Ludwig Kappos

YNICL Journal 2025 Journal Article

TIME: Tractography-Informed myelin estimation

• Sara Bosticardo
• Matteo Battocchio
• Mario Ocampo-Pineda
• Alessandro Cagol
• Po- Jui Lu
• Esther Ruberte
• Nina De Oliveira S. Siebenborn
• Xinjie Chen

Investigating myelin integrity within multiple sclerosis (MS) lesions and in normal-appearing white matter is crucial for understanding demyelination and remyelination processes. While most approaches assess global myelin changes or compare lesions with homologous regions in healthy controls, they do not allow direct within-tract comparisons between lesional and non-lesional tissue. We introduce the tractography-informed myelin estimate (TIME), a novel map designed to quantify tract-specific myelin loss. TIME integrates tractography with myelin-sensitive imaging, such as myelin volume fraction, to compare lesional and non-lesional segments within the same white matter tract. By modeling local deviations from the expected myelin volume fraction signal along streamlines, TIME captures tract-specific myelin damage while accounting for within-tract variability. TIME is based on a microstructure-informed tractography framework, with an extra compartment to model signal loss caused by lesions. We evaluated TIME in 159 MS patients, assessing its association with neurological disability at baseline and longitudinally over a median follow-up of two years. At baseline, higher myelin loss captured by TIME was significantly associated with worse disability (β = 0.14, p = 0.015). Longitudinally, greater baseline disability predicted faster TIME-quantified myelin loss, which was in turn associated with a higher risk of disability worsening. In contrast, lesion-averaged myelin volume fraction showed no significant associations with either baseline disability or its progression. TIME provides a detailed, tract-specific assessment of myelin damage, providing greater sensitivity than conventional metrics, highlighting its potential as a biomarker in MS.

YNICL Journal 2023 Journal Article

Personalized maps of T1 relaxometry abnormalities provide correlates of disability in multiple sclerosis patients

• Xinjie Chen
• Sabine Schädelin
• Po-Jui Lu
• Mario Ocampo-Pineda
• Matthias Weigel
• Muhamed Barakovic
• Esther Ruberte
• Alessandro Cagol

OBJECTIVES AND AIMS: Quantitative MRI (qMRI) has greatly improved the sensitivity and specificity of microstructural brain pathology in multiple sclerosis (MS) when compared to conventional MRI (cMRI). More than cMRI, qMRI also provides means to assess pathology within the normal-appearing and lesion tissue. In this work, we further developed a method providing personalized quantitative T1 (qT1) abnormality maps in individual MS patients by modeling the age dependence of qT1 alterations. In addition, we assessed the relationship between qT1 abnormality maps and patients' disability, in order to evaluate the potential value of this measurement in clinical practice. METHODS: We included 119 MS patients (64 relapsing-remitting MS (RRMS), 34 secondary progressive MS (SPMS), 21 primary progressive MS (PPMS)), and 98 Healthy Controls (HC). All individuals underwent 3T MRI examinations, including Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) for qT1 maps and High-Resolution 3D Fluid Attenuated Inversion Recovery (FLAIR) imaging. To calculate personalized qT1 abnormality maps, we compared qT1 in each brain voxel in MS patients to the average qT1 obtained in the same tissue (grey/white matter) and region of interest (ROI) in healthy controls, hereby providing individual voxel-based Z-score maps. The age dependence of qT1 in HC was modeled using linear polynomial regression. We computed the average qT1 Z-scores in white matter lesions (WMLs), normal-appearing white matter (NAWM), cortical grey matter lesions (GMcLs) and normal-appearing cortical grey matter (NAcGM). Lastly, a multiple linear regression (MLR) model with the backward selection including age, sex, disease duration, phenotype, lesion number, lesion volume and average Z-score (NAWM/NAcGM/WMLs/GMcLs) was used to assess the relationship between qT1 measures and clinical disability (evaluated with EDSS). RESULTS: = 0.099, β = 0.269, 97.5 % CI = 0.078 to 0.461, p = 0.007). CONCLUSIONS: We showed that personalized qT1 abnormality maps in MS patients provide measures related to clinical disability, supporting the use of those maps in clinical practice.

