Nicole Mueller-Lenke

Association of regional gray matter volume loss and progression of white matter lesions in multiple sclerosis - A longitudinal voxel-based morphometry study.

Previous studies have established regional gray matter (GM) volume loss in multiple sclerosis (MS) but the relationship between development of white matter (WM) lesions and changes of regional GM volumes is unclear. The present study addresses this issue by means of voxel-based morphometry (VBM). T1-weighted three-dimensional magnetic resonance imaging (MRI) data from MS patients followed up for 12 months were analyzed using VBM. An analysis of covariance model assessed with cluster size inference (all corrected for multiple comparisons, p<0.01) was used to compare GM volumes between baseline and follow-up while controlling for age, gender, and disease duration. Lesion burden, i.e. volumes of T1 hypointense and T2 hyperintense lesions and the number of new T2 lesions at year one, was also determined. Comparing all MS patients (n=211) longitudinally, GM volume remained unchanged during one year-follow-up. Focusing on patients with relapsing remitting MS (RRMS) (n=151), significant cortical GM volume reductions between baseline and follow-up scans were found in the anterior and posterior cingulate, the temporal cortex, and cerebellum. Within the RRMS group, those patients with increasing T2 and T1 lesion burden (n=45) showed additional GM volume loss during follow-up in the frontal and parietal cortex, and precuneus. In contrast, patients lacking an increase in WM lesion burden (n=44) did not show any significant GM changes. The present study suggests that the progression of regional GM volume reductions is associated with WM lesion progression and occurs predominantly in fronto-temporal cortical areas.

Switching from natalizumab to fingolimod A randomized, placebo-controlled study in RRMS

Objective: To investigate the effect of different natalizumab washout (WO) periods on recurrence of MRI and clinical disease activity in patients switching from natalizumab to fingolimod. Methods: In this multicenter, double-blind, placebo-controlled trial (TOFINGO), patients with relapsing-remitting multiple sclerosis (RRMS) were randomized 1:1:1 to 8-, 12-, or 16-week WO followed by fingolimod treatment over 32 weeks from last natalizumab infusion (LNI). Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24. Results: Of 142 enrolled and randomized patients, 112 (78.9%) completed the study (8 weeks, n = 41/50; 12 weeks, n = 31/42; 16 weeks, n = 40/50). Number (95% confidence interval [CI]) of active (new/newly enlarged T2) lesions from LNI through 8 weeks of fingolimod treatment (primary outcome) was similar in the 8-week (2.1 [1.7–2.6]) and 12-week WO groups (1.7 [1.3–2.2]) and higher in the 16-week WO group (8.2 [7.3–9.1]). During the WO period only, the number (95% CI) of active lesions increased with increasing WO duration (8 weeks, 0.4 [0.2–0.6]; 12 weeks, 2.1 [1.6–2.6]; 16 weeks, 3.6 [3.0–4.2]). Over the 24 weeks from LNI, gadolinium-enhancing T1 lesion counts were lower in the 8-week WO group (14.1 [5.67–22.53]) than in the 12-week (21.3 [1.41–41.19]) or 16-week (18.5 [8.40–28.60]) WO groups. More patients were relapse-free in the 8-week (88%) and 12-week (91%) WO groups than the 16-week WO group (84%). Sixty-eight percent of patients experienced adverse events (mostly mild/moderate), with similar incidence across groups. No unusually severe relapses or opportunistic infections occurred. Conclusions: Initiating fingolimod therapy 8–12 weeks after natalizumab discontinuation is associated with a lower risk of MRI and clinical disease reactivation than initiation after 16-week WO. Classification of evidence: This study provides Class II evidence that for patients with RRMS switching from natalizumab to fingolimod, shorter natalizumab WO periods are associated with less MRI disease activity than are longer WO periods.

