Decreased gray matter (GM) volumes have been shown at the diagnosis of multiple sclerosis (MS), suggestive of early neurodegeneration processes preceding clinical symptoms. The onset and progression rate of atrophy in early stages and across large time spans in MS is still, however, uncertain.
To analyze cortical atrophy rates in relation to the patient age vs. disease duration, to find a possible impact of age-at-onset on atrophy progression and to retropolate the time of the brain atrophy onset, based on the progression rate and trajectories.
Standardized high-resolution brain volumetric imaging was performed in the Stockholm Prospective Assessment of MS (StopMS) study. A total of 1085 MS patients (age: 11-79 years, disease duration: 0-48 years) were included and 3642 brain MRI scans were performed. FSL-SIENAX was used to evaluate the normalized cortical GM volume and further analyzed using R-libraries. Cortical atrophy rates were assessed in relation to age and disease duration respectively and stratified into five age-at-onset subgroups: <20, 20-30, 30-40, 40-50, >50 years. Locally estimated scatterplot smoothing - LOESS and linear regressions were used to calculate atrophy rates for each subgroup for the first, last and all MRI scans performed per patient (range 1-14 scans per person, median 3 scans) between the ages 17 and 60 years, and duration 0-40 years. Demographic and clinical data were available from the Swedish MS Registry.
Cortical atrophy had a clearly linear progression with patient age. At the group level, the normalized cortical GM volume decreased by 3.1 ml/year. The corresponding annual cortical atrophy rates were 0.43% at age 17 and 0.53% at age 60. Patients with later onset started with lower cortical volume, following a similar linear age trajectory as patients with earlier onset. Similar findings were found for both sexes and all MS subtypes. Primary progressive MS patients, older at diagnosis, had the correspondingly lower cortical volume at their time of diagnosis. Retropolation of cortical atrophy trajectory along the linear age-related slopes to normative values suggested that MS atrophy can possibly start as early as at the age of 13 (time of puberty). Similar GM volume analyses vs. disease duration (instead of age) showed separate atrophy trajectories, where each age-at-onset subgroup started with 350 ml difference in volume at the time of onset and followed its own quasi-linear trajectory. Early age-at-onset subgroups had a higher atrophy rate with disease duration and a late age-at-onset subgroups had the lower rates.
Cortical atrophy progresses linearly from around the time of puberty, i.e. typically before the first reported MS symptom and appears largely independent of reported time of MS onset, diagnosis, or a subtype. Assessments of neurodegeneration in MS should preferably be analyzed in relation to the patient's age rather than the disease duration.