Eric Larson - US grants

The goal of this proposal is to establish a population based registry of patients with Alzheimer's type dementia (DAT) and other dementias and to collect epidemiologic, genetic (pedigree), and clinical information for the investigation of etiologic factors related to DAT. Group Health Cooperative (GHC) central membership (approx. 25,000 over age 60) will form the population base. Incident cases of probable dementia presenting to GHC facilities will be identified, screened, and diagnostically evaluated. Approximately 150 of the projected 230 new dementia cases occurring yearly are expected to DAT. Since the registry is population based, incidence rates can be calculated. Sensitivity and specificity of the screening device will be evaluated; eventually accuracy of the clinical diagnosis also will be evaluable because neuropathologic data will be collected for validation of the clinical diagnosis of DAT. This registry will serve as the primary resource for future population based studies of the etiology of DAT and other types of dementia in conjunction with the University of Washington Alzheimer's Disease Research Center.

Existing studies suggest that, while the overall prevalence rates of dementia in Japan and the U.S. are similar, the relative prevalence of Alzheimer's disease (AD) to vascular dementia (VaD) is much greater in the U.S. It is not known whether these differences result from differing study methods or whether they reflect underlying differences in the incidence of dementia subtypes in the two countries with concomitant differences in genetic susceptibility and/or exposure to environmental risk factors. Results from a prevalence survey of a total population of Japanese-Americans aged 65 and over living in King County, WA show that prevalence rates more closely resemble those of Caucasian populations than native Japanese. We propose to (1) follow this cohort over the next five years to (2) determine age- and sex-specific incidence rates of dementia and its subtypes; (3) follow existing prevalent and developing incident cases to monitor the clinical and neuropsychological progression and describe survival in AD and VaD cases, (4) conduct prospective risk factor analyses, including survival analyses, of genetic (apolipoprotein E and family history) and environmental factors for AD and VaD, particularly those affected by lifestyle and diet, and examine potential interactions between genes and environment on the risk of dementia and its subtypes; (5) compare prevalence, incidence as well as relative and attributable risks with methodologically standardized studies in Honolulu, Hiroshima and Machida City. The baseline examination (1992- 1994) contained nearly 2,000 individuals; to cohort of cognitively intact persons contains approximately 1,650. The cognitively intact cohort will be screened every two years, the persons with cognitive impairment are followed annually. Pending the results of an analysis of our screening strategy during the currently funded grant period, we plan to screen the cognitively intact cohort every two years using a cutoff score of 81/100 on the Cognitive Abilities Screening Instrument (CASI) and/or a decline of 7 points at any CASI level, to estimate age and sex-specific incidence rates. Patients scoring below the cut scores will have routine, standardized neurologic and neuropsychological evaluations. The followup of the cohort to the year 2001 will yield approximately 127 new cases of dementia. Risk factors for dementia subtypes will be examined in this group, including possible protective factors which show preliminary associations with cognitive impairment and prevalent disease, such as estrogen therapy replacement, head circumference and the apolipoprotein E-e2 (apoE) allele. Changes over time in CASI scores in the cognitively intact cohort also will be analyzed with regard to apoE genotype and other host factors. Finally, standardization efforts between the study sites will focus on the enhancement of the uniformity of diagnostic methods, and cross-site data analysis to compare rates and risk factors.

Literature from Japan suggests that the prevalence rate of vascular dementia far exceeds that of Alzheimer's disease in that country. In the U.S., the opposite trend is observed. However, direct comparison of prevalence rates is confounded by the lack of standardized diagnostic criteria. A population-based study of dementia in Japanese-Americans over age 65 residing in King County, WA is proposed. The project has five main aims: (1) to establish age- and gender-specific prevalence rates for dementia subtypes in this population, (2) to gather information on potential risk factors for dementia, specifically for Alzheimer's disease, (3) to follow prevalent cases longitudinally to describe disease progression and survival in dementia subtypes, and to obtain autopsy diagnosis on cases dying during the course of the study, (4) to develop a cognitively intact fixed cohort, and (5) to compare our assessments of Japanese-American elderly to parallel studies being conducted in Honolulu, Hawaii and Japan. The base population will be censused to identify persons of Japanese-American origin over age 65. A screening instrument (CAST) will be administered to all identified persons. A validation study will determine the CAST cut-off score, and this score will determine whether or not a person continues the diagnostic process or becomes a member of the cognitively intact cohort. Persons screening positive will be referred to an algorithmic evaluation, which will determine whether cognitive impairment was acquired and progressive, and if so, whether associated with cerebrovascular disease or not. Persons determined to have such a dementia will be further referred to a clinical evaluation for conventional diagnosis. The first two phases are designed in parallel with methods used in Honolulu, Hawaii, where the Honolulu Heart Watch cohort is being evaluated for prevalence and incidence of dementia. Methods in Japan will also be standardized with those in Honolulu. Cross-national comparison of prevalence rates of dementia associated with cerebrovascular disease and primary degenerative dementia will use diagnostic classifications from the algorithmic evaluation. Clinical evaluations in the proposed study will be based on the CERAD battery (Consortium to Establish a. Registry for Alzheimer's Disease). A case-control study will be conducted to examine risk factors using both prevalent and incident cases. Prevalent cases will be followed to study disease progression and survival among dementia subtypes, and to obtain neuropathologic diagnoses for cases who die during the course of the study. During the study period, a fixed cohort of cognitively intact persons will bc formed and monitored bi-annually. A renewal application will be submitted for continued followup of the cohort, to study incidence and risk factors associated with dementia subtypes in this ethnic population.