YNICL Journal 2023 Journal Article

The spatio-temporal relationship between concurrent lesion and brain atrophy changes in early multiple sclerosis: A post-hoc analysis of the REFLEXION study

• Giordano Gentile
• Rozemarijn M. Mattiesing
• Iman Brouwer
• Ronald A. van Schijndel
• Bernard M.J. Uitdehaag
• Jos W.R. Twisk
• Ludwig Kappos
• Mark S. Freedman

BACKGROUND: White matter (WM) lesions and brain atrophy are present early in multiple sclerosis (MS). However, their spatio-temporal relationship remains unclear. METHODS: Yearly magnetic resonance images were analysed in 387 patients with a first clinical demyelinating event (FCDE) from the 5-year REFLEXION study. Patients received early (from baseline; N = 258; ET) or delayed treatment (from month-24; N = 129; DT) with subcutaneous interferon beta-1a. FSL-SIENA/VIENA were used to provide yearly percentage volume change of brain (PBVC) and ventricles (PVVC). Yearly total lesion volume change (TLVC) was determined by a semi-automated method. Using linear mixed models and voxel-wise analyses, we firstly investigated the overall relationship between TLVC and PBVC and between TLVC and PVVC in the same follow-up period. Analyses were then separately performed for: the untreated period of DT patients (first two years), the first year of treatment (year 1 for ET and year 3 for DT), and a period where patients had received at least 1 year of treatment (stable treatment; ET: years 2, 3, 4, and 5; DT: years 4 and 5). RESULTS: Whole brain: across the whole study period, lower TLVC was related to faster atrophy (PBVC: B = 0.046, SE = 0.013, p < 0.001; PVVC: B = -0.466, SE = 0.118, p < 0.001). Within the untreated period of DT patients, lower TLVC was related to faster atrophy (PBVC: B = 0.072, SE = 0.029, p = 0.013; PVVC: B = -0.917, SE = 0.306, p = 0.003). A similar relationship was found within the first year of treatment of ET patients (PBVC: B = 0.081, SE = 0.027, p = 0.003; PVVC: B = -1.08, SE = 0.284, p < 0.001), consistent with resolving oedema and pseudo-atrophy. Voxel-wise: overall, higher TLVC was related to faster ventricular enlargement. Lower TLVC was related to faster widespread atrophy in year 1 in both ET (first year of treatment) and DT (untreated) patients. In the second untreated year of DT patients and within the stable treatment period of ET patients (year 4), faster periventricular and occipital lobe atrophy was associated with higher TLVC. CONCLUSIONS: WM lesion changes and atrophy occurred simultaneously in early MS. Spatio-temporal correspondence of these two processes involved mostly the periventricular area. Within the first year of the study, in both treatment groups, faster atrophy was linked to lower lesion volume changes, consistent with higher shrinking and disappearing lesion activity. This might reflect the pseudo-atrophy phenomenon that is probably related to the therapy driven (only in ET patients, as they received treatment from baseline) and "natural" (both ET and DT patients entered the study after a FCDE) resolution of oedema. In an untreated period and later on during stable treatment, (real) atrophy was related to higher lesion volume changes, consistent with increased new and enlarging lesion activity.

YNICL Journal 2022 Journal Article

A comparative assessment of myelin-sensitive measures in multiple sclerosis patients and healthy subjects

• Reza Rahmanzadeh
• Matthias Weigel
• Po-Jui Lu
• Lester Melie-Garcia
• Thanh D. Nguyen
• Alessandro Cagol
• Francesco La Rosa
• Muhamed Barakovic

