Changes In Normal-appearing White Matter Research Articles

Advances in Vascular Cognitive Impairment

Advances in Vascular Cognitive Impairment

Blood–brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis

Background and aimThe pathogenesis of cerebral small-vessel disease (SVD) is incompletely understood. Endothelial dysfunction has been implicated and may result in increased blood–brain barrier (BBB) permeability with leakage of blood...

Preactive lesions in multiple sclerosis

Knowledge of the early pathological changes observed in multiple sclerosis (MS) has advanced by implementation of many improved pathological, biochemical and imaging techniques. This review highlights the accumulating evidence for early pathological changes we term 'preactive lesions', characterized by clusters of activated microglia in otherwise normal-appearing white matter. Compelling evidence is accumulating for pathological changes in normal-appearing white matter of MS patients, which occur before the actual development of the active demyelinating lesion. Focal disorder has been documented in normal-appearing white matter of MS months to years before the appearance of gadolinium-enhancing lesions. In these foci, clusters of activated microglia are found in the absence of demyelination and clear leukocyte infiltration, distinguishing them from the traditional demyelinating active and chronic active lesions. Although the events that give rise to preactive lesions are still to be identified, oligodendrocyte abnormalities appear to be crucially involved. Importantly, preactive lesions do not always develop into demyelinating lesions but often appear to resolve without subsequent disorder. Preactive lesions in MS represent early stages in the formation of destructive MS lesions. As many of them spontaneously resolve, they are expected to hold important clues to stop the inflammatory process in MS.

A comparative study of MR diffusion tensor imaging histogram between clinically isolated syndrome and relapsing-remitting multiple sclerosis in normal appearing white matter and grey matter

Objective To investigate whether abnormalities can be detected in normal-appearing white matter(NAWM)and normal-appearing white matter(NAGM)in patients with clinically isolated syndrome(CIS)and comparing them to the abnormalities in relapsing-remitting multiple sclerosis(RRMS)by using diffusion tensor imaging(DTI)histogram.To detect the potential relationship between DTI indices of NAWM,NAGM and patient's clinical condition.Methods Nineteen patients with CIS,19 clinically diagnosed RRMS patients and 19 sex-and age-matched healthy volunteers were included in this study.Conventional MRI and DTI images were obtained using Siemens 1.5 T Magnetom sonata scanner.DTI histograms of NAWM and NAGM were obtained after post-processing.The mean value,peak height,peak location of the histogram were used for analysis.All data was statistically processed with SPSS for Windows.Results NAWM average MD was higher and FA was lower in RRMS[MD(0.83±0.04)×10-3mm2/s,FA 0.36±0.03]when compared to CIS[MD(0.79±0.02)×10-3mm2/s,FA 0.40±0.02]and control[MD(0.78±0.02)×10-3mm2/s,FA 0.41±0.01](P＜0.01).But no statistically significant difference was found between CIS and control.The peak height of NAWM average MD histogram was significantly lower in CIS than control(P＜0.05),while the peak location of average FA histogram shifted to the left(P＜0.01).Patients with CIS[(1.08±0.06)×10-3mm2/s]showed significantly higher NAGM average MD than control[(1.03±0.05)×10-3mm2/s](P＜0.05),but,lower than RRMS[(1.18±0.12)×10-3mm2/s](P＞0.01).There were no correlation between DTI indices and EDSS scores in patients with CIS.Moderate correlation between NAGM average MD(r=0.568,P＜0.05)and EDSS scores were found in patient with RRMS.Conclusion NAWM and NAGM abnormalities do occur in CIS which can be detected by DTI.The underlying pathological changes in NAWM and NAGM in CIS may be milder than RRMS as demonstrated by DTI histogram. Key words: Multiple sclerosis; Diffusion magnetic resonance imaging

Serial diffusion tensor imaging to characterize radiation-induced changes in normal-appearing white matter following radiotherapy in patients with adult low-grade gliomas

