjectiveThe aim of this study is to investigate the statistical significance of complementary qMTI parameters including magnetization transfer rate (Ksat)2 and longitudinal relaxation time under MT saturation pulse (T1sat)3 compared to magnetization transfer ratio (MTR)4 and longitudinal relaxation time (T1)5 in relapsing remitting multiple sclerosis (RRMS)6 patients. MethodsIn this study, conventional MRI protocols as well as MT-3DSPGR imaging were performed on twelve clinically definite RRMS patients and twelve age-matched controls. Two general methodologies were utilized for qMTI calculations, including global volumetric measurement of MTI-T1 parameters using a pixel-based analysis method throughout the brain white matter and the regional assessments within classified MS lesions with respect to their hypointensities on T1-weighted scans. MTI-T1 parameters of segmented lesions and normal appearing white matter (NAWM)7 in RRMS patients were evaluated in comparison with normal white matter (NWM)8 of control subjects. ResultsSignificant reductions of MTR and Ksat values in isointense (p<0.0001), mild (p<0.0001) and severe hypointense lesions in comparison with NAWM on T1-weighted scans, were associated with considerable increases in both tissue relaxation times with and without MT pulse, T1sat (p<0.0001) and T1 (p<0.0001) respectively. Similar significant changes of quantitative MT imaging parameters and T1 values were also seen in non-lesion areas of NAWM in MS patients compared to those of NWM in healthy volunteers. ConclusionComplementary qMT imaging parameter contributes to the magnetization transfer phenomenon including Ksat and T1sat can provide more reliable information about the magnitudes and mechanisms of myelin destruction in multiple sclerosis compared to the conventional MTR and T1 relaxation time values.

Microstructural white matter changes preceding white matter hyperintensities in migraine.

We used magnetization transfer imaging to assess white matter tissue integrity in migraine, to explore whether white matter microstructure was more diffusely affected beyond visible white matter hyperintensities (WMHs), and to explore whether focal invisible microstructural changes precede visible focal WMHs in migraineurs. We included 137 migraineurs (79 with aura, 58 without aura) and 74 controls from the Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA) study, a longitudinal population-based study on structural brain lesions in migraine patients, who were scanned at baseline and at a 9-year follow-up. To assess microstructural brain tissue integrity, baseline magnetization transfer ratio (MTR) values were calculated for whole brain white matter. Baseline MTR values were determined for areas of normal-appearing white matter (NAWM) that had progressed into MRI-detectable WMHs at follow-up and compared to MTR values of contralateral NAWM. MTR values for whole brain white matter did not differ between migraineurs and controls. In migraineurs, but not in controls, NAWM that later progressed to WMHs at follow-up had lower mean MTR (mean [SD] 0.354 [0.009] vs 0.356 [0.008], p = 0.047) at baseline as compared to contralateral white matter. We did not find evidence for widespread microstructural white matter changes in migraineurs compared to controls. However, our findings suggest that a gradual or stepwise process might be responsible for evolution of focal invisible microstructural changes into focal migraine-related visible WMHs.

Pittsburgh compound-B PET white matter imaging and cognitive function in late multiple sclerosis

Background: There is growing interest in white matter (WM) imaging with positron emission tomography (PET). Objectives: We studied the association of cognitive function in late multiple sclerosis (MS) with cortical and WM Pittsburgh compound-B PET (PiB-PET) binding. Methods: In the population-based Mayo Clinic Study of Aging, 24 of 4869 participants had MS (12 underwent PiB-PET). Controls were age and sex matched (5:1). We used automated or semi-automated processing for quantitative image analyses and conditional logistic regression for group differences. Results: MS patients had lower memory (p = 0.03) and language (p = 0.02) performance; smaller thalamic volumes (p = 0.003); and thinner temporal (p = 0.001) and frontal (p = 0.045) cortices on magnetic resonance imaging (MRI) than controls. There was no difference in global cortical PiB standardized uptake value ratios between MS and controls (p = 0.35). PiB uptake was lower in areas of WM hyperintensities compared to normal-appearing white matter (NAWM) in MS (p = 0.0002). Reduced PiB uptake in both the areas of WM hyperintensities (r = 0.65; p = 0.02) and NAWM (r = 0.69; p = 0.01) was associated with decreased visuospatial performance in MS. Conclusion: PiB uptake in the cortex in late MS is not different from normal age-matched controls. PiB uptake in the WM in late MS may be a marker of the large network structures’ integrity such as those involved in visuospatial performance.

