Previous diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI) studies have been used mainly independently to study changes in structural connectivity (SC) of white matter (WM) tracts^1,2 and functional connectivity (FC) of cortical regions^3,4 associated with normal aging. However, the relationship between SC and FC in the context of normal aging remains unknown. A multi-modal analytic approach of DTI and rs-fMRI can simultaneously investigate the relationship between SC and FC changes during aging, and may also help to unravel the complex connectivity changes that occur in age-related diseases, such as dementia. The objective of this work was to investigate SC and FC across the adult lifespan in healthy individuals and to explore their relationship.Healthy participants (n=183; male/female=70/113) aged 18 – 87 years underwent 3 T imaging (Discovery 750; GE Healthcare). DTI acquisition used a single-shot spin-echo echo-planar imaging (EPI) sequence (TE/TR=78/9000 ms) with diffusion sensitizing gradients applied in 31 directions (b=1000 s/mm2) and 4 b=0 volumes. rs-fMRI acquisition used a single-shot gradient-echo EPI sequence (TE/TR=27 ms/2000 ms) to acquire 150 whole brain volumes over 5 minutes. A resting-state network (RSN) template⁵ was used to define cortical brain regions related to seven RSNs (40 cortical regions across both hemispheres). These RSNs were transformed from the template to each subject’s native space for analysis using an in-house automated processing pipeline. Deterministic tractography was performed to delineate WM tracts between pairs of regions within each RSN. Mean, radial, and axial diffusivity (MD, RD, AD) and fractional anisotropy (FA) of WM tracts were computed as measures of SC. Similarly, Pearson correlations of average BOLD signal time series between pairs of regions within each RSN were computed as a measure of FC. A linear model was used to fit the average SC and FC measures with age for each RSN. Further, Pearson correlation coefficients were computed for all SC and FC measures versus age. The absolute rate of change (i.e., slope of the linear trajectory) and correlation coefficients of all measures were ranked to compare the magnitude of change among all RSNs. Finally, the relationship between each SC measure versus FC was investigated using Spearman correlation. P-values <0.05 were considered significant.In general, SC and FC changed linearly with age for all RSNs (Fig 1). FC was negatively correlated (p <0.05) with age in all RSNs except one network (Visual). Similarly, FA was negatively correlated (p <0.001) with age in all RSNs. MD, RD, and AD were generally positively correlated (p <0.001) with age; however, AD remained unchanged in 3 RSNs (Somato-motor, Dorsal and Ventral Attention). The Ventral Attention and Limbic RSNs demonstrated the greatest rate of change and the strongest correlation with age for both FA and FC, whereas the Visual RSN demonstrated the smallest rate of change and weakest correlation with age for the same measures. The rank order of MD, RD, and AD change with age were not consistent with FC (Fig 2). Finally, the Spearman correlation coefficients did not reveal any statistically significant relationship between SC measures (i.e., FA, MD, RD, AD) and FC. The observed age-related changes in both SC and FC among all 7 RSNs are consistent with published independent DTI^1,2 and rs-fMRI^3,4 human brain aging studies. In addition, our results are consistent with a recent multi-modal graph analysis study⁶ where the authors demonstrated a decrease in both FC and FA within RSNs with age in healthy participants. In this study, SC was not correlated with FC in the healthy adult lifespan. The causal relationship between SC and FC age-related changes cannot be addressed in the present study. Future longitudinal studies may elucidate causality, to investigate a possible temporal lag in structural or functional connectivity changes in healthy aging. The multi-modal analysis approach of using DTI and rs-fMRI data simultaneously may also provide further understanding of cognitive decline that often accompanies aging and cognitive impairment due to age-related neurodegenerative diseases such as dementia.