Sex-specific signatures of intrinsic hippocampal networks and regional integrity underlying cognitive status in multiple sclerosis

Abstract

The hippocampus is an anatomically compartmentalized structure imbedded in highly wired networks that are essential for cognitive functions. 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 relation 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 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 among cognitive/memory performance and the network topology in female patients suggests a greater entrainment of brain’s reserve. These results may serve to adapt sex-targeted neuropsychological interventions.

Structural and functional brain damage in women with multiple sclerosis: A mini-review of neuroimaging sex-based studies

“…Increased functional connectivity between different brain regions as a compensatory mechanism for their more extensive GM loss was found in MMS compared to WMS in the study of Sanchis-Segura et al (26). In contrast, some other studies have found worse regional GM damage and related bigger network reorganization in WMS (32). By modeling single-subject intrinsic networks and quantifying subfield volumetric variations, sex-related differences in hippocampal vulnerability were found in a large 2 years longitudinal study of early RRMS (disease duration <5 years) patients compared to age matched controls (32).…”

“…In contrast, some other studies have found worse regional GM damage and related bigger network reorganization in WMS (32). By modeling single-subject intrinsic networks and quantifying subfield volumetric variations, sex-related differences in hippocampal vulnerability were found in a large 2 years longitudinal study of early RRMS (disease duration <5 years) patients compared to age matched controls (32). MMS and WMS were matched for disease duration, cognitive scores, T2HL volumes and hippocampal volume.…”

“…To the best of our knowledge, only few studies have investigated sex-related changes of brain networks in MS ( 26 , 32 , 33 ). In more details, brain networks have been investigated with the use of functional MRI techniques to investigate brain plasticity as an adaptive or maladaptive mechanism in response to brain MS damage ( 34 ).…”

“…Furthermore, longitudinally, WMS developed an even more clustered network organization along with widespread regional tissue loss. Moreover, changes in hippocampal network and anatomical organization worsen overtime in WMS and were tightly related to cognitive performance, suggesting that sex influences cognition ( 32 ). Indeed, despite of the absence of sex-related differences in cognitive/memory performance over time, a strong interrelation between hippocampal network properties and cognitive/memory performance was found only in WMS ( 32 ).…”

Longitudinal changes of deep gray matter shape in multiple sclerosis

“…One limitation of this study is related to the lack of a control group of healthy subjects, which would have possibly allowed for a more clear differentiation between age-related and MS-specific DGM shape changes. In addition, DGM structures with an established central role for cognitive symptoms in MS( Ciolac et al, 2021 , Rocca et al, 2018 ) were not evaluated in our work. Future studies should consider including these structures, especially when cognitive disability in MS is being the main study focus.…”