Spatiotemporal distribution pattern of white matter lesion volumes and their association with regional grey matter volume reductions in relapsing-remitting multiple sclerosis

The association of white matter (WM) lesions and grey matter (GM) atrophy is a feature in relapsing‐remitting multiple sclerosis (RRMS). The spatiotemporal distribution pattern of WM lesions, their relations to regional GM changes and the underlying dynamics are unclear. Here we combined parametric and non‐parametric voxel‐based morphometry (VBM) to clarify these issues. MRI data from RRMS patients with progressive (PLV, n = 45) and non‐progressive WM lesion volumes (NPLV, n = 44) followed up for 12 months were analysed. Cross‐sectionally, the spatial WM lesion distribution was compared using lesion probability maps (LPMs). Longitudinally, WM lesions and GM volumes were studied using FSL‐VBM and SPM5‐VBM, respectively. WM lesions clustered around the lateral ventricles and in the centrum semiovale with a more widespread pattern in the PLV than in the NPLV group. The maximum local probabilities were similar in both groups and higher for T2 lesions (PLV: 27%, NPLV: 25%) than for T1 lesions (PLV: 15%, NPLV 14%). Significant WM lesion changes accompanied by cortical GM volume reductions occured in the corpus callosum and optic radiations (P = 0.01 corrected), and more liberally tested (uncorrected P < 0.01) in the inferior fronto‐occipital and longitudinal fasciculi, and corona radiata in the PLV group. Not any WM or GM changes were found in the NPLV group. In the PLV group, WM lesion distribution and development in fibres, was associated with regional GM volume loss. The different spatiotemporal distribution patterns of patients with progressive compared to patients with non‐progressive WM lesions suggest differences in the dynamics of pathogenesis. Hum Brain Mapp, 2010.

Longitudinal gray matter changes in multiple sclerosis—Differential scanner and overall disease-related effects

Voxel‐based morphometry (VBM) has been used repeatedly in single‐center studies to investigate regional gray matter (GM) atrophy in multiple sclerosis (MS). In multi‐center trials, across‐scanner variations might interfere with the detection of disease‐specific structural abnormalities, thereby potentially limiting the use of VBM. Here we evaluated longitudinally inter‐site differences and inter‐site comparability of regional GM in MS using VBM. Baseline and follow up 3D T1‐weighted magnetic resonance imaging (MRI) data of 248 relapsing‐remitting (RR) MS patients, recruited in two clinical centers, (center1/2: n = 129/119; mean age 42.6 ± 10.7/43.3 ± 9.3; male:female 33:96/44:75; median disease duration 150 [72–222]/116 [60–156]) were acquired on two different 1.5T MR scanners. GM volume changes between baseline and year 2 while controlling for age, gender, disease duration, and global GM volume were analyzed. The main effect of time on regional GM volume was larger in data of center two as compared to center one in most of the brain regions. Differential effects of GM volume reductions occured in a number of GM regions of both hemispheres, in particular in the fronto‐temporal and limbic cortex (cluster P corrected <0.05). Overall disease‐related effects were found bilaterally in the cerebellum, uncus, inferior orbital gyrus, paracentral lobule, precuneus, inferior parietal lobule, and medial frontal gyrus (cluster P corrected <0.05). The differential effects were smaller as compared to the overall effects in these regions. These results suggest that the effects of different scanners on longitudinal GM volume differences were rather small and thus allow pooling of MR data and subsequent combined image analysis. Hum Brain Mapp, 2011.

Multivariate pattern classification of gray matter pathology in multiple sclerosis

Univariate analyses have identified gray matter (GM) alterations in different groups of MS patients. While these methods detect differences on the basis of the single voxel or cluster, multivariate methods like support vector machines (SVM) identify the complex neuroanatomical patterns of GM differences. Using multivariate linear SVM analysis and leave-one-out cross-validation, we aimed at identifying neuroanatomical GM patterns relevant for individual classification of MS patients. We used SVM to separate GM segmentations of T1-weighted three-dimensional magnetic resonance (MR) imaging scans within different age- and sex-matched groups of MS patients with either early (n=17) or late MS (n=17) (contrast I), low (n=20) or high (n=20) white matter lesion load (contrast II), and benign MS (BMS, n=13) or non-benign MS (NBMS, n=13) (contrast III) scanned on a single 1.5 T MR scanner. GM patterns most relevant for individual separation of MS patients comprised cortical areas of all the cerebral lobes as well as deep GM structures, including the thalamus and caudate. The patterns detected were sufficiently informative to separate individuals of the respective groups with high sensitivity and specificity in 85% (contrast I), 83% (contrast II) and 77% (contrast III) of cases. The study demonstrates that neuroanatomical spatial patterns of GM segmentations contain information sufficient for correct classification of MS patients at the single case level, thus making multivariate SVM analysis a promising clinical application.

