Decreased hippocampal neurite density in middle-aged/aging adults following prenatal exposure to higher levels of maternal inflammation

In animal models, exposure to heightened maternal inflammation in utero is associated with altered offspring hippocampal development, including reduced dendritic arborization and density. However, the effects of prenatal maternal inflammation (PNMI) on offspring hippocampal microstructure in humans remains unclear. Here, we examined the relationship between exposure to PNMI and neurite density in the hippocampus and its subfields among offspring during late middle age. Participants included 72 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Data for four inflammatory biomarkers (IL-6, IL-8, IL-1 receptor antagonist [IL-1RA], and soluble TNF receptor-II [sTNF-RII]) were available from first and second trimester maternal sera. Neurite density in the offspring hippocampus and its subfields was estimated using microstructural modeling of offsprings diffusion-weighted Magnetic Resonance Imaging data (mean age of offspring at imaging = 59 years; 51% male). We estimated the relationship between each biomarker and region-of-interests neurite density. Higher first trimester maternal IL-1RA and IL-6 levels were associated with lower offspring hippocampal neurite density. These relationships were specific to the CA3, CA4, dentate gyrus, and subiculum subfields. In addition, higher second trimester IL-6 was associated with lower subiculum neurite density. Our findings reveal that exposure to heightened prenatal levels of maternal inflammation is linked to altered offspring hippocampal microstructure in late middle age, which could have implications for memory decreases during this period and may be relevant for understanding risk of aging-related cognitive changes. Significance StatementThe contribution of prenatal maternal inflammation (PNMI) to offspring brain microstructure in later life is well established in animal models but poorly understood in humans. Our study discovered long-lasting impacts of elevated PNMI during early mid-gestation on the structural integrity of the hippocampus in offspring during late middle age. Our findings underscore the potential role of prenatal insults in aging-related neurological and cognitive decline, as the observed degradation in hippocampal microstructure is present over half a century following exposure.