TY - JOUR
T1 - Detection of grey matter microstructural substrates of neurodegeneration in multiple sclerosis
AU - Krijnen, Eva A.
AU - Russo, Andrew W.
AU - Salim Karam, Elsa
AU - Lee, Hansol
AU - Chiang, Florence L.
AU - Schoonheim, Menno M.
AU - Huang, Susie Y.
AU - Klawiter, Eric C.
N1 - Funding Information: E.A.K., A.W.R., E.S.K., H.L. and F.L.C. report no conflicts of interest. M.M.S. serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay and Merck. S.Y.H. has received consulting fees and research grants from Siemens Healthineers. E.C.K. has received consulting fees from Banner Life Sciences, Galen/Atlantica, Genentech, Greenwich Biosciences and OM1, and research funds from Abbvie, Biogen and Genentech. Funding Information: This work was supported by The McCourt Foundation and National Institutes of Health under grant numbers P41-EB015896, P41-EB030006, U01-EB026996, R01-NS118187 and K23-NS096056. Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2023
Y1 - 2023
N2 - Multiple sclerosis features complex pathological changes in grey matter that begin early and eventually lead to diffuse atrophy. Novel approaches to image grey-matter microstructural alterations in vivo are highly sought after and would enable more sensitive monitoring of disease activity and progression. This cross-sectional study aimed to assess the sensitivity of high-gradient diffusion MRI for microstructural tissue damage in cortical and deep grey matter in people with multiple sclerosis and test the hypothesis that reduced cortical cell body density is associated with cortical and deep grey-matter volume loss. Forty-one people with multiple sclerosis (age 24-72, 14 females) and 37 age- and sex-matched healthy controls were scanned on a 3 T Connectom MRI scanner equipped with 300 mT/m gradients using a multi-shell diffusion MRI protocol. The soma and neurite density imaging model was fitted to high-gradient diffusion MRI data to obtain estimates of intra-neurite, intra-cellular and extra-cellular signal fractions and apparent soma radius. Cortical and deep grey-matter microstructural imaging metrics were compared between multiple sclerosis and healthy controls and correlated with grey-matter volume, clinical disability and cognitive outcomes. People with multiple sclerosis showed significant cortical and deep grey-matter volume loss compared with healthy controls. People with multiple sclerosis showed trends towards lower cortical intra-cellular signal fraction and significantly lower intra-cellular and higher extra-cellular signal fractions in deep grey matter, especially the thalamus and caudate, compared with healthy controls. Changes were most pronounced in progressive disease and correlated with the Expanded Disability Status Scale, but not the Symbol Digit Modalities Test. In multiple sclerosis, normalized thalamic volume was associated with thalamic microstructural imaging metrics. Whereas thalamic volume loss did not correlate with cortical volume loss, cortical microstructural imaging metrics were significantly associated with thalamic volume, and not with cortical volume. Compared with the short diffusion time (Δ= 19 ms) achievable on the Connectom scanner, at the longer diffusion time of Δ= 49 ms attainable on clinical scanners, multiple sclerosis-related changes in imaging metrics were generally less apparent with lower effect sizes in cortical and deep grey matter. Soma and neurite density imaging metrics obtained from high-gradient diffusion MRI data provide detailed grey-matter characterization beyond cortical and thalamic volumes and distinguish multiple sclerosis-related microstructural pathology from healthy controls. Cortical cell body density correlates with thalamic volume, appears sensitive to the microstructural substrate of neurodegeneration and reflects disability status in people with multiple sclerosis, becoming more pronounced as disability worsens.
AB - Multiple sclerosis features complex pathological changes in grey matter that begin early and eventually lead to diffuse atrophy. Novel approaches to image grey-matter microstructural alterations in vivo are highly sought after and would enable more sensitive monitoring of disease activity and progression. This cross-sectional study aimed to assess the sensitivity of high-gradient diffusion MRI for microstructural tissue damage in cortical and deep grey matter in people with multiple sclerosis and test the hypothesis that reduced cortical cell body density is associated with cortical and deep grey-matter volume loss. Forty-one people with multiple sclerosis (age 24-72, 14 females) and 37 age- and sex-matched healthy controls were scanned on a 3 T Connectom MRI scanner equipped with 300 mT/m gradients using a multi-shell diffusion MRI protocol. The soma and neurite density imaging model was fitted to high-gradient diffusion MRI data to obtain estimates of intra-neurite, intra-cellular and extra-cellular signal fractions and apparent soma radius. Cortical and deep grey-matter microstructural imaging metrics were compared between multiple sclerosis and healthy controls and correlated with grey-matter volume, clinical disability and cognitive outcomes. People with multiple sclerosis showed significant cortical and deep grey-matter volume loss compared with healthy controls. People with multiple sclerosis showed trends towards lower cortical intra-cellular signal fraction and significantly lower intra-cellular and higher extra-cellular signal fractions in deep grey matter, especially the thalamus and caudate, compared with healthy controls. Changes were most pronounced in progressive disease and correlated with the Expanded Disability Status Scale, but not the Symbol Digit Modalities Test. In multiple sclerosis, normalized thalamic volume was associated with thalamic microstructural imaging metrics. Whereas thalamic volume loss did not correlate with cortical volume loss, cortical microstructural imaging metrics were significantly associated with thalamic volume, and not with cortical volume. Compared with the short diffusion time (Δ= 19 ms) achievable on the Connectom scanner, at the longer diffusion time of Δ= 49 ms attainable on clinical scanners, multiple sclerosis-related changes in imaging metrics were generally less apparent with lower effect sizes in cortical and deep grey matter. Soma and neurite density imaging metrics obtained from high-gradient diffusion MRI data provide detailed grey-matter characterization beyond cortical and thalamic volumes and distinguish multiple sclerosis-related microstructural pathology from healthy controls. Cortical cell body density correlates with thalamic volume, appears sensitive to the microstructural substrate of neurodegeneration and reflects disability status in people with multiple sclerosis, becoming more pronounced as disability worsens.
KW - advanced diffusion imaging
KW - grey matter
KW - multiple sclerosis
KW - neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=85163129609&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/braincomms/fcad153
DO - https://doi.org/10.1093/braincomms/fcad153
M3 - Article
C2 - 37274832
SN - 2632-1297
VL - 5
JO - Brain Communications
JF - Brain Communications
IS - 3
M1 - fcad153
ER -