White matter microstructure on diffusion tensor imaging is associated with conventional magnetic resonance imaging findings and cognitive function in adolescents born preterm

Infants born preterm are at high risk of cognitive disability and associated deficits that persist into adolescence and young adulthood.1,2 These deficits have been attributed to a distinctive pattern of periventricular white matter injury within a global pattern of neonatal encephalopathy.3 A cascade of adverse events begins with ischemia and/or hypoxia. Free radical-mediated injury to oligodendrocyte progenitors ultimately disrupts the maturation of myelin-producing cells.4 Improvements in neonatal intensive care have led to a substantial reduction in the prevalence of cystic periventricular white matter injury.4 However, evidence of non-focal white matter injury can be found on conventional magnetic resonance imaging (MRI) and is associated with adverse outcomes.5 Diffusion tensor imaging (DTI) is an MRI technique for characterizing the microstructural properties of white matter,6 based on the rate and diffusion of water in the brain.7 In white matter, water diffusion is anisotropic, relatively unimpeded in the direction of the axon, and restricted in directions perpendicular to the axon. The rate of diffusion along the principal axis is called axial diffusivity and the perpendicular rate of diffusion is called radial diffusivity. Fractional anisotropy is a value between zero and 1.0 derived from these measures that indicates the degree of anisotropy. Factors that reduce diffusion perpendicular to the orientation of the axon include dense axonal packing, large axonal diameters, and high levels of myelination. Because these factors increase with age and decrease with injury and illness, higher fractional anisotropy values are generally considered as an index of maturity and good health.7,8 However, high fractional anisotropy values have also been found in clinical populations in which disruption of connectivity was expected.9–11 Many DTI studies in adolescents and adults who were born preterm have found lower fractional anisotropy values across many white matter regions.12–15 However, a few studies do not replicate this pattern. Frye et al.16 found no consistent differences in fractional anisotropy on association tracts when comparing 16-year-olds born preterm and at term. Kontis et al.17 found no differences in fractional anisotropy or mean diffusivity in the corpus callosum between very preterm and term groups. A recent study by Allin et al.18 found that, among adults who were born preterm, fractional anisotropy was lower in some tracts but higher in other tracts than among a comparison group. Discrepancies across studies may be related to the participants’ degree of illness in the newborn period. Near-term imaging of children born preterm shows that complications of preterm birth, not pre term birth per se, are associated with injury to white matter.19 Many studies report positive associations between DTI measures and a variety of neurocognitive and neurobehavioral functions in preterm children.9,10 Such findings are also inconsistent. Some studies find associations of function with white matter volume but not fractional anisotropy in preterm groups.16 The first goal of this study was to compare white matter microstructure in two cohorts of children and adolescents, one born preterm and one born at term. Distinctive features of this sample were that the participants were born across the spectrum of gestational age (24–36wks) and that the mean IQ was within the average range.17,18 We hypothesized that we would find lower fractional anisotropy and higher radial diffusivity in children born preterm than in those born at term, controlling for age at DTI.20 The second goal was to understand the factors associated with microstructural properties of white matter within the preterm group. We hypothesized that fractional anisotropy values would be lower in males than in females;14,21 that fractional anisotropy would be positively associated with gestational age/birthweight12,15 and IQ;12,14,15 and that fractional anisotropy would be negatively associated with the degree of injury on conventional MRI.