Progressive change in primary progressive multiple sclerosis normal-appearing white matter: a serial diffusion magnetic resonance imaging study

In spite of marked disability, patients with primary progressive multiple sclerosis (PPMS) display smaller lesion volumes on conventional magnetic resonance imaging (MRI) compared with other forms of multiple sclerosis (MS). Hence, damage to the normal-appearing brain tissue (NABT) may play an important role in explaining the pathogenesis of disability in PPMS. Diffusion-weighted MRI (DW-MRI) probes water diffusion in vivo that can be altered by pathologic changes. Using DW-MRI we investigated diffusion in the NABT of 15 patients with PPMS over one year. The average apparent diffusion coefficient (ADCav) was measured in 10 regions of interest located in the normal-appearing thalamus and the normal-appearing white matter (NAWM). Six healthy subjects served as a reference. In contrast to healthy subjects, patients with PPMS showed an increment within 12 months of the ADCav in NAWM which was associated with an increase of the T2- and T1-lesion volumes. The ADCav in frontal NAWM was associated with disability as measured by the MS Functional Composite Measure. Serial DW-MRI depicts progressive changes in the NAWM of patients with PPMS. Our preliminary findings suggest that the processes causing structural damage in NAWM and lesions in patients with PPMS are partially linked and that changes of water diffusion in NAWM depicted by DW-MRI are clinically relevant.     

Gray matter alterations in early aging: A diffusion magnetic resonance imaging study

Many studies have observed altered neurofunctional and structural organization in the aging brain. These observations from functional neuroimaging studies show a shift in brain activity from the posterior to the anterior regions with aging (PASA model), as well as a decrease in cortical thickness, which is more pronounced in the frontal lobe followed by the parietal, occipital, and temporal lobes (retrogenesis model). However, very little work has been done using diffusion MRI (dMRI) with respect to examining the structural tissue alterations underlying these neurofunctional changes in the gray matter. Thus, for the first time, we propose to examine gray matter changes using diffusion MRI in the context of aging. In this work, we propose a novel dMRI based measure of gray matter “heterogeneity” that elucidates these functional and structural models (PASA and retrogenesis) of aging from the viewpoint of diffusion MRI. In a cohort of 85 subjects (all males, ages 15–55 years), we show very high correlation between age and “heterogeneity” (a measure of structural layout of tissue in a region‐of‐interest) in specific brain regions. We examine gray matter alterations by grouping brain regions into anatomical lobes as well as functional zones. Our findings from dMRI data connects the functional and structural domains and confirms the “retrogenesis” hypothesis of gray matter alterations while lending support to the neurofunctional PASA model of aging in addition to showing the preservation of paralimbic areas during healthy aging. Hum Brain Mapp 35:3841–3856, 2014. © 2013 Wiley Periodicals, Inc.     

Grey matter abnormalities in multiple sclerosis: proton magnetic resonance spectroscopic imaging

Pathologically defined abnormalities in the cortical gray matter (GM) are well described in multiple sclerosis (MS) but are infrequently seen by conventional magnetic resonance imaging (MRI). We systematically evaluated 52 relapsing-remitting MS patients and 20 normal volunteers with high resolution MRI and short echo proton magnetic resonance spectroscopic imaging (MRSI). Individual tissue contributions to the spectroscopic voxels were estimated based on MRI that incorporated both CSF suppression and magnetization transfer, or double inversion images in which both CSF and GM were suppressed. Strong resonances in the 0.8 to 1.5 p.p.m. spectral region were observed in 13 MS patients. Image segmentation based on the MRI characteristics of tissues contributing to the spectroscopic voxels showed that these additional peaks originated mainly from GM. The presence of these additional peaks suggests that the normal appearance GM on MRI, is biochemically abnormal in a substantial proportion of relapsing-remitting MS patients.     

