J.J.G. Geurts

Accumulation of cortical lesions in MS: relation with cognitive impairment.

Background Gray matter (GM) lesions are frequently found in multiple sclerosis (MS) and their in-vivo detection has been improved using new magnetic resonance imaging sequences, such as double inversion recovery (DIR). However, little is known about progression of GM lesions over time. Objective To study the longitudinal behavior of GM lesions and to explore their relation to cognitive impairment in MS. Methods DIR images were acquired from 13 MS patients and seven healthy controls at two time points with a median interval of 3 years. At follow-up, all subjects underwent cognitive testing. Lesions were classified as white matter, cortical or hippocampal lesions. Results In patients, median cortical lesion number had increased from 18 to 26 at follow-up (P = 0.01), median white matter (WM) lesion number had increased from 56 to 65 (P = 0.02), and no significant increase over time was found for hippocampal lesions. Cortical lesion number at follow-up was significantly higher in secondary progressive (SP) than in relapsing-remitting patients. Significant relations were found between cortical and WM lesion number at follow-up on the one hand and visuospatial memory and processing speed on the other hand. Hippocampal lesion number was related to visuospatial memory. Conclusion Cortical lesions increase significantly over a 3-year time period, are most frequent in SP patients, and are associated with cognitive impairment.

Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis

Focal lesions and brain atrophy are the most extensively studied aspects of multiple sclerosis (MS), but the image acquisition and analysis techniques used can be further improved, especially those for studying within-patient changes of lesion load and atrophy longitudinally. Improved accuracy and sensitivity will reduce the numbers of patients required to detect a given treatment effect in a trial, and ultimately, will allow reliable characterization of individual patients for personalized treatment. Based on open issues in the field of MS research, and the current state of the art in magnetic resonance image analysis methods for assessing brain lesion load and atrophy, this paper makes recommendations to improve these measures for longitudinal studies of MS. Briefly, they are (1) images should be acquired using 3D pulse sequences, with near-isotropic spatial resolution and multiple image contrasts to allow more comprehensive analyses of lesion load and atrophy, across timepoints. Image artifacts need special attention given their effects on image analysis results. (2) Automated image segmentation methods integrating the assessment of lesion load and atrophy are desirable. (3) A standard dataset with benchmark results should be set up to facilitate development, calibration, and objective evaluation of image analysis methods for MS.

Multicontrast MR imaging at 7T in multiple sclerosis: highest lesion detection in cortical gray matter with 3D-FLAIR

BACKGROUND AND PURPOSE: 7T MR imaging has led to improved detection and classification of cortical MS lesions, mainly based on T2*-weighted gradient-echo sequences. Depiction of cortical GM by using the recommended MS imaging protocol has not yet been investigated at 7T. We aimed to investigate prospectively which recommended sequence for clinical use has the highest value at 7T, in terms of GM and WM lesion detection. MATERIALS AND METHODS: Thirty-seven patients with MS (mean age, 43.8 years; 25 women) and 7 healthy controls (mean age, 40.4 years; 5 women) underwent multicontrast 7T MR imaging including the recommended clinical 2D-T2WI, 3D-T1WI, 3D-FLAIR, and GM-specific 3D-DIR. Lesions were scored and categorized anatomically by 3 raters, in consensus. The value of sequences was evaluated lesion-wise and patient-wise (Wilcoxon signed-rank test). RESULTS: At 7T, 3D-FLAIR detected the highest number of total cortical GM lesions (217), 89% more than 3D-DIR and 87% and 224% more than 2D-T2WI and 3D-T1WI. Patient-wise analysis showed that this difference between 3D-FLAIR and 3D-DIR was statistically significant (P < .04), and most pronounced for the number of mixed lesions (P < .03). 3D-FLAIR also detected the highest number of total WM lesions (2605), but the difference with 3D-DIR and 3D-T1WI was not significant. CONCLUSIONS: When using recommended clinical sequences at 7T, the best way to detect cortical GM lesions is with 3D-FLAIR and not by GM-specific 3D-DIR or by conventional 2D-T2WI and 3D-T1WI sequences.

What Explains Gray Matter Atrophy in Long-standing Multiple Sclerosis?

