Parental age effects on neonatal white matter development

Oliver Gale-Grant,Daan Christiaens,Lucilio Cordero-Grande,Andrew Chew,Shona Falconer,Antonios Makropoulos,Nicholas Harper,Anthony N Price,Jana Hutter,Emer Hughes,Suresh Victor,Serena J Counsell,Daniel Rueckert,Joseph V Hajnal,A David Edwards,Jonathan O'Muircheartaigh,Dafnis Batalle

doi:10.1016/j.nicl.2020.102283

Oliver Gale-Grant, Daan Christiaens + Show 15 more

Open Access

https://doi.org/10.1016/j.nicl.2020.102283

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Abstract

ObjectiveAdvanced paternal age is associated with poor offspring developmental outcome. Though an increase in paternal age-related germline mutations may affect offspring white matter development, outcome differences could also be due to psychosocial factors. Here we investigate possible cerebral changes prior to strong environmental influences using brain MRI in a cohort of healthy term-born neonates. MethodsWe used structural and diffusion MRI images acquired soon after birth from a cohort (n = 275) of healthy term-born neonates. Images were analysed using a customised tract based spatial statistics (TBSS) processing pipeline. Neurodevelopmental assessment using the Bayley-III scales was offered to all participants at age 18 months. For statistical analysis neonates were compared in two groups, representing the upper quartile (paternal age ≥38 years) and lower three quartiles. The same method was used to assess associations with maternal age. ResultsIn infants with older fathers (≥38 years), fractional anisotropy, a marker of white matter organisation, was significantly reduced in three early maturing anatomical locations (the corticospinal tract, the corpus callosum, and the optic radiation). Fractional anisotropy in these locations correlated positively with Bayley-III cognitive composite score at 18 months in the advanced paternal age group. A small but significant reduction in total brain volume was also observed in in the infants of older fathers. No significant associations were found between advanced maternal age and neonatal imaging. ConclusionsThe epidemiological association between advanced paternal age and offspring outcome is extremely robust. We have for the first time demonstrated a neuroimaging phenotype of advanced paternal age before sustained parental interaction that correlates with later outcome.

Highlights

Mean paternal age is increasing in many countries and advanced paternal age is strongly associated with an increased risk to offspring of multiple neurodevelopmental disorders including schizophrenia (Fountoulakis et al, 2018), bipolar disorder (Chudal et al, 2014) and autism (Khandwala et al, 2018), as well as non-clinical negative outcomes such as poor academic achievement (D'Onofrio et al, 2014).Despite ample epidemiological evidence, the mechanism by which this risk is conferred is not clear
tract based spatial statistics (TBSS) revealed 3 clusters of significant difference in Fractional anisotropy (FA) between the offspring of older and younger fathers after accounting for maternal age, age at birth and age at scan as confounding factors, with lower FA values observed in the offspring of older fathers: within the genu of the corpus callosum; the left corticospinal tract; and the left optic radiation (Fig. 1A)
Similar patterns of difference were observed in Mean diffusivity (MD) and radial diffusivity (RD) no areas of statistical significance were observed in axial diffusivity (AD) (Fig. 1B, C)

Summary

Introduction

Mean paternal age is increasing in many countries and advanced paternal age is strongly associated with an increased risk to offspring of multiple neurodevelopmental disorders including schizophrenia (Fountoulakis et al, 2018), bipolar disorder (Chudal et al, 2014) and autism (Khandwala et al, 2018), as well as non-clinical negative outcomes such as poor academic achievement (D'Onofrio et al, 2014).Despite ample epidemiological evidence, the mechanism by which this risk is conferred is not clear. Mean paternal age is increasing in many countries and advanced paternal age is strongly associated with an increased risk to offspring of multiple neurodevelopmental disorders including schizophrenia (Fountoulakis et al, 2018), bipolar disorder (Chudal et al, 2014) and autism (Khandwala et al, 2018), as well as non-clinical negative outcomes such as poor academic achievement (D'Onofrio et al, 2014). Mechanisms of transcriptional control, including DNA methylation, become more error prone with age (Horvath, 2013). Few studies have observed associations of advanced maternal age and childhood neuropsychiatric outcome (Sandin et al, 2012).

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