Deep Grey Matter Injury in Multiple Sclerosis: A NAIMS Consensus Statement

Daniel Ontaneda; Praneeta C. Raza; Kedar R. Mahajan; Douglas L. Arnold; Michael G. Dwyer; Susan A. Gauthier; Douglas N. Greve; Daniel M. Harrison; Roland G. Henry; David K. B. Li; Caterina Mainero; Wayne Moore; Sridar Narayanan; Jiwon Oh; Raihaan Patel; Daniel Pelletier; Alexander Rauscher; William D. Rooney; Nancy L. Sicotte; Roger Tam; Daniel S. Reich; Christina J. Azevedo

Disclosures

Brain. 2021;144(7):1974-1984.

Abstract and Introduction

Abstract

Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability.

Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter.

Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.

Introduction

Multiple sclerosis has traditionally been viewed as a white matter disease, with focal lesions resulting in neuronal injury and tissue destruction.^[1,2] However, detailed neuropathological examination also reveals extensive pathology in cortical and deep grey matter (DGM).^[3] While the mechanisms of DGM injury vary across structures, the net effect of this pathology can be examined in vivo using MRI. Volume loss/atrophy of the thalamus and other DGM structures has been well-documented in multiple sclerosis using MRI and is clinically relevant.^[4–9] The precise mechanisms of DGM loss remain to be fully elucidated and likely represent a complex interplay between the various aspects of pathology in multiple sclerosis.

Conventional MRI can be used to measure DGM volume and lesions. However, DGM lesions are best visualized at 7 T,^[10,11] are more difficult to visualize at conventional field strengths, and have even been considered a red flag for a diagnosis of multiple sclerosis.^[12] Advanced techniques, such as functional MRI (fMRI), diffusion tensor MRI, relaxometry and magnetic resonance (MR) spectroscopy, can quantify additional changes in DGM structures.^[13–15] With recent advances in imaging, there is an opportunity to satisfy an unmet need to fully characterize DGM injury in multiple sclerosis and develop measures for use in clinical care and research. A better understanding of the mechanisms of DGM injury will provide fundamental knowledge about the pathophysiology of multiple sclerosis and may enable more efficient clinical trial design for neuroprotective therapies.

1 2 3 4 5 6 7

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Table 1. Histopathological and MRI findings in DGM and related grey matter regions in multiple sclerosis
DGM Structure	Histopathological findings						MRI findings
	Lesions	Normal-appearing tissue					MRI findings
	Focal lesions present^16–18	Diffuse inflammatory infiltrate^16,17	Activated microglia^16–18	Iron deposition^16,*	Neuronal loss^16,17	Markers of oxidative stress¹⁶	Early volume loss^19–21	DGM lesions MRI-visible^22–24	Iron accumulation^25–27
Thalamus^16–20,22	+++	+	+	+	+	+	+++	+++	+
Caudate^16,17,20,23	+++	+	+	+	+	+	++	+	+
Putamen^{16,17,19,20,23}	++	+	+	+	+	+	+++	+	+
Globus pallidus^16,17	++	+	+	+	+	+	NA	NA	+
Substantia nigra¹⁷	+	+	NA	NA	NA	NA	NA	NA	NA
Amygdala¹⁷	+	+	NA	NA	NA	NA	NA	NA	NA
Hypothalamus^17,28	+++	+	+	NA	+	NA	NA	NA	NA
Hippocampus^29–32	+++	NA	+	NA	+	NA	+	+++	NA

NA = not available.
*Did not reach statistical significance.

