Cardiac output, cerebral blood flow and cognition in patients with severe aortic valve stenosis undergoing transcatheter aortic valve implantation: design and rationale of the CAPITA study.

BACKGROUND: Approximately one-third of patients with symptomatic severe aortic valve stenosis who are scheduled for transcatheter aortic valve implantation (TAVI) have some degree of cognitive impairment. TAVI may have negative cognitive effects due to periprocedural micro-emboli inducing cerebral infarction. On the contrary, TAVI may also have positive cognitive effects due to increases in cardiac output and cerebral blood flow (CBF). However, studies that systematically assess these effects are scarce. Therefore, the main aim of this study is to assess cerebral and cognitive outcomes in patients with severe aortic valve stenosis undergoing TAVI. STUDY DESIGN: In the prospective CAPITA (CArdiac OutPut, Cerebral Blood Flow and Cognition In Patients With Severe Aortic Valve Stenosis Undergoing Transcatheter Aortic Valve Implantation) study, cerebral and cognitive outcomes are assessed in patients undergoing TAVI. One day before and 3 months after TAVI, patients will undergo echocardiography (cardiac output, valve function), brain magnetic resonance imaging (CBF, structural lesions) and extensive neuropsychological assessment. To assess longer-term effects of TAVI, patients will again undergo echocardiography and neuropsychological assessment 1 year after the procedure. The co-primary outcome measures are change in CBF (in ml/100 g per min) and change in global cognitive functioning (Z-score) between baseline and 3­month follow-up. Secondary objectives include change in cardiac output, white matter hyperintensities and other structural brain lesions. (ClinicalTrials.gov identifier NCT05481008) CONCLUSION : The CAPITA study is the first study designed to systematically assess positive and negative cerebral and cognitive outcomes after TAVI. We hypothesise that TAVI improves cardiac output, CBF and cognitive functioning.

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

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.

Opportunities for Understanding MS Mechanisms and Progression With MRI Using Large-Scale Data Sharing and Artificial Intelligence.

Patients with multiple sclerosis (MS) have heterogeneous clinical presentations, symptoms, and progression over time, making MS difficult to assess and comprehend in vivo. The combination of large-scale data sharing and artificial intelligence creates new opportunities for monitoring and understanding MS using MRI. First, development of validated MS-specific image analysis methods can be boosted by verified reference, test, and benchmark imaging data. Using detailed expert annotations, artificial intelligence algorithms can be trained on such MS-specific data. Second, understanding disease processes could be greatly advanced through shared data of large MS cohorts with clinical, demographic, and treatment information. Relevant patterns in such data that may be imperceptible to a human observer could be detected through artificial intelligence techniques. This applies from image analysis (lesions, atrophy, or functional network changes) to large multidomain datasets (imaging, cognition, clinical disability, genetics). After reviewing data sharing and artificial intelligence, we highlight 3 areas that offer strong opportunities for making advances in the next few years: crowdsourcing, personal data protection, and organized analysis challenges. Difficulties as well as specific recommendations to overcome them are discussed, in order to best leverage data sharing and artificial intelligence to improve image analysis, imaging, and the understanding of MS.

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

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.

Manual and automated tissue segmentation confirm the impact of thalamus atrophy on cognition in multiple sclerosis: A multicenter study.

BACKGROUND AND RATIONALE: Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining. METHODS: Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor. RESULTS: In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values < 0.001). All methods significantly distinguished CI from CP MS patients, except manual outlines of the left thalamus (p = 0.23). Poorer global neuropsychological test performance was significantly associated with smaller thalamus volumes bilaterally using all methods. Vendor significantly affected the findings. CONCLUSION: Automated and manual thalamus segmentation consistently demonstrated an association between thalamus atrophy and cognitive impairment in MS. However, a proportional bias in smaller thalami and choice of MRI acquisition system might impact the effect size of these findings.

Reduced accuracy of MRI deep grey matter segmentation in multiple sclerosis: an evaluation of four automated methods against manual reference segmentations in a multi-center cohort.

