Cardiac Comorbidities and Their Effect in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is characterised by neurodevelopmental and behavioural deficits, while having associated comorbidities, amongst which cardiac are common. ASD and congenital heart disease (CHD) are linked on a functional and genetic level. Most work focuses on CHD-related neurodevelopmental abnormalities; less so on ASD-related cardiac abnormalities. The first aim of this work is the identification of the cardiac phenotype associated with prominent genetic contributors of ASD. The second aim is the interrogation of the association between the cardiac and neuroanatomical phenotypes observed. We hypothesize the existence of cardiac abnormalities and their association to neuroanatomy in the presence of ASD-related genetic abnormalities.ASD presents high etiological and phenotypic heterogeneity. Preclinical studies allow for rigorous experimental design using numerous animal models, which together provide an approximation to the disorder. We firstly reviewed the types of animal models and phenotyping methods employed in preclinical studies, along with the most prominent treatments considered. High variability was documented. Identification of common mechanistic processes, arising from diverse genetic causes, enabling patient stratification, seems essential for future treatment development. For the purposes of this dissertation, mouse models of ASD were used, while high-frequency ultrasound biomicroscopy (UBM) and magnetic resonance imaging (3D ex-vivo structural MRI) were chosen for the cardiac and neuroanatomical phenotyping respectively. The prevalence of cardiac comorbidities was investigated in 9 ASD-related genetic mouse models (Arid1b(+/-), Chd8(+/-), 16p11.2 (deletion), Sgsh(+/-), Sgsh(-/-), Shank3 Dexon 4-9(+/-), Shank3 Dexon 4-9(-/-), Fmr1(-/-), Vps13b(+/-)), and pooled wild-type littermates (WTs). Mutant groups (MUTs) presented small-scale alterations in cardiac structure and function. Among MUTs there were more cardiac differences, primarily in structural measures, than between MUTs and WTs, recapitulating the characteristic ASD heterogeneity. The association of the cardiac comorbidities on neuroanatomy was interrogated for 6 of these models (Arid1b(+/-), 16p11.2 (deletion), Sgsh(+/-), Sgsh(-/-), Fmr1(-/-), Vps13b(+/-)), for which brain MRIs were obtained. Using blind source separation (BSS) analysis, we identified three mechanisms driving the heart-brain interactions. The first is the autonomic regulation of the heart by the brain, the second is the effect cardiac function has on the brain through blood flow and the supply of necessary oxygen and nutrients, and the third involves a congenital cardiac malformation impacting lower order brain functions, such as motor regulation. The second and third mechanisms were also identified in the International Mouse Phenotyping Consortium (IMPC) dataset, comprising of a different set of cardiac measures and neuroanatomical information for mouse models of the same type of genetic contributors of ASD (www.mousephenotype.org) (Dickinson et al. 2016), after performing the same analysis, supporting the generalisability of our findings. Our results shed light on the presence and role of cardiac comorbidities in ASD. Furthermore, they demonstrate the impact of even non-lethal cardiac abnormalities on development, recapitulating already established clinical observations in non-ASD cases. This dissertation highlights additional potential aetiologies of the observed neuroanatomical particularities in ASD, which, if validated in humans, can have an important clinical impact, in prognosis, prevention and treatment.

Advisor: Lerch, Jason P.