The aim of this study was to ascertain whether diffusion tensor imaging (DTI) metrics fractional anisotropy (FA), mean diffusivity (MD), linear case (CL), planar case (CP), spherical case (CS)-can characterize a threshold dose and temporal evolution of changes in normal-appearing white matter (NAWM) of adults with low-grade gliomas (LGGs) treated with radiation therapy (RT). Conventional and DTI imaging were performed before RT in 5 patients and subsequently, on average, at 3 months (n = 5), 8 months (n = 3), and 14 months (n = 5) following RT for a total of 18 examinations. Isodose distribution at 5-Gy intervals were visualized in all the slices of fluid attenuated inversion recovery (FLAIR) and the corresponding DTI images without diffusion sensitization (b0DTI). The latter were exported for relative quantitative analysis. Compared to pre-RT values, FA and CL decreased, whereas CS increased at 3 and 8 months and recovered partially at 14 months for the dose bins >55 Gy and 50-55 Gy. For the 45 50 Gy bin, the FA and CL decreased with an increase in CS at 3 months; no further change was seen at 8 or 14 months. For the >55 Gy and 50-55 Gy bins, CP decreased and MD increased at 3 months and returned to baseline at 8 months following RT. Radiation-induced changes in NAWM can be detected at 3 months after RT, with changes in FA, CL, and CS (but not CP or MD) values seen at a threshold dose of 45-50 Gy. A partial recovery was evident by 14 months to regions that received doses of 50-55 Gy and >55 Gy, thus providing an objective measure of radiation effect on NAWM.

Radiation-Induced Changes in Normal-Appearing White Matter in Patients With Cerebral Tumors: A Diffusion Tensor Imaging Study

To quantify the radiation-induced changes in normal-appearing white matter before, during, and after radiotherapy (RT) in cerebral tumor patients. Twenty-five patients with low-grade glioma, high-grade glioma, or benign tumor treated with RT were studied using diffusion tensor magnetic resonance imaging. The biologically corrected doses ranged from 50 to 81 Gy. The temporal changes were assessed before, during, and to 45 weeks after the start of RT. The mean diffusivity of water (<D>), fractional anisotropy of diffusion, diffusivity perpendicular (lambdaperpendicular) and parallel (lambda||) to white matter fibers were calculated in normal-appearing genu and splenium of the corpus callosum. In the genu and splenium, fractional anisotropy decreased and <D>, lambda||, lambdaperpendicular increased linearly and significantly with time (p<0.01). At 45 weeks after the start of RT, lambdaperpendicular had increased approximately 30% in the genu and splenium, and lambda|| had increased 5% in the genu and 9% in the splenium, suggesting that demyelination is predominant. The increases in lambdaperpendicular and lambda|| were dose dependent, starting at 3 weeks and continuing to 32 weeks from the start of RT. The dose-dependent increase in lambdaperpendicular and lambda|| was not sustained after 32 weeks, indicating the transition from focal to diffuse effects. The acute and subacute changes in normal-appearing white matter fibers indicate radiation-induced demyelination and mild structural degradation of axonal fibers. The structural changes after RT are progressive, with early dose-dependent demyelination and subsequent diffuse dose-independent demyelination and mild axonal degradation. Diffusion tensor magnetic resonance imaging is potentially a biomarker for the assessment of radiation-induced white matter injury.

