Spatial patterns of brain lesions assessed through covariance estimations of lesional voxels in multiple Sclerosis: The SPACE-MS technique

Abstract

Anisotropy; Lesion spatial distribution; Multiple sclerosis

Anisotropia; Distribució espacial de la lesió; Esclerosi múltiple

Anisotropía; Distribución espacial de la lesión; Esclerosis múltiple

Predicting disability in progressive multiple sclerosis (MS) is extremely challenging. Although there is some evidence that the spatial distribution of white matter (WM) lesions may play a role in disability accumulation, the lack of well-established quantitative metrics that characterise these aspects of MS pathology makes it difficult to assess their relevance for clinical progression. This study introduces a novel approach, called SPACE-MS, to quantitatively characterise spatial distributional features of brain MS lesions, so that these can be assessed as predictors of disability accumulation. In SPACE-MS, the covariance matrix of the spatial positions of each patient’s lesional voxels is computed and its eigenvalues extracted. These are combined to derive rotationally-invariant metrics known to be common and robust descriptors of ellipsoid shape such as anisotropy, planarity and sphericity. Additionally, SPACE-MS metrics include a neuraxis caudality index, which we defined for the whole-brain lesion mask as well as for the most caudal brain lesion. These indicate how distant from the supplementary motor cortex (along the neuraxis) the whole-brain mask or the most caudal brain lesions are.

We applied SPACE-MS to data from 515 patients involved in three studies: the MS-SMART (NCT01910259) and MS-STAT1 (NCT00647348) secondary progressive MS trials, and an observational study of primary and secondary progressive MS. Patients were assessed on motor and cognitive disability scales and underwent structural brain MRI (1.5/3.0 T), at baseline and after 2 years. The MRI protocol included 3DT1-weighted (1x1x1mm3) and 2DT2-weighted (1x1x3mm3) anatomical imaging. WM lesions were semiautomatically segmented on the T2-weighted scans, deriving whole-brain lesion masks. After co-registering the masks to the T1 images, SPACE-MS metrics were calculated and analysed through a series of multiple linear regression models, which were built to assess the ability of spatial distributional metrics to explain concurrent and future disability after adjusting for confounders.

Patients whose WM lesions laid more caudally along the neuraxis or were more isotropically distributed in the brain (i.e. with whole-brain lesion masks displaying a high sphericity index) at baseline had greater motor and/or cognitive disability at baseline and over time, independently of brain lesion load and atrophy measures. In conclusion, here we introduced the SPACE-MS approach, which we showed is able to capture clinically relevant spatial distributional features of MS lesions independently of the sheer amount of lesions and brain tissue loss. Location of lesions in lower parts of the brain, where neurite density is particularly high, such as in the cerebellum and brainstem, and greater spatial spreading of lesions (i.e. more isotropic whole-brain lesion masks), possibly reflecting a higher number of WM tracts involved, are associated with clinical deterioration in progressive MS. The usefulness of the SPACE-MS approach, here demonstrated in MS, may be explored in other conditions also characterised by the presence of brain WM lesions.

Carmen Tur is currently being funded by a Junior Leader La Caixa Fellowship. The project that gave rise to these results received the support of a fellowship from ”la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/PI20/11760008. She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by the Merck Foundation. In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She has also received honoraria from Roche and Novartis. Francesco Grussu has received funding under the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 634541, from the Engineering and Physical Sciences Research Council (EPSRC EP/R006032/1, M020533/1) and Rosetrees Trust (UK), and is now supported by PREdICT (a study funded by AstraZeneca in Spain). Ferran Prados was supported by the Guarantors of Brain and the National Institute for Health Research, University College London Hospitals Biomedical Research Centre. Rosa Cortese is supported by the ECTRIMS-MAGNIMS fellowships programme. Alberto Calvi is supported by ECTRIMS-MAGNIMS fellowship (2018), Guarantors of Brain “Entry” clinical fellowship (2019) and the UK MS Society PhD studentship (2020). Declan Chard is a consultant for Biogen and Hoffmann-La Roche. In the last 3 years, he has received research funding from the International Progressive MS Alliance, the UK MS Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. Jeremy Chataway, in the last three years, has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society. A local principal investigator for commercial trials funded by: Actelion, Biogen, Novartis and Roche; has received an investigator grant from Novartis; and has taken part in advisory boards/consultancy for Azadyne, Biogen, Celgene, Janssen, MedDay, Merck, Novartis and Roche. Alan J Thompson acknowledges grant support from the National Institute for Health Research HTA and BRC, and has received honoraria for consultancy from Eisai and Abbvie (paid to Institution), support for travel for consultancy from the International Progressive MS Alliance and National MS Society (USA), and receives an honorarium from SAGE Publishers as Editor-in-Chief of Multiple Sclerosis Journal. Olga Ciccarelli is supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre. OC also receives research grant support from the MS Society of Great Britain and Northern Ireland, and the NIHR UCLH Biomedical Research Centre. She is an Associate Editor for Neurology, for which he receives an honorarium. Claudia A.M. Gandini Wheeler-Kingshott has received research grants (principal investigator and co-applicant) from the UK MS Society (#77), Wings for Life (#169111), BRC (#BRC704/CAP/CGW), UCL Global Challenges Research Fund (GCRF), MRC (#MR/S026088/1), Ataxia UK. CGWK is a shareholder in Queen Square Analytics Ltd.