Grant: Operating Grant

For decades, conventional approaches to neurodegenerative research have not paid much attention to the diversity within clinical diagnostic groups when looking at brain-behavior relationships. Analyzing correlations using discrete clinical diagnostic groups is limited as it fails to capture the entirety of an individual's unique genome. The complex interplay between genetic and the clinical expression of the disease needs to be addressed by large-scale prospective clinical-imaging-genetic studies. In the last two decades, the Sunnybrook Dementia Study has been acquiring longitudinal data from consenting patients assessed in the Cognitive Neurology Memory clinics at Sunnybrook Health Sciences Centre, U of Toronto, who undergo standardized imaging, cognitive, mood and daily function measures and give blood samples for genetic testing. We have accumulated over 1200 participants, 830 blood samples and 170 autopsies. We propose to capitalize on this well-characterized group of patients to do clinical-imaging-genetic investigations with our collaborators at the Centre for Research in Neurodegenerative Disease (CRND), using our banked DNA samples, neuroimaging analysis and postmortem techniques. The main goal is to discover novel contributions of genetic variants to neuroimaging measures across the entire cohort blinded to clinical diagnosis. Other goals include evaluating the effects of genetic variation and small vessel disease burden on clinical progression rates, neuropsychiatric symptoms, and cognitive patterns. The results will provide new insights into correlations between genetic markers and areas of brain shrinkage associated with different types of dementia, as well as small vessel disease. Understanding these patterns may help to improve diagnosis, to customize treatment, and to better monitor disease-modifying therapies currently under investigation should they become applicable to everyday practice.