Ruth O'Hara, Ph.D. - US grants

DESCRIPTION (provided by applicant): This is a resubmission of a proposal to investigate the relationships among sleep disordered breathing, APOE genotype and cognition. Sleep disordered breathing increases with age and is associated with impaired cognition. The APOE e4 allele has recently been associated with sleep disordered breathing, particularly Obstructive Sleep Apnea Syndrome (OSAS). The e4 allele is an established risk factor for cognitive decline and the development of dementia. This raises an important issue: is the negative impact of APOE e4 allele on cognition and risk for dementia risk due to OSAS? Specifically, in a population already susceptible to accelerated cognitive decline, how do APOE e4 genotype status, presence or development of OSAS and the combination of APOE e4 status and OSAS further accelerate cognitive decline? We are aware of no studies which have directly examined these issues. To address this knowledge gap effectively requires longitudinal collection of data and analytic techniques designed specifically to identify "moderators" and "mediators" of cognitive decline. We propose to investigate this issue in a group of 150 older adults, 60 years of age and older who will be followed longitudinally for 4 years. Assessments of cognitive function and OSAS will be conducted at baseline and annually, with APOE status determined at baseline. The following hypotheses will be tested. Hypothesis 1: In older adults, 3 risk factors, sleep disordered breathing, APOE e4 genotype and age and their interactions will predict rate of decline in performance on measures of cognition. Hypothesis 2: APOE e4 moderates the effect of sleep disordered breathing on cognitive decline. Hypothesis 3: Sleep disordered breathing will mediate any negative impact of APOE e4 on cognitive decline. There are currently no effective treatments for cognitive decline or MCI, but there are effective treatments for OSAS. Reducing cognitive impairment and delaying the onset of AD has significant clinical and economic benefits. Thus, the answer to this question could significantly enhance our therapeutic approach to cognitive impairment in older adults.

DESCRIPTION (provided by applicant): This application aims to delineate the neural basis of late life anxiety and depressive disorders. As many as 15% of adults over the age of 60 years in the U.S. suffer from anxiety or depressive disorders. These disorders in late life are disabling, reduce the quality of life, impair cognitive processing and increase morbidity and mortality. Little is known about the neurocircuitry underlying these disorders in older adults, an issue that is further complicated by the neurodegenerative changes that accompany the aging process. Increased characterization of the neural basis of late life mood and anxiety disorders is essential for increasing our understanding of a) the etiology of these disorders; b) their differential diagnosis; c) their relationship to age- related neurodegeneration and cognitive decline; d) vulnerability and resilience factors; e) predictors of treatment response; and also for the f) establishment of the basis for development of rational therapeutics targeting defined neural circuits. We propose to provide this much-needed neurobiological foundation by investigating in patients with late life depression and anxiety innovative fMRI paradigms that we have utilized to identify differential neural substrates of depression and anxiety in young adults that both characterize and distinguish these disorders. To achieve our objective of characterizing late life MDD and GAD at a neural circuit level, we will apply these neuroimaging probes to 160 older adults (>60 years old) falling equally into four groups: GAD only, MDD only, comorbid GAD/MDD and healthy controls, while also examining non- emotional cognitive control processes that parallel emotion regulatory ones, and assessing a range of cognitive functions through neuropsychological testing. Our Specific Aims, based on our preliminary data and considerations regarding age-related cognitive decline, are: Aim 1: To examine if fMRI measures of emotional processing and regulation are associated with different patterns of impaired neurocircuitry in late life GAD versus late life MDD. Aim 2: To examine if neurocircuitry abnormalities in co-morbid late life GAD and MDD are additive. Aim 3: To examine if dysregulation of emotional processing in late life GAD and MDD is due to impaired executive control during cognitive processing.

