The etiology of Alzheimer's disease (AD) is not yet known, therapies are not yet available, yet its debilitating effects will impact ~ 10 million in th US alone by 2050. Early imaging of AD phenotypes and measurable outcomes of proposed therapies are urgently needed. This K01 award will allow the candidate, Alexandra Badea, PhD, to train at Duke University Medical Center to develop into an independent investigator in quantitative methods for assessing neurodegenerative diseases in small animal models. The goal is to achieve through training a multidisciplinary perspective on disease biomarkers. This will be possible under guidance from experienced mentors with distinct expertise, all located on the Duke University West Campus. Dr. G Allan Johnson, director of the Center for In Vivo Microscopy (CIVM) is an expert in preclinical animal imaging. The imaging equipment at CIVM can offer an integrated view on aspects of brain structure and function in small animal models. Dr. Carol Colton laboratory examines the role of the innate immune response in the brain and its role in neurodegeneration. Her CVN mouse offers a model in which AD most pathologies are replicated and therapies can be tested. Dr. William Wetsel, director of the Neuroendocrine and Behavioral Facility at Duke is an expert on behavioral assays that will independently evaluate disease progression. The training process will cover: 1) neuroanatomy, pathology, and behavior in the context of AD-like pathology;2) imaging protocol de- sign and MR sequence programming;3) advanced image processing, statistics, and multimodal integration;4) responsible conduct of research. We will focus on integrating high-resolution imaging with cognitive measures, to provide multivariate biomarkers for AD models. The candidate expects to advance methods for: 1) image analysis for morphometry, with a focus on diffusion tensor and vascular data;2) integration of multiple anatomical, physiological and cognitive markers.
The Specific Aims will address: 1) the value of magnetic resonance histology and diffusion tensor imaging in charting AD like phenotypes;2) in vivo multivariate imaging biomarkers addressing the vascular aspect;3) the relationship of imaging markers with cognitive and olfactory deficits, and the rescue of these phenotypes response following intranasal therapy. This award will help establish a timeline of imaging and cognitive changes in mouse models of AD, and provide anatomical, vascular and cognitive markers for disease progression, and as measurable outcomes of putative therapies. The proposed training will equip the candidate with unique a set of skills to become a thought leader in multidisciplinary approaches for characterizing models of neurodegenerative diseases, such as AD, and evaluating proposed therapies.
Currently we do not fully understand the mechanisms that lead to dementia, nor can we detect early onset, nor effective therapies. This presents a growing problem since rates of dementia will rise significantly as people live longer. Translational studies in mouse models of Alzheimer's disease (AD) can provide accelerated methods to identify biomarkers of the disease based on anatomy and vascular parameter. Mouse models age and progress faster, allowing to efficiently examine the longitudinal disease progression, and to measure the out- come of new therapies. The proposed project will use multivariate mouse brain imaging techniques, and behavioral approaches to identify biomarkers of AD, their spatiotemporal relationships, and measurable changes with novel therapies that aim to rescue these phenotypes.
|Graña, Gilberto David; Hutson, Kendall A; Badea, Alexandra et al. (2017) The organization of frequency and binaural cues in the gerbil inferior colliculus. J Comp Neurol 525:2050-2074|
|Badea, Alexandra; Kane, Lauren; Anderson, Robert J et al. (2016) The fornix provides multiple biomarkers to characterize circuit disruption in a mouse model of Alzheimer's disease. Neuroimage 142:498-511|
|Bhagat, Srishti L; Qiu, Sunny; Caffall, Zachary F et al. (2016) Mouse model of rare TOR1A variant found in sporadic focal dystonia impairs domains affected in DYT1 dystonia patients and animal models. Neurobiol Dis 93:137-45|
|Wang, Xiaoming; Bey, Alexandra L; Katz, Brittany M et al. (2016) Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat Commun 7:11459|
|Calabrese, Evan; Badea, Alexandra; Cofer, Gary et al. (2015) A Diffusion MRI Tractography Connectome of the Mouse Brain and Comparison with Neuronal Tracer Data. Cereb Cortex 25:4628-37|
|Borg, Jana Schaich; Vu, Mai-Anh; Badea, Cristian et al. (2015) Localization of Metal Electrodes in the Intact Rat Brain Using Registration of 3D Microcomputed Tomography Images to a Magnetic Resonance Histology Atlas. eNeuro 2:|
|Calabrese, Evan; Badea, Alexandra; Coe, Christopher L et al. (2015) A diffusion tensor MRI atlas of the postmortem rhesus macaque brain. Neuroimage 117:408-16|
|Ashbrook, David G; Delprato, Anna; Grellmann, Claudia et al. (2014) Transcript co-variance with Nestin in two mouse genetic reference populations identifies Lef1 as a novel candidate regulator of neural precursor cell proliferation in the adult hippocampus. Front Neurosci 8:418|
|Calabrese, Evan; Badea, Alexandra; Coe, Christopher L et al. (2014) Investigating the tradeoffs between spatial resolution and diffusion sampling for brain mapping with diffusion tractography: time well spent? Hum Brain Mapp 35:5667-85|
|Johnson, G Allan; Calabrese, Evan; Little, Peter B et al. (2014) Quantitative mapping of trimethyltin injury in the rat brain using magnetic resonance histology. Neurotoxicology 42:12-23|
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