HIV-Associated Alterations in Normal-Appearing White Matter

There are conflicting reports of adverse HIV-associated alterations in white matter integrity as measured by diffusion tensor imaging (DTI). We sought to address these conflicting reports by assessing, on a voxel-by-voxel basis, HIV-associated regional changes in radiologically defined normal-appearing white matter (NAWM) integrity using high-resolution DTI. 30 HIV-seropositive (SP) and 30 HIV-seronegative (SN) nondemented, community-dwelling participants underwent DTI to derive whole-brain measures of white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD]). For each participant, the white matter T2 volume was thresholded to remove regions of abnormal signal, resulting in a NAWM mask, which was then applied to the FA and MD volumes to extract voxel-wise NAWM measures of white matter integrity. Voxel-wise group comparisons of FA and MD were conducted (P < 0.005, extent threshold 5 voxels) while controlling for age and substance-abuse history. There were no significant differences between the groups for demographic or cognitive performance variables. Summary whole-brain measures of FA and MD were equivalent between the SP and SN samples. Among the SP sample, history of substance abuse was associated with significantly increased whole-brain NAWM MD, and coinfection with hepatitis C virus (HCV) was associated with a trend for increased MD. Correlations between whole-brain NAWM FA and MD with cognitive performance measures were not significant. Regional analyses of DTI measures revealed variable differences in NAWM FA in the SP sample, with findings of both decreased and increased FA. Differences in NAWM MD were more consistent, with widespread increases noted in the SP sample compared to the SN sample. Eight of the 10 regions displaying significantly increased FA in the SP sample were also found to have significantly increased MD compared to the SN sample. Decreased white matter integrity is present even in radiologically defined NAWM in nondemented, community-dwelling patients with HIV. The decrease in NAWM integrity is best seen in increases in MD, a measure of generalized tissue breakdown. Indications of NAWM axonal integrity (FA) present a more complicated picture, with both decreased FA and increased FA in the SP sample. Our findings of variable HIV-associated FA changes in NAWM may account for previous conflicting reports of changes in DTI parameters in this population. The results of our study suggest that HIV infection contributes to variable changes in DTI values, reflecting both direct loss of axonal integrity and a loss of complexity to the underlying axonal matrix.

Targeting Inflammatory Demyelinating Lesions to Sites of Wallerian Degeneration

In Theiler’s murine encephalomyelitis virus (TMEV) infection, an animal model for multiple sclerosis (MS), axonal injury precedes inflammatory demyelinating lesions, and the distribution of axonal damage present during the early phase of infection corresponds to regions where subsequent demyelination occurs during the chronic phase. We hypothesized that axonal damage recruits inflammatory cells to sites of Wallerian degeneration, leading to demyelination. Three weeks after TMEV infection, axonal degeneration was induced in the posterior funiculus of mice by injecting the toxic lectin Ricinus communis agglutinin (RCA) I into the sciatic nerve. Neuropathology was examined 1 week after lectin injection. Control mice, infected with TMEV but receiving no RCA I, had inflammatory demyelinating lesions in the anterior/lateral funiculi. Other control mice that received RCA I alone did not develop inflammatory lesions. In contrast, RCA I injection into TMEV-infected mice induced lesions in the posterior funiculus in addition to the anterior/lateral funiculi. We found no differences in lymphoproliferative responses or antibody titers against TMEV among the groups. This suggests that axonal degeneration contributes to the recruitment of inflammatory cells into the central nervous system by altering the local microenvironment. In this scenario, lesions develop from the axon (inside) to the myelin (outside) (Inside-Out model).

Magnetic resonance spectroscopy features of normal-appearing white matter in patients with acute brucellosis

We aimed to evaluate whether the subtle metabolic cerebral changes are present in normal-appearing white matter on conventional MRI, in patients with acute brucellosis, by using MR spectroscopy (MRS). Sixteen patients with acute brucellosis and 13 healthy control subjects were investigated with conventional MRI and single-voxel MRS. Voxels were placed in normal-appearing parietal white matter (NAPWM). N-Acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios were calculated. There was no significant difference between the study subjects and the control group in NAA/Cr ratios obtained from NAPWM. However, the Cho/Cr ratios were significantly higher in patients with acute brucellosis compared to controls ( p = 0.01). MRS revealed metabolic changes in normal-appearing white matter of patients with brucellosis. Brucellosis may cause subtle cerebral alterations, which may only be discernible with MRS. Increased Cho/Cr ratio possibly represents an initial phase of inflammation and/or demyelination process of brucellosis.

