Pilot Projects:

Year 4 Pilot Project 1

Principal Investigator: Craig Stark, Ph.D.
Title: Functional Imaging of Hippocampal Subfields in MCI

The objective of this application is to better understand the nature of the changes in the medial temporal lobe memory system associated with aging and Mild Cognitive Impairment (MCI). Our Specific Aim is to characterize aging and MCI-related functional changes using BOLD fMRI in the medial temporal lobe system. We will assess changes in activity using high-resolution fMRI sufficient to resolve activity within hippocampal subfields in MCI patients aged 65-85 and age and gender-matched controls. The proposed experiments and methods will provide a clearer picture of the changes in computations that occur with MCI, and the specific locus of these alterations. This will help us make the critical link between animal and human studies, and therefore enhance our understanding of aging and dementia. With further development, this study combined with our current program of research will lead to a better characterization of the nature of the cognitive changes associated with aging and age-related disorders. It will also ultimately pave the way to identifying new pre-clinical markers and developing new therapies to decelerate progression to dementia.

Year 4 Pilot Project 2

Principal Investigator: Matt Blurton-Jones
Tile: The Role of Neurogenesis in the Pathogenesis of Alzheimer’s Disease

Mounting evidence suggests that adult neural stem cells (NSCs) play a critical role in the processing, storage, and/or retrieval of memories. Interestingly, neurogenesis is altered in patients with Alzheimer disease (AD) and several key proteins implicated in the disease, including presenilin and amyloid precursor protein (APP), modulate NSC survival and differentiation. Animal studies also demonstrate that paradigms that increase neurogenesis; including exercise, learning, enrichment, or fluoxetine, also improve spatial memory in transgenic mouse models of AD. Taken together, these studies suggest that deficits in neurogenesis may contribute to cognitive dysfunction in AD. However, to clearly establish a link between neurogenesis, memory, and AD, in vivo imaging of neurogenesis is essential. Here we propose to utilize two novel inducible transgenic mouse models of neural stem cell ablation to establish the utility of the 1H-MR spectroscopy biomarker and clearly define the population of cells this biomarker represents. Once this population is defined we will also utilize 1H-MR spectroscopy to examine the impact of AD-related pathology on neurogenesis in the triple transgenic mouse model of AD (3xTg-AD). Our findings should help to enable future studies to investigate the role of neurogenesis in aging and Alzheimer disease.

Year 4 Pilot Project 3

Principal Investigator: Tom Lane, Ph.D.
Title: Viral Infection Affects AD Neuropathology

The central hypothesis of this proposal is that inflammation in response to viral infection accelerates and exacerbates the development of neuropathological correlates of AD including deposition of amyloid-b (Ab) plaques and neurofibrillary tangles. To address this, we will infect 3XTg-AD with mouse hepatitis virus (MHV, a positive-strand RNA virus that is a member of the Coronaviridae family) and evaluate if the severity of AD-associated neuropathology is increased as well as determine if onset of AD-associated neuropathology is accelerated. Therefore, this proposal will determine i) if viral infection modulates the severity of AD-pathology in genetically susceptible mice and ii) if age of mouse and/or compartment infected e.g. CNS or periphery influences neuropathological outcomes. As the population increases, the number of aged individuals will rise as will the number of people developing AD. Compelling evidence suggests that repeated exposure to infectious agents e.g. viruses may initiate and/or accelerate AD. This proposal will use relevant experimental models to address the underlying mechanisms by which this may occur.