Evaluation of the Effect of Fingolimod Treatment on Microglial Activation Using Serial PET Imaging in Multiple Sclerosis.

Traditionally, multiple sclerosis (MS) has been considered a white matter disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial activation, also takes place outside the plaque areas, that is, in areas of normal-appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using 18-kDa translocator protein (TSPO)-binding radioligands and PET. It is unknown whether fingolimod affects microglial activation in MS. The aim of this study was to investigate whether serial PET can be used to evaluate the effect of fingolimod treatment on microglial activation. Methods: Ten relapsing-remitting MS patients were studied using the TSPO radioligand 11C-(R)-PK11195. Imaging was performed at baseline and after 8 and 24 wk of fingolimod treatment. Eight healthy individuals were imaged for comparison. Microglial activation was evaluated as distribution volume ratio of 11C-(R)-PK11195. Results: The patients had MS for an average of 7.9 ± 4.3 y (mean ± SD), their total relapses averaged 4 ± 2.4, and their Expanded Disability Status Scale was 2.7 ± 0.5. The patients were switched to fingolimod because of safety reasons or therapy escalation. The mean washout period before the initiation of fingolimod was 2.3 ± 1.1 mo. The patients were clinically stable on fingolimod. At baseline, microglial activation was significantly higher in the combined NAWM and GM areas of MS patients than in healthy controls (P = 0.021). 11C-(R)-PK11195 binding was reduced (-12.31%) within the combined T2 lesion area after 6 mo of fingolimod treatment (P = 0.040) but not in the areas of NAWM or GM. Conclusion: Fingolimod treatment reduced microglial/macrophage activation at the site of focal inflammatory lesions, presumably by preventing leukocyte trafficking from the periphery. It did not affect the widespread, diffuse microglial activation in the NAWM and GM. The study opens new vistas for designing future therapeutic studies in MS that use the evaluation of microglial activation as an imaging outcome measure.

Characterization of Microcirculation in Multiple Sclerosis Lesions by Dynamic Texture Parameter Analysis (DTPA)

ObjectiveTexture analysis is an alternative method to quantitatively assess MR-images. In this study, we introduce dynamic texture parameter analysis (DTPA), a novel technique to investigate the temporal evolution of texture parameters using dynamic susceptibility contrast enhanced (DSCE) imaging. Here, we aim to introduce the method and its application on enhancing lesions (EL), non-enhancing lesions (NEL) and normal appearing white matter (NAWM) in multiple sclerosis (MS).MethodsWe investigated 18 patients with MS and clinical isolated syndrome (CIS), according to the 2010 McDonald's criteria using DSCE imaging at different field strengths (1.5 and 3 Tesla). Tissues of interest (TOIs) were defined within 27 EL, 29 NEL and 37 NAWM areas after normalization and eight histogram-based texture parameter maps (TPMs) were computed. TPMs quantify the heterogeneity of the TOI. For every TOI, the average, variance, skewness, kurtosis and variance-of-the-variance statistical parameters were calculated. These TOI parameters were further analyzed using one-way ANOVA followed by multiple Wilcoxon sum rank testing corrected for multiple comparisons.ResultsTissue- and time-dependent differences were observed in the dynamics of computed texture parameters. Sixteen parameters discriminated between EL, NEL and NAWM (pAVG = 0.0005). Significant differences in the DTPA texture maps were found during inflow (52 parameters), outflow (40 parameters) and reperfusion (62 parameters). The strongest discriminators among the TPMs were observed in the variance-related parameters, while skewness and kurtosis TPMs were in general less sensitive to detect differences between the tissues.ConclusionDTPA of DSCE image time series revealed characteristic time responses for ELs, NELs and NAWM. This may be further used for a refined quantitative grading of MS lesions during their evolution from acute to chronic state. DTPA discriminates lesions beyond features of enhancement or T2-hypersignal, on a numeric scale allowing for a more subtle grading of MS-lesions.

