Trajectories and sex differences of brain structure, oxygenation and perfusion functions in normal aging

Background: Brain structure, oxygenation and perfusion are important factors in aging. Coupling between regional cerebral oxygen consumption and perfusion also reflects functions of neurovascular unit (NVU). Their trajectories and sex differences during normal aging important for clinical interpretation are still not well defined. In this study, we aim to investigate the relationship between brain structure, functions and age, and exam the sex disparities.

Method: A total of 137 healthy subjects between 20∼69 years old were enrolled with conventional MRI, structural three-dimensional T₁-weighted imaging (3D-T₁WI), 3D multi-echo gradient echo sequence (3D-mGRE), and 3D pseudo-continuous arterial spin labeling (3D-pCASL). Oxygen extraction fraction (OEF) and cerebral blood flow (CBF) were respectively reconstructed from 3D-mGRE and 3D-pCASL images. Cerebral metabolic rate of oxygen (CMRO₂) were calculated as follows: $\text{CMR}{O}_2=\text{CBF}·\text{OEF}·{\left[H\right]}_a$, ${\left[H\right]}_a$=7.377 μmol/mL. Brains were segmented into global gray matter (GM), global white matter (WM), and 148 cortical subregions. OEF, CBF, CMRO₂, and volumes of GM/WM relative to intracranial volumes (rel_GM/rel_WM) were compared between males and females. Generalized additive models were used to evaluate the aging trajectories of brain structure and functions. The coupling between OEF and CBF was analyzed by correlation analysis. P or P_FDR < 0.05 was considered statistically significant.

Results: Females had larger rel_GM, higher CMRO₂ and CBF of GM/WM than males (P < 0.05). With control of sex, CBF of GM significantly declined between 20 and 32 years, CMRO₂ of GM declined subsequently from 33 to 41 years and rel_GM decreased significantly at all ages (R² = 0.27, P < 0.001; R² = 0.17, P < 0.001; R² = 0.52, P < 0.001). In subregion analysis, CBF declined dispersedly while CMRO₂ declined widely across most subregions of the cortex during aging. Robust negative coupling between OEF and CBF was found in most of the subregions (r range = -0.12∼-0.48, P_FDR < 0.05).

Conclusion: The sex disparities, age trajectories of brain structure and functions as well as the coupling of NVU in healthy individuals provide insights into normal aging which are potential targets for study of pathological conditions.