TY - JOUR
T1 - Brain atrophy rates vary with age in relapsing-remitting multiple sclerosis
AU - Kaçar, Sezgi
AU - van Nederpelt, David R
AU - Jelgerhuis, Julia R
AU - Coerver, Eline M E
AU - Killestein, Joep
AU - Sormani, Maria Pia
AU - Ciccarelli, Olga
AU - Arnold, Douglas L
AU - van Kempen, Zoé L E
AU - Uitdehaag, B M J
AU - Barkhof, Frederik
AU - Koch, Marcus W
AU - Schoonheim, Menno M
AU - Eshaghi, Arman
AU - Strijbis, Eva M M
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: https://creativecommons.org/licenses/by-nc/4.0/.
PY - 2026/7
Y1 - 2026/7
N2 - BACKGROUND: Brain atrophy is increasingly used as an outcome measure in clinical trials in relapsing-remitting multiple sclerosis (RRMS), but little is known about how chronological age interacts with MS-specific effects. For instance, while annual brain atrophy rates typically increase with age in healthy individuals, MS patients tend to exhibit decreasing atrophy rates over time.METHODS: We investigated the relationship between age and brain volume in a large dataset of 4241 trial participants with RRMS. We used pooled individual-participant data from phase 3 clinical trials with 96 weeks follow-up, which included both active treatment and placebo/comparator arms. Participants were categorised into seven groups based on chronological age (18-24 years, 25-30 years, 31-35 years, 36-40 years, 41-45 years, 46-50 years, 51-56 years). We performed multilevel linear mixed-effects regression analyses to examine differences between age groups in normalised whole brain volume (NWBV), thalamus grey matter volume (NThGMV), grey matter volume (NGMV) and white matter volume at baseline and their changes over follow-up. We also studied how disease duration influenced these relationships using similar models.RESULTS: Older participants showed significantly lower NWBV, NGMV and NThGMV at baseline than younger participants. Most importantly, older participants exhibited lower rates of atrophy during follow-up, particularly in the thalamus. This association was consistent across all disease duration subgroups.CONCLUSIONS: Older participants had more severe atrophy when enrolled into trials, but slower (thalamic) atrophy rates, independent of disease duration over time. Together, these findings emphasise that age should be taken into account when designing clinical trials that use brain atrophy as an outcome measure.
AB - BACKGROUND: Brain atrophy is increasingly used as an outcome measure in clinical trials in relapsing-remitting multiple sclerosis (RRMS), but little is known about how chronological age interacts with MS-specific effects. For instance, while annual brain atrophy rates typically increase with age in healthy individuals, MS patients tend to exhibit decreasing atrophy rates over time.METHODS: We investigated the relationship between age and brain volume in a large dataset of 4241 trial participants with RRMS. We used pooled individual-participant data from phase 3 clinical trials with 96 weeks follow-up, which included both active treatment and placebo/comparator arms. Participants were categorised into seven groups based on chronological age (18-24 years, 25-30 years, 31-35 years, 36-40 years, 41-45 years, 46-50 years, 51-56 years). We performed multilevel linear mixed-effects regression analyses to examine differences between age groups in normalised whole brain volume (NWBV), thalamus grey matter volume (NThGMV), grey matter volume (NGMV) and white matter volume at baseline and their changes over follow-up. We also studied how disease duration influenced these relationships using similar models.RESULTS: Older participants showed significantly lower NWBV, NGMV and NThGMV at baseline than younger participants. Most importantly, older participants exhibited lower rates of atrophy during follow-up, particularly in the thalamus. This association was consistent across all disease duration subgroups.CONCLUSIONS: Older participants had more severe atrophy when enrolled into trials, but slower (thalamic) atrophy rates, independent of disease duration over time. Together, these findings emphasise that age should be taken into account when designing clinical trials that use brain atrophy as an outcome measure.
KW - MULTIPLE SCLEROSIS
UR - https://www.scopus.com/pages/publications/105029282125
U2 - 10.1136/jnnp-2025-337779
DO - 10.1136/jnnp-2025-337779
M3 - Article
C2 - 41638890
SN - 0022-3050
VL - 97
SP - 581
EP - 590
JO - Journal of neurology, neurosurgery, and psychiatry
JF - Journal of neurology, neurosurgery, and psychiatry
IS - 7
M1 - 337779
ER -