Normal-appearing White Matter Regions Research Articles

Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

Previous authors have shown that the transverse relaxivity R(2)* and frequency shifts that characterize gradient echo signal decay in magnetic resonance imaging are closely associated with the distribution of iron and myelin in the brain's white matter. In multiple sclerosis, iron accumulation in brain tissue may reflect a multiplicity of pathological processes. Hence, iron may have the unique potential to serve as an in vivo magnetic resonance imaging tracer of disease pathology. To investigate the ability of iron in tracking multiple sclerosis-induced pathology by magnetic resonance imaging, we performed qualitative histopathological analysis of white matter lesions and normal-appearing white matter regions with variable appearance on gradient echo magnetic resonance imaging at 7 Tesla. The samples used for this study derive from two patients with multiple sclerosis and one non-multiple sclerosis donor. Magnetic resonance images were acquired using a whole body 7 Tesla magnetic resonance imaging scanner equipped with a 24-channel receive-only array designed for tissue imaging. A 3D multi-gradient echo sequence was obtained and quantitative R(2)* and phase maps were reconstructed. Immunohistochemical stainings for myelin and oligodendrocytes, microglia and macrophages, ferritin and ferritin light polypeptide were performed on 3- to 5-µm thick paraffin sections. Iron was detected with Perl's staining and 3,3'-diaminobenzidine-tetrahydrochloride enhanced Turnbull blue staining. In multiple sclerosis tissue, iron presence invariably matched with an increase in R(2)*. Conversely, R(2)* increase was not always associated with the presence of iron on histochemical staining. We interpret this finding as the effect of embedding, sectioning and staining procedures. These processes likely affected the histopathological analysis results but not the magnetic resonance imaging that was obtained before tissue manipulations. Several cellular sources of iron were identified. These sources included oligodendrocytes in normal-appearing white matter and activated macrophages/microglia at the edges of white matter lesions. Additionally, in white matter lesions, iron precipitation in aggregates typical of microbleeds was shown by the Perl's staining. Our combined imaging and pathological study shows that multi-gradient echo magnetic resonance imaging is a sensitive technique for the identification of iron in the brain tissue of patients with multiple sclerosis. However, magnetic resonance imaging-identified iron does not necessarily reflect pathology and may also be seen in apparently normal tissue. Iron identification by multi-gradient echo magnetic resonance imaging in diseased tissues can shed light on the pathological processes when coupled with topographical information and patient disease history.

Multiple sclerosis normal‐appearing white matter: Pathology–imaging correlations

The study was undertaken to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis brains. Brain tissues were obtained through a rapid postmortem protocol that included in situ magnetic resonance imaging (MRI). Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) regions that were abnormal on all images (T2T1MTR lesions); (2) NAWM regions with slightly abnormal MTR located close to white matter lesions (sa-WM Close); (3) NAWM regions with slightly abnormal MTR located far from lesions (sa-WM Far); and (4) NAWM regions with normal MTR (NAWM). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins, and blood vessels. Forty-eight ROIs from 4 secondary progressive MS brains were analyzed. sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged major histocompatibility complex II(+) microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area, and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in nonlesional white matter (WM) were correlated with activated microglia, but not with axonal or myelin integrity. The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.

Evaluation of Normal Appearing White Matter in Multiple Sclerosis

The aim of this study was to determine diffusion magnetic resonance imaging (MRI), magnetization transfer (MT) imaging and multivoxel MR spectroscopy findings in plaques, periplaque white matter and normal appearing white matter (NAWM) regions in multiple sclerosis (MS) and to correlate the findings with the expanded disability status scale (EDSS). A total of 30 patients with MS and 30 healthy control subjects were studied and apparent diffusion coefficient (ADC) values, MT ratio (MTR), N-acetyl-aspartate/creatine (NAA/Cr) and choline/creatine (Cho/Cr) ratios were measured in plaques, periplaques and NAWM regions and compared with the control subjects. The MTR and NAA/Cr ratio were decreased more in plaques than periplaques and NAWM, in contrast ADC values and Cho/Cr ratios were highest in plaques and higher in periplaques than in NAWM. Decreased MTR and NAA/Cr in NAWM demonstrated moderate inverse correlations (r = - 0.604, p < 0.001 and r = - 0.494, p < 0.001, respectively) while Cho/Cr ratios and ADC of NAWM demonstrated weak linear correlations (r = 0.370, p = 0.004, r = 0.297, p = 0.021 respectively) with EDSS. The MS, MTR and MR spectroscopy findings were found to be useful for detecting subtle abnormalities in NAWM. Although ADC values were significantly altered in plaque and periplaque regions a significance difference was not found in NAWM.