Effect of immunomodulatory medication on regional gray matter loss in relapsing–remitting multiple sclerosis — a longitudinal MRI study

Prevention of global gray matter (GM) volume changes in multiple sclerosis (MS) are an objective in clinical trials, but the effect of immunomodulatory medication on regional GM atrophy progression is unclear. MRIs from 86 patients with relapsing-remitting MS (RRMS) followed up for 24 months were analyzed using voxel-based morphometry. An analysis of covariance model (cluster threshold, corrected p<0.05) was used to compare GM volumes between baseline and follow-up while stratified by immunomodulatory medication (IM): Interferone INF-beta-1a (n=34), INF-beta-1b (n=16), glatiramer acetate (GA) (n=15), and no-immunomodulatory treatment (n=21). In the INF-beta-1a/1b group (n=50), significant GM volume reductions were observed during follow-up in fronto-temporal, cingulate and cerebellar cortical brain regions, without significant differences between the INF-beta-1a and INF-beta-1b patients. In the GA group and in unmedicated patients, no significant regional GM volume reductions were observed. In contrast to GA, INF-beta-1a/1b treatment was associated with GM volume reductions in hippocampal/parahippocampal and anterior cingulate cortex. This is the first longitudinal study investigating the effects of IMs on GM in RRMS. Results suggest differences in the dynamics of regional GM volume atrophy in differentially treated or untreated RRMS patients.

Progression in disability and regional grey matter atrophy in relapsing-remitting multiple sclerosis.

Background: In multiple sclerosis (MS) regional grey matter (GM) atrophy has been associated with disability progression. Objective: The aim of this study was to compare regional GM volume changes in relapsing–remitting MS (RRMS) patients with progressive and stable disability, using voxel-based morphometry (VBM). Methods: We acquired baseline and 1-year follow-up 3-dimensional (3D) T1-weighted magnetic resonance imaging (MRI) data of RRMS patients, using two 1.5-Tesla scanners. Patients were matched pair-wise with respect to age, gender, disease duration, medication, scanner and baseline Expanded Disability Status Scale (EDSS) into 13 pairs, with either progressive EDSS (≥ 1 point change y-1) or stable EDSS, as well as into 29 pairs with either progressive Multiple Sclerosis Functional Composite (MSFC) at ≥ 0.25% decrease in y-1 in any component, or stable MSFC. We analysed longitudinal regional differences in GM volumes in the progressive and stable EDSS and MSFC groups, respectively, using VBM. Results: Significant GM volume reductions occurred in the right precuneus, in the progressive EDSS group. Differential between-group effects occurred in the right precuneus and in the postcentral gyrus. Further longitudinal GM volume reductions occurred in the right orbicular gyrus, in the progressive MSFC group, but no between-group differences were observed (non-stationary cluster-wise inference, all Pcorrected < 0.05). Conclusion: These results suggested a direct association of disability progression and regional GM atrophy in RRMS.