Correlation of magnetization transfer and diffusion magnetic resonance imaging in multiple sclerosis

The aim of this study was to correlate diffusion to magnetization transfer (MT) magnetic resonance imaging (MRI) results in multiple sclerosis (MS), in order to establish if the former technique provides complementary information. Magnetization transfer ratio (MTR) and apparent diffusion coefficient (ADC) were measured in 156 different regions of interest (ROIs) of 14 MS patients, where 84 corresponded to T1 hypointense lesions, 60 to T1 isointense lesions and 12 to regions of normal appearing white matter (NAWM). MTR mean value was higher for T1 isointense than for T1 hypointense lesions, and lower when compared to NAWM. ADC mean value for T1 isointense lesions was higher than for NAWM, but lower than for T1 hypointense lesions. A significant negative correlation was found between ADC and MTR for hypointense lesions (Pearson's r = -0.758, P < 0.001), whereas this correlation was much weaker for T1 isointense lesions (Pearson's r= -0.256, P = 0.049). There was no correlation between ADC and MTR for NAWM. The fact that ADC and MTR show a strong correlation only for T1 hypointense lesions indicates that, when tissue integrity is not severely compromised, as in the case of T1 isointense lesions or NAWM, ADC and MTR might be sensitive to different pathological processes.     

A study of the mechanisms of normal-appearing white matter damage in multiple sclerosis using diffusion tensor imaging

Diffusion tensor imaging (DTI) investigates brain tissue microstructure in vivo. In multiple sclerosis (MS) Wallerian degeneration of axons traversing focal lesions is a potential mechanism of damage in normal-appearing white matter. In vivo evidence for this hypothesis is limited. The present study investigated the relationship between DTI-derived indices in the normal-appearing corpus callosum (CC) and the lesion loads (LLs) in connected cerebral regions. DTI was performed in 39 MS patients and in 21 age-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) were estimated in the genu, body and splenium of CC. Patients showed lower FA and higher MD in the CC than controls and both correlated with the total LL (r = −0.56 and r = 0.54, p < 0.0001). The LL of individual cerebral lobes correlated with both FA and MD in the corresponding callosal regions, with the body showing the strongest correlations with frontal and parietal LL (p < 0.0001). The strong correlations between DTI indices in the CC and the extent of lesions in connected brain regions support the hypothesis that Wallerian degeneration of axons transected by remote, but connected focal lesions, is an important pathogenic mechanism of damage in MS. Received: 16 July 2002, Received in revised form: 8 October 2002, Accepted: 14 October 2002 Correspondence to Prof. A. J. Thompson     

A quantitative study of water diffusion in multiple sclerosis lesions and normal-appearing white matter using echo-planar imaging

OBJECTIVES: We used an optimized echo-planar pulse sequence for isotropically weighted diffusion imaging (1) to measure mean diffusivity (D) in lesions and normal-appearing white matter (NAWM) in the entire brain from patients with mildly disabling relapsing-remitting multiple sclerosis (MS), (2) to compare the D of NAWM from patients with that of white matter from normal controls, (3) to evaluate whether lesions classified on the basis of their appearance on enhanced T1-weighted scans have different D, and (4) to investigate the relationship between diffusion changes in lesions and NAWM. METHODS: Dual-echo and diffusion-weighted scans were obtained from 35 patients with relapsing-remitting MS and 24 sex- and age-matched normal controls. Postcontrast T1-weighted images were also obtained from the patients. After creating D maps and image coregistration, D values were measured for MS lesions larger than 5 mm and for 22 NAWM areas from each subject. RESULTS: All NAWM areas studied had significantly higher D in patients than in controls. A total of 173 lesions were identified on the dual-echo scans from patients. The average D for these lesions was significantly higher than that of NAWM. Twenty-two lesions were enhancing and 60 were classified as T1-hypointense. No significant difference in D values was found between enhancing and nonenhancing lesions, while the average D of T1-hypointense lesions was significantly higher than the average D of T1-isointense lesions. There was no significant correlation between the average D in lesions and NAWM. CONCLUSIONS: This study shows that diffusion-weighted imaging is able to identify MS lesions with severe tissue disruption. It also shows that widespread increased diffusion can be measured in the NAWM from patients with MS, and suggests that such changes are, at least partially, independent of larger abnormalities.     