Quantitative magnetization transfer and myelin water imaging of the evolution of acute multiple sclerosis lesions

Quantitative magnetization transfer imaging provides in vivo estimates of liquid and semisolid constituents of tissue, while estimates of the liquid subpopulations, including myelin water, can be obtained from multicomponent T(2) analysis. Both methods have been suggested to provide improved myelin specificity compared to conventional MRI. The goal of this study was to investigate the sensitivity of each technique to the progression of acute, gadolinium-enhancing regions of multiple sclerosis. Magnetization transfer and T(2) relaxometry data were acquired longitudinally over the course of 1 year in five relapsing-remitting multiple sclerosis patients and in five healthy controls. Parametric maps were analyzed in enhancing lesions and normal-appearing white matter regions. Quantitative magnetization transfer parameters in lesions were most abnormal at the time of enhancement and followed a pattern of recovery over subsequent months. Lesion myelin water fraction was abnormal but did not show a significant trend over time. Quantitative magnetization transfer was able to track the degree and timing of the partial recovery in enhancing multiple sclerosis lesions in a small group of patients, while the recovery was not detected in myelin water estimates, possibly due to their large variability. Our data suggest the recovery is characterized by quick resolution of inflammation and a slower remyelination process.

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.

Serial Changes in the White Matter Diffusion Tensor Imaging Metrics in Moderate Traumatic Brain Injury and Correlation with Neuro-Cognitive Function

Diffuse axonal injury (DAI) that follows traumatic brain injury (TBI) is thought to be a major contributor to neurocognitive dysfunction that sometimes follows TBI. Conventional magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and neuropsychological tests (NPT) were performed on 38 TBI patients [hemorrhagic DAI (H-DAI, n=8), non-hemorrhagic (Nh-DAI, n=7), with no apparent DAI on conventional MRI (NA-DAI, n=23)] with a Glasgow Coma Scale score ranging between 9 and 13. The fractional anisotropy (FA) and mean diffusivity (MD) were quantified from different regions of the corpus callosum (CC), and peri-ventricular white matter (PWM) within 5-14 days and 6 months following TBI. Patients in all three groups showed decreased FA in the anterior limb of the internal capsule (ALIC) and the posterior limb of the internal capsule (PLIC), while the genu of the CC showed a decrease in the H-DAI group during the early period following TBI that persisted 6 months later, which appeared to be consistent with axonopathy. In patients without abnormalities on conventional MRI and DTI in the initial phase, a significant decrease in FA and increase in MD were observed in a few regions of the CC at 6 months, which was suggestive of demyelination/gliosis. The changes in FA and MD in the CC and PWM at 6 months follow-up showed significant correlation with some of the NPT performed in the three groups. DTI demonstrates axonopathy in the acute stage, as well as at secondary stages, at 6 months post-injury in the CC and PWM in regions of normal-appearing white matter on conventional MRI.

Characteristics of Abnormal Diffusivity in Normal-Appearing White Matter Investigated with Diffusion Tensor MR Imaging in Tuberous Sclerosis Complex

Although patients with tuberous sclerosis complex (TSC) manifest various structural abnormalities, we hypothesized that white matter (WM) structures that appear normal on conventional MR imaging may be accompanied by microstructural changes, such as gliosis and myelinization defects. Our objective was to determine in vivo whether there was evidence for WM microstructural changes by using diffusion tensor imaging (DTI). We used DTI to evaluate diffusivity and anisotropy in normal-appearing WM (NAWM) of 6 children with TSC and 12 age-matched control subjects. The anterior and posterior limbs of the internal capsule, the external capsule, and the genu and splenium of the corpus callosum were assessed. We hypothesized that previously reported DTI abnormalities of NAWM in patients with TSC may not be equal in all diffusion directions as measured by the major, middle, and minor eigenvalues. When combining NAWM regions in patients with TSC, we observed a significant increase in mean diffusivity (P = .003) and a decrease in anisotropy (P = .03) compared with those of controls. However, the increase in diffusivity was more pronounced in directions orthogonal to the axons measured by the minor and middle eigenvalues (P = .005) than by the major eigenvalue (P = .02). Our findings revealed a decrease in anisotropy and an increase in longitudinal and radial diffusivities in NAWM beyond the location of TSC lesions seen on conventional MR imaging. The axonal microstructural changes suggested by our study may be related to changes in myelin packing due to giant cells accompanied by gliosis and myelination defects known to occur in TSC WM.