The University of Washington, Group Health Cooperative Alzheimer's Disease patient Registry (ADPR) is a model incident case registry for dementia and Alzheimer~s disease developed in 1986 in response to a National Institute of Aging request for proposals. This application is a competing continuation of the ADPR. The application proposes to continue follow-up of cases enrolled between January 1987 and may 1996, during which approximately 1,000 patients were enrolled. These cases have been and will continue to be part of ongoing studies of diagnostic markers, natural history and have served as sources of cases for other investigators at the University of Washington and throughout the country. During the last funding cycle, we established a cohort of 2,58 persons over age 65 from the Group Health enrollment. Based on biennial follow-up examinations, we are detecting all incident cases of Alzheimer~s disease and related dementias from this cohort. This application proposes to continue our follow-up and maintenance of this cohort. Our goal is to estimate age-group specific incident rates of Alzheimer~s disease and related dementias and to test environmental and genetic risk factors which have been previously identified in case-control studies. In addition, the methods of the cohort study have been standardized to companion cross-cultural studies of Japanese-Americans in Honolulu and Seattle, and Japanese in Hiroshima. Since these studies have similar design and data collection protocols, we propose to compare our results wit the results from these affiliated cross-cultural studies, comparing incidence rates, distribution of dementia subtypes, and distribution of risk factors in different sites. The cohort study design affords the opportunity to reduce bias in measurement of exposure and allows us to obtain truly incident dementia cases. The parallel cross- cultural studies offer a unique opportunity to take advantage of the natural variation in environmental exposures that occurs with population migration. Migration studies have traditionally been helpful in determining whether there are modifiable risk factors for prevention of important chronic diseases.

2008 EAPSI Fellowship
This award supports a U.S. graduate student to conduct an individual research project at one of seven locations in East Asia and the Pacific region (Australia, China, Japan, Korea, New Zealand, Singapore, Taiwan). The research project will provide the student with a first-hand mentored research experience, an introduction to science and science policy infrastructure, and an orientation to the culture and language of the location. The primary goals of the East Asia Summer Institute program are to expose students to science and engineering in the context of a research laboratory, and to initiate early-career professional relationships that will foster research collaborations with foreign counterparts in the future.

DESCRIPTION (provided by applicant): The ability to pay attention to sound sources of interest is critical for verbal communication in many situations. When multiple talkers are speaking simultaneously, being able to direct and redirect attention is necessary to extract relevant information. However, the neural processing involved in directing auditory attention is not fully understood. Moreover, establishing how top-down control of attention interacts with the bottom-up differentiability of sound sources provides a critical first step in understanding how hearing deficits can impact effective cognitive control; understanding this issue could inform the design of improved coding algorithms for hearing aids and cochlear implants. Previous neuroimaging studies in both audition and vision have implicated the involvement of several cortical structures in the voluntary switching of attention using spatial information, but the mechanisms and dynamics of switching attention using non-spatial information are unknown. We will study orientation and switching of auditory attention based on non-spatial stimulus features in behavioral and neuroimaging studies of human subjects performing psychoacoustical tasks. To capture cortical dynamics, we will employ a multimodal imaging approach, combining the temporal resolution provided by magneto- and electro-encephalography (M-EEG) while co-constraining the localization of cortical activation using anatomical magnetic resonance imaging (MRI) scans. Our first aim is to perform a set of psychophysical experiments designed to examine the cost of switching attention based on non-spatial stimulus features as a function of the peripheral separability of competing sounds. Our second aim is to use neuroimaging techniques to examine the cortical dynamics of switching attention based on non-spatial features. By combining psychophysics and neuroimaging, we will determine the temporal dynamics of the cortical network involved in orientation and switching of auditory attention. This research will allow us to better understand how the auditory system enables us to communicate effectively in challenging acoustic environments.

