Kristen M. Kennedy - US grants

Project Summary/ Abstract The objectives of this Pathway to Independence Award (K99/R00) for Kristen Kennedy, Ph.D., are to expand the candidate's expertise in the field of cognitive neuroscience, to enable her to investigate novel questions regarding the role of white matter integrity in supporting age-related functional reorganization, and to transition successfully to an independent scientist in a tenure-track position at a research university. Combining structural and functional measures of brain integrity is a major goal in the field of the cognitive neuroscience of aging, and knowledge gained from this study should bring us closer to understanding how brain structure affects the brain's functional reorganization and the compensatory nature of that reorganization. The central aim of this project is to investigate the role of white matter structural connectivity in bilateral recruitment and to examine the compensatory nature of this functional reorganization. The hypotheses will be tested in a lifespan sample of adults using Diffusion Tensor Imaging, measures of cognitive performance, and a semantic judgment functional MRI task from which we can measure a bilateral activity index. The specific aims of this proposal are: 1) To test the hypothesis that white matter connectivity governs age-related bilateral recruitment; 2) To combine white matter integrity and cognitive performance to determine the compensatory nature of age-related bilateral recruitment; and 3) To experimentally manipulate task demands to test the hypothesis that white matter connectivity becomes more important in supporting bilateral recruitment as difficulty increases. Because the candidate's ultimate goal is to secure a tenure-track faculty position in a research-oriented university, award of this proposal will facilitate acquiring that position well-prepared for the transition from mentored to independent work and with the professional skills necessary to manage a neuroimaging lab. Lastly, award of this proposal will allow the candidate to prepare and submit a major research proposal (R01) at an earlier stage than would be possible without this K99/R00 mechanism.

PROPOSAL SUMMARY (ABSTRACT) Distinguishing normal from pathological aging (such as Alzheimer?s Disease) is a major scientific goal. The projects in this application seek to utilize longitudinal design, neuroimaging techniques, and carefully selected candidate genes (single nucleotide polymorphisms; SNPs) to help uncover biological mechanisms in individual differences in brain and cognitive aging. This within-­person approach is necessary to track how an individual (of any age) ages across time, and to selectively investigate the role of specific risk/protective factors while holding other variables constant (within-­person design). Here we leverage data collected from R00 NIA award on 190 individuals aged 20-­94 years to begin Wave 2 follow-­up in Year 1 and Wave 3 in Year 4 of the proposed project. This will allow for three waves of data spanning 6.5 years in a five-­year study, providing crucial information about individual differences in brain and cognitive aging. Specifically, this project aims to capitalize on the known biological effects of SNPs in the dopaminergic system (COMTval158 and DRD2 C/T) and in the regulation of neuroplasticity (BDNFval66met). Aging is accompanied by stark diminution to the dopamine neurons and those major brain regions they originate from and innervate. However, the brain is surprisingly plastic to these changes, and a major factor in regulating neuroplasticity is brain-­derived growth factor. The first specific aim of the project is to investigate within-­person change in persons with or without predisposition to reduced availability of dopamine in the synapses in frontal-­parietal and fronto-­striatal brain regions. We will examine change in ability to modulate this circuitry in functional MRI studies of cognitive challenge over the course of three follow-­up points. We will further examine the brain structural changes (degradation of white matter connectivity, cortical thinning) that may mediate this change in neural function, as well as cognitive decline or preservation that results from these changes. The second specific aim will similarly examine within-­person changes in modulation of brain activation to difficulty in persons with or without predisposition to reduced availability of neuroplasticity factors, particularly in limbic circuitry and the changes to brain structure that may mediate these functional changes and predict cognitive outcome. Our third aim utilizes an innovative neuroimaging technique, NODDI (neurite orientation dispersion and density imaging), to image with more specificity than previously possible the neurites which form synaptic units. We will introduce this in Wave 2, with follow-­up in Wave 3 to measure change in dendrite/synaptic density, another marker of neuroplasticity. We will then further associate level and change in dendritic density in individuals based on genetic risk for reduced BDNF levels and at risk for Alzheimer?s Disease by examining neurite density in amyloid positive vs amyloid negative individuals, as well as those with APOEe4 positivity. Understanding biological mechanisms that guide individuals toward normal or pathological aging, like Alzheimer?s Disease, will help identify whom may respond best to future interventions to increase resilience to aging?s effects.

PROJECT SUMMARY Can regular mental exercises in building cognitive maps delay the onset of Alzheimer?s disease (AD) or decelerate the progression of AD? The neuropathology of Alzheimer?s disease (AD) begins in the entorhinal cortex, leading to spatial navigation impairment that differentiates patients with mild cognitive impairment (MCI) and AD from healthy aging adults. Specifically, MCI and AD patients suffer declining abilities to allocentric navigation that requires developing a cognitive map (aka mental map) as an internal representation of the environment with places and features independent of one?s current location or orientation. A system of spatial cells in the hippocampal formation subserves cognitive map building with the spatial periodicity of grid- cell firing fields to form the brain?s metric coordinate system for allocentric navigation. Studies showed that grid cells could gradually lose their spatial periodicity during periods of reduced theta oscillations and hippocampal inactivation. Will mental exercises in building cognitive maps excite theta oscillations and hippocampal activation and strengthen spatial periodicity of grid-cell firing fields? Findings of structural brain changes in London taxi drivers and spatial information retrieval support the potential of such excitatory effects. Further, less is known about the role of the posterior parietal cortex (PPC) in the storage and retrieval of cognitive maps, and how this region changes with AD. The proposed study hypothesizes that regular mental exercises on cognitive map building can evoke such excitatory effects to delay AD onset and decelerate AD progression. In this exploratory proposal, we venture into the links amongst geographic environments, allocentric navigation, cognitive maps, and AD development: a more complex environment imposes a higher demand on cognitive maps to navigate even on daily commutes and routine errands, and frequent mental exercises of building and retrieving cognitive maps lead to preservation of spatial cognition relevant gray matter regions and consequently impede AD development. We will use data from the National Alzheimer?s Coordinating Center (NACC) and US-based Health and Retirement Study (HRS), respectively (1) to compare MCI/AD populations in geographic areas with varying degrees of environmental complexity and (2) to investigate MCI/AD populations with occupations of high dependency on cognitive maps, such as realtors, police officers, first responders, and the other occupations. The NACC databases contain participant?s 3-digit zip-codes and types of residence which will allow MCI/AD mapping to potential neighborhoods across the US, whereas HRS restricted data include occupation data and cross-wave geographic information at street-level. Findings from the exploratory project will support subsequent experimental research to model the role of gray matter volume, refine the research framework of the excitatory effects of environment complexity and cognitive mapping to MCI/AD development, and examine the potential MCI/AD detriments of GPS-enabled navigation devices.