Application of voxelwise analysis in the detection of regions of reduced fractional anisotropy in multiple sclerosis patients

To investigate the utility of voxelwise analysis in the detection of lesions in the normal appearing white matter (NAWM) of individual multiple sclerosis (MS) patients. Diffusion tensor imaging (DTI) was performed on 10 normal controls and six patients with MS lesions. The fractional anisotropy (FA) maps derived from the diffusion-weighted images were then spatially normalized (via an affine transformation) into Montreal Neurological Institute (MNI) space, and the normalized FA map of each of the patients was compared voxelwise with the normalized FA maps of the group of normals in a one-sample t-test (P = 0.0001). Two independent board-certified neuroradiologists reviewed the data. In the patient data for all six cases, the two reviewers determined detection sensitivities of 72% and 96% for the voxelwise technique based on known fluid-attenuated inversion-recovery (FLAIR) lesions. In addition, between the two reviewers, nine NAWM regions exhibiting FA reductions were identified in the six patients. However, numerous regions of abnormal FA were detected that were attributed to poor intersubject image registration. Voxelwise analysis of spatially normalized FA maps has the potential to identify regions of FA reduction in lesions and in the NAWM of individual MS patients in a rapid and reproducible fashion. J. Magn. Reson. Imaging 2007;26:552-556. (c) 2007 Wiley-Liss, Inc.

3D 1H MRSI of brain tumors at 3.0 tesla using an eight‐channel phased‐array head coil

To implement proton magnetic resonance spectroscopic imaging (1H MRSI) at 3 Tesla (3T) using an eight-channel phased-array head coil in a population of brain-tumor patients. A total of 49 MRI/MRSI examinations were performed on seven volunteers and 34 patients on a 3T GE Signa EXCITE scanner using body coil excitation and reception with an eight-channel phased-array head coil. 1H MRSI was acquired using point-resolved spectroscopy (PRESS) volume selection and three-dimensional (3D) phase encoding using a 144-msec echo time (TE). The mean choline to N-acetyl aspartate ratio (Cho/NAA) was similar within regions of normal-appearing white matter (NAWM) in volunteers (0.5 +/- 0.04) and patients (0.6 +/- 0.1, P = 0.15). This ratio was significantly higher in regions of T2-hyperintensity lesion (T2L) relative to NAWM for patients (1.4 +/- 0.7, P = 0.001). The differences between metabolite intensities in lesions and NAWM were similar, but there was an increase in SNR of 1.95 when an eight-channel head coil was used at 3T vs. previous results at 1.5T. The realized increase in SNR means that clinically relevant data can be obtained in five to 10 minutes at 3T and used to predict the spatial extent of tumor in a manner similar to that previously used to acquire 1.5T data in 17 minutes.

Multiple sclerosis: T-cell receptor expression in distinct brain regions

Multiple sclerosis (MS) is an inflammatory demyelinating disease where T cells attack the brain and the spinal cord. It is known that often particular T-cell clones are expanded in the target tissue, but it is still unknown, whether identical T-cell clones are present at distinct anatomical sites, or whether the T-cell spectrum is locally diverse. Therefore we compared the T-cell receptor (TCR) repertoire in distinct lesions and normal-appearing white matter (NAWM) from post-mortem brains of four MS patients. We analysed 19 lesions (inactive demyelinated, 15; slowly expanding chronic, 3; active lesions, 1) and 5 NAWM regions. The TCR beta-chain repertoire was investigated by CDR3 spectratyping. For each anatomical site 325 semi-nested PCR reactions were performed. About 800 Vbeta-NDN-Jbeta combinations were sequenced. Each of the four patients had distinct T-cell clones that were present in more than two anatomically distinct regions. These clones were not restricted to lesions, but were also present in NAWM. Some clones were present in all investigated lesions, and additionally, in NAWM sites. A single T-cell clone was detected in nine different sites in one patient. None of the clones was shared among different patients. Thus, pervasive T-cell clones exist in distinct regions of MS brain, and these clones are 'private' (unique) to individual patients. Analysis of the hypervariable NDN region revealed 'silent' nucleotide exchanges, i.e. nucleotide exchanges that code for identical amino acids. Such silent nucleotide exchanges suggest that the corresponding T-cell clones were recruited and stimulated by particular antigens. To attribute some of the pervasive clones to particular T-cell subsets, we isolated individual CD8+ T cells from cryosections by laser microdissection and characterized their TCR by single-cell PCR. These experiments revealed that at least some of the pervasive T-cell clones belonged to the CD8+ compartment, supporting the pathogenic relevance of this T-cell subset.

