Age-Related Decline in Myelin Markers and Oligodendrocyte Density in Rhesus Macaque Prefrontal Cortex

Age-related alterations in myelin are a prominent feature of brain aging, yet how myelin-associated markers and oligodendrocyte lineage cell populations change across the primate lifespan remains incompletely characterized. Here, we provide a multimodal, cross-sectional analysis of myelin-related imaging and cellular markers in the prefrontal cortex (PFC) of age-matched both male and female rhesus macaques across postnatal development and aging using a multimodal approach combining magnetic resonance imaging (MRI), histological analysis, immunohistochemistry, and RNAscope in situ hybridization. We quantified regional gray and white matter volumes and myelin water fraction measures in prefrontal cortex (PFC) subregions BA9 and BA46 across four age groups: 5, 10, 15, and 30 years. Myelin water fraction and regional brain volumes exhibited age-dependent increases from childhood through adolescence, peaking at 15 years, followed by a decline in aged animals. Histological analyses revealed age-associated changes in myelin organization and the presence of myelin fragments within Iba1-positive microglia, along with dynamic alterations in the density of cells expressing oligodendrocyte lineage-associated markers, including Olig2 and oligodendrocyte precursor cell (OPC)-associated markers, in BA9 and BA46. OPC density displayed a nonlinear, age-associated pattern across developmental and aging stages, coinciding temporally with changes in myelin-associated imaging measures. Our findings define an age-related framework of myelin alterations and oligodendrocyte lineage markers in the primate prefrontal cortex. This work establishes a reference dataset for oligodendrocyte lineage dynamics across the lifespan in a translationally relevant primate model, providing a foundation for future mechanistic and interventional studies of myelin maintenance during brain aging.