Spatial statistics and point pattern analysis reveal lifespan trajectories of microglial density and clustering in the primate hippocampus

The hippocampus undergoes substantial structural remodeling across the lifespan, yet how its resident immune cells, microglia, reorganize during development and aging remains poorly understood in primates. We quantified microglial density and spatial organization across hippocampal subfields in 15 female rhesus macaques spanning late gestation (gestational day 140) to advanced age (32.4 years) using tissue from the MacBrain Resource Center. Animals were grouped as perinatal (GD140-7 days postnatal), postnatal (2.5-6 months), juvenile/adult (11.4 months-9.8 years), and aged (18.7-32.4 years). Microglial density exhibited a U-shaped trajectory, declining during early postnatal life before increasing through adulthood and aging, with the dentate gyrus showing the greatest age-related change. Nearest-neighbor distance followed an inverse pattern, indicating maximal microglial dispersion during the postnatal period. Ripley's H-function analysis revealed age-dependent alterations in microglial territorial organization, including an expanded exclusion radius in aged animals. Tile-based spatial analyses further identified increased microglial clustering within CA1 in the aged group. In the oldest animal, regions of microglial clustering corresponded with amyloid-β and phosphorylated tau immunoreactivity. Together, these findings demonstrate dynamic lifespan-dependent remodeling of microglial spatial organization and establish a quantitative framework for studying neuroimmune architecture in the aging primate hippocampus.