Novel metrics of brain dynamics in Alzheimer’s disease

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PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a progressive neurological disorder that adversely affects cognition and daily functioning in older adults. Functional MRI is a non-invasive and widely available neuroimaging tool that can be used to identify early manifestations of AD, which can then be used as a complimentary biomarker to enrich clinical trials with those patients most likely to decline. Recent investigations have suggested that the core brain abnormalities in AD may not arise from structural or even functional connectivity, but rather the timing of brain activity. Abnormal brain timing is an intuitive mechanism for decreased cognitive flexibility, and may serve as a biomarker for mild cognitive impairment (MCI) and AD. The purpose of this study is to investigate how changes in the temporal duration of functional connectivity are related to MCI and AD. The specific aims are: 1) Characterize the temporal aspects of functional connectivity in cognitively intact individuals and those with cognitive impairment (MCI and AD); 2) Examine the evolution of sustained and lag-based connectivity in individuals with cognitive impairment and establish which biological and cognitive factors predict change; and 3) Evaluate the predictive performance of sustained and lag-based connectivity as a biomarker for cognitive impairment. This proposal is designed to facilitate the career development of Dr. Jace King in acquiring the necessary training, practical experience, and knowledge to become a lead investigator in brain related dysfunction associated with MCI and AD. To excel as an independent researcher, Dr. King will obtain research skills in the following areas: 1) neuropsychological, neurobiological and clinical manifestations of AD; 2) longitudinal study design and analysis; and 3) advanced statistical methods involved in machine learning with an emphasis on how these tools can be used to conduct behavioral phenotyping. This research will be conducted at the University of Utah and supported by a multidisciplinary mentorship team with collaborative experience but distinct expertise. Dr. Duff (primary mentor) is an expert in the neuropsychological assessment of MCI and AD. Dr. Foster (co-mentor) is an expert in the diagnosis and treatment of AD. Dr. Minoshima (co-mentor) is internationally known for his discovery of early signs of AD and dissemination of diagnostic statistical mapping technology. Dr. Phillips (co-mentor) has expertise in machine learning and advanced statistics. Dr. Zielinski’s (co-mentor) expertise are in multimodal MRI analysis and longitudinal study design. Complimenting this team is a dedicated team of consultants with expertise in AD diagnosis and treatment, advanced statistical modeling, and advanced fMRI data analysis. Successful completion of this award will provide the applicant with the background and training necessary to pursue an R01 application to investigate longitudinal brain function in aging populations. The proposed research makes significant contributions to the field as it has the potential to provide novel insights in the cognitive neural mechanisms underlying AD, which will aid in the implementation of targeted intervention and prevention efforts.