Disruption of structural connectome hierarchy in age-related hearing loss.

Introduction: Age-related hearing loss (ARHL) is a common sensory disability among older adults and is considered a risk factor for the development of dementia. Previous work has shown altered brain connectome topology in ARHL, including abnormal nodal strength and clustering coefficient. However, whether ARHL affects the hierarchical organization of structural connectome and how these alterations relate to transcriptomic signatures remain unknown. Methods: Here, we apply a gradient mapping framework to the structural connectome derived from diffusion magnetic resonance imaging. We focus on the first three structural gradients that reflect distinct hierarchical organization of structural connectome, and assess ARHL-related changes. Results: We find that, compared to controls, ARHL patients exhibit widespread disruptions of structural connectome organization, spanning from primary sensory areas (e.g., somatomotor network) to high-order association areas (e.g., default mode network). Subsequently, by employing subcortical-weighted gradients derived from weighting cortical gradients by subcortical-cortical connectivity, we observe that ARHL patients show significantly altered subcortical-cortical connectivity in the left caudate, left nucleus accumbens, right hippocampus, and right amygdala. Finally, we investigate the relationship between gene expression and alterations in structural gradients. We observe that these alterations in structural gradients are associated with weighted gene expression profiles, with relevant genes preferentially enriched for inorganic ion transmembrane transport and terms related to regulating biological processes. Discussion: Taken together, these findings highlight that ARHL is associated with abnormal structural connectome hierarchy and reveal the transcriptomic relevance of these abnormalities, contributing to a richer understanding of the neurobiological substrates in ARHL.