Age at MS Disease Onset Affects Pathophysiology, Gray and White Matter

Raffaello Bonacchi, MD

Data from a hypothesis-driven, cross-sectional study suggested that age at disease onset influences brain gray matter volume (GMV) and white matter (WM) microstructural abnormalities in multiple sclerosis (MS). Furthermore, the results also indicated that younger patients with the disease were more resilient to MS-related damage, but with increasing disease-duration (DD), they began to experience the loss of WM integrity first, followed by GM atrophy, and then disability.

Led by Raffaello Bonacchi, MD, Division of Neuroscience, Vita-Salute San Raffaele University, this study compared 2 DD-matched cohorts of pediatric-onset MS (POMS; n = 67) and adult-onset MS (AOMS; n = 143), along with 208 healthy controls (HC). Each patient had 3T MRI acquisition along with neurologic examination, with rating on Expanded Disability Status Scale (EDSS), assessment of DD, and administration of the 9-Hole Peg Test, Timed 25-Foot Walk, and Paced Auditory Serial Addition Test, as part of the Multiple Sclerosis Functional Composite (MSFC).

Patients’ time to reach clinical and MRI milestones were assessed with a product-limit approach. At the DD 1-year mark, GMV and WM fractional anisotropy (FA) were not altered in POMS, whereas they were already abnormal in patients with AOMS (P ranging from 0.03 to <.001), compared with HCs. Those with AOMS also showed a reduction of all global and regional GMV metrics (P ≤ .01), as well as of FA values of global WM, inferior longitudinal fasciculus, uncinate fasciculus, and corticospinal tract (P ranging from 0.02 to 0.05).

READ MORE: Comprehensive Care and Collaboration for Multiple Sclerosis

Ten years into their DD, patients with AOMS had lower global and regional GMV as compared with those with POMS (P ranging from 0.005 to 0.02). At this time, the 2 groups showed no difference in global and regional WM FA values.

At the DD 20-year mark, investigators found no significant between-group differences between the age of onset for any of the MRI variables. This stayed consistent at DD 30 years; however, those in the POMS group had more abnormal FA values of global WM, uncinate fasciculus, and middle cerebellar peduncle (P ranging from 0.01 to 0.05).

"From a clinical perspective, this study indirectly supports the use of highly effective disease-modifying treatments from the early stages of disease in patients with POMS, even in the absence of persistent physical disability, given they might reduce the amount of neuroaxonal damage,and we found more pronounced WM and GM integrity loss over time in POMS vs AOMS," the study authors wrote. "However, future long-term longitudinal studies on treatment efficacy, also considering time to treatment initiation, are needed for conclusive evidence."

Associations with DD in patients with POMS and patients with AOMS were studied using linear models. Using this, investigators found the crossing-point of regression lines in POMS and AOMS to be 20 years of DD for GMV and 14 years for WM FA. Additionally, the median crossing-point of regression lines between the groups was 21 years of DD for regional GMB, frontal lobe, parietal lobe, middle-to-posterior cingulate cortex, and basal ganglia.

The time to clinical and MRI milestones was different between the 2 MS groups. For POMS, the median time to reach EDSS of 3.0 was 29 years of DD compared with 19 years for those with AOMS (P <.001). The median age to reach that milestone was 46 and 53 years, respectively, for patients with POMS and AOMS (P <.001). Although the groups did not differ in terms of median time to reach EDSS scores of 6.0, the median age was younger for those with POMS vs AOMS (47 vs 60 years; P <.001).

Patients with POMS had a median of 31 years of PDD to reach PASAT-3 z score –1.645 compared to 26 years for those with AOMS (P = .01). Furthermore, the median time to reach MSFC z score –1.645 and GMV z score –1.645 was 29 and 24 years of DD for those with POMS vs 21 and 18 years of DD for those with AOMS, respectively. The median DD to reach brain WM FA z score­ –1.645 did not differ between POMS and AOMS (19 vs 17 years; P = .36), whereas median age was 37 years in the POMS group compared to 52 in the AOMS group (P <.001).

Have you nominated your Giant of Multiple Sclerosis? Help us recognize and celebrate pioneers, innovators, and leaders in MS. Nominate today.

REFERENCE
Bonacchi R, Meani A, Pagani E, et al. Association of age at onset with gray matter volume and white matter microstructural abnormalities in people with multiple sclerosis. Neurology. 2021;97(20): e2007-e2019. doi:10.1212/WNL.0000000000012869