INTRODUCTION: Multiple Sclerosis (MS) is a common neurological disease primarily characterized by myelin damage in lesions and in normal - appearing white and gray matter (NAWM, NAGM). Several quantitative MRI (qMRI) methods are sensitive to myelin characteristics by measuring specific tissue biophysical properties. However, there are currently few studies assessing the relative reproducibility and sensitivity of qMRI measures to MS pathology in vivo in patients. METHODS: We performed two studies. The first study assessed of the sensitivity of qMRI measures to MS pathology: in this work, we recruited 150 MS and 100 healthy subjects, who underwent brain MRI at 3 T including quantitative T1 mapping (qT1), quantitative susceptibility mapping (QSM), magnetization transfer saturation imaging (MTsat) and myelin water imaging for myelin water fraction (MWF). The sensitivity of qMRIs to MS focal pathology (MS lesions vs peri-plaque white/gray matter (PPWM/PPGM)) was studied lesion-wise; the sensitivity to diffuse normal appearing (NA) pathology was measured using voxel-wise threshold-free cluster enhancement (TFCE) in NAWM and vertex-wise inflated cortex analysis in NAGM. Furthermore, the sensitivity of qMRI to the identification of lesion tissue was investigated using a voxel-wise logistic regression analysis to distinguish MS lesion and PP voxels. The second study assessed the reproducibility of myelin-sensitive qMRI measures in a single scanner. To evaluate the intra-session and inter-session reproducibility of qMRI measures, we have investigated 10 healthy subjects, who underwent two brain 3 T MRIs within the same day (without repositioning), and one after 1-week interval. Five region of interest (ROIs) in white and deep grey matter areas were segmented, and inter- and intra- session reproducibility was studied using the intra-class correlation coefficient (ICC). Further, we also investigated the voxel-wise reproducibility of qMRI measures in NAWM and NAGM. RESULTS: qT1 and QSM showed the highest sensitivity to distinguish MS focal WM and cortical pathology from peri-plaque WM (P < 0.0001), although QSM also showed the highest variance when applied to lesions. MWF and MTsat exhibited the highest sensitivity to NAWM pathology (P < 0.01). On the other hand, qT1 appeared to be the most sensitive measure to NAGM pathology (P < 0.01). All myelin-sensitive qMRI measures exhibited high inter/intra sessional ICCs in various WM and deep GM ROIs, in NAWM and in NAGM (ICC 0.82 ± 0.12). CONCLUSION: This work shows that the applied qT1, MWF, MTsat and QSM are highly reproducible and exhibit differential sensitivity to focal and diffuse WM and GM pathology in MS patients.

YNICL Journal 2022 Journal Article

Brain atrophy measurement over a MRI scanner change in multiple sclerosis

• Tim Sinnecker
• Sabine Schädelin
• Pascal Benkert
• Esther Ruberte
• Michael Amann
• Johanna M. Lieb
• Yvonne Naegelin
• Jannis Müller

BACKGROUND: A change in MRI hardware impacts brain volume measurements. The aim of this study was to use MRI data from multiple sclerosis (MS) patients and healthy control subjects (HCs) to statistically model how to adjust brain atrophy measures in MS patients after a major scanner upgrade. METHODS: We scanned 20 MS patients and 26 HCs before and three months after a major scanner upgrade (1.5 T Siemens Healthineers Magnetom Avanto to 3 T Siemens Healthineers Skyra Fit). The patient group also underwent standardized serial MRIs before and after the scanner change. Percentage whole brain volume changes (PBVC) measured by Structural Image Evaluation using Normalization of Atrophy (SIENA) in the HCs was used to estimate a corrective term based on a linear model. The factor was internally validated in HCs, and then applied to the MS group. RESULTS: Mean PBVC during the scanner change was higher in MS than HCs (-4.1 ± 0.8 % versus -3.4 ± 0.6 %). A fixed corrective term of 3.4 (95% confidence interval: 3.13-3.67)% was estimated based on the observed average changes in HCs. Age and gender did not have a significant influence on this corrective term. After adjustment, a linear mixed effects model showed that the brain atrophy measures in MS during the scanner upgrade were not anymore associated with the scanner type (old vs new scanner; p = 0.29). CONCLUSION: A scanner change affects brain atrophy measures in longitudinal cohorts. The inclusion of a corrective term based on changes observed in HCs helps to adjust for the known and unknown factors associated with a scanner upgrade on a group level.

YNIMG Journal 2022 Journal Article

Bundle myelin fraction (BMF) mapping of different white matter connections using microstructure informed tractography

• Simona Schiavi
• Po-Jui Lu
• Matthias Weigel
• Antoine Lutti
• Derek K. Jones
• Ludwig Kappos
• Cristina Granziera
• Alessandro Daducci

To date, we have scarce information about the relative myelination level of different fiber bundles in the human brain. Indirect evidence comes from postmortem histology data but histological stainings are unable to follow a specific bundle and determine its intrinsic myelination. In this context, quantitative MRI, and diffusion MRI tractography may offer a viable solution by providing, respectively, voxel-wise myelin sensitive maps and the pathways of the major tracts of the brain. Then, "tractometry" can be used to combine these two pieces of information by averaging tissue features (obtained from any voxel-wise map) along the streamlines recovered with diffusion tractography. Although this method has been widely used in the literature, in cases of voxels containing multiple fiber populations (each with different levels of myelination), tractometry provides biased results because the same value will be attributed to any bundle passing through the voxel. To overcome this bias, we propose a new method - named "myelin streamline decomposition" (MySD) - which extends convex optimization modeling for microstructure informed tractography (COMMIT) allowing the actual value measured by a microstructural map to be deconvolved on each individual streamline, thereby recovering unique bundle-specific myelin fractions (BMFs). We demonstrate the advantage of our method with respect to tractometry in well-studied bundles and compare the cortical projection of the obtained bundle-wise myelin values of both methods. We also prove the stability of our approach across different subjects and different MRI sensitive myelin mapping approaches. This work provides a proof-of-concept of in vivo investigations of entire neuronal pathways that, to date, are not possible.