Axonal Damage But No Increased Glial Cell Activity in the Normal-Appearing White Matter of Patients with Clinically Isolated Syndromes Suggestive of Multiple Sclerosis Using High-Field Magnetic Resonance Spectroscopy

Proton MR spectroscopy ((1)H-MR spectroscopy) is a well-established method for the in vivo investigation of the normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS). Metabolic changes in NAWM are of special interest in patients with clinically isolated syndromes (CIS) suggestive of MS regarding further prognostic classifications. The purpose of this study was to investigate metabolic alterations in NAWM in patients with CIS with use of high-field (1)H-MR spectroscopy and to compare the results to those in patients with an early course of MS. With use of a 3T whole-body MR imaging system, single-voxel (1)H-MR spectroscopy (PRESS; TR: 2000 ms; TE: 38 ms and 140 ms) of the parietal NAWM was performed in 20 control subjects, 36 patients with CIS, and 12 patients with MS. Metabolite ratios and concentrations of N-acetylaspartate (tNAA), myo-inositol (mIns), choline, and total creatine (tCr) were determined. Compared with the control group, mean NAWM mIns concentrations were significantly elevated in the MS group (4.56 mmol/L versus 3.75 mmol/L, P = .02) but not in the CIS group (4.04 mmol/L, P = .44). The higher concentration of mIns in the MS group was also reflected in the increased Ins/tCr ratio (P = .02). The mean NAWM tNAA was significantly decreased in both patient groups compared with the control group (CIS, 13.42 mmol/L, P = .02; MS, 12.77 mmol/L versus 14.51 mmol/L, P = .008). A significant increase of the activity of the glial cells can only be observed in patients with an established diagnosis of MS but not in patients with CIS. Axonal damage occurs already during the first demyelinating episode in patients with CIS as well as in patients with definite MS.

Fractal dimension and white matter changes in multiple sclerosis

The brain white matter (WM) in multiple sclerosis (MS) suffers visible and non-visible (normal-appearing WM (NAWM)) changes in conventional magnetic resonance (MR) images. The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of a complex object. Our aim was to assess the usefulness of FD analysis in the measurement of WM abnormalities in conventional MR images in patients with MS, particularly to detect NAWM changes. First, we took on a voxel-based morphometry approach optimized for MS to obtain the segmented brain. Then, the FD of the whole grey–white matter interface (WM border) and skeletonized WM was calculated in patients with MS and healthy controls. To assess the FD of the NAWM, we focused our analysis on single sections without lesions at the centrum semiovale level. We found that patients with MS had a significant decrease in the FD of the entire brain WM compared with healthy controls. Such a decrease of the FD was detected not only on MR image sections with MS lesions but also on single sections with NAWM. Taken together, the results showed that FD identifies changes in the brain of patients with MS, including in NAWM, even at an early phase of the disease. Thus, FD might become a useful marker of diffuse damage of the central nervous system in MS.

Gray and normal-appearing white matter in multiple sclerosis: an MRI perspective

Besides focal white matter lesions, multiple sclerosis brain tissue also displays abnormalities in the gray matter and the normal-appearing white matter. Recent advances in magnetic resonance imaging studies of both types of tissue are discussed. Herein, normal-appearing white matter abnormalities are being found in quantitative magnetic resonance investigations, consistent with a limited degree of axonal damage and/or demyelination, and an increase of glial cells, but the specific nature of the histopathological changes underlying the quantitative magnetic resonance abnormalities remains unclear. Gray matter studies have demonstrated that much of the disease process remains undetected by conventional magnetic resonance imaging. Although newly developed techniques, such as 3D double-inversion recovery, may greatly improve detection of cortical pathology, it remains important to investigate the resultant effects on the cortical tissue alongside this, by studying integrity of normal-appearing cortical tissue through quantitative magnetic resonance studies, as well as the net neurodegenerative effect through measurements of cortical thickness and cortical atrophy (rates). To improve our understanding of normal-appearing white and gray matter changes, their mutual relations, and their relations to clinical changes, further in vivo magnetic resonance imaging studies are required. Specifically, it is proposed that more spatially specific investigations, ideally utilizing subject-specific anatomical information from, for example, diffusion fiber-tracking techniques, could be used to gain more insight into the relations between normal-appearing white matter changes, cortical changes, magnetic resonance visible focal-lesions, and physical and cognitive deficits.

