The hippocampus is a complex anatomical structure with a fine-tuned intrinsic network architecture, shaped by functional and structural compartmentalization. The hippocampus is affected early in multiple sclerosis (MS) and besides focal neuroinflammatory damage, network disruption is thought to account for cognitive deficits in MS. Given the sex-related vulnerability to cognitive decline in MS, sex-driven differences in hippocampal networks and regional integrity can be hypothesized.
To characterize sex effects on hippocampal network organization and subfield integrity, and their relation to cognitive performance.
In a cohort of 476 MS patients (age 35±10 years), 337 females and 139 males with a disease duration of 16±14 months were imaged on a 3T MRI scanner at baseline and after 2 years. A control group of healthy subjects (HS, n=110, age 34±15 years, 54 females) was included. Volumes of 12 hippocampal subfields were quantified and fed into the reconstruction of the single-subject morphometric networks and analyzed within the graph theoretical framework. Sex-related differences in network and subfield properties were evaluated with linear mixed-effects models, adjusted for age, center and total hippocampal volume; p-values are reported after Bonferroni correction for multiple comparisons.
At baseline, both female and male patients displayed higher clustering (p<0.05) compared to HS. Female patients had higher clustering (p<0.05) but equally efficient network organization (local and global efficiency, p>0.05) compared to male patients. At follow-ups, independently of sex, patients had increased modularity, clustering and global efficiency, however, with higher values in female patients (all p<0.05). Both female and male patients had lower volumes in almost all subfields compared to HS. Female patients had smaller parasubiculum and presubiculum but larger molecular layer as compared to male patients. Over time, female patients had more widespread regional volumetric reduction compared to male patients. Cognitive performance was positively associated with clustering (r=0.27, p<0.01), local (r=0.25, p<0.01) and global efficiency (r=0.24, p<0.01) only in female but not in male patients.
Our findings suggest a more clustered and modular network architecture in female patients despite a more extensive local atrophy over time. The stronger association of cognitive performance with intrinsic hippocampal connectivity may explain cognitive reserve in female patients. These results may serve for sex-targeted neuropsychological interventions.