Sex-specific signatures of intrinsic hippocampal networks and regional integrity underlying cognitive status in multiple sclerosis
Authors: Ciolac Dumitru , Gonzalez-Escamilla Gabriel , Radetz Angela , Fleischer Vinzenz , Person Maren , Johnen Andreas , Landmeyer Nils C , Krämer Julia , Muthuraman Muthuraman , Meuth Sven G , Groppa Sergiu 
Published: August 2021

Abstract
The hippocampus is an anatomically compartmentalized structure embedded in highly wired networks that are essential for cognitive functions. The hippocampal vulnerability has been postulated in acute and chronic neuroinflammation in multiple sclerosis, while the patterns of occurring inflammation, neurodegeneration or compensation have not yet been described. Besides focal damage to hippocampal tissue, network disruption is an important contributor to cognitive decline in multiple sclerosis patients. We postulate sex-specific trajectories in hippocampal network reorganization and regional integrity and address their relationship to markers of neuroinflammation, cognitive/memory performance and clinical severity. In a large cohort of multiple sclerosis patients (n = 476; 337 females, age 35 ± 10 years, disease duration 16 ± 14 months) and healthy subjects (n = 110, 54 females; age 34 ± 15 years), we utilized MRI at baseline and at 2-year follow-up to quantify regional hippocampal volumetry and reconstruct single-subject hippocampal networks. Through graph analytical tools we assessed the clustered topology of the hippocampal networks. Mixed-effects analyses served to model sex-based differences in hippocampal network and subfield integrity between multiple sclerosis patients and healthy subjects at both time points and longitudinally. Afterwards, hippocampal network and subfield integrity were related to clinical and radiological variables in dependency of sex attribution. We found a more clustered network architecture in both female and male patients compared to their healthy counterparts. At both time points, female patients displayed a more clustered network topology in comparison to male patients. Over time, multiple sclerosis patients developed an even more clustered network architecture, though with a greater magnitude in females. We detected reduced regional volumes in most of the addressed hippocampal subfields in both female and male patients compared to healthy subjects. Compared to male patients, females displayed lower volumes of para- and presubiculum but higher volumes of the molecular layer. Longitudinally, volumetric alterations were more pronounced in female patients, which showed a more extensive regional tissue loss. Despite a comparable cognitive/memory performance between female and male patients over the follow-up period, we identified a strong interrelation between hippocampal network properties and cognitive/memory performance only in female patients. Our findings evidence a more clustered hippocampal network topology in female patients with a more extensive subfield volume loss over time. A stronger relation between cognitive/memory performance and the network topology in female patients suggests greater entrainment of the brain’s reserve. These results may serve to adapt sex-targeted neuropsychological interventions.