PROJECT 1: NEUROIMAGING OF HIPPOCAMPAL SUBFIELDS IN OLDER ADULTS &MCI A major goal for health research in the U.S. is to discover new disease-modifying therapies and target individuals susceptible to AD as early as possible. Episodic memory deficits and changes in the medial temporal lobes have been highlighted both in healthy aging and for their potential as early markers of AD. We propose to collect a comprehensive set of behavioral and high-resolution neuroimaging data from (1) healthy elderly individuals, (2) elderly individuals with diagnosed amnestic mild cognitive impairment (aMCI), and (3) elderly individuals with milder impairments who do not reach criteria for an MCI diagnosis, but are nevertheless impaired on memory tests (amnetic, early impairment - aEI). We will use these data to test several key predictions of a neurocognitive model of age-related memory impairment. This work is based on converging insights from computational models as well as behavioral, electrophysiological, and neuroanatomical findings in rodent models of aging that place emphasis on the role of the dentate gyrus in pattern separation (the ability to isolate similar memories from each other). The model posits that memory impairments in the course of aging and early dementia are due to the degradation in input to the dentate gyrus and CAS region from layer II entorhinal cortex neurons, which leaves the system with an impaired ability to perform pattern separation. We propose to test predictions of this model using targeted behavioral assays sensitive to hippocampal and perforant path integrity as well as cutting-edge neuroimaging techniques (high-resolution functional and structural MRI, resting state functional connectivity, ultrahigh-resolution microstructural diffusion tensor imaging). We predict that compared to healthy elderly, those with memory impairments will have behavioral deficits consistent with reductions in pattern separation and that these are tied to structural and functional changes in the dentate gyrus, the CA3, and their perforant path input. We will also investigate the modulatory effect of individual differences in our healthy elderly group, as well as the potential effect of ApoE4 genetic susceptibility. This rich dataset will also be useful beyond our hypotheses and questions. Thus, we will work with the ADRC's Data Core to generate new hypotheses, accurately quantify our outcome measures in a reliable way, and conduct statistically rigorous analyses that combine multiple imaging modalities with behavioral and neuropsychological data in order to isolate useful biomarkers that accurately discrminate among groups and potentially predict conversion from healthy aging to dementia.

Public Health Relevance

The rise in the population over 65 is leading to increased numbers of AD cases. Outside of AD, one of the primary complaints and deficits observed with aging is a decline in learning and memory function, leading to decreased quality of life and a greater burden pn families and social services. Understanding the neural mechanisms that underlie these age-related deficits and their relationship to deficits related to the earliest stages of AD is crucial to paving the way to improving treatments for both normal and pathological changes.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Specialized Center (P50)
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National Institute on Aging Initial Review Group (NIA)
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University of California Irvine
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Mitchell, Joel C; Dick, Malcolm B; Wood, Amanda E et al. (2015) The utility of the Dementia Severity Rating Scale in differentiating mild cognitive impairment and Alzheimer disease from controls. Alzheimer Dis Assoc Disord 29:222-8
Robinson, John L; Molina-Porcel, Laura; Corrada, Maria M et al. (2014) Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old. Brain 137:2578-87
Blurton-Jones, Mathew; Spencer, Brian; Michael, Sara et al. (2014) Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. Stem Cell Res Ther 5:46
Berchtold, Nicole C; Sabbagh, Marwan N; Beach, Thomas G et al. (2014) Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease. Neurobiol Aging 35:1961-72
Iulita, M Florencia; Do Carmo, Sonia; Ower, Alison K et al. (2014) Nerve growth factor metabolic dysfunction in Down's syndrome brains. Brain 137:860-72
Holler, Christopher J; Davis, Paulina R; Beckett, Tina L et al. (2014) Bridging integrator 1 (BIN1) protein expression increases in the Alzheimer's disease brain and correlates with neurofibrillary tangle pathology. J Alzheimers Dis 42:1221-7
Pensalfini, Anna; Albay 3rd, Ricardo; Rasool, Suhail et al. (2014) Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques. Neurobiol Dis 71:53-61
Sosa, Lucas J; Postma, Nienke L; Estrada-Bernal, Adriana et al. (2014) Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome. FASEB J 28:195-205
Perluigi, Marzia; Pupo, Gilda; Tramutola, Antonella et al. (2014) Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain. Biochim Biophys Acta 1842:1144-53
Di Domenico, Fabio; Pupo, Gilda; Tramutola, Antonella et al. (2014) Redox proteomics analysis of HNE-modified proteins in Down syndrome brain: clues for understanding the development of Alzheimer disease. Free Radic Biol Med 71:270-80

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