Healthy aging is accompanied by disruptions in the functional modular organization of the human brain. Cross-sectional studies have shown age-related reductions in the functional segregation and distinctiveness of brain networks. However, less is known about the longitudinal changes in brain functional modular organization and their associations with aging-related cognitive decline. We examined age-and aging-related changes in functional architecture of the cerebral cortex using a dataset comprising a cross-sectional healthy young cohort of 57 individuals (mean +/- SD age, 23.71 +/- 3.61 years, 22 males) and a longitudinal healthy elderly cohort of 72 individuals (mean +/- baseline age, 68.22 +/- 5.80 years, 39 males) with 2-3 time points (18-24 months apart) of task-free fMRI data. We found both cross-sectional (elderly vs young) and longitudinal (in elderly) global decreases in network segregation (decreased local efficiency), integration (decreased global efficiency), and module distinctiveness (increased participation coefficient and decreased system segregation). At the modular level, whereas cross-sectional analyses revealed higher participation coefficient across all modules in the elderly compared with young participants, longitudinal analyses revealed focal longitudinal participation coefficient increases in three higher-order cognitive modules: control network, default mode network, and salience/ventral attention network. Cross-sectionally, elderly participants also showed worse attention performance with lower local efficiency and higher mean participation coefficient, and worse global cognitive performance with higher participation coefficient in the dorsal attention/control network. These findings suggest that healthy aging is associated with whole-brain connectome-wide changes in the functional modular organization of the brain, accompanied by loss of functional segregation, particularly in higher-order cognitive networks.