In-vivo tissue characterization of multiple sclerosis and other white matter diseases using magnetic resonance based techniques

In several white matter diseases of the central nervous system (CNS), and in particular in multiple sclerosis (MS), conventional magnetic resonance imaging (MRI) has proved to be sensitive for detecting lesions and their changes over time. However, conventional MRI is not able to characterize and quantify the tissue damage within and outside such lesions. Other quantitative MR techniques, including proton MR spectroscopy (¹H-MRS), magnetization transfer MRI (MT-MRI) and diffusion-weighted MRI (DW-MRI) have the potential to overcome this limitation and, as a consequence, to provide additional information about the nature and the extent of tissue damage, which would be inevitably lost when only conventional MRI is obtained. Metrics derived from MT- and DW-MRI can quantify the structural changes occurring within and outside lesions visible on conventional MRI scans. ¹H-MRS could add information on the biochemical nature of such changes. The application of these MR techniques to the study of MS is increasing dramatically our understanding of how MS causes irreversible disability and it is likely to provide useful insights into the pathophysiology of other diseases of the CNS in the near future. Received: 14 July 2001, Accepted: 16 July 2001     

Nuclear magnetic resonance imaging in multiple sclerosis

Ten patients with definite multiple sclerosis underwent hydrogen nuclear magnetic resonance imaging with a 3.5 kilogauss superconducting magnet, using the inversion recovery and spin-echo techniques of signal acquisition. Results were compared with high-resolution x-ray computed tomography. Spin-echo images demonstrated abnormal regions as areas of variably increased signal intensity. The contrast between abnormal and normal white matter improved as the intervals between sequential radiofrequency pulses and between pulse administration and signal sampling were increased. Inversion recovery images demonstrated abnormal areas as regions of decreased signal intensity but did not visualize lesions as well as spin-echo imaging. Spin-echo and inversion recovery imaging each demonstrated more extensive abnormalities than did computed tomography.     

Diffusion magnetic resonance imaging in multiple sclerosis

Multiple sclerosis (MS) is considered the most common inflammatory autoimmune neurologic disorder and the most frequent cause of nontraumatic neurologic disability in young and middle-age adults. This article reviews the basic features of its magnetic resonance (MR) imaging lesions and, primarily, the use of diffusion MR imaging, which is increasingly applied to assess patients with MS, not only to investigate plaques but also the normal-appearing white matter, gray matter, optic nerve, and spinal cord, because of its ability to detect and quantify disease-related pathologic conditions of the central nervous system.     

Enhanced magnetic resonance imaging in multiple sclerosis

Gadolinium-enhanced magnetic resonance imaging (MRI) is very sensitive in the detection of active lesions of multiple sclerosis (MS) and has become a valuable tool to monitor the evolution of the disease either natural or modified by treatment. In the past few years, several studies, on the one hand, have assessed several ways to increase the sensitivity of enhanced MRI to disease activity and, on the other, have investigated in vivo the nature and evolution of enhancing lesions using different non-conventional MR techniques to better define the relationship between enhancement and tissue loss in MS. The present review is a summary of these studies whose results are discussed in the context of MS clinical trial planning and monitoring. Multiple Sclerosis (2000) 6 320 - 326     

Selective vulnerability of cerebral white matter in a murine model of multiple sclerosis detected using diffusion tensor imaging

In this study, axial (lambda(parallel)) and radial (lambda(perpendicular)) diffusivities derived from diffusion tensor imaging (DTI) were used to evaluate white matter injury in brains of mice affected by experimental autoimmune encephalomyelitis (EAE). Sixteen female C57BL/6 mice were immunized with amino acids 35-55 of myelin oligodendrocyte glycoprotein (MOG(35-55)). Three months after immunization, optic nerve and tract were severely affected with 19% and 18% decrease in lambda(parallel) respectively, suggesting the presence of axonal injury. In addition, a 156% and 86% increase in lambda( perpendicular) was observed in optic nerve and tract respectively, suggestive of myelin injury. After in vivo DTI, mice were perfusion fixed and immunohistochemistry for the identification of myelin basic protein (MBP) and phosphorylated neurofilament (pNF) was performed to verify the presence of axonal and myelin injury. The present study demonstrated that the visual pathway is selectively affected in MOG(35-55) induced murine EAE and these injuries are non-invasively detectable using lambda(parallel) and lambda( perpendicular).     