Whole-Brain T1 Mapping in Multiple Sclerosis: Global Changes of Normal-appearing Gray and White Matter

To prospectively investigate whether T1 changes in normal-appearing white matter (WM) and normal-appearing gray matter (GM) in multiple sclerosis (MS) are global or regional and their relationship to disease type. The institutional ethics review board approved study; written informed consent was obtained. Whole-brain T1 maps were obtained in 67 patients with MS and 24 healthy control subjects with three-dimensional fast low-angle shot flip angle-array method, with correction for B(1) imperfections. Analysis of variance was performed on T1 histogram parameters of global normal-appearing WM and GM. Regional mean T1 values were analyzed with a multilevel approach. Multiple linear regression analysis was performed to investigate associations with clinical disability and overall atrophy. For patients, T2 lesion load was determined. T1 histograms of normal-appearing WM had significantly higher peak positions for patients with MS (792 msec +/- 36 in secondary progressive [SP] MS) than for control subjects (746 msec +/- 23) and were significantly broader and lower (all P < .001). Histograms for cortical normal-appearing GM were significantly shifted (peak positions, 1263 msec +/- 44 in control subjects and 1355 msec +/- 62 in patients with SP MS) (P < .001). Histogram peak positions were significantly higher in SP MS than in relapsing-remitting (RR) and primary progressive MS (P < .05). In SP disease, at least 31% of normal-appearing WM and 20% of cortical normal-appearing GM were affected. In MS, T1 was significantly elevated in all normal-appearing WM and cortical normal-appearing GM regions (all P < .01) but was elevated only in the thalamus in deep GM (P < .05). Cortical T1 histogram peak position was associated with clinical disability; T2 lesion load was not. Results suggest that a global disease process affects large parts of both normal-appearing WM and GM in MS and effects are worse for SP MS than for RR MS.

MRI quantification of gray and white matter damage in patients with early–onset multiple sclerosis

Contrary to what happens in adult-onset multiple sclerosis (MS), in a previous preliminary magnetic resonance imaging (MRI) study we showed only subtle normal-appearing brain tissue changes in patients with earlyonset MS. Our objective was to evaluate the presence and extent of tissue damage in the brain normalappearing white matter (NAWM) and gray matter (GM) from a larger population of patients with earlyonset MS. Using diffusion tensor (DT) and magnetization transfer (MT) MRI, we obtained DT and MT ratio (MTR) maps of the NAWM and GM from 23 patients with early-onset MS and 16 sex- and age-matched healthy volunteers. Compared with healthy volunteers, patients with early-onset MS had significantly increased average MD (p = 0.02) and FA peak height (p = 0.007) and decreased average FA (p <0.0001) of the NAWM. Brain dual-echo lesion load was significantly correlated with average FA (r = -0.48, p = 0.02) and with FA peak height (r = 0.45, p = 0.03) of the NAWM. No MTR and diffusion changes were detected in the GM. This study confirms the paucity of the 'occult' brain tissue damage in patients with earlyonset MS. It also suggests that in these patients GM is spared by the disease process and that NAWM changes are likely to be secondary to Wallerian degeneration of fibers passing through macroscopic lesions.