Pattern of hemodynamic impairment in multiple sclerosis: Dynamic susceptibility contrast perfusion MR imaging at 3.0 T

This study aimed to determine regional pattern of tissue perfusion in the normal-appearing white matter (NAWM) of patients with primary-progressive (PP), relapsing-remitting (RR) multiple sclerosis (MS) and healthy controls, and to investigate the association between perfusion abnormalities and clinical disability. Using dynamic susceptibility contrast (DSC) perfusion MRI at 3 T, we studied 22 patients with clinically definite MS, 11 with PP-MS and 11 with RR-MS and 11 age- and gender-matched healthy volunteers. The MRI protocol included axial dual-echo, dynamic susceptibility contrast enhanced (DSC) T2*-weighted and post-contrast T1-weighted images. Absolute cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the periventricular, frontal, occipital NAWM and in the splenium of the corpus callosum. Compared to controls, CBF and CBV were significantly lower in all NAWM regions in both PP-MS patients (p values from <0.0001 to 0.001) and RR-MS (p values from <0.0001 to 0.020). Compared to RR-MS, PP-MS patients showed significantly lower CBF in the periventricular NAWM (p=0.002) and lower CBV in the periventricular and frontal NAWM (p values: 0.0029 and 0.022). EDSS was significantly correlated with the periventricular CBF (r=−0.48, p=0.0016) and with the periventricular and frontal CBV (r=−0.42, p=0.015; r=−0.35, p=0.038, respectively). This study suggests that the hemodynamic abnormalities of NAWM have clinical relevance in patients with MS. DSC perfusion MRI might provide a relevant objective measure of disease activity and treatment efficacy.

IC-P-068: Diffusion tensor imaging of normal appearing white matter in MCI and AD

Structural magnetic resonance imaging (MRI) studies on mild cognitive impairment (MCI) and Alzheimer's disease (AD) have largely focused on the brain's cortical gray matter. However, cellular degeneration in cortical structures is usually accompanied by concomitant degeneration of axonal processes from these dying neurons. Pathoanatomical and imaging studies have confirmed both macroscopic and microscopic white matter changes in patients with AD. We propose that microstructural changes in subcortical brain regions should also be detectable in MCI. To examine the microstructural integrity of subcortical white mater in subjects with amnestic MCI and mild AD using diffusion tensor imaging (DTI). Elderly subjects with normal cognition (n=5), MCI (n=6) and mild AD (n=4) were recruited from our Alzheimer's Disease Research Center. Petersen criteria were used to diagnose amnestic MCI, and NINCDS–ADRDA criteria to diagnose AD. Normal appearing white matter (NAWM) was defined by normal signal intensity on standard T1–weighted, T2–weighted and FLAIR images. DTI images were acquired using a single shot, pulsed gradient, echo planar imaging protocol with twelve non–collinear gradient directions. Fractional anisotropy (FA), axial diffusivity (DA) and radial diffusivity (DR) of NAWM regions in the frontal, temporal, parietal and occipital lobes were measured and compared across the three groups using ANOVA with post–hoc Scheffe tests. Both AD and MCI subjects demonstrated significantly lower FA in frontal and temporal NAWM compared with normal control subjects (AD/MCI/normal = 0.28/0.28/0.35 in frontal NAWM, F=6.61, df =2, p<0.01; AD/MCI/normal = 0.41/0.44/0.52 in temporal NAWM, F=14.2, df =2, p<0.001). Radial diffusivity (DR) was significantly greater in AD and MCI subjects compared to normal controls in parietal NAWM (AD/MCI/normal = 0.62/0.60/0.56, F=11.9, df=2, p<0.001). Even in NAWM, we found evidence for microstructural changes in AD and MCI. These changes were present in brain regions serving higher cortical functions (frontal, temporal and parietal lobes), but not in regions serving primary functions (occipital lobe), and are consistent with a hypothesized loss of axonal processes in affected regions.

Preferential occult injury of corpus callosum in multiple sclerosis measured by diffusion tensor imaging.

