Quantitative T1 brain mapping in early relapsing-remitting multiple sclerosis: longitudinal changes, lesion heterogeneity and disability
Authors: Harper James G. , York Elizabeth N. , Meijboom Rozanna , Kampaite Agniete , Thrippleton Michael J. , Kearns Patrick K. A. , Valdés Hernández Maria del C. , Chandran Siddharthan , Waldman Adam D. ,   On behalf of the FutureMS consortium, Akula Amit , Baranzini Sergio , Barret Fiona , Bastin Mark , Batchelor Chris , Beswick Emily , Brown Fraser , Brunton Tracy , Carod Artal Javier , Chang Jessie , Chen Yingdi , Colville Shuna , Connick Peter , Cooper Annette , Cranley Denise , Dakin Rachel , Dhillon Baljean , Elliott Liz , Finlayson James , Foley Peter , Glasmacher Stella , Grossart Angus , Haagenrud Haane , Hafezi Katarzyna , Harrison Emily , Harroud Adil , Hathorn Sara , Hopkins Tracey , Hunt David , Hutchison Aidan , Jardine Charlotte , Jayprakash Kiran , Justin Matt , Kennedy Gwen , Kessler Lucy , Kleynhans Michaela , Larraz Juan , Love Katherine , Lyle Dawn , MacDonald James , MacDougall Niall , MacFarlane Jen , Macfarlane Lesley , Maclean Alan , MacLennan Bev , MacLeod Margaret-Ann , Macleod Nicola , Mahad Don , Martin Sarah-Jane , McCarthy Conni , McMahon Lynn , Mollison Daisy , Megson Ian , Mollison Daisy , Monaghan Mary , Murphy Lee , Murray Katy , Newton Judith , Kwong Julian Ng Kee , O’Riordan Jonathan , Perry David , Quigley Suzanne , Scotson Adam , Semple Scott , Stenson Amy , Stuart Michaela , Weaver Christine , Webb Stuart , Weller Belinda , White Nicole , Williams Anna , Wiseman Stewart , Wong Charis , Wong Michael , Woodward Rosie 
Published: November 2023

Abstract
Objectives
To quantify brain microstructural changes in recently diagnosed relapsing-remitting multiple sclerosis (RRMS) using longitudinal T1 measures, and determine their associations with clinical disability.

Methods
Seventy-nine people with recently diagnosed (< 6 months) RRMS were recruited from a single-centre cohort sub-study, and underwent baseline and 1-year brain MRI, including variable flip angle T1 mapping. Median T1 was measured in white matter lesions (WML), normal-appearing white matter (NAWM), cortical/deep grey matter (GM), thalami, basal ganglia and medial temporal regions. Prolonged T1 (≥ 2.00 s) and supramedian T1 (relative to cohort WML values) WML voxel counts were also measured. Longitudinal change was assessed with paired t-tests and compared with Bland-Altman limits of agreement from healthy control test-retest data. Regression analyses determined relationships with Expanded Disability Status Scale (EDSS) score and dichotomised EDSS outcomes (worsening or stable/improving).

Results
Sixty-two people with RRMS (mean age 37.2 ± 10.9 [standard deviation], 48 female) and 11 healthy controls (age 44 ± 11, 7 female) contributed data. Prolonged and supramedian T1 WML components increased longitudinally (176 and 463 voxels, respectively; p < .001), and were associated with EDSS score at baseline (p < .05) and follow-up (supramedian: p < .01; prolonged: p < .05). No cohort-wide median T1 changes were found; however, increasing T1 in WML, NAWM, cortical/deep GM, basal ganglia and thalami was positively associated with EDSS worsening (p < .05).

Conclusion
T1 is sensitive to brain microstructure changes in early RRMS. Prolonged WML T1 components and subtle changes in NAWM and GM structures are associated with disability.

Clinical relevance statement
MRI T1 brain mapping quantifies disability-associated white matter lesion heterogeneity and subtle microstructural damage in normal-appearing brain parenchyma in recently diagnosed RRMS, and shows promise for early objective disease characterisation and stratification.

Key Points
• Quantitative T1 mapping detects brain microstructural damage and lesion heterogeneity in recently diagnosed relapsing-remitting multiple sclerosis.
• T1 increases in lesions and normal-appearing parenchyma, indicating microstructural damage, are associated with worsening disability.
• Brain T1 measures are objective markers of disability-relevant pathology in early multiple sclerosis.

Graphical abstract