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

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Abstract

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.

Highlights

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Accurate measurement of brain GM atrophy in MS is hampered by various physiological, pathological and technical factors.
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Challenges to achieve accuracy in quantification and interpretation of atrophy in MS are discussed.
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Recommendations on how to achieve reliable measurement and interpretation of GM atrophy in MS are suggested.

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Most cited references 100

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We present a novel skull-stripping algorithm based on a hybrid approach that combines watershed algorithms and deformable surface models. Our method takes advantage of the robustness of the former as well as the surface information available to the latter. The algorithm first localizes a single white matter voxel in a T1-weighted MRI image, and uses it to create a global minimum in the white matter before applying a watershed algorithm with a preflooding height. The watershed algorithm builds an initial estimate of the brain volume based on the three-dimensional connectivity of the white matter. This first step is robust, and performs well in the presence of intensity nonuniformities and noise, but may erode parts of the cortex that abut bright nonbrain structures such as the eye sockets, or may remove parts of the cerebellum. To correct these inaccuracies, a surface deformation process fits a smooth surface to the masked volume, allowing the incorporation of geometric constraints into the skull-stripping procedure. A statistical atlas, generated from a set of accurately segmented brains, is used to validate and potentially correct the segmentation, and the MRI intensity values are locally re-estimated at the boundary of the brain. Finally, a high-resolution surface deformation is performed that accurately matches the outer boundary of the brain, resulting in a robust and automated procedure. Studies by our group and others outperform other publicly available skull-stripping tools. Copyright 2004 Elsevier Inc.

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Alexandra Kutzelnigg, Claudia Lucchinetti, Christine Stadelmann … (2005)

Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.

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Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions.

J Peterson, L. Bo, S Mörk … (2001)

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes motor, sensory, and cognitive deficits. The present study characterized demyelinated lesions in the cerebral cortex of MS patients. One hundred twelve cortical lesions were identified in 110 tissue blocks from 50 MS patients. Three patterns of cortical demyelination were identified: Type I lesions were contiguous with subcortical white matter lesions; Type II lesions were small, confined to the cortex, and often perivascular; Type III lesions extended from the pial surface to cortical layer 3 or 4. Inflammation and neuronal pathology were studied in tissue from 8 and 7 patients, respectively. Compared to white matter lesions, cortical lesions contained 13 times fewer CD3-positive lymphocytes (195 vs 2,596/mm3 of tissue) and 6 times fewer CD68-positive microglia/macrophages (11,948 vs 67,956/mm3 of tissue). Transected neurites (both axons and dendrites) occurred at a density of 4,119/mm3 in active cortical lesions, 1,107/mm3 in chronic active cortical lesions, 25/mm3 in chronic inactive cortical lesions, 8/mm3 in myelinated MS cortex, and 1/mm3 in control cortex. In active and chronic active cortical lesions, activated microglia closely apposed and ensheathed apical dendrites, neurites, and neuronal perikarya. In addition, apoptotic neurons were increased significantly in demyelinated cortex compared to myelinated cortex. These data support the hypothesis that demyelination, axonal transection, dendritic transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients.

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Author and article information

Contributors

Alexandra de Sitter

Journal

Journal ID (nlm-ta): Neuroimage Clin

Journal ID (iso-abbrev): Neuroimage Clin

Title: NeuroImage : Clinical

Publisher: Elsevier

ISSN (Electronic): 2213-1582

Publication date PMC-release: 26 April 2018

Publication date Collection: 2018

Publication date (Electronic): 26 April 2018

Volume: 19

Pages: 466-475

Affiliations

[a ]Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands

[b ]Medical Image Analysis Center (MIAC AG) Basel, Switzerland

[c ]Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy

[d ]NMR Research Unit, Department of Neuroinflammation, Queen Square MS Centre, UCL Institute of Neurology, London, UK

[e ]Multiple Sclerosis Centre, Neurology Section, Department of Neurosciences, Biomedicine and Movements, University of Verona, Italy

[f ]Anatomy & Neurosciences, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands

[g ]Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

[h ]Servei de Neurologia/Neuroimmunologia, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

[i ]Department of Neurology & Division of Neuroradiology, Vascular and Interventional Radiology, Department of Radiology, Medical University of Graz, Austria

[j ]Unitat de Ressonància Magnètica (Servei de Radiologia), Hospital universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

[k ]Institutes of Neurology and Healthcare Engineering, UCL, London, UK

Author notes

[* ]Corresponding author. a.desitter@ 123456vumc.nl

[1]

Equal contribution.

[2]

The members of the MAGNIMS Study Group Steering Committee are: F Barkhof and H Vrenken (VU University Medical Center, Amsterdam, Netherlands), O Ciccarelli and T Yousry (Queen Square MS Centre, UCL Institute of Neurology, London, UK), N De Stefano (University of Siena, Siena, Italy), C Enzinger (Department of Neurology, Medical University of Graz, Graz, Austria), M Filippi and M A Rocca (San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy), J L Frederiksen (Rigshospitalet Glostrup and University of Copenhagen, Copenhagen, Denmark), C Gasperini (San Camillo-Forlanini Hospital, Rome, Italy), L Kappos (University of Basel, Basel, Switzerland), J Palace (University of Oxford Hospitals Trust, Oxford, UK), A Rovira and J Sastre-Garriga (Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain).

Article

Publisher ID: S2213-1582(18)30132-3

DOI: 10.1016/j.nicl.2018.04.023

PMC ID: 6030805

PubMed ID: 29984155

SO-VID: 3e765b8f-7626-4251-8b7d-1bc261e257ca

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 25 September 2017

Date revision received : 28 March 2018

Date accepted : 22 April 2018

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

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Most cited references 100

A hybrid approach to the skull stripping problem in MRI.

Cortical demyelination and diffuse white matter injury in multiple sclerosis.

Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions.

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