To investigate the feasibility of diffusion tensor imaging (DTI) assessment of microscopic fiber tract injury in the corpus callosum (CC) and other normal-appearing white matter (NAWM) in patients with early multiple sclerosis (MS). DTI was performed in 12 healthy volunteers and 15 patients who have relatively short disease duration (mean = 2.7 years). Both fractional anisotropy (FA) and mean diffusivity (MD) were obtained in different regions of normal-appearing CC (NACC) and NAWM in frontal and occipital regions. The data showed significantly lower FA (P < 0.001) and higher MD (P < 0.04) for NACC regions, but not for frontal and occipital NAWM regions, in patients than in those in healthy volunteers after Bonferroni adjustment. The increase of MD in the entire NACC regions was correlated with the total cerebral lesion volume (r = 0.75, P = 0.001) in patients. The water diffusion changes indicate that in the early phase of disease there is a preferential occult injury of CC, which is likely due to the Wallerian degeneration from distant lesions.

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.

Intra-voxel and inter-voxel coherence in patients with multiple sclerosis assessed using diffusion tensor MRI.

Previous diffusion tensor magnetic resonance imaging (DT-MRI) studies reported mean diffusivity () and fractional anisotropy (FA) changes in lesions and normal-appearing white matter (NAWM) of patients with multiple sclerosis (MS), but neglected the additional information which can be obtained by the analysis of the inter-voxel coherence (C). The present study is based on a large sample of patients with MS and it is aimed at assessing the potential role of C in the quantification of MS-related tissue damage of T2-visible lesions and NAWM. We obtained dual-echo, T1-weighted and DT-MRI scans from 78 patients with relapsing-remitting (RR), secondary progressive (SP), or primary progressive (PP) MS and from 26 healthy volunteers. We calculated, FA and C of T2-hyperintense lesions, T1-isointense lesions, T1-hypointense lesions and several areas of the NAWM. and FA of the majority of NAWM regions studied from MS patients were different from the corresponding quantities of the white matter from controls. NAWM C from patients was lower than white matter C from controls only for the parietal pericallosal areas. SPMS patients had higher corpus callosum and lower corpus callosum FA and C than patients with either RRMS or PPMS. Average lesion was higher, and average FA and C lower than the corresponding quantities measured in the NAWM. Average T1-hypointense lesion was higher and average FA lower than the corresponding quantities of T1-isointense lesions, whereas average C of these two lesion populations were not different. SPMS had higher average lesion than both PPMS and RRMS patients. NAWM and C of the corpus callosum were moderately correlated with disability. This study confirms the role of DT-MRI metrics to identify MS lesions with different amounts of tissue damage and to detect diffuse changes in the NAWM. It also shows that measuring C enables us to obtain additional information about tissue damage, which is complementary to that given by the analysis of and FA.

Multiple sclerosis: diffusion tensor MR imaging for evaluation of normal-appearing white matter.

To determine whether the normal-appearing white matter (NAWM) regions surrounding and remote from multiple sclerosis (MS) plaques have abnormal diffusional anisotropy and to compare anisotropy maps with apparent diffusion coefficient (ADC) maps for sensitivity in the detection of white matter (WM) abnormalities. Conventional and diffusion tensor magnetic resonance (MR) imaging examinations were performed in 26 patients with MS and in 26 age-matched control subjects. Fractional anisotropy (FA) and ADC maps were generated and coregistered with T2-weighted MR images. Uniform regions of interest were placed on plaques, periplaque white matter (PWM) regions, NAWM regions in the contralateral side of the brain, and WM regions in control subjects to obtain FA and ADC values, which were compared across the WM regions. The mean FA was 0.280 for plaques, 0.383 for PWM, 0.493 for NAWM, and 0.537 for control subject WM. The mean ADC was 1.025 x 10(-3) mm(2)/sec for plaques, 0.786 x 10(-3) mm(2)/sec for PWM, 0.739 x 10(-3) mm(2)/sec for NAWM, and 0.726 x 10(-3) mm(2)/sec for control subject WM. Significant differences in anisotropy and ADC values were observed among all WM regions (P <.001 for all comparisons, except ADC in NAWM vs control subject WM [P =.018]). The anisotropy and ADC values were abnormal in all WM regions in the patients with MS and were worse in the periplaque regions than in the distant regions. Diffusion tensor MR imaging may be more accurate than T2-weighted MR imaging for assessment of disease burden.

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.

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

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

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.

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.