In this K02 Independent Scientist Career Development Award, the candidate seeks to build upon his background in functional and structural neuroimaging and use multimodal neuroimaging to understand the evolution of cognitive disorders, such as Parkinson's disease dementia (PDD) and Alzheimer's disease (AD). The K02 will provide the candidate protected time for research and career development activities that will enhance the clinical applicability of his imaging expertise and assure excellence in the responsible conduct of human subject research. The proposed projects use multimodal magnetic resonance imaging (MRI) to examine structural and functional differences in the brains of patients with PDD and AD relative to elderly controls. The overall goal of the research is to better understand the selective vulnerability of brain regions to synuclein and amyloid pathology and to understand how cognitive deficits in dementia relate to underlying damage in brain structure and circuitry. Specifically, clinically and neuropsychologically characterized controls and subjects with PDD and AD will undergo a baseline and followup resting MRI protocol of around 30 minutes that will allow the following measurements: 1) regional volume of cortical and subcortical structures, 2) white matter integrity in tracts identified using probabilistic atlas-based diffusion tensor tractography, 3) functional connectivity within anatomically-defined regions of the default network, and 4) interval change in volume of cortical and subcortical structures using nonlinear registration of serial image datasets. High throughput processing streams are in place for efficiently capturing the structural measures obtained from each procedure, and the candidate's laboratory has added expertise in functional connectivity analysis. Thus, the proposed research will allow new insight into the structural and functional consequences of neurodegenerative disease.
NARRATIVE: The proposed research aims to improve understanding of the effects of dementia on brain structure using noninvasive brain imaging. Such information may help researchers evaluate disease-modifying effects of new therapies designed to target different causes of dementia. Rapid quantitative assessment of brain structure might be practical in the clinical setting to assist clinicians in making earlier and more accurate diagnoses of neurodegenerative diseases.
|Desikan, R S; Schork, A J; Wang, Y et al. (2015) Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus. Mol Psychiatry 20:1588-95|
|Reas, Emilie T; Brewer, James B (2015) Mean signal and response time influences on multivoxel signals of contextual retrieval in the medial temporal lobe. Brain Behav 5:e00302|
|Desikan, Rahul S; Schork, Andrew J; Wang, Yunpeng et al. (2015) Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease. Circulation 131:2061-9|
|Yu, Peng; Sun, Jia; Wolz, Robin et al. (2014) Operationalizing hippocampal volume as an enrichment biomarker for amnestic mild cognitive impairment trials: effect of algorithm, test-retest variability, and cut point on trial cost, duration, and sample size. Neurobiol Aging 35:808-18|
|Desikan, Rahul S; Thompson, Wesley K; Holland, Dominic et al. (2014) The role of clusterin in amyloid-Î²-associated neurodegeneration. JAMA Neurol 71:180-7|
|Gimbel, Sarah I; Brewer, James B (2014) Elaboration versus suppression of cued memories: influence of memory recall instruction and success on parietal lobe, default network, and hippocampal activity. PLoS One 9:e89037|
|Desikan, R S; Rafii, M S; Brewer, J B et al. (2013) An expanded role for neuroimaging in the evaluation of memory impairment. AJNR Am J Neuroradiol 34:2075-82|
|Reas, Emilie T; Brewer, James B (2013) Retrieval search and strength evoke dissociable brain activity during episodic memory recall. J Cogn Neurosci 25:219-33|
|Hales, J B; Brewer, J B (2013) Parietal and frontal contributions to episodic encoding of location. Behav Brain Res 243:16-20|
|Desikan, R S; McEvoy, L K; Holland, D et al. (2013) Apolipoprotein E epsilon4 does not modulate amyloid-Î²-associated neurodegeneration in preclinical Alzheimer disease. AJNR Am J Neuroradiol 34:505-10|
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