Table 2. MRI contrasts in DGM
Contrast	Utility	Acquisition comments
T₁-weighted^10,60,61	Anatomical identification of boundaries and segmentation for volumetric assessments; potentially useful for lesion identification	High resolution images can be obtained with relatively short acquisition time; substantial experience in multicentre applications; thalamus may be difficult to segment due to high myelin content
T₂-weighted⁶² or T₂-FLAIR	Identification of focal demyelinating lesions Intrinsic changes in T₂ signal, some sensitivity to iron	Quick acquisition; substantial experience in multicentre applications
T₁ relaxation^63,64	Quantitative measure, can differentiate different DGM structures and subregions	Requires multiple acquisitions hence multicentre applications have been limited, but newer single-sequences approaches (e.g. MP2RAGE) may alleviate these drawbacks
T₂ relaxation^64,65	Quantitative measure, has some sensitivity to iron content in DGM, short component is particularly sensitive to myelin	Time consuming, with limited success in multicentre applications
T₂*^11,56,66,67	Sensitive to iron and myelin content and blood vessels in DGM, also ideal to identify boundaries of iron-containing deep grey matter structures	High resolution can be attained with relatively quick acquisition times; multicentre application is relatively straightforward; less useful at 1.5 T
Double inversion recovery⁶⁸	Sensitive to detection of DGM lesions	Feasible, and may also allow identification of few DGM lesions but sensitivity unknown
Quantitative susceptibility mapping⁶⁹	Sensitive to iron, myelin and blood vessels; can differentiate diamagnetic and paramagnetic changes	Feasible, but post-processing required; less useful at 1.5 T
Diffusion weighted imaging⁷⁰	Useful sensitive to microstructural	Typically lower resolution than other sequences; acquisition times are long for more complex biophysical models, which are not routinely available on commercial scanners; limited success in multicentre studies
Magnetization transfer imaging^71,72	Sensitive to deep grey matter demyelination and useful for thalamic segmentation	Feasible clinical acquisition times; needs careful normalization for multicentre application

Authors and Disclosures

Daniel Ontaneda,¹, Praneeta C. Raza,¹, Kedar R. Mahajan,¹, Douglas L. Arnold,², Michael G. Dwyer,³, Susan A. Gauthier,⁴, Douglas N. Greve,^5,6, Daniel M. Harrison,⁷, Roland G. Henry,^8,9, David K. B. Li,¹⁰, Caterina Mainero,^5,6, Wayne Moore,¹¹, Sridar Narayanan,², Jiwon Oh,¹², Raihaan Patel,^13,14, Daniel Pelletier,¹⁵, Alexander Rauscher,¹⁶, William D. Rooney,¹⁷, Nancy L. Sicotte,¹⁸, Roger Tam,^10,19, Daniel S. Reich²⁰ and Christina J. Azevedo¹⁵, on behalf of the North American Imaging in Multiple Sclerosis Cooperative (NAIMS)

1 Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland, OH 44195, USA
2 McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada
3 Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, The State University of New York, Buffalo, NY 14214, USA
4 Department of Neurology, Weill Cornell Medicine, New York, NY 10021, USA
5 Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA 02129, USA
6 Department of Radiology, Harvard Medical School, Boston, MA 02129, USA
7 Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
8 Department of Neurology, Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA
9 The UC San Francisco and Berkeley Bioengineering Graduate Group, University of California San Francisco, San Francisco, CA 94143, USA
10 Department of Radiology and Medicine (Neurology), University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
11 Department of Pathology and Laboratory Medicine, and International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
12 Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, Ontario M5B 1W8, Canada
13 Cerebral Imaging Centre, Douglas Mental Health University Institute, Verdun, Quebec H4H 1R3, Canada
14 Department of Biological and Biomedical Engineering, McGill University, Montreal, Quebec H3A 2B4, Canada
15 Department of Neurology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
16 Physics and Astronomy, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
17 Advanced Imaging Research Center, Oregon Health and Science University, Portland, OR 97239, USA
18 Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
19 Biomedical Engineering, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
20 Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20824, USA

Correspondence to
Daniel Ontaneda 9500 Euclid Ave, U10 Mellen Center Cleveland, OH 44195, USA E-mail: ontaned@ccf.org