MRI Pattern Recognition in Multiple Sclerosis Normal-Appearing Brain Areas

ObjectiveHere, we use pattern-classification to investigate diagnostic information for multiple sclerosis (MS; relapsing­remitting type) in lesioned areas, areas of normal­appearing grey matter (NAGM), and normal-appearing white matter (NAWM) as measured by standard MR techniques.MethodsA lesion mapping was carried out by an experienced neurologist for Turbo Inversion Recovery Magnitude (TIRM) images of individual subjects. Combining this mapping with templates from a neuroanatomic atlas, the TIRM images were segmented into three areas of homogenous tissue types (Lesions, NAGM, and NAWM) after spatial standardization. For each area, a linear Support Vector Machine algorithm was used in multiple local classification analyses to determine the diagnostic accuracy in separating MS patients from healthy controls based on voxel tissue intensity patterns extracted from small spherical subregions of these larger areas. To control for covariates, we also excluded group-specific biases in deformation fields as a potential source of information.ResultsAmong regions containing lesions a posterior parietal WM area was maximally informative about the clinical status (96% accuracy, p<10−13). Cerebellar regions were maximally informative among NAGM areas (84% accuracy, p<10−7). A posterior brain region was maximally informative among NAWM areas (91% accuracy, p<10−10).InterpretationWe identified regions indicating MS in lesioned, but also NAGM, and NAWM areas. This complements the current perception that standard MR techniques mainly capture macroscopic tissue variations due to focal lesion processes. Compared to current diagnostic guidelines for MS that define areas of diagnostic information with moderate spatial specificity, we identified hotspots of MS associated tissue alterations with high specificity defined on a millimeter scale.

Brain tissue sodium concentration in multiple sclerosis: a sodium imaging study at 3 tesla

Neuro-axonal degeneration occurs progressively from the onset of multiple sclerosis and is thought to be a significant cause of increasing clinical disability. Several histopathological studies of multiple sclerosis and experimental autoimmune encephalomyelitis have shown that the accumulation of sodium in axons can promote reverse action of the sodium/calcium exchanger that, in turn, leads to a lethal overload in intra-axonal calcium. We hypothesized that sodium magnetic resonance imaging would provide an indicator of cellular and metabolic integrity and ion homeostasis in patients with multiple sclerosis. Using a three-dimensional radial gradient-echo sequence with short echo time, we performed sodium magnetic resonance imaging at 3 T in 17 patients with relapsing-remitting multiple sclerosis and in 13 normal subjects. The absolute total tissue sodium concentration was measured in lesions and in several areas of normal-appearing white and grey matter in patients, and corresponding areas of white and grey matter in controls. A mixed model analysis of covariance was performed to compare regional tissue sodium concentration levels in patients and controls. Spearman correlations were used to determine the association of regional tissue sodium concentration levels in T(2)- and T(1)-weighted lesions with measures of normalized whole brain and grey and white matter volumes, and with expanded disability status scale scores. In patients, tissue sodium concentration levels were found to be elevated in acute and chronic lesions compared to areas of normal-appearing white matter (P < 0.0001). The tissue sodium concentration levels in areas of normal-appearing white matter were significantly higher than those in corresponding white matter regions in healthy controls (P < 0.0001). The tissue sodium concentration value averaged over lesions and over regions of normal-appearing white and grey matter was positively associated with T(2)-weighted (P < or = 0.001 for all) and T(1)-weighted (P < or = 0.006 for all) lesion volumes. In patients, only the tissue sodium concentration value averaged over regions of normal-appearing grey matter was negatively associated with the normalized grey matter volume (P = 0.0009). Finally, the expanded disability status scale score showed a mild, positive association with the mean tissue sodium concentration value in chronic lesions (P = 0.002), in regions of normal-appearing white matter (P = 0.004) and normal-appearing grey matter (P = 0.002). This study shows the feasibility of using in vivo sodium magnetic resonance imaging at 3 T in patients with multiple sclerosis. Our findings suggest that the abnormal values of the tissue sodium concentration in patients with relapsing-remitting multiple sclerosis might reflect changes in cellular composition of the lesions and/or changes in cellular and metabolic integrity. Sodium magnetic resonance imaging has the potential to provide insight into the pathophysiological mechanisms of tissue injury when correlation with histopathology becomes available.