YNICL Journal 2022 Journal Article

Longitudinal changes of deep gray matter shape in multiple sclerosis

• Charidimos Tsagkas
• Emanuel Geiter
• Laura Gaetano
• Yvonne Naegelin
• Michael Amann
• Katrin Parmar
• Athina Papadopoulou
• Jens Wuerfel

OBJECTIVE: This study aimed to investigate longitudinal deep gray matter (DGM) shape changes and their relationship with measures of clinical disability and white matter lesion-load in a large multiple sclerosis (MS) cohort. MATERIALS AND METHODS: A total of 230 MS patients (179 relapsing-remitting, 51 secondary progressive; baseline age 44.5 ± 11.3 years; baseline disease duration 12.99 ± 9.18) underwent annual clinical and MRI examinations over a maximum of 6 years (mean 4.32 ± 2.07 years). The DGM structures were segmented on the T1-weighted images using the "Multiple Automatically Generated Templates" brain algorithm. White matter lesion-load was measured on T2-weighted MRI. Clinical examination included the expanded disability status scale, 9-hole peg test, timed 25-foot walk test, symbol digit modalities test and paced auditory serial addition test. Vertex-wise longitudinal analysis of DGM shapes was performed using linear mixed effect models and evaluated the association between average/temporal changes of DGM shapes with average/temporal changes of clinical measurements, respectively. RESULTS: A significant shrinkage over time of the bilateral ventrolateral pallidal and the left posterolateral striatal surface was observed, whereas no significant shape changes over time were observed at the bilateral thalamic and right striatal surfaces. Higher average lesion-load was associated with an average inwards displacement of the global thalamic surface with relative sparing on the posterior side (slight left-side predominance), the antero-dorso-lateral striatal surfaces bilaterally (symmetric on both sides) and the antero-lateral pallidal surface (left-side predominance). There was also an association between shrinkage of large lateral DGM surfaces with higher clinical motor and cognitive disease severity. However, there was no correlation between any DGM shape changes over time and measurements of clinical progression or lesion-load changes over time. CONCLUSIONS: This study showed specific shape change of DGM structures occurring over time in relapse-onset MS. Although these shape changes over time were not associated with disease progression, we demonstrated a link between DGM shape and the patients' average disease severity as well as white matter lesion-load.

YNICL Journal 2022 Journal Article

The spatio-temporal relationship between white matter lesion volume changes and brain atrophy in clinically isolated syndrome and early multiple sclerosis

• Rozemarijn M. Mattiesing
• Giordano Gentile
• Iman Brouwer
• Ronald A. van Schijndel
• Bernard M.J. Uitdehaag
• Jos W.R. Twisk
• Ludwig Kappos
• Mark S. Freedman

BACKGROUND: White matter lesions and brain atrophy are both present early in multiple sclerosis. However, the spatio-temporal relationship between atrophy and lesion processes remains unclear. METHODS: Yearly magnetic resonance images were analyzed in 392 patients with clinically isolated syndrome from the 5-year REFLEX/REFLEXION studies. Patients received early treatment (from baseline; N = 262) or delayed treatment (from month-24; N = 130) with subcutaneous interferon beta-1a. Global and central atrophy were assessed using FSL-SIENA to provide yearly percentage volume change of brain and ventricles, respectively. Yearly total lesion volume change was calculated by subtracting the sum of the negative lesion volume change (disappearing + shrinking) from the positive lesion volume change (new + enlarging) for each yearly interval, as determined by an in-house developed semi-automated method. Using linear mixed models, during the period where patients had received ≥1 year of treatment, we investigated whether total lesion volume change was associated with percentage brain volume change or percentage ventricular volume change in the next year, and vice versa. RESULTS: Higher total lesion volume change was related to significantly faster global atrophy (percentage brain volume change) in the next year (B = - 0.113, SE = 0.022, p < 0.001). In patients receiving early treatment only, total lesion volume change was also associated with percentage ventricular volume change in the next year (B = 1.348, SE = 0.181, p < 0.001). Voxel-wise analyses showed that in patients receiving early treatment, higher total lesion volume change in years 2, 3, and 4 was related to faster atrophy in the next year, and in year 4 this relationship was stronger in patients receiving delayed treatment. Interestingly, faster atrophy was related to higher total lesion volume change in the next year (percentage brain volume change: B = - 0.136, SE = 0.062, p = 0.028; percentage ventricular volume change: B = 0.028, SE = 0.008, p < 0.001). CONCLUSIONS: Higher lesion volume changes were associated with faster atrophy in the next year. Interestingly, there was also an association between faster atrophy and higher lesion volume changes in the next year.