3D GRASE arterial spin labelling reveals an inverse correlation of cortical perfusion with the white matter lesion volume in MS

Background: We hypothesized that in multiple sclerosis (MS) patients, reduced cortical perfusion is associated with chronic white matter injury. Objective: To investigate the influence of different clinical and magnetic resonance imaging characteristics on cortical perfusion. Methods: Cerebral blood flow (CBF) was assessed by applying a pulsed arterial spin labelling (ASL) technique combined with single-shot 3D-GRASE (gradient-spin echo) in a cohort of 165 MS patients with a relapsing–remitting (n=123) or secondary progressive disease course (n=42). Mean age was 45.4 years (20–68 years), mean disease duration was 14.2 years (1–48 years). Results: Mean cortical CBF was 45.6 ml/100g per min (SD: 7.8 ml/100g per min). Stepwise multiple linear regression models were calculated to investigate the relationship between different factor sets and mean CBF. The model with the highest adjusted coefficient of determination included T2 lesion load, age, gender and disease duration as significant factors. Post-hoc Spearman rank correlation revealed significant correlation of adjusted CBF with T2 lesion load (t=−0.35, p=1*10–6), with age (t =−0.34, p=4*10–6), and with disease duration (t=0.16, p=0.03), while Expanded Disability Status Scale (EDSS) did not reach significance in either model. Conclusion: This study suggests that the amount of white matter lesions indicates a reduced metabolic demand and reduced perfusion at a cortical level.

Spatiotemporal distribution of white matter lesions in relapsing-remitting and secondary progressive multiple sclerosis

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. MS lesions show a typical distribution pattern and primarily affect the white matter (WM) in the periventricular zone and in the centrum semiovale. Objective: To track lesion development during disease progression, we compared the spatiotemporal distribution patterns of lesions in relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS). Methods: We used T1 and T2 weighted MR images of 209 RRMS and 62 SPMS patients acquired on two different 1.5 Tesla MR scanners in two clinical centers followed up for 25 (± 1.7) months. Both cross-sectional and longitudinal differences in lesion distribution between RRMS and SPMS patients were analyzed with lesion probability maps (LPMs) and permutation-based inference. Results: MS lesions clustered around the lateral ventricles and in the centrum semiovale. Cross-sectionally, compared to RRMS patients, the SPMS patients showed a significantly higher regional probability of T1 hypointense lesions (p≤0.03) in the callosal body, the corticospinal tract, and other tracts adjacent to the lateral ventricles, but not of T2 lesions (peak probabilities were RRMS: T1 9%, T2 18%; SPMS: T1 21%, T2 27%). No longitudinal changes of regional T1 and T2 lesion volumes between baseline and follow-up scan were found. Conclusion: The results suggest a particular vulnerability to neurodegeneration during disease progression in a number of WM tracts.

Teriflunomide slows BVL in relapsing MS

Objective: To assess, using structural image evaluation using normalization of atrophy (SIENA), the effect of teriflunomide, a once-daily oral immunomodulator, on brain volume loss (BVL) in patients with relapsing forms of MS enrolled in the phase 3 TEMSO study. Methods: TEMSO MR scans were analyzed (study personnel masked to treatment allocation) using SIENA to assess brain volume changes between baseline and years 1 and 2 in patients treated with placebo or teriflunomide. Treatment group comparisons were made via rank analysis of covariance. Results: Data from 969 patient MRI visits were included in this analysis: 808 patients had baseline and year 1 MRI; 709 patients had baseline and year 2 MRI. Median percentage BVL from baseline to year 1 and year 2 for placebo was 0.61% and 1.29%, respectively, and for teriflunomide 14 mg, 0.39% and 0.90%, respectively. BVL was lower for teriflunomide 14 mg vs placebo at year 1 (36.9% relative reduction, p = 0.0001) and year 2 (30.6% relative reduction, p = 0.0001). Teriflunomide 7 mg was also associated with significant reduction in BVL vs placebo over the 2-year study. The significant effects of teriflunomide 14 mg on BVL were observed in both patients with and without on-study disability worsening. Conclusions: The significant reduction of BVL vs placebo over 2 years achieved with teriflunomide is consistent with its effects on delaying disability worsening and suggests a neuroprotective potential. Classification of evidence: Class II evidence shows that teriflunomide treatment significantly reduces BVL over 2 years vs placebo. ClinicalTrials.gov identifier: NCT00134563.