3 T MRI relaxometry detects T2 prolongation in the cerebral normal-appearing white matter in multiple sclerosis

MRI at 3 T has increased sensitivity in detecting overt multiple sclerosis (MS) brain lesions; a growing body of data suggests clinically relevant damage occurs in the normal-appearing white matter (NAWM). We tested a novel pulse sequence to determine whether 3 T MRI spin–spin relaxometry detected damage in NAWM of MS patients (n=13) vs. age-matched normal controls [(NL) (n=11)]. Baseline characteristics of the MS group were: age (mean±SD) 42.5±5.4 (range 33–51 years), disease duration 9.0±6.4 (range 1–22 years), Expanded Disability Status Scale score 2.5±1.7 (range 1–6.5). Brain MRI measures, obtained at 3 T, included global and regional NAWM transverse relaxation rate [R2 (=1/T2)], derived from 3D fast spin-echo T2 prepared images, and global white matter volume fraction derived from SPGR images. The regional NAWM areas investigated were the frontal lobe, parietal lobe, and the genu and splenium of the corpus callosum. Mean NAWM R2 was lower (indicating T2 prolongation) in MS than NL in the whole brain (p=0.00047), frontal NAWM (p=0.00015), parietal NAWM (p=0.0069) and callosal genu (p=0.0019). Similarly, R2 histogram peak position was lower in NAWM in MS than NL in the whole brain (p=0.019). However, the normalized WM volume fractions were similar in both MS and NL (p>0.1). This pilot study suggests that a novel 3D fast spin-echo pulse sequence at 3 T, used to derive R2 relaxation maps, can detect tissue damage in the global and regional cerebral NAWM of MS patients that is missed by conventional lesion and atrophy measures. Such findings may represent demyelination, inflammation, glial proliferation and axonal loss.

Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter.

To prospectively determine hemodynamic changes in the normal-appearing white matter (NAWM) of patients with relapsing-remitting multiple sclerosis (RR-MS) by using dynamic susceptibility contrast material-enhanced perfusion magnetic resonance (MR) imaging. Conventional MR imaging (which included acquisition of pre- and postcontrast transverse T1-weighted, fluid-attenuated inversion recovery, and T2-weighted images) and dynamic susceptibility contrast-enhanced T2*-weighted MR imaging were performed in 17 patients with RR-MS (five men and 12 women; median age, 38.4 years; age range, 27.6-56.9 years) and 17 control patients (seven men and 10 women; median age, 42.0 years; age range, 18.7-62.5 years). Absolute cerebral blood volume (CBV), absolute cerebral blood flow (CBF), and mean transit time (MTT) (referenced to an arterial input function by using an automated method) were determined in periventricular, intermediate, and subcortical regions of NAWM at the level of the lateral ventricles. Least-squares regression analysis (controlled for age and sex) was used to compare perfusion measures in each region between patients with RR-MS and control patients. Repeated-measures analysis of variance and the Tukey honestly significant difference test were used to perform pairwise comparison of brain regions in terms of each perfusion measure. Each region of NAWM in patients with RR-MS had significantly decreased CBF (P <.005) and prolonged MTT (P <.001) compared with the corresponding region in control patients. No significant differences in CBV were found between patients with RR-MS and control patients in any of the corresponding areas of NAWM examined. In control patients, periventricular NAWM regions had significantly higher CBF (P =.03) and CBV (P =.04) than did intermediate NAWM regions. No significant regional differences in CBF, CBV, or MTT were found in patients with RR-MS. The NAWM of patients with RR-MS shows decreased perfusion compared with that of controls.

Water diffusion is elevated in widespread regions of normal-appearing white matter in multiple sclerosis and correlates with diffusion in focal lesions.

Pathological changes in the normal-appearing white matter in multiple sclerosis are well recognised, but their relationship to pathology in focal lesions is not well understood. Magnetic resonance diffusion imaging is sensitive to abnormalities in the integrity, size and geometry of water spaces in brain tissue. This study investigated the anatomical distribution of normal-appearing white matter diffusion abnormalities and their relationship to diffusion in focal lesions in multiple sclerosis (MS). The average apparent diffusion coefficient (ADCav) was measured by three-axis echoplanar diffusion imaging in normal-appearing white matter regions and lesions throughout the brain in 40 patients, and in white matter in 14 matched controls. The correlation between the ADCav in normal-appearing white matter and lesions was determined. In controls and patients, diffusion was highest in the corpus callosum. Patients had a higher mean ADCav than controls in widespread regions including the corpus callosum, cerebellar, temporal and occipital normal-appearing white matter. Mean normal-appearing white matter ADCav correlated strongly with mean lesion ADCav (r = 0.67, P < 0.001). This study demonstrates that water diffusion is elevated in widespread areas of normal-appearing white matter in MS, and is correlated with diffusion in lesions. These findings suggest that the pathogenetic mechanisms causing tissue damage in lesions and normal-appearing white matter are at least partly linked.