Molecules affecting myelin stability: A novel hypothesis regarding the pathogenesis of multiple sclerosis

In this Mini-Review we present a new hypothesis in support of the neurodegenerative theory as a mechanism for the pathogenesis of multiple sclerosis (MS). The pathogenesis of MS results from changes in two distinct CNS compartments. These are the "myelin" and "nonmyelin" compartments. The myelin compartment is where primary demyelination, amidst attempts at remyelination, is superseded in the CNS by ongoing disease. Recent evidence obtained via magnetic resonance imaging and spectroscopy techniques supports the view that the normal-appearing white matter (NAWM) in the MS brain is altered. Several biochemical changes in NAWM have been determined. These include the cationicity of myelin basic protein (MBP) as a result of the action of peptidyl argininedeiminase (PAD) activity converting arginyl residues to citrulline. The accompanying loss of positive charge makes myelin susceptible to vesiculation and MBP more susceptible to proteolytic activity. An increase of MBP autocatalysis in the MS brain might also contribute to the generation of immunodominant epitopes. Accompanying the destruction of myelin in the myelin compartment is the activation of astrocytes and microglia. These contribute to the inflammatory response and T-cell activation leading to autoimmunity. The complex environment that exists in the demyelinating brain also affects the "nonmyelin" compartment. The inappropriate up-regulation of molecules, including those of the Jagged-1-Notch-1 signal transduction pathway, affects oligodendrocyte precursor cell (OPC) differentiation. Other effectors of oligodendrocyte maturation include stathmin, a microtubule-destabilizing protein, which prevents healing in the demyelinating brain. The hypothesis we present suggests a therapeutic strategy that should 1) target the effectors within the myelin compartment and 2) enable resident OPC maturation in the nonmyelin compartment, allowing for effective repair of myelin loss. The net effect of this new therapeutic strategy is the modification of the disease environment and the stimulation of healing and repair.

Diffusion tensor imaging of cerebral white matter in patients with myotonic dystrophy

To determine whether myotonic dystrophy (MyD) patients have diffusion tensor abnormalities suggestive of microstructural changes in normal-appearing white matter (NAWM). Conventional and diffusion tensor magnetic resonance images of the brain were obtained in 19 MyD patients and 19 age-matched normal control subjects. Fractional anisotropy (FA) and mean diffusivity (MD) values were calculated in white matter lesions (WMLs) and NAWM in MyD patients and in the white matter of normal control subjects. Differences between WML and NAWM values and between MyD patient and control subject values were analyzed statistically. Significantly lower FA and higher MD values were found in all regions of interest in the NAWM of MyD patients than in the white matter of control subjects (P<0.01), as well as significantly lower FA and higher MD values in WMLs than in NAWM of MyD patients (P < 0.05). There was no significant correlation of mean FA or MD values in NAWM with patient age, age at onset, or duration of illness (P>0.1). Diffusion tensor imaging analysis suggests the presence of diffuse microstructural changes in NAWM of MyD patients that may play an important role in the development of disability.

Biophysical changes in normal-appearing white matter and subcortical nuclei in late-life major depression detected using magnetization transfer

Neuroanatomical changes have been identified in patients diagnosed with late-life major depressive disorder (MDD) compared with controls. These primarily comprise a decrease in focal brain volumes and an increase in MRI-determined high intensity lesions that are largely confined to the white matter. The physiological status of normal-appearing white matter in patients with MDD remains unknown. Magnetization transfer (MT) is a relatively new neuroimaging technique that permits us to examine the biophysical characteristics of specific brain regions. Using MT, we studied eight patients with late-life MDD and eight non-depressed controls. MT ratios (MTR), which reflect the integrity of the macromolecular protein pool, were ascertained in normal-appearing white matter and subcortical nuclei. Patients had significantly lower MTRs in the genu and splenium of the corpus callosum, the right caudate nucleus and putamen, and the occipital white matter compared with controls. The findings indicate that the structure of the macromolecular protein matrix may be compromised in normal-appearing white matter and critical subcortical nuclei in patients with late-life major depression. These changes may provide important substrates to mood disorders and have implications for neuronal connectivity and its role in the pathophysiology of late-life depression.

