Reduced cholinergic basal forebrain integrity links neonatal complications and adult cognitive deficits after premature birth

Background Premature-born individuals have an increased risk for long-term neurocognitive impairments. In animal models, the development of the cholinergic basal forebrain (cBF) is selectively vulnerable to adverse effects of perinatal stressors, and impaired cBF integrity results in lasting cognitive deficits. We hypothesized that in premature-born individuals cBF integrity is impaired and mediates adult cognitive impairments associated with prematurity. Methods We used MRI-based volumetric assessments of a cytoarchitectonically defined cBF region-of-interest to determine differences in cBF integrity between 99 adults who were born very preterm and/or with very low birth weight (VP/VLBW) and 106 term born controls from the same birth cohort. MRI-derived cBF volumes were studied in relation to neonatal clinical complications after delivery as well as intelligence measures (IQ) in adulthood. Results In VP/VLBW adults, cBF volumes were significantly reduced compared to term-born adults (-4.5%, F(1, 202) = 11.82, p = 0.001). Lower cBF volume in VP/VLBW adults was specifically associated with both neonatal complications (rpart(92) = -0.35, p < 0.001) and adult IQ (rpart(88) = 0.33, p = 0.001) even after controlling for global gray matter and white matter volume. In an additional path analytic model, cBF volume significantly mediated the association between neonatal complications and adult cognitive deficits. Conclusions Results provide first time evidence in humans that cBF integrity is impaired after premature birth and links neonatal complications with long-term cognitive outcome. Data suggest that cholinergic system abnormalities may play a relevant role for long-term neurocognitive impairments associated with premature delivery