PURPOSEnTo identify the measures of focal and diffuse white matter (WM) abnormalities that are related to whole-brain, deep, and cortical gray matter (GM) atrophy in long-standing multiple sclerosis (MS).nnnMATERIALS AND METHODSnThe institutional review board approved the study; all subjects gave written informed consent. Magnetic resonance (MR) imaging was performed at 3 T in 208 patients with MS of long-standing duration (disease duration ≥ 10 years) and in 60 healthy control subjects. Normalized GM volume (NGMV), normalized WM volume (NWMV), normalized deep GM volume (NDGMV), cortical thickness, and normalized lesion volume (NLV) were quantified. Tissue integrity of normal-appearing WM (NAWM) and lesions was measured by using diffusion-tensor MR imaging. Multivariate associations between measures of GM atrophy and WM abnormalities were assessed in the patient group by using multiple linear regression.nnnRESULTSnNGMV, NDGMV, and cortical thickness were reduced in patients with MS (all P < .001). The final model for NGMV consisted of NWMV, NLV, and patient age and sex (adjusted R(2) = 0.58, P < .001). NWMV, NLV, and patient sex were the explanatory variables for NDGMV (adjusted R(2) = 0.75, P < .001). The model for cortical thickness consisted of fractional anisotropy of NAWM, NLV, and patient age and sex (adjusted R(2) = 0.32, P < .001). The relationship between GM atrophy and WM abnormalities was weaker in primary and secondary progressive disease than in relapsing-remitting disease.nnnCONCLUSIONnWhole-brain and deep GM atrophy were particularly explained by WM atrophy and lesion volume, while cortical atrophy was associated with NAWM integrity loss. The weaker relationship between GM atrophy and WM abnormalities in patients with progressive disease might indicate a more independent neurodegenerative disease process in these patients.

Magnetization transfer ratio measurement in multiple sclerosis normal-appearing brain tissue: limited differences with controls but relationships with clinical and MR measures of disease

We investigated the magnetization transfer ratio (MTR) of normal-appearing white (NAWM) and grey matter (NAGM) in a relatively large group of multiple sclerosis (MS) patients, and the relations of MTR changes with clinical disability. MTR was measured in 66 MS patients (12 PP, 35 RR, 19 SP) and 23 healthy controls, using a whole-brain 3D-FLASH technique corrected post-hoc for B1-induced variation. Histogram parameters of conservatively selected NAWM and cortical NAGM were analysed using Bonferroni-corrected ANOVA with age as covariate. Additionally, manually outlined regions of interest were analysed using a multilevel method. Lesions had low MTR (mean 22.7±6.9%), but NAWM exhibited limited changes: MTR histogram peak position was 32.8±1.0% in controls and 32.4±0.9% in MS patients, with a significant decrease compared to controls only in SPMS patients (31.9±1.1%, p=0.045). Cortical NAGM histograms did not differ significantly between patients and controls. In SPMS, regional mean MTR was significantly decreased in corpus callosum and hippocampus. MTR histogram parameters of NAGM and NAWM were correlated with EDSS and MSFC scores, with lesion volume and with normalized brain volume. We conclude that disease-induced MTR changes were small in MS NAWM and NAGM, but did correlate with clinical decline, lesion volume and overall cerebral atrophy. Multiple Sclerosis 2007; 13: 708-716. http://msj.sagepub.com

Improved detection of active multiple sclerosis lesions: 3D subtraction imaging.

PURPOSEnTo examine the benefits of using near-isotropic single-slab three-dimensional (3D) magnetic resonance (MR) imaging for the creation of subtraction images and to evaluate their performance in the detection of active multiple sclerosis (MS) brain lesions in comparison with two-dimensional (2D) subtraction images.nnnMATERIALS AND METHODSnThe study protocol was approved by the local ethics review board and all subjects gave written informed consent before investigation. Three-dimensional MR sequences, including double inversion-recovery, fluid-attenuated inversion recovery, T2-weighted, and T1-weighted magnetization-prepared rapid acquisition gradient-echo (MP-RAGE), and corresponding 2D sequences were performed twice in 14 patients (eight women, six men; mean age, 37.6 years) with MS and nine age-matched healthy control subjects (three women, six men; mean age, 31.7 years). Active lesions were scored by two independent raters, followed by a consensus reading. Lesion counts were evaluated by using negative binomial regression; interrater agreement was evaluated by using intraclass correlation coefficient.nnnRESULTSnThree-dimensional subtraction images had less residual misregistration and flow artifacts and depicted higher numbers of active lesions with greater interobserver agreement compared with 2D subtraction images. Among the 3D sequences, MP-RAGE subtraction imaging enabled detection of a significantly higher mean number of positive active MS lesions compared with 2D subtraction imaging (2.8 versus 1.7, P = .012), particularly infratentorial lesions (0.6 vs 0.1, P < .05), and a substantially higher (nonsignificant) mean number of small (<3 mm) lesions (0.6 vs 0.1, P > .05).nnnCONCLUSIONnThree-dimensional subtraction imaging, after image registration, produced better image quality, leading to increased detection of active MS lesions with greater interobserver agreement in comparison with 2D subtraction imaging; 3D MP-RAGE subtraction imaging represents a promising technique to increase sensitivity in ascertaining lesion dissemination in time and increase the power of MR imaging metrics for the evaluation of treatment effects in clinical trials.

