Diverse clinical presentation in neurodevelopmental disorders (NDDs) leads to difficulty in matching individuals with effective treatments. Autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) are the two most prevalent neurodevelopmental disorders (NDDs), characterized by deficits in communication, social interactions, and behaviours. There is high within-diagnosis heterogeneity and striking overlap between diagnoses. The literature suggests that current diagnostic criteria do not align well with behaviour metrics. Therefore, identifying novel biomarkers underlying behaviour in NDDs may provide a reliable way to group individuals with similar behavioural phenotypes. This thesis examines how gut-immune biology is linked to clinical heterogeneity in children with NDDs. The first study used unsupervised machine learning to cluster typically developing (TD), ADHD, and ASD participants by their behaviour metrics in a diagnosis-agnostic approach. The results produced a six-cluster solution, five of which were a mix of all diagnostic categories. Further, gastrointestinal (GI) symptoms were mapped to the clusters, revealing a link between constipation, social communication deficits and restrictive-repetitive behaviours. The second study used hierarchical clustering to group TD and NDD participants based on a profile of gut and inflammatory markers. Participants clustered into two biotypes, both containing TD and NDD participants. Additionally, using regression analysis, novel markers were linked to anxiety. The third study evaluated the multisite biospecimen collection protocol of the Province of Ontario Neurodevelopmental Disorders (POND) Network. The final study used biospecimens collected from the POND network to phenotype peripheral blood mononuclear cells in TD and NDD participants. In NDD groups, monocyte and B cell activation markers were differentially expressed compared to TD. Overall, this thesis demonstrates that gut-immune mechanisms contribute to clinical heterogeneity in a subset of people and contribute to the search for biomarkers in NDDs. / Thesis / Doctor of Philosophy (PhD) / Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are diagnosed based on behavioural symptoms. However, symptoms can vary a lot from person to person, and some symptoms are shared between ASD and ADHD. Understanding the biological reasons for symptom differences between people can help pinpoint treatments which work best for an individual. This thesis looks at the role of the gut and immune system in ASD and ADHD. Blood samples and behaviour questionnaires were collected to study how immune cells, inflammation, and intestinal permeability shape behaviour symptoms. The results show that diagnosis is not the most accurate way to group people. Anxiety symptoms were different when people were grouped based on their inflammation levels. Also, specific immune cells appear to work differently in people with ASD and ADHD. These findings clarify some of the biology that affects behavioural symptoms in ASD and ADHD.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/29441 |
| Date | January 2024 |
| Creators | Cleary, Shane |
| Contributors | Foster, Jane, Neuroscience |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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