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The increasing number of Canadians with dementia is projected to reach one million by 2033. The most common cause of dementia is Alzheimer’s disease (AD). Modifiable risk factors for AD, including dietary factors, should be investigated to inform recommendations for disease prevention. Dietary fatty acids, including polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs), are modifiable dietary components. PUFAs affect immune functions in the periphery and the central nervous system (CNS). Microglia are CNS immune cells that release inflammatory mediators including chemokines, cytokines, reactive nitrogen species (RNS) and reactive oxygen species (ROS). In AD, microglia are chronically activated by abnormal proteins, which results in excessive production of inflammatory mediators, promoting neuron death. The fatty acids studied in this thesis included the n-3 and n-6 PUFAs α-linolenic acid (ALA) and linoleic acid (LA), the MUFA oleic acid (OA), and the SFA stearic acid (SA). While this thesis presents experiments containing two glucose conditions, effects of fatty acids on the microglial release of RNS, ROS, monocyte chemoattractant protein (MCP)-1 and neurotoxins were examined using high glucose conditions (17.0-17.3 mM). Gas chromatography assessed fatty acid content of cells exposed to fatty acids in the presence of 5.6 mM and 17.0 mM glucose. The Griess assay assessed RNS, followed by immunoblotting for inducible nitric oxide synthase (iNOS). Chemiluminescence was used to measure ROS, and enzyme-linked immunosorbent assays were used to detect MCP-1. Neuronal SH-SY5Y cells were incubated with supernatants from microglia exposed to fatty acid to assess impact of released neurotoxins. In activated BV-2 microglia cultured in high glucose media (17.0 mM), fatty acids ALA and LA reduced microglial RNS release, and LA reduced the expression of iNOS. In microglia cultured in high glucose media (17.0-17.3 mM), no effects of fatty acids on phagocytosis, ROS release and MCP-1 release were identified. Except for SA, each fatty acid studied did not affect neurotoxic microglial secretions. My thesis demonstrates that dietary fatty acids inhibit select immune responses of microglia cultured in high glucose (17.0 mM). This data extends our knowledge basis needed for evidence-based dietary recommendations to prevent CNS inflammation.

Background It is not known whether early intervention can improve long-term autism symptom outcomes. We aimed to follow-up the Preschool Autism Communication Trial (PACT), to investigate whether the PACT intervention had a long-term effect on autism symptoms and continued effects on parent and child social interaction. Methods PACT was a randomised controlled trial of a parent-mediated social communication intervention for children aged 2–4 years with core autism. Follow-up ascertainment was done at three specialised clinical services centres in the UK (London, Manchester, and Newcastle) at a median of 5·75 years (IQR 5·42–5·92) from the original trial endpoint. The main blinded outcomes were the comparative severity score (CSS) from the Autism Diagnostic Observation Schedule (ADOS), the Dyadic Communication Assessment Measure (DCMA) of the proportion of child initiatiations when interacting with the parent, and an expressive-receptive language composite. All analyses followed the intention-to-treat principle. PACT is registered with the ISRCTN registry, number ISRCTN58133827. Findings 121 (80%) of the 152 trial participants (59 [77%] of 77 assigned to PACT intervention vs 62 [83%] of 75 assigned to treatment as usual) were traced and consented to be assessed between July, 2013, and September, 2014. Mean age at follow-up was 10·5 years (SD 0·8). Group difference in favour of the PACT intervention based on ADOS CSS of log-odds effect size (ES) was 0·64 (95% CI 0·07 to 1·20) at treatment endpoint and ES 0·70 (95% CI −0·05 to 1·47) at follow-up, giving an overall reduction in symptom severity over the course of the whole trial and follow-up period (ES 0·55, 95% CI 0·14 to 0·91, p=0·004). Group difference in DCMA child initiations at follow-up showed a Cohen's d ES of 0·29 (95% CI −0.02 to 0.57) and was significant over the course of the study (ES 0·33, 95% CI 0·11 to 0·57, p=0·004). There were no group differences in the language composite at follow-up (ES 0·15, 95% CI −0·23 to 0·53). Interpretation The results are the first to show long-term symptom reduction after a randomised controlled trial of early intervention in autism spectrum disorder. They support the clinical value of the PACT intervention and have implications for developmental theory. Funding Medical Research Council. Background It is not known whether early intervention can improve long-term autism symptom outcomes. We aimed to follow-up the Preschool Autism Communication Trial (PACT), to investigate whether the PACT intervention had a long-term effect on autism symptoms and continued effects on parent and child social interaction. Methods PACT was a randomised controlled trial of a parent-mediated social communication intervention for children aged 2–4 years with core autism. Follow-up ascertainment was done at three specialised clinical services centres in the UK (London, Manchester, and Newcastle) at a median of 5·75 years (IQR 5·42–5·92) from the original trial endpoint. The main blinded outcomes were the comparative severity score (CSS) from the Autism Diagnostic Observation Schedule (ADOS), the Dyadic Communication Assessment Measure (DCMA) of the proportion of child initiatiations when interacting with the parent, and an expressive-receptive language composite. All analyses followed the intention-to-treat principle. PACT is registered with the ISRCTN registry, number ISRCTN58133827. Findings 121 (80%) of the 152 trial participants (59 [77%] of 77 assigned to PACT intervention vs 62 [83%] of 75 assigned to treatment as usual) were traced and consented to be assessed between July, 2013, and September, 2014. Mean age at follow-up was 10·5 years (SD 0·8). Group difference in favour of the PACT intervention based on ADOS CSS of log-odds effect size (ES) was 0·64 (95% CI 0·07 to 1·20) at treatment endpoint and ES 0·70 (95% CI −0·05 to 1·47) at follow-up, giving an overall reduction in symptom severity over the course of the whole trial and follow-up period (ES 0·55, 95% CI 0·14 to 0·91, p=0·004). Group difference in DCMA child initiations at follow-up showed a Cohen's d ES of 0·29 (95% CI −0.02 to 0.57) and was significant over the course of the study (ES 0·33, 95% CI 0·11 to 0·57, p=0·004). There were no group differences in the language composite at follow-up (ES 0·15, 95% CI −0·23 to 0·53). Interpretation The results are the first to show long-term symptom reduction after a randomised controlled trial of early intervention in autism spectrum disorder. They support the clinical value of the PACT intervention and have implications for developmental theory. Funding Medical Research Council.