YNICL Journal 2021 Journal Article

Development and evaluation of a manual segmentation protocol for deep grey matter in multiple sclerosis: Towards accelerated semi-automated references

• Alexandra de Sitter
• Jessica Burggraaff
• Fabian Bartel
• Miklos Palotai
• Yaou Liu
• Jorge Simoes
• Serena Ruggieri
• Katharina Schregel

BACKGROUND: Deep grey matter (dGM) structures, particularly the thalamus, are clinically relevant in multiple sclerosis (MS). However, segmentation of dGM in MS is challenging; labeled MS-specific reference sets are needed for objective evaluation and training of new methods. OBJECTIVES: This study aimed to (i) create a standardized protocol for manual delineations of dGM; (ii) evaluate the reliability of the protocol with multiple raters; and (iii) evaluate the accuracy of a fast-semi-automated segmentation approach (FASTSURF). METHODS: A standardized manual segmentation protocol for caudate nucleus, putamen, and thalamus was created, and applied by three raters on multi-center 3D T1-weighted MRI scans of 23 MS patients and 12 controls. Intra- and inter-rater agreement was assessed through intra-class correlation coefficient (ICC); spatial overlap through Jaccard Index (JI) and generalized conformity index (CIgen). From sparse delineations, FASTSURF reconstructed full segmentations; accuracy was assessed both volumetrically and spatially. RESULTS: All structures showed excellent agreement on expert manual outlines: intra-rater JI > 0.83; inter-rater ICC ≥ 0.76 and CIgen ≥ 0.74. FASTSURF reproduced manual references excellently, with ICC ≥ 0.97 and JI ≥ 0.92. CONCLUSIONS: The manual dGM segmentation protocol showed excellent reproducibility within and between raters. Moreover, combined with FASTSURF a reliable reference set of dGM segmentations can be produced with lower workload.

YNICL Journal 2021 Journal Article

GAMER MRI: Gated-attention mechanism ranking of multi-contrast MRI in brain pathology

• Po-Jui Lu
• Youngjin Yoo
• Reza Rahmanzadeh
• Riccardo Galbusera
• Matthias Weigel
• Pascal Ceccaldi
• Thanh D. Nguyen
• Pascal Spincemaille

INTRODUCTION: During the last decade, a multitude of novel quantitative and semiquantitative MRI techniques have provided new information about the pathophysiology of neurological diseases. Yet, selection of the most relevant contrasts for a given pathology remains challenging. In this work, we developed and validated a method, Gated-Attention MEchanism Ranking of multi-contrast MRI in brain pathology (GAMER MRI), to rank the relative importance of MR measures in the classification of well understood ischemic stroke lesions. Subsequently, we applied this method to the classification of multiple sclerosis (MS) lesions, where the relative importance of MR measures is less understood. METHODS: GAMER MRI was developed based on the gated attention mechanism, which computes attention weights (AWs) as proxies of importance of hidden features in the classification. In the first two experiments, we used Trace-weighted (Trace), apparent diffusion coefficient (ADC), Fluid-Attenuated Inversion Recovery (FLAIR), and T1-weighted (T1w) images acquired in 904 acute/subacute ischemic stroke patients and in 6,230 healthy controls and patients with other brain pathologies to assess if GAMER MRI could produce clinically meaningful importance orders in two different classification scenarios. In the first experiment, GAMER MRI with a pretrained convolutional neural network (CNN) was used in conjunction with Trace, ADC, and FLAIR to distinguish patients with ischemic stroke from those with other pathologies and healthy controls. In the second experiment, GAMER MRI with a patch-based CNN used Trace, ADC and T1w to differentiate acute ischemic stroke lesions from healthy tissue. The last experiment explored the performance of patch-based CNN with GAMER MRI in ranking the importance of quantitative MRI measures to distinguish two groups of lesions with different pathological characteristics and unknown quantitative MR features. Specifically, GAMER MRI was applied to assess the relative importance of the myelin water fraction (MWF), quantitative susceptibility mapping (QSM), T1 relaxometry map (qT1), and neurite density index (NDI) in distinguishing 750 juxtacortical lesions from 242 periventricular lesions in 47 MS patients. Pair-wise permutation t-tests were used to evaluate the differences between the AWs obtained for each quantitative measure. RESULTS: In the first experiment, we achieved a mean test AUC of 0.881 and the obtained AWs of FLAIR and the sum of AWs of Trace and ADC were 0.11 and 0.89, respectively, as expected based on previous knowledge. In the second experiment, we achieved a mean test F1 score of 0.895 and a mean AW of Trace = 0.49, of ADC = 0.28, and of T1w = 0.23, thereby confirming the findings of the first experiment. In the third experiment, MS lesion classification achieved test balanced accuracy = 0.777, sensitivity = 0.739, and specificity = 0.814. The mean AWs of T1map, MWF, NDI, and QSM were 0.29, 0.26, 0.24, and 0.22 (p < 0.001), respectively. CONCLUSIONS: This work demonstrates that the proposed GAMER MRI might be a useful method to assess the relative importance of MRI measures in neurological diseases with focal pathology. Moreover, the obtained AWs may in fact help to choose the best combination of MR contrasts for a specific classification problem.