Progressive gray matter damage in patients with relapsing-remitting multiple sclerosis: a longitudinal diffusion tensor magnetic resonance imaging study

BACKGROUND: Diffusion tensor magnetic resonance imaging (DT MRI) has the potential to provide in vivo information about tissue microstructure. In multiple sclerosis (MS), DT MRI has disclosed the presence of occult structural damage in the normal-appearing brain tissues. OBJECTIVE: To investigate whether DT MRI is sensitive to longitudinal changes of brain damage that may occur beyond the resolution of T2-weighted images in patients with relapsing-remitting MS. DESIGN: Twenty-six untreated patients with relapsing-remitting MS were followed up for 18 months. Dual-echo, DT and postcontrast T1-weighted MRIs of the brain were obtained at baseline and then every 3 months. Mean diffusivity (D) histograms of normal-appearing gray (GM) and white matter were produced. Total T2-hyperintense and T1-hypointense lesion volumes; normalized whole brain tissue, GM, and white matter volumes; percentage brain volume change between the study entry and exit images; average lesion D; and fractional anisotropy were also calculated. RESULTS: During the study period, a significant decrease of normalized whole brain tissue, average lesion fractional anisotropy and normal-appearing GM D histogram peak height, and a significant increase of average normal-appearing GM D and T2-hyperintense lesion volumes were observed. Changes of normal-appearing GM diffusivity were independent of the concomitant changes of normalized whole brain tissue and GM volumes. CONCLUSIONS: The DT MRI findings show progressive microstructural changes in the normal-appearing GM of patients with untreated relapsing-remitting MS. Such changes do not reflect a concomitant development of brain atrophy and confirm the importance of GM pathology in MS.     

Diffusion tensor magnetic resonance imaging in multiple sclerosis

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.     

Lessons from magnetic resonance imaging in multiple sclerosis

Magnetic resonance imaging is a potent diagnostic tool in multiple sclerosis: it can reveal dissemination of lesions in both space and time in many patients with isolated neurological syndromes. Many more new lesions occur than clinical relapses. A consistent very early event is the breakdown of the blood-brain barrier which is largely repaired over weeks, leading to marked changes in the size of acute lesions. Chronic lesions show persistent oedema and enlarge through cycles of renewed peripheral activity. The vascular changes reflect inflammation: the resulting MRI changes provide, for the first time, a non-invasive means of monitoring disease activity and its modification by treatment.     

Proton magnetic resonance spectroscopy of normal appearing white matter in familial and sporadic multiple sclerosis

Objective To assess metabolite levels in normal–appearing white matter in sporadic and familial multiple sclerosis (MS). Methods Using H–MRS and applying one voxel measure we assessed NAA/Cho,NAA/Cr and Cho/Cr ratios in 26 patients with sporadic and in 25 with familial MS and compared them with healthy subjects. Results In both MS groups NAA/Cho and NAA/Cr ratio were significantly lower than in healthy individuals whereas Cho/Cr ratio was higher in MS patients. In sporadic MS patients NAA/Cho and NAA/Cr ratios were lower, although not significantly, than in familial cases. The Cho/Cr ratio was similar in both MS groups. Conclusion These results suggest that subtle differences in H–MRS measures corresponding to axonal rather than to myelin pathology might occur in sporadic and familial MS.     

Normal-appearing white matter changes in multiple sclerosis: the contribution of magnetic resonance techniques.

Several magnetic resonance (MR) techniques have proved to be sensitive enough to detect the subtle pathological changes that post-mortem studies showed to occur in the normal-appearing white matter (NAWM) from patients with multiple sclerosis (MS). Although these abnormalities can be detected in other neurological conditions, they seem to be more frequent and diffuse in MS. However, the contribution of NAWM changes to the diagnosis is still unclear. Their nature is also unknown and perhaps differs in different phases and clinical manifestations of the disease. Nevertheless, the extent and severity of NAWM damage seems to be relevant in causing disability and influencing the clinical evolution in MS patients. This review will summarize the present knowledge about MR-detected NAWM changes in MS and their relevance to the diagnosis and the understanding of disease evolution.     

Overview of imaging in multiple sclerosis and white matter disease

MR imaging is the dominant paraclinical test for evaluating multiple sclerosis (MS) because of its exquisite sensitivity to white matter pathology. Knowledge of the signal characteristics of MS lesions, anatomic distribution of lesions, differential diagnosis, and most important, the clinical context, markedly improve the specificity of the MR examination. MR imaging findings can be used to predict future conversion to clinically definite MS before a second clinical exacerbation.