Competing interests
D.O. reports research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis. Consulting fees from Biogen Idec, Genentech/Roche, Genzyme, Novartis, and Merck. K.R.M. reports research support from the National MS Society and National Institute of Health. D.L.A. reports personal compensation for serving as a Consultant for Alexion, Biogen, Celgene, Frequency Therapeutics, GENeuro, Genentech, Merck/EMD Serono, Novartis, Roche, and Sanofi. D.L.A. has an ownership interest in NeuroRx. M.G.D reports research support from the National Institutes of Health, National Multiple Sclerosis Society, Novartis, Merck, and Bristol Myers Squibb. Consulting fees from Novartis, Bristol Myers Squibb, and Keystone Heart. S.A.G reports research support from the National Institutes of Health, Genentech, Genzyme, and Mallinckrodt. Consulting fees from Biogen Idec. D.N.G. reports no competing interests related to this work; research support from the National Institutes of Health grants R01EB023281, R01NS105820, and R01NS112161. D.M.H. reports research support from the National Institutes of Health, National Multiple Sclerosis Society, Genentech, and EMD-Serono. Consulting fees from Biogen, Genentech, EMD-Serono, and Sanofi-Genzyme. Royalties and writing fees from UpToDate Inc. and the American College of Physicians. R.G.H. reports consulting fees from Roche/Genentech, Atara, Sanofi/Genzyme, Celgene/Bristol Myers Squibb, MEDDAY, QIA Consulting and grants from Roche/Genentech, MEDDAY, and Atara. D.K.B.L. has received research funding from the Canadian Institute of Health Research and Multiple Sclerosis Society of Canada. He is Emeritus Director of the UBC MS/MRI Research Group which has been contracted to perform central analysis of MRI scans for therapeutic trials with Roche and Sanofi-Genzyme. The UBC MS/MRI Research Group has also received grant support for investigator-initiated studies from Sanofi-Genzyme, Novartis and Roche. He has served on the PML-MS Steering Committee for Biogen. He has given lectures, supported by non-restricted education grants from Academy of Health Care Learning, Biogen, Consortium of MS Centers and Sanofi-Genzyme. C.M. has received funding from Sanofi-Genzyme, EMD Serono, Genentech, the MS National Society, the National Institute of Health and the Department of Defense outside the scope of this work. W.M. reports current research funding from the Multiple Sclerosis Society of Canada. At the time of this conference he was a member of the Medical Advisory Committee of the Multiple Sclerosis Society of Canada. In the past, he has received a grant in aid of research from Berlex Canada, has been a consultant for Schering, and received an honorarium from Teva for teaching. S.N. reports research funding from the Canadian Institutes of Health Research, the Myelin Repair Foundation and Immunotec; consulting fees from Genentech; part-time employment with NeuroRx Research. J.O. reports esearch support from the MS Society of Canada, Brain Canada, National MS Society, Biogen-Idec, Roche, EMD-Serono. Consulting fees from Biogen-Idec, EMD-Serono, Sanofi-Genzyme, Roche, Novartis, BMS, and Alexion. D.P. has received consulting fees from Biogen, Roche, Sanofi Genzyme, Novartis, and EMD Serono. A.R. has received research funding from the Canadian Institutes of Health Research and the National Multiple Sclerosis Society. W.D.R. reports research support from the National Institutes of Health, Conrad N. Hilton Foundation, Paul G. Allen Family Foundation, Race to Erase MS Foundation, and Revalesio, Inc. N.L.S. reports research support from the National MS Society, Patient Centered Outcomes Research Institute, and the National Institute of Health. R.T. reports grants from Multiple Sclerosis Society of Canada, Natural Sciences and Engineering Research Council of Canada, Mitacs, Praxis Spinal Cord Institute, and UBC Data Science Institute. D.S.R is supported by the Intramural Research Program of NINDS, NIH. C.J.A. has received consulting fees from Guerbet LLC, Genentech, Biogen Idec, Novartis, Sanofi Genzyme, EMD Serono, and Alexion Pharmaceuticals, outside the submitted work. All other authors report no competing interests.