YNIMG Journal 2019 Journal Article

Clinical associations of T2-weighted lesion load and lesion location in small vessel disease: Insights from a large prospective cohort study

• Anna Altermatt
• Laura Gaetano
• Stefano Magon
• Lorena Bauer
• Regina Feurer
• Hans Gnahn
• Julia Hartmann
• Christian L. Seifert

Background Subcortical T2-weighted (T2w) lesions are very common in older adults and have been associated with dementia. However, little is known about the strategic lesion distribution and how lesion patterns relate to vascular risk factors and cognitive impairment. Aim The aim of this study was to analyze the association between T2w lesion load and location, vascular risk factors, and cognitive impairment in a large cohort of older adults. Methods 1017 patients participating in a large prospective cohort study (INtervention project on cerebroVAscular disease and Dementia in the district of Ebersberg, INVADE II) were analyzed. Cerebral T2w white matter and deep grey matter lesions, the so-called white matter hyperintensities (WMHs), were outlined semi-automatically on fluid attenuated inversion recovery images and normalized to standard stereotaxic space (MNI152) by non-linear registration. Patients were assigned to either a low-risk or a high-risk group. The risk assessment considered ankle brachial index, intima media thickness, carotid artery stenosis, atrial fibrillation, previous cerebro-/cardiovascular events and peripheral artery disease as well as a score based on cholesterol levels, blood pressure and smoking. Separate lesion distributions were obtained for the two risk groups and compared using voxel-based lesion-symptom mapping. Moreover, we assessed the relation between lesion location and cognitive impairment (demographically adjusted z-scores of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery Plus, CERAD-NAB Plus) using voxel-based statistics (α = 0. 05). Results A total of 878 out of 1017 subjects (86%) had evaluable MRI data and were included in the analyses (mean age: 68. 2 ± 7. 6 years, female: 515). Patients in the high-risk group were characterized by a significantly higher age, a higher proportion of men, a higher lesion load (p < 0. 001), and a worse performance in some of the cognitive subdomain scores (p < 0. 05). Voxels with significant associations to the subjects' cerebrovascular risk profiles were mainly found at locations of the corpus callosum, superior corona radiata, superior longitudinal fasciculus, internal and external capsule, and putamen. While several cognitive domains have shown significant associations with the participants’ total lesion burden (p < 0. 05), no focal WMH locations were found to be associated with cognitive impairment. Conclusion Age, gender, several cognitive scores, and WMH lesion load were shown to be significantly associated with vascular risk factors in a population of older, but cognitively preserved adults. Vascular risk factors seem to promote lesion formation most severely at well-defined locations. While lesion load showed weak associations to some cognitive scores, no focal locations causing specific cognitive disturbances were identified in this large cohort of older adults.

