2017 — 2021 |
Gordon, Brian Andrew |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Neuroimaging Markers of Emerging Dysfunction in Preclinical Alzheimer Disease
The objective of this proposal is to support the candidate's development and transition into an independent researcher. The outlined training plan will equip the applicant with the necessary skills to conduct innovative work that spans both primary research and clinical domains. The accrual of Alzheimer's disease (AD) pathology can begin decades before the onset of cognitive symptoms. Higher levels of pathology increase the risk of dementia, but the relationship between pathology and cognition is imperfect. Functional magnetic resonance imaging (fMRI) provides a way to non-invasively assess the integrity of networks in the brain that support cognition. As such it may provide a better measure of the brain's health than biomarkers of pathology alone. Prior work using fMRI has almost exclusively utilized only episodic memory tasks. This approach is limited as AD leads to deficits beyond memory domains. The goal of Aim 1 is to characterize alterations in neural activity related to preclinical levels of AD pathology using three tasks that respectively target attentional control, working memory, and episodic memory. The goal of Aim 2 is to compare the sensitivity of these task-based fMRI paradigms to resting-state fMRI. The goal of Aim 3 is to relate task-based fMRI data to longitudinal cognition and the transition from cognitive normality to an impaired state. This work will improve our understanding of the relationship between AD pathology and neuronal activity, as well as the relationship between such fMRI activity and longitudinal cognition.
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2019 — 2021 |
Gordon, Brian Andrew |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Domitly Inherited Alzheimer Network: Project 2
Project 2: Tau SUMMARY Alzheimer's disease (AD) is a growing worldwide health crisis. It is critical to develop biomarkers to identify individuals at high risk for AD, better understand the biological underpinnings of the disease, and to develop new therapeutic agents. Autosomal dominant AD (ADAD) is a rare form of the disease (<1%) that is caused by mutations in one of three genes. Individuals with these mutations develop dementia at a relatively young age that is heritable within families. This provides a unique cohort of individuals where it is possible to predict the disease stage of individuals relative to their estimated years to symptom onset (EYO) even decades before they show cognitive decline. During the initial funding periods DIAN investigators have mapped out a sequential progression of biomarkers; first, measures of beta-amyloid become abnormal, followed by metabolism, measures of tau pathology, loss of grey matter, and eventually cognitive decline. Work by DIAN investigators and others suggests that the abnormal accumulation of tau pathology may be a key factor in this cascade that impacts the transition from cognitive normality to impairment. However, prior work examining tau has previously been limited only to one biomarker measured in the cerebrospinal fluid (CSF). While informative, this solitary measure may not adequately convey the role tau pathology plays in AD. This project seeks to understand new measures of tau pathology in the DIAN cohort to further elucidate the role this protein plays in ADAD. Aim 1 explores tau pathology measured using three different positron emission tomography (PET) compounds to map the spread of tau pathology in the brain. This will quantify the amount as well as location of pathological burden in the brain. Aim 2 uses post mortem brain tissue to validate these tracers and learn more about the sensitivity and specific of these three compounds. This is critical before these PET tracers can be used broadly for research and clinical purposes. Aim 3 uses mass spectrometry to quantify novel forms of tau which have distinct structural properties (e.g. different phosphorylation or cleavage sites). These novel forms of tau will be measured in the CSF, brain tissue, and human cell models of AD and is a strong compliment to the tau PET imaging. The rationale for this proposal is that better understanding the temporal and spatial evolution of tau pathology is critical to understanding the pathobiology of AD and for formulating successful therapeutic trials. These three Aims are highly collaborative with the other Projects and Cores, and will provide new insights in the role tau pathology plays in AD.
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