Introduction: Preterm brain injury, commonly manifest as cerebral palsy (CP) is a major public health issue. The cause of injury is multifactorial, however, exposure to systemic inflammation is a major risk factor for injury and long-term disability. Preclinical studies have focused on the neurological consequences of acute fetal infection/inflammation. However, this is analogous to neonatal sepsis which does not reflect the moderate level of inflammation observed in many preterm infants, and is confounded by severe injury. Therefore, we aimed to test the hypothesis that moderate systemic inflammation alters white matter development, and that associated neuropathological changes can be detected using magnetic resonance imaging (MRI).
Materials and methods: Chronically instrumented preterm fetal sheep (0.7 gestation) were randomly assigned to receive either saline (control; n=7) or LPS infusion (200 ng over 24h then doubled every 24h for 96 h to induce moderate systemic inflammation; n=8). 10 days after infusion, fetal brains were collected for histopathology and diffusion tensor MRI.
Results: Moderate systemic inflammation caused a small but significant reduction in mean arterial blood pressure and increased carotid perfusion between 48 and 96 h (P<0.05 vs control), but was not associated with hypotension, tachycardia or increased femoral arterial perfusion. In the periventricular and white matter, systemic inflammation increased astrocyte infiltration and microglial activation (P<0.05 vs. control), and reduced total numbers of (Olig-2+) oligodendrocytes (P<0.05 vs. control). Cellular abnormalities in LPS exposed fetuses were associated with increased fractional anisotropy and reduced orientation dispersion index on diffusion tensor MRI (P<0.05 vs. control).
Discussion: Moderate systemic inflammation is associated with neuroinflammation and impaired oligodendrocyte survival in the periventricular white matter which can be detected using diffusion tensor MRI.