YNIMG Journal 2017 Journal Article

Performance of five research-domain automated WM lesion segmentation methods in a multi-center MS study

• Alexandra de Sitter
• Martijn D. Steenwijk
• Aurélie Ruet
• Adriaan Versteeg
• Yaou Liu
• Ronald A. van Schijndel
• Petra J.W. Pouwels
• Iris D. Kilsdonk

Background and Purpose In vivoidentification of white matter lesions plays a key-role in evaluation of patients with multiple sclerosis (MS). Automated lesion segmentation methods have been developed to substitute manual outlining, but evidence of their performance in multi-center investigations is lacking. In this work, five research-domain automated segmentation methods were evaluated using a multi-center MS dataset. Methods 70 MS patients (median EDSS of 2. 0 [range 0. 0–6. 5]) were included from a six-center dataset of the MAGNIMS Study Group (www. magnims. eu) which included 2D FLAIR and 3D T1 images with manual lesion segmentation as a reference. Automated lesion segmentations were produced using five algorithms: Cascade; Lesion Segmentation Toolbox (LST) with both the Lesion growth algorithm (LGA) and the Lesion prediction algorithm (LPA); Lesion-Topology preserving Anatomical Segmentation (Lesion-TOADS); and k-Nearest Neighbor with Tissue Type Priors (kNN-TTP). Main software parameters were optimized using a training set (N = 18), and formal testing was performed on the remaining patients (N = 52). To evaluate volumetric agreement with the reference segmentations, intraclass correlation coefficient (ICC) as well as mean difference in lesion volumes between the automated and reference segmentations were calculated. The Similarity Index (SI), False Positive (FP) volumes and False Negative (FN) volumes were used to examine spatial agreement. All analyses were repeated using a leave-one-center-out design to exclude the center of interest from the training phase to evaluate the performance of the method on ‘unseen’ center. Results Compared to the reference mean lesion volume (4. 85 ± 7. 29 mL), the methods displayed a mean difference of 1. 60 ± 4. 83 (Cascade), 2. 31 ± 7. 66 (LGA), 0. 44 ± 4. 68 (LPA), 1. 76 ± 4. 17 (Lesion-TOADS) and −1. 39 ± 4. 10 mL (kNN-TTP). The ICCs were 0. 755, 0. 713, 0. 851, 0. 806 and 0. 723, respectively. Spatial agreement with reference segmentations was higher for LPA (SI = 0. 37 ± 0. 23), Lesion-TOADS (SI = 0. 35 ± 0. 18) and kNN-TTP (SI = 0. 44 ± 0. 14) than for Cascade (SI = 0. 26 ± 0. 17) or LGA (SI = 0. 31 ± 0. 23). All methods showed highly similar results when used on data from a center not used in software parameter optimization. Conclusion The performance of the methods in this multi-center MS dataset was moderate, but appeared to be robust even with new datasets from centers not included in training the automated methods.

YNIMG Journal 2016 Journal Article

Power estimation for non-standardized multisite studies

• Anisha Keshavan
• Friedemann Paul
• Mona K. Beyer
• Alyssa H. Zhu
• Nico Papinutto
• Russell T. Shinohara
• William Stern
• Michael Amann

A concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this assumption, we provide a new statistical framework and derive a power equation to define inclusion criteria for a set of sites based on the variability of their scaling factors. We estimated the scaling factors of 20 scanners with heterogeneous hardware and sequence parameters by scanning a single set of 12 subjects at sites across the United States and Europe. Regional volumes and their scaling factors were estimated for each site using Freesurfer's segmentation algorithm and ordinary least squares, respectively. The scaling factors were validated by comparing the theoretical and simulated power curves, performing a leave-one-out calibration of regional volumes, and evaluating the absolute agreement of all regional volumes between sites before and after calibration. Using our derived power equation, we were able to define the conditions under which harmonization is not necessary to achieve 80% power. This approach can inform choice of processing pipelines and outcome metrics for multisite studies based on scaling factor variability across sites, enabling collaboration between clinical and research institutions.

YNIMG Journal 2015 Journal Article

Comparison between balanced steady-state free precession and standard spoiled gradient echo magnetization transfer ratio imaging in multiple sclerosis: methodical and clinical considerations

• Michael Amann
• Till Sprenger
• Yvonne Naegelin
• Julia Reinhardt
• Pascal Kuster
• Jochen G. Hirsch
• Ludwig Kappos
• Ernst-Wilhelm Radue

