The differential impact of oxytocin receptor (OXTR) genotypes on the risk of autism spectrum disorder (ASD) and resulting social communication deficits

Background: Autism spectrum disorder (ASD) is multifactorial and is likely the result of complex interactions between multiple environmental and genetic factors. Recently, it has been suggested that each symptom cluster of the disorder, such as poor social communication, may be mediated by different genetic influences. Genes in the oxytocin pathway, which mediates social behaviours in humans, have been studied with single nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) being implicated in ASD. This thesis examines the presence of different oxytocin receptor genotypes, and their associations with ASD and resulting social communication deficits. Methods: The relationship between four OXTR variants and ASD was evaluated in 607 ASD simplex (SPX) families. Cases were compared to their unaffected siblings using a conditional logistic approach. Odds ratios and associated 95 percent confidence intervals were obtained. A second sample of 235 individuals with a diagnosis of ASD was examined to evaluate whether these four OXTR variants were associated with social communication scores on the Autism Diagnostic Interview – Revised (ADI-R). Parameter estimates and associated 95 percent confidence intervals were generated using a linear regression approach. Multiple testing issues were addressed using false discovery adjustments. Results: The rs53576 AG genotype was significantly associated with a lower risk of ASD (OR = 0.707, 95% CI: 0.512-0.975). A single genotype (AG) provided by the rs2254298 marker was found to be significantly associated with higher social communication scores (Parameter estimate = 1.833, SE = 0.762, p = 0.0171). This association was also seen in a Caucasian only and mothers as the respondent samples. No association was significant following false discovery rate adjustments. Conclusion: The findings from these studies provide limited support for the role of OXTR SNPs in ASD, especially in social communication skills. The clinical significance of these associations remains unknown, however, it is likely that these associations do not play a role in the severity of symptoms associated with ASD. Rather, they may be important in the appearance of social deficits due to the rs2254298 markers association with enlarged amygdalas.

COGNITIVE ASSESSMENT USING THE KINARM EXOSKELETON ROBOT IN PATIENTS WITH TRANSIENT ISCHEMIC ATTACK

Background: Transient ischemic attack (TIA) is a condition causing focal neurological deficits lasting less than 24hrs. TIA patients present similarly to other conditions with rapid onset of neurological symptoms such as migraine. The accurate diagnosis of TIA is critical because it serves as a warning for subsequent stroke. Furthermore, cognitive deficit associated with TIA may predict the development of dementia. Therefore, characterizing the cognitive symptoms of TIA patients and discriminating these patients from those with similar symptoms is important for proper diagnosis and treatment. Currently the diagnosis of TIA is made on clinical and radiographic evidence. Robotic assessment, with instruments such as the KINARM, may improve the identification of cognitive impairment in TIA patients. Methods: In this prospective cohort study, two KINARM tests, trail making task (TMT) and spatial span task (SST), were used to detect cognitive deficits. Two study groups were made. The TIA group was tested at 5 time points over the span of a year. The migraine active control group had one initial visit and another a year later. Both of these groups were compared to a normative database of approximately 400 healthy volunteers. From this database age and sex matched normative data was used to calculate Z-scores for the TMT. The Montreal Cognitive Assessment (MoCA) was also administered to both groups. Results: 31 participants were recruited, 20 TIA group and 11 active controls (mean ± SD age= 66 ± 11.3 and 62 ± 14.5). There was no significant difference in TIA and active control group MoCA scores. The TMT was able to detect cognitive impairment in TIA and migraine group. Also, both KINARM tasks could detect significant differences in performance between TIA and migraine patients while the MoCA could not. Changes in TIA and migraine performance on the MoCA, TMT, and SST were observed. Conclusions: The robotic KINARM exoskeleton can be used to assess cognitive deficits in TIA patients.