Olfactory dysfunction and limbic volumetric changes in relapsing-remitting and secondary progressive multiple...

To compare olfactory performance and olfactory-related brain region volumes between patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) and to examine the relationship between olfactory performance and regional brain volumes.

This prospective cross-sectional study included 65 patients with MS (43 RRMS and 22 SPMS). Olfactory function was assessed using the Sniffin' Sticks-12 Odor Identification Test. Bilateral volumes of the hippocampus, amygdala, entorhinal cortex, and insular cortex were obtained from three-dimensional T1-weighted MRI using the vol2Brain automated analysis pipeline available through the volBrain platform. Both raw and total intracranial volume (TIV)-normalized regional volumes were analyzed. For volumetric outcomes, multivariable analyses were adjusted for age, sex, and TIV, whereas analyses of olfactory performance were adjusted for age and sex. Additional sensitivity analyses incorporated disease duration and EDSS.

In unadjusted comparisons, patients with SPMS had significantly lower Sniffin' Sticks-12 scores than those with RRMS (p = 0.004), and raw hippocampal volume was significantly lower in the SPMS group (p = 0.028). However, after adjustment for age, sex, and TIV, clinical subtype was not independently associated with hippocampal, amygdala, entorhinal cortex, or insular cortex volume (all p > 0.05). These findings remained non-significant in sensitivity analyses additionally accounting for disease duration and EDSS. The between-group difference in Sniffin' Sticks-12 scores was also attenuated after adjustment for age and sex (B = - 1.06; 95% CI, - 2.15 to 0.04; p = 0.058) and remained non-significant in further sensitivity analyses. No significant correlations were observed between Sniffin' Sticks-12 scores and regional volumetric measures.

Although patients with SPMS showed poorer olfactory performance and lower raw hippocampal volume in unadjusted comparisons, clinical subtype was not independently associated with regional brain volumes after adjustment for age, sex, and TIV, and the olfactory difference did not reach statistical significance after adjustment for age and sex. Furthermore, olfactory performance was not directly associated with regional volumetric measures, suggesting that olfactory dysfunction in MS may reflect mechanisms beyond regional structural volume alone.