A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Genetic testing for this pathogenic mutation is challenging due to its GC rich, repetitive nature. I developed PCR based assays to detect the presence of the pathogenic variant, which were used in screening an archival cohort of Scottish ALS patients, and have also been implemented within a diagnostic setting. These PCR assays allow amplification of larger repeat expansions than have previously been reported, and can determine whether a C9orf72 expansion of greater than 100 repeats is present or not. It is not well understood how the repeat expansion leads to disease, but several potential mechanisms have been hypothesised, including reduced expression, RNA toxicity and protein toxicity via dipeptide repeat proteins produced through repeat associated non-AUG translation. Motor neurons are an understandably well studied target in amyotrophic lateral sclerosis, however the role of glia, particularly oligodendrocytes, in the pathogenesis of the disease has recently been highlighted from studies on rodent models and post mortem tissue. To investigate the effect of the C9orf72 repeat expansion on oligodendrocytes, we have applied a differentiation protocol to hiPSCs with the expansion and controls, including an isogenic control which has been generated in the lab. There was no difference in the production of neuronal and glial cell types between these cell lines. I went on to look for evidence of the main proposed pathological mechanisms of C9orf72 repeat expansions: loss of function or gain of function through either RNA or protein toxicity. hiPSC derived oligodendrocytes from both carrier and control showed low expression of C9orf72 mRNA, and there was no difference due to the presence of a repeat expansion. Carrier hiPSC derived oligodendrocytes displayed sense RNA foci, which did not appear to have an effect on cellular morphology. The detection of dipeptide repeat proteins proved challenging, and the results were inconclusive as to their presence in hiPSC derived oligodendrocytes. I went on to show there was no evidence of mislocalisation of TDP-43 in C9orf72 carrier oligodendrocytes. Finally, the study showed similar levels of cell death in basal conditions in carrier and control cells, and no clear difference in the response to endoplasmic reticulum stress. Further research will be required to elucidate the role of oligodendrocytes in C9orf72 related amyotrophic lateral sclerosis.

Due to the fastest growing senior population, age-related cognitive impairments, including Alzheimer's disease, are becoming among the most common diseases in the United States. Currently, prevention through delay is considered the best way to tackle Alzheimer's disease and related dementia, as there is no known cure for those diseases. Early detection is crucial, in that screening individuals with Mild Cognitive Impairment may delay its onset and progression. For my dissertation work, I investigate how computing technologies can help medical practitioners detect and monitor cognitive impairment due to dementia, and I develop a computerized sketch-based screening tool. In this dissertation, I present the design, implementation, and evaluation of the ClockMe System, a computerized Clock Drawing Test. The traditional Clock Drawing Test (CDT) is a rapid and reliable instrument for the early detection of cognitive dysfunction. Neurologists often notice missing or extra numbers in the clock drawings of people with cognitive impairments and use scoring criteria to make a diagnosis and treatment plan. The ClockMe System includes two different applications - (1) the ClockReader for the patients who take the Clock Drawing Test and (2) the ClockAnalyzer for clinicians who use the CDT results to make a diagnosis or to monitor patients. The contributions of this research are (1) the creation of a computerized screening tool to help clinicians identify cognitive impairment through a more accessible and quick-and-easy screening process; (2) the delivery of computer-collected novel behavioral data, which may offer new insights and a new understanding of a patient's cognition; (3) an in-depth understanding of different stakeholders and the identification of their common user needs and desires within a complicated healthcare workflow system; and (4) the triangulation of multiple data collection methods such as ethnographical observations, interviews, focus group meetings, and quantitative data from a user survey in a real-world deployment study.