Amygdala volume changes as a potential marker of multiple sclerosis progression: links to EDSS scores and PIRA.

Introduction: Brain atrophy may be a promising marker of relapsing-remitting multiple sclerosis (RRMS) progression, yet it remains underutilized in clinical practice. This exploratory study evaluated correlations between disability-as measured by the Expanded Disability Status Scale (EDSS) and progression independent of relapse activity (PIRA)-and volumetric changes in RRMS patients treated with cladribine tablets (CLAD) or alemtuzumab (ALEM). Methods: Clinical and magnetic resonance imaging (MRI) data from patients with RRMS were retrospectively analyzed at four time points: pretreatment and annually over three years of follow-up. Volumetric measurements were obtained using FreeSurfer. Annual volumetric and EDSS changes were pooled together to assess short-term associations and patient-wise longitudinal analyses were performed. Results: 33 patients treated with CLAD and 19 patients treated with ALEM were included. Analyzing year-to-year correlations, a significant positive correlation was found between EDSS and amygdala volume changes (p = 0.00009, η²=0,15657). It was also observed for the pallidum (p=0,02605, η²=0,05384). On the contrary, a negative correlation between thalamic volume changes and EDSS in CLAD group was noted (p=0,04551, η²=0,07203).When comparing annual percentage volume changes across three groups-years with EDSS progression (n = 10), regression (n = 11), and no changes (n = 74)-significant differences were reported in amygdala (p=0,00640; 1.98%, -4%, -0.8%), thalamus (p = 0,04390; -0.54%, 2.98%, 0.1%) and pallidum (p = 0,02904; 1.98%, -6.96%, -0.23%). Finally, among the 10 patients with EDSS progression, an increase in amygdala volume was observed in 3 patients with PIRA, whereas it was not seen in the 7 patients whose EDSS progression was associated with relapsing activity (p = 0.0188; 4.60% vs. 0.004%). Conclusion: Over three years of follow-up in RRMS patients, EDSS progression was positively associated with increases in amygdala-and, to a lesser extent, pallidum-volumes, while worsening disability correlated with thalamic atrophy. Notably, amygdala enlargement was exclusive to patients with PIRA versus relapse-associated worsening, highlighting its potential as a volumetric biomarker of disease progression. However it was exploratory, hypothesis-generating observation and further studies are warranted to validate these findings and elucidate the underlying mechanisms.