Judy Pa - US grants

DESCRIPTION (provided by applicant): The objective of this proposal is to support the candidate's development into an independent clinical researcher. The outlined training plan will equip the applicant with the necessary skills to conduct patient- oriented research with specific didactic training in biostatistics, neuroanatomy, behavioral neurology, and the ethical and responsible conduct of basic and clinical research. The overall goal of this project is to determine whether functional brain alterations in attention and memory systems may better elucidate early vulnerable brain regions in MCI patients at risk for cognitive decline. It remains poorly understood why some MCI patients progress to dementia, exhibiting selective vulnerability of cognitive-specific brain regions, while others remain stable or even improve. Alterations in brain activation have been exclusively assessed using episodic memory tasks. This approach remains limited in scope as many MCI patients exhibit pronounced deficits in both attention/executive function and memory domains. To accomplish this goal, our proposal will focus on a functional MRI paradigm of attention and memory in which subjects must first maintain focus during an anticipation period (attention) and then encode and recognize a visually-presented stimulus (memory). We will investigate the differential, task-specific activation of select brain regions in MCI patients and healthy controls. In addition, the neural response during the attention and memory phases will be compared to brain atrophy and cognitive performance. The goal of Aim 1 is to characterize alterations in neural activity during an attention and memory paradigm and assess the relationship between functional and structural MRI in MCI patients. The goal of Aim 2 is to measure the association between traditional neuropsychological tests of attention and memory and functional brain activation. The long-term objectives of this research are to investigate fluctuations in underlying neural networks of attention and memory in a large-scale, longitudinal study of MCI and healthy controls. In future research, we would collect multiple time points of fMRI and cognitive data and investigate changes in the underlying BOLD signal as cognition declines, improves, or remains stable. This will improve our understanding of the relationship between the BOLD signal and cognition. Ultimately, this will allow us to determine the utility of early neural fluctuations as a biomarker of those with or at risk for cognitive decline. RELEVANCE (See instructions): Although there are great advances being made on understanding AD and other dementias, there are still no effective methods available for early diagnosis. The identification of MCI patients who are likely to suffer from further cognitive decline is a critical, public health issue, but no effective biomarkers have yet been identified. Functional MRI is a promising new method for in vivo investigation of early neural changes in those with or at risk for cognitive decline.

DESCRIPTION (provided by applicant): This is the revised application NIH R01-AG046928-01, titled Effects of physical activity on brain function and network connectivity in MCI. The overall goal of this project is to assess the effect of physical activity on remediating early impairments in brain function in sedentary older adults at risk for Alzheimer's disease (AD). AD is the most common cause of cognitive impairment in older adults. The need for effective treatments has become imperative, as 36 million people worldwide are affected and counting. The results from several large pharmacological trials have been sobering with a lack of significant clinical outcomes, prompting a paradigm shift to initiate treatment earlier in the disease process and explore non-pharmacological interventions. Physical activity has recently emerged as a promising intervention for delaying disease onset and slowing cognitive decline in AD. However, the effect of physical activity on neurobiological mechanisms of action, such as brain activity and network function in at risk older adults with mild cognitive impairment (MCI), a preclinical stage of AD, remains largely unexplored. Thus, there is a need for well-designed randomized controlled trials (RCT) examining functional brain health outcomes of physical activity intervention in this vulnerable population. The objective of this proposal is to evaluate physical activity as an intervention for improving functional brain health by remediating hippocampal dysfunction and enhancing functional network connectivity in MCI. Using a unique interdisciplinary approach of modern neuroscientific methodology in an RCT, a comprehensive set of outcomes will be evaluated. This project will recruit 90 sedentary participants between 50-85 years of age with amnestic MCI. Consistent with the current Surgeon General's recommendation on moderate-intensity exercise, participants will be randomly assigned to one of three home-based groups for a 6-month intervention period: 1) aerobic walking for 150 mins/week, 2) stretching active-control for 150 mins/week, and 3) health education non-active control, with 30 participants in each group. We will examine the effects of physical activity on th primary neuroimaging outcomes of regional BOLD activity in the hippocampal, functional connectivity between the prefrontal cortex and hippocampus, and intrinsic connectivity of the default mode and executive networks. Additionally, we will examine secondary outcomes of brain volume, cognition, function, and serum biomarkers associated with physical activity. The effect of regional AD pathology on change in the outcome measures will be examined using amyloid PET.

PROJECT SUMMARY Women are more than twice as likely than men to develop Alzheimer?s disease (AD). Indeed, 2/3 of AD cases in the US are women despite an equal incidence of apolipoprotein-?4 genotype (APOE4), the major genetic AD risk factor, across genders. Thus far, few factors that influence this relationship in women have been discovered, in large part because there has not been a targeted, systematic evaluation of women?s risk in a comprehensive dataset. The goal of this project is to investigate interactions between gender and genetics, such as APOE4 gene dose, on brain morphometry, cognitive decline, and clinical conversion to AD. This project will leverage existing longitudinal cohorts from more than 2700 participants with longitudinal follow-up visits to evaluate the relationship between gender and genetic interactions on changes in brain morphometry, cognitive function, and clinical diagnosis using cohorts enriched for APOE4 homozygotes. Equipped with a large, harmonized dataset, we anticipate enriched scientific discovery of interactions between gender and genetic risk factors for Alzheimer?s disease following these specific goals: 1) Analyze differential brain deformation and cognitive decline by gender and genetic status, 2) Examine the predictive utility of subtle brain deformation on subsequent cognitive function and clinical progression by gender and genetic status, and 3) Conduct exploratory gender X genetic associations with AD risk and analysis of gender X APOE4 associations in ongoing clinical trials paradigms as proof-of-concept. With a rich accumulation of brain, cognitive, and clinical variables proposed in this study, we will carefully pursue scientific discovery of gender- specific AD phenotypes.

PROJECT SUMMARY The overarching goal of this project is to use a novel virtual reality (VR) physical and cognitive intervention aimed at improving brain health and cognition in older adults with mild cognitive impairment (MCI), a risk factor for Alzheimer's disease (AD). AD is the most common cause of cognitive impairment in older adults and affects 36 million people worldwide. Results from several large pharmacological trials have been sobering with no effective treatments for halting, slowing, or preventing the disease. Exercise has emerged as an exciting, lifestyle intervention to help mitigate cognitive loss or delay the onset of dementia. However, to fully leverage exercise benefits in this at-risk population, training the brain to learn and engage in a cognitively- stimulating and physically-demanding environment may be key to effective therapies. Controlled cognitively- challenging environments created in a VR setting provide an adaptable and safe environment for improving cognitive dysfunction in older adults at risk for AD. While a large body of literature has found that exercise enhances cognition, very few studies have coupled physical and cognitive activity in a VR environment, simultaneously. By engaging and challenging spatial memory during moderate-to-vigorous intensity exercise over time, memories for newly acquired information may be stronger and longer-lasting than either physical or cognitive activity alone. Therefore, in this project, we aim to use an integrated, ecologically valid, and meaningful physical and cognitive intervention in VR that targets the hippocampus, a key region of interest in older adults at risk for AD. We will recruit and randomize 150 older adults to participate in the intervention (combined physical and cognitive VR program), active control (physical cycling only), or passive control (cognitive VR only) group to investigate changes in cognition, brain function, blood-based biomarkers, and physical health in old adults (55-80 years old) with early mild cognitive impairment. Results from this study will provide new evidence for the benefits of a novel combined VR intervention that target physical and cognitive health, simultaneously.