Autism Spectrum Disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder. Hundreds of genes contribute to the risk to develop ASD with no individual genetic locus accounting for more than 1% of cases. This raises the issue of whether, and how such diverse mechanisms converge on a smaller number of biological pathways that ultimately result in one phenotype, namely ASD. The inability to study neurons and brains from living subjects has blocked progress toward understanding the cellular and molecular mechanisms underlying ASD and other neurodevelopmental disorders. Neurons derived from human induced pluripotent stem cell (hiPSC) recapitulate multiple stages of in vivo neural development in vitro. Because they retain the genetic makeup of the patient they enable in vitro studies of neurons that harbor the complex genetic background associated with ASD. Deriving neurons from hiPSCs is labor intensive and costly, and to date studies have examined very small numbers of patients. hiPSC studies of the scope required to capture idiopathic ASD have not been possible, entirely limiting our ability to determine the mechanistic underpinnings of this form of the disorder. We propose to conduct an investigation of hiPSC derived neurons on an unprecedented scale by leveraging our California Institute for Regenerative Medicine (CIRM) funded existing collection of over 300 hiPSCs, to examine 100 individuals with idiopathic ASD and 100 age- and sex-matched controls. We will use commercially derived neurons (iCell Neurons) which are a >95% pure population of glutamatergic (excitatory) and GABAergic (inhibitory) neurons. To identify dysregulated molecular pathways in these neurons we will sequence the human transcriptome at three time points during maturation of the neurons. We will also conduct assays of cell viability, morphology, neurite outgrowth using live cell imaging, and function through calcium imaging. We aim to identify dysregulated molecular pathways in these hiPSC-derived neurons from individuals with ASD, by identifying genes that are differentially expressed from controls at each time point and perform a factorial analysis to study interactive effects between time point and disease variable. This will identify genes showing differentiation- induced expression changes across neuronal differentiation in individuals with ASD. We will identify key drivers of biological pathway changes using Weighted Gene Co-expression Network Analysis (WGCNA). Finally, we will relate gene expression profiles to cellular and behavioral phenotypes.

Contact PD/PI: Cullen, Mark R. 0. Overall: Abstract The mission of Spectrum, Stanford's CTSA-supported research Hub, is to transform clinical and translational research and education at Stanford and across the Hub network to make it more effective at discovering and implementing data-driven strategies to serve the health needs of individuals and the population and to disseminate that knowledge to trainees and the public. Spectrum's programs are designed to extend from the earliest stages of the translational pipeline to the ?final mile? of implementation science at the patient and population levels. During the next five years, Spectrum will leverage the gains and achievements made over the past decade, our institutional strengths and resources, and advancements in the focus of the national network of CTSA Hubs to nurture an innovative and collaborative workforce that can transfer health discoveries from the University to patients and the community. Spectrum's purpose is to support essential resources and educational opportunities to ensure the current and ongoing success of this mission. To that end, our first overarching aim is to educate the next generation of investigators who make up the clinical and translational research (CTR) ?workforce? with the skills to carry out innovative clinical, translational, and implementation research to meet the opportunities and challenges of health- care delivery and wellness maintenance in the 21st Century. Our second overarching aim is to maximize community engagement and team science to ensure that the products of our research benefit all segments of the population including special populations, people with rare diseases, minorities and women, vulnerable populations such as children and the elderly, and the medically underserved. Our third overarching aim is to create an institutional home that provides investigative teams with ready access to the methods, processes, services, and assessment tools necessary to efficiently translate those discoveries that will substantially alter health outcomes in order to directly improve the health and well-being of individuals and the population. Finally, our fourth overarching aim is to develop informatics-based CTR methods, processes, services, and assessment tools necessary to efficiently translate discoveries into improved health outcomes while reducing costs, promoting compliance, and ensuring data availability. Such enhancements will broadly facilitate our CTR mission. With Spectrum's strong track record of accomplishments, supportive institutional environment, well- developed infrastructure and leadership, and our ever-expanding network of collaborators, including health-care systems, other Hubs, and community partners, we are well-positioned to execute on our vision for the next five years. Page 173 Project Summary/Abstract Contact PD/PI: Cullen, Mark R. 0. Overall: Narrative The mission of Spectrum, Stanford University's CTSA-supported Hub, is to transform clinical and translational research and education (CTRE) to ultimately serve the present and future health needs of individuals and the population. Spectrum will support essential resources and educational opportunities in four broad areas, i.e., innovative translational discoveries, team science approaches, innovative training methods for the CTR workforce, and good stewardship of all resources, to ensure the current and ongoing success of this mission. To achieve its mission, Spectrum will work closely with its local, regional, and national partners, including and especially with the other Hubs in the CTSA Consortium, while using a series of well validated metrics to continuously assess and improve performance. Page 174