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Parental Age Effects On Neonatal White Matter Development

O Gale-Grant1,2, D Christiaens1, L Cordero-Grande1, A Chew1, S Falconer1, A Makropoulos3, N Harper1, A Price1, J Hutter1, E Hughes1, S Victor1, S Counsell1, D Rueckert3, J Hajnal1, J O’Muircheartaigh1,2,4, D 
1. Centre for the Developing Brain, King’s College London, London, UK. 2. MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK. 3. Department of Computing, Imperial College London, Exhibition Rd, London, UK. 4. Department of Forensic and Neurodevelopmental Science, King’s College London, London, UK 
Introduction (include hypothesis) 
An increased risk of neuropsychiatric disorder is observed in the offspring of older fathers. An age related increase in paternal germline mutations or age related epigenetic differences may explain this association, however adverse outcomes could also be due to early childhood psychosocial factors1. We used neonatal MRI to investigate the theory that paternal age may be associated with altered white matter microstructure, a neuroimaging phenotype associated with both genetic risk factors and later neurodevelopmental outcome. 
Methods (include source of funding and ethical approval if required) 
Following ethical approval, structural and diffusion-weighted brain MR images were acquired soon after birth in 275 healthy term-born neonates as part of the Developing Human Connectome Project. Neurodevelopmental assessment was done at 18 months using the Bayley-III Scales. Individuals were split into groups representing the upper quartile (paternal age ≥38 years, maternal age ≥37 years) and the lower three quartiles of parental age at conception for analysis. Fractional anisotropy maps were generated for each subject, and nonparametric permutation inference statistics were used to identify white matter areas of significance. 
In the advanced paternal age group fractional anisotropy was significantly reduced (p<0.01) in three early myelinating anatomical locations; the L corticospinal tract (shown here), the corpus collosum, and the L optic radiation after correction for covariates. There was however no association between maternal age and offspring white matter microstructure. The fractional anisotropy of the most significant cluster of difference, the corticospinal tract, correlated strongly with Bayley-III cognitive composite score at 18 months in the group of advanced paternal age (r2 =0.15, p=0.002) but not in those with younger fathers. 
To date evidence of the link between paternal age and offspring neurodevelopmental outcome is from large scale epidemiological studies1. We have now demonstrated a neonatal neuroimaging phenotype of advanced paternal age before sustained parental interaction that correlates with later outcome. 
1. Hultman, C.M., et al., Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry, 2011. 16(12): p. 1203-12. 

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