Different pathological processes like demyelination and axonal loss can alter the magnetisation transfer ratio (MTR) in brain tissue. The standard method to measure this effect is to scan the respective tissue twice, one with and one without a specific saturation pulse. A major drawback of this technique based on spoiled gradient echo (GRE) sequences relates to its long acquisition time due to the saturation pulses. Recently, an alternative concept for MT imaging based on balanced steady state free precession (bSSFP) has been proposed. Modification of the duration of the radiofrequency pulses for imaging allows scanning MT sensitive and non-sensitive images. The steady-state character of bSSFP with high intrinsic signal-to-noise ratio (SNR) allows three-dimensional (3D) whole brain MTR at high spatial resolution within short and thus clinically feasible acquisition times. In the present study, both bSSFP-MT and 2D GRE-MT imaging were used in a cohort of 31 patients with multiple sclerosis (MS) to characterize different normal appearing (NA) and pathological brain structures. Under the constraint of identical SNR and scan time, a 3. 4 times higher voxel size could be achieved with bSSFP. This increased resolution allowed a more accurate delineation of the different brain structures, especially of cortex, hippocampus and MS lesions. In a multiple linear regression model, we found an association between MTR of cortical lesions and a clinical measure of disability (r= −0. 407, p=0. 035) in the bSSFP dataset only. The different relaxation weighting of the base images (T2/T1 in bSSFP, proton density in GRE) had no effects besides a larger spreading of the MTR values of the different NA structures. This was demonstrated by the nearly perfect linearity between the NA matter MTR of both techniques as well as in the absolute MTR differences between NA matter and the respective lesions.

YNICL Journal 2015 Journal Article

Subcortical brain segmentation of two dimensional T1-weighted data sets with FMRIB's Integrated Registration and Segmentation Tool (FIRST)

• Michael Amann
• Michaela Andělová
• Armanda Pfister
• Nicole Mueller-Lenke
• Stefan Traud
• Julia Reinhardt
• Stefano Magon
• Kerstin Bendfeldt

Brain atrophy has been identified as an important contributing factor to the development of disability in multiple sclerosis (MS). In this respect, more and more interest is focussing on the role of deep grey matter (DGM) areas. Novel data analysis pipelines are available for the automatic segmentation of DGM using three-dimensional (3D) MRI data. However, in clinical trials, often no such high-resolution data are acquired and hence no conclusions regarding the impact of new treatments on DGM atrophy were possible so far. In this work, we used FMRIB's Integrated Registration and Segmentation Tool (FIRST) to evaluate the possibility of segmenting DGM structures using standard two-dimensional (2D) T1-weighted MRI. In a cohort of 70 MS patients, both 2D and 3D T1-weighted data were acquired. The thalamus, putamen, pallidum, nucleus accumbens, and caudate nucleus were bilaterally segmented using FIRST. Volumes were calculated for each structure and for the sum of basal ganglia (BG) as well as for the total DGM. The accuracy and reliability of the 2D data segmentation were compared with the respective results of 3D segmentations using volume difference, volume overlap and intra-class correlation coefficients (ICCs). The mean differences for the individual substructures were between 1.3% (putamen) and -25.2% (nucleus accumbens). The respective values for the BG were -2.7% and for DGM 1.3%. Mean volume overlap was between 89.1% (thalamus) and 61.5% (nucleus accumbens); BG: 84.1%; DGM: 86.3%. Regarding ICC, all structures showed good agreement with the exception of the nucleus accumbens. The results of the segmentation were additionally validated through expert manual delineation of the caudate nucleus and putamen in a subset of the 3D data. In conclusion, we demonstrate that subcortical segmentation of 2D data are feasible using FIRST. The larger subcortical GM structures can be segmented with high consistency. This forms the basis for the application of FIRST in large 2D MRI data sets of clinical trials in order to determine the impact of therapeutic interventions on DGM atrophy in MS.

YNIMG Journal 2012 Journal Article

Multivariate pattern classification of gray matter pathology in multiple sclerosis

• Kerstin Bendfeldt
• Stefan Klöppel
• Thomas E. Nichols
• Renata Smieskova
• Pascal Kuster
• Stefan Traud
• Nicole Mueller-Lenke
• Yvonne Naegelin

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. 5T 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.

YNIMG Journal 2009 Journal Article

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

• Kerstin Bendfeldt
• Pascal Kuster
• Stefan Traud
• Hanspeter Egger
• Sebastian Winklhofer
• Nicole Mueller-Lenke
• Yvonne Naegelin
• Achim Gass

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.

YNIMG Journal 2001 Journal Article

Altered functional activation in MS patients with reduced attentional performance demonstrated with functional MRI

• Iris-Katharina Penner
• Martin Rausch
• Martin Hardmeier
• Ludwig Kappos
• Ernst-Wilhelm Radü