Thalamic neurodegeneration in relapsing-remitting multiple sclerosis.

To define the extent of neuronal injury and loss in thalamic gray matter in patients with relapsing-remitting (RR) MS and to characterize how these neuronal pathologic changes are related to disease duration. The authors studied 14 patients with RRMS (Expanded Disability Status Scale score, mean 3.25, range 2.0 to 6.0) and 14 (8 men, 6 women) age-matched healthy controls. Structural MR and MRS studies were performed in a single scanning session using a 3T MR system. N-acetylaspartate (NAA) concentrations (a measure of the apparent neuronal density) were decreased approximately 11% in the thalami of the patients with RRMS relative to controls (p < 0.05). The patients with RRMS also had an almost 25% lower mean normalized thalamic volume than controls (p < 0.005). Decreases in thalamic NAA concentration correlated strongly with thalamic volume loss for individual patients (r = 0.85, p < 0.01). Both the NAA concentration (r = -0.48, p = 0.044) and normalized thalamic volume (r = -0.60, p = 0.01) were correlated inversely with disease duration. There was a trend for a correlation between the thalamic NAA/creatine (Cr) ratio and the NAA/Cr in the frontal normal-appearing white matter (r = 0.56, p < 0.08). The reduction of both NAA concentration and thalamic volume suggests that a neurodegenerative component may contribute to the pathology of MS even in the earlier RR stage. The trend toward a relationship between thalamic NAA/Cr and distant normal-appearing white matter changes implies that there may be a common mechanism for the white matter axonal loss and thalamic neuronal injury.

The relationship between lesion and normal appearing brain tissue abnormalities in early relapsing remitting multiple sclerosis.

In multiple sclerosis (MS), pathological changes have been found both in macroscopic lesions and normal appearing tissue. Magnetisation transfer ratio (MTR) and T1 relaxation time are abnormal in normal appearing tissues in established MS. This study used these MR techniques in early MS to study normal appearing tissues and lesions. The purpose was to determine whether abnormalities are already detectable in normal appearing tissues in early MS, and if so how they correlate with lesion characteristics. Twenty two patients with early relapsing remitting (RR) MS (median disease duration 2 years, range 7 months-3 years) and 11 age-matched controls were studied. MTR and T1 relaxation times were measured in 9 regions of normal appearing white matter (NAWM) and 7 of normal appearing grey matter (NAGM). Gadolinium enhancing, T1-hypointense and T2 lesion loads were measured in all patients. When all regions were combined, there was a significant difference between patient and control NAWM for both T1 and MTR; T1 was abnormal in 6/9 and MTR in 3/9 NAWM regions. Global assessment of NAGM revealed a significant difference between patients and controls for Ti but not for MTR; T1 was significantly abnormal only in frontal NAGM. There was no significant correlation between NAWM T1 or MTR and any of the lesion load measurements. This study reveals quantitative MR abnormalities in both NAWM and NAGM in early RR MS, with more extensive changes in the former. The lack of correlation between NAWM and lesion abnormalities suggests that they have developed by at least partly independent mechanisms. T1 may be more sensitive than MTR in detecting subtle pathological changes in NAWM and NAGM.

Magnetic resonance imaging findings predicting subsequent disease course in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis.

This review summarizes the main contributions given by magnetic resonance imaging (MRI) to predict disease evolution in patients at presentation with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS). In these patients, the extent of lesions on T2-weighted scans of the brain is a robust predictor of the subsequent development of clinically definite MS (CDMS), moderate to severe disability and new MRI lesions. The risk of developing CDMS in patients with CIS is further increased when some of these lesions are enhancing or when additional lesions are seen on T2-weighted scans of the spinal cord. Recent studies using new MRI techniques have shown that irreversible tissue disruption is an early event in the course of MS and that subtle normal-appearing white matter changes occur in patients with CIS and are associated with an increased risk of developing CDMS. These findings are changing our views of how to monitor early MS evolution and of early MS treatment strategy.