BACKGROUND: Deep grey matter (DGM) atrophy in multiple sclerosis (MS) and its relation to cognitive and clinical decline requires accurate measurements. MS pathology may deteriorate the performance of automated segmentation methods. Accuracy of DGM segmentation methods is compared between MS and controls, and the relation of performance with lesions and atrophy is studied. METHODS: On images of 21 MS subjects and 11 controls, three raters manually outlined caudate nucleus, putamen and thalamus; outlines were combined by majority voting. FSL-FIRST, FreeSurfer, Geodesic Information Flow and volBrain were evaluated. Performance was evaluated volumetrically (intra-class correlation coefficient (ICC)) and spatially (Dice similarity coefficient (DSC)). Spearman's correlations of DSC with global and local lesion volume, structure of interest volume (ROIV), and normalized brain volume (NBV) were assessed. RESULTS: ICC with manual volumes was mostly good and spatial agreement was high. MS exhibited significantly lower DSC than controls for thalamus and putamen. For some combinations of structure and method, DSC correlated negatively with lesion volume or positively with NBV or ROIV. Lesion-filling did not substantially change segmentations. CONCLUSIONS: Automated methods have impaired performance in patients. Performance generally deteriorated with higher lesion volume and lower NBV and ROIV, suggesting that these may contribute to the impaired performance.

Urgent challenges in quantification and interpretation of brain grey matter atrophy in individual MS patients using MRI.

Atrophy of the brain grey matter (GM) is an accepted and important feature of multiple sclerosis (MS). However, its accurate measurement is hampered by various technical, pathological and physiological factors. As a consequence, it is challenging to investigate the role of GM atrophy in the disease process as well as the effect of treatments that aim to reduce neurodegeneration. In this paper we discuss the most important challenges currently hampering the measurement and interpretation of GM atrophy in MS. The focus is on measurements that are obtained in individual patients rather than on group analysis methods, because of their importance in clinical trials and ultimately in clinical care. We discuss the sources and possible solutions of the current challenges, and provide recommendations to achieve reliable measurement and interpretation of brain GM atrophy in MS.

Agreement of MSmetrix with established methods for measuring cross-sectional and longitudinal brain atrophy.

INTRODUCTION: Despite the recognized importance of atrophy in multiple sclerosis (MS), methods for its quantification have been mostly restricted to the research domain. Recently, a CE labelled and FDA approved MS-specific atrophy quantification method, MSmetrix, has become commercially available. Here we perform a validation of MSmetrix against established methods in simulated and in vivo MRI data. METHODS: Whole-brain and gray matter (GM) volume were measured with the cross-sectional pipeline of MSmetrix and compared to the outcomes of FreeSurfer (cross-sectional pipeline), SIENAX and SPM. For this comparison we investigated 20 simulated brain images, as well as in vivo data from 100 MS patients and 20 matched healthy controls. In fifty of the MS patients a second time point was available. In this subgroup, we additionally analyzed the whole-brain and GM volume change using the longitudinal pipeline of MSmetrix and compared the results with those of FreeSurfer (longitudinal pipeline) and SIENA. RESULTS: In the simulated data, SIENAX displayed the smallest average deviation compared with the reference whole-brain volume (+ 19.56 ± 10.34 mL), followed by MSmetrix (- 38.15 ± 17.77 mL), SPM (- 42.99 ± 17.12 mL) and FreeSurfer (- 78.51 ± 12.68 mL). A similar pattern was seen in vivo. Among the cross-sectional methods, Deming regression analyses revealed proportional errors particularly in MSmetrix and SPM. The mean difference percentage brain volume change (PBVC) was lowest between longitudinal MSmetrix and SIENA (+ 0.16 ± 0.91%). A strong proportional error was present between longitudinal percentage gray matter volume change (PGVC) measures of MSmetrix and FreeSurfer (slope = 2.48). All longitudinal methods were sensitive to the MRI hardware upgrade that occurred during the time of the study. CONCLUSION: MSmetrix, FreeSurfer, FSL and SPM show differences in atrophy measurements, even at the whole-brain level, that are large compared to typical atrophy rates observed in MS. Especially striking are the proportional errors between methods. Cross-sectional MSmetrix behaved similarly to SPM, both in terms of mean volume difference as well as proportional error. Longitudinal MSmetrix behaved most similar to SIENA. Our results indicate that brain volume measurement and normalization from T1-weighted images remains an unsolved problem that requires much more attention.