Diffusion tensor magnetic resonance imaging in multiple sclerosis.

To quantify, using diffusion tensor imaging (DTI), the tissue damage in lesions and normal-appearing white matter (NAWM) from a large cohort of patients with MS and to investigate the magnitude of the correlation between DTI-derived metrics and clinical disability. Dual-echo and DTI scans were obtained from 78 patients with relapsing-remitting, secondary progressive, or primary progressive MS and from 20 normal control participants. Post-contrast T1-weighted images were also obtained from the patients. After creating mean diffusivity (D) and fractional anisotropy (FA) images and image coregistration, D and FA values were measured for 4846 lesions (3207 nonenhancing T1-isointense, 1511 nonenhancing T1-hypointense, and 128 enhancing), 497 NAWM areas from patients, and 160 white matter areas from the controls. The average lesion D was higher and the average lesion FA was lower than the corresponding quantities of the NAWM (p < 0.001). The values of enhancing and nonenhancing lesions were not different, whereas enhancing lesions had lower FA (p < 0.001). T1-hypointense lesions had higher D and lower FA than T1-isointense lesions (p < 0.001). NAWM of patients had higher and lower FA than white matter of controls (p = 0.01). Significant correlations were found between T1 and T2 lesion volume and and FA of lesions and NAWM. In the overall patient sample, a moderate correlation was also found between lesion D and the Expanded Disability Status Scale score (r = 0.28, p = 0.01). However, the r value of this correlation was 0.48 in patients with secondary progressive MS, whose disability was also correlated with average lesion FA (r = -0.50). The results of this study show that DTI is able to identify MS lesions with severe tissue damage and to detect changes in the NAWM. They also indicate that DTI-derived measures are correlated with clinical disability, especially in patients with secondary progressive MS, thus suggesting a role for DTI in monitoring advanced phases of the disease.

Weekly diffusion-weighted imaging of normal-appearing white matter in MS.

To elucidate the dynamics and the nature of normal-appearing white matter (NAWM) changes preceding new lesion formation in MS, the authors obtained weekly diffusion-weighted images for 12 weeks from 6 patients. NAWM areas subsequently involved by enhancement had a significant increase in mean diffusivity values starting 6 weeks before the appearance of enhancement (p values ranging between < 0.0001 and 0.04). This suggests that focal edema and demyelination play a part in the NAWM changes preceding new lesion formation in MS.

The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study.

The idea that the initiating event in the formation of all new multiple sclerosis lesions is a focal blood-brain barrier (BBB) leakage associated with perivascular inflammation has been challenged recently by the observation of subtle abnormalities in some quantitative magnetic resonance (MR) parameters (including the magnetization transfer ratio) prior to lesion enhancement. MR diffusion imaging can non-invasively quantify the average apparent diffusion coefficient (ADC(av)), a measure of water molecule random motion that is sensitive to pathological change in multiple sclerosis lesions and to abnormalities in the normal-appearing white matter (NAWM). We therefore used MR diffusion imaging to investigate the dynamic evolution of water diffusion measurements in new enhancing multiple sclerosis lesions, in the NAWM from which they arise, and in anatomically matched contralateral NAWM regions from which no visible lesions develop. Gadolinium diethylenetriaminepentaacetic acid (Gd)-enhanced MRI and MR diffusion studies were performed monthly for 1 year in five multiple sclerosis patients with clinically and radiologically active disease. The ADC(av) was calculated at each time point of the study (before, during and after lesion appearance on Gd-enhanced scans) for each new enhancing lesion, and for regions matched for size and position in the contralateral NAWM. A steady and moderate increase in ADC(av) in prelesion NAWM was observed, which was followed by a rapid and marked increase at the time of Gd enhancement and a slower decay after the cessation of enhancement. In matched contralateral NAWM regions there was a significant but milder increase in ADC(av) at the time of the first noted lesion enhancement. These findings indicate that new focal lesions associated with frank BBB leakage are preceded by subtle, progressive alterations in tissue integrity beyond the resolution of conventional MRI. The increases in ADC(av) in anatomically matched contralateral regions after lesions have appeared supports the concept that structural damage in lesions causes damage or dysfunction in connected areas of NAWM.