Diffusely abnormal white matter in progressive multiple sclerosis: in vivo quantitative MR imaging characterization and comparison between disease types.

BACKGROUND AND PURPOSE: Recent postmortem studies in MS brain suggest that the severity of changes in DAWM can be measured by using quantitative MR imaging. This study aimed to characterize DAWM in vivo by using 4 quantitative MR imaging measures and to explore differences between MS disease types. MATERIALS AND METHODS: In 17 patients with chronic MS (7 PP, 10 SP), quantitative MR imaging was performed at 1.5T, yielding whole-brain voxelwise maps of T1, MTR, ADC, and FA. ROIs were placed to obtain values for DAWM, NAWM, and WM lesions. A general linear mixed-model analysis was used to compare T1, MTR, ADC, and FA between tissue types and disease types. RESULTS: Values of T1, MTR, ADC, and FA for DAWM were intermediate to those observed in NAWM and WM lesions. In patients with SPMS, DAWM was significantly different from both WM lesions and NAWM regarding all 4 measures, while in patients with PPMS, DAWM differed significantly from NAWM regarding T1, MTR, and FA and from lesions only regarding FA. Most interesting, DAWM differed between disease types: DAWM in patients with SPMS exhibited significantly higher T1 and lower MTR than did DAWM in patients with PPMS. CONCLUSIONS: In vivo T1, MTR, ADC, and FA reflect the variable severity of pathologic changes in DAWM in MS. Moreover, these quantitative MR imaging measures suggest that DAWM may differ between PPMS and SPMS.

Long-Interval T2-Weighted Subtraction Magnetic Resonance Imaging A Powerful New Outcome Measure in Multiple Sclerosis Trials

To compare long‐interval T2‐weighted subtraction (T2w‐Sub) imaging with monthly gadolinium‐enhanced T1‐weighted (Gd‐T1w) imaging for (1) detection of active lesions, (2) assessment of treatment efficacy, and (3) statistical power, in a multiple sclerosis (MS), phase 2, clinical trial setting.

Changes in functional network centrality underlie cognitive dysfunction and physical disability in multiple sclerosis

Background: Cognitive dysfunction in multiple sclerosis (MS) has a large impact on the quality of life and is poorly understood. Objective: The aim of this study was to investigate functional network integrity in MS, and relate this to cognitive dysfunction and physical disability. Methods: Resting state fMRI scans were included of 128 MS patients and 50 controls. Eigenvector centrality mapping (ECM) was applied, a graph analysis technique that ranks the importance of brain regions based on their connectivity patterns. Significant ECM changes were related to physical disability and cognitive dysfunction. Results: In MS patients, ECM values were increased in bilateral thalamus and posterior cingulate (PCC) areas, and decreased in sensorimotor and ventral stream areas. Sensorimotor ECM decreases were related to higher EDSS (rho = −0.24, p = 0.007), while ventral stream decreases were related to poorer average cognition (rho = 0.23, p = 0.009). The thalamus displayed increased connectivity to sensorimotor and ventral stream areas. Conclusion: In MS, areas in the ventral stream and sensorimotor cortex appear to become less central in the entire functional network of the brain, which is associated with clinico-cognitive dysfunction. The thalamus, however, displays increased connectivity with these areas. These findings may aid in further elucidating the function of functional reorganization processes in MS.

Perivascular spaces in MS patients at 7 Tesla MRI : A marker of neurodegeneration?

Background: Virchow-Robin spaces (VRS) are associated with vascular and neurodegenerative disease. In multiple sclerosis (MS), VRS have been associated with neuroinflammation. Ultra-high field imaging may be used to gain insight in these contradictory findings. Objective: The objective of this paper is to analyze VRS in MS patients using high-resolution 7 Tesla (T) MRI. Additionally, we investigated whether the widening of VRS is related to inflammatory or neurodegenerative aspects of MS. Methods: Thirty-four MS patients and 11 healthy controls were examined at 7T. Number and size of VRS were measured on three-dimensional (3D) T1-weighted images, and 3D fluid-attenuated inversion recovery (FLAIR) images were used for MS lesion detection. Brain atrophy was quantified by computing supratentorial brain volume fraction (sBVF). VRS counts were correlated with clinical variables, lesion count and sBVF. Results: MS patients displayed more VRS (median 11) than healthy controls (median four), p = 0.001. VRS size did not differ between both groups. VRS count in MS patients was associated with sBVF (rho = −0.40, p = 0.02), but not with lesion count (p = 0.22). Conclusions: The 7T MRI reveals increased numbers of VRS in MS. The finding that VRS are associated with supratentorial brain atrophy, but not with lesion count, suggests that VRS might rather serve as a neurodegenerative than an inflammatory marker in MS.