ABSTRACT Genetic risk for AD now clearly highlights the potential for multiple molecular drivers and perhaps multiple pathogenic pathways, including forms of AD that derive from disease causing mutations in PSEN1 or PSEN2, increased risk from APOE ?4, and sporadic disease that does not have identified genetic risk. Regardless of genetic risk, AD is a chronic illness whose ultimate clinical expression as dementia follows years if not decades of injury, response to injury, consumption of reserve, and compensation. Moreover, as highlighted at the 2013 AD Related Dementias summit, longitudinal population-based cohort studies have repeatedly observed that AD most commonly is co-morbid with vascular brain injury (VBI) and less commonly with Lewy body disease (LBD). Finally, these same longitudinal cohort studies have revealed individuals who had high levels of AD neuropathologic change but no significant clinical expression ? a state of apparent resilience to AD. Here we propose to enable progress in precision medicine for AD by vastly improving the molecular characterization of disease and sharing this unique resource with the community of scientists. Indeed, much of our knowledge about injury/response to injury in AD is based on histopathologic assessments rooted in technology that is about 140 years old. Emerging technologies now permit a depth of molecular phenotyping that until recently was difficult even to imagine. We hypothesize that determining quantitative, high dimensional protein phenotypes from carefully clinically characterized individuals from longitudinal cohorts who have donated their brains for research will illuminate components of AD that currently are obscured by limited standard neuropathologic assessments. We will use this novel approach to test our hypothesis through three Specific Aims. In Aim 1, we will collect proteomics data on post-mortem brain samples from the University of Washington Alzheimer's Disease Research Center and the Adult Changes in Thought Study using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy known as data independent acquisition (DIA). DIA enables the comprehensive and systematic sampling of protein digests. This data acquisition will create a permanent digital molecular archive of this unique and highly valuable sample collection. In Aim 2, we will analyze the molecular phenotype of three groups that will be critical to precision medicine for AD: (i) different genetic risk, (ii) common co-morbidities, and (iii) resilience to AD neuropathologic change. We anticipate identifying a molecular signature that is predictive of cognitive impairment as a replacement for traditional histopathological assessment. In Aim 3, we will make our data available through a novel cloud based solution, called the Chorus Project (http://chorusproject.org), engineered to enable big data reanalysis by the community of scientists. We will develop a novel query engine that will enable informatics experts without knowledge of the complexities of mass spectrometry signal processing to perform reanalysis of our data.

The overarching goals of this R01 proposal are to leverage extensive existing clinical imaging data from a well- characterized cohort of older adults to improve scientific understanding of potential mechanisms by which anticholinergic medications (Aim 1) and glucose metabolism (Aim 2) lead to dementia and Alzheimer?s disease risk, and to provide a valuable resource that characterizes longitudinal changes in brain structure over time for this cohort of older adults (Aim 3). The proposal builds on the resources of the Adult Changes in Thought (ACT) study. ACT is situated within Kaiser Permanente Washington, known until February 2017 as Group Health, which has extensive clinical data resources including laboratory data stretching back to 1988 and pharmacy data stretching back to 1977. These data have enabled study investigators to develop longitudinal exposure models to identify risk factors for Alzheimer?s disease and dementia, including strong anticholinergic drugs (Aim 1) and glucose levels (Aim 2). Little is known about imaging correlates of these exposures. Some 2300+ clinical MRI scans have been performed on 1432 ACT participants but they currently are stored in records departments at dozens of hospitals and are not available for research. The investigators propose to reclaim the scan data for research and to obtain follow-up scans on living participants with a single existing scan. This economical approach will enable the investigators to obtain longitudinal (at least 2 year and in most cases much longer interval) imaging data on over 600 well-characterized study participants. The investigators propose to have trained neuroradiologists apply NIH Neuroimaging Common Data Elements (CDEs) to extract data from these scans, and will use image thresholding software to robustly measure volumes of large structures such as ventricles and total brain. The investigators will use these data in Bayesian modeling approaches to test hypotheses regarding the effects of anticholinergic medications on changes in ventricular enlargement and brain atrophy (Aim 1) and regarding the effects of high glucose levels on white matter hyperintensities (Aim 2). The investigators propose to store de-identified raw scan data, imaging CDEs, and data gleaned from brain volume analyses at the Laboratory of Neuro Imaging (LONI) to ensure promulgation to the broader research community (Aim 3).

Integrating computing into science, technology, engineering, and math (STEM) education at the K-12 level is critical to creating a competitive, innovative workforce that is capable of the computational thinking needs of the future. Efforts to increase intrinsic interest in math and data science have proven difficult to apply evenly across gender, race, and socio-economic factors. This research project will assist in creating a more stable, ethical, and inclusive data science workforce by broadening interest in data science to a more diverse population of students. This research spans the fields of game design, human computer interaction, machine learning, curriculum design and educational assessment by integrating a STEM+C based curriculum directly into Minecraft. It advances knowledge in game-based learning and produces an infrastructure that will serve as a vital computing resource for middle and high school educators that will be sustained beyond the current project. As computing has become integral to the practice of science, technology, engineering and mathematics (STEM), the STEM+Computing program seeks to address emerging challenges in computational STEM areas through the applied integration of computational thinking and computing activities within STEM teaching and learning in early childhood education through high school (preK-12).

A key initiative of STEM+C is to cultivate the skills for the next generation of data scientists, information scientists, and engineers in the nation. A virtual world provides a technique to engage the next generation of students in a fun and intuitive manner. A virtual world is developed around fundamental activities, or gameplay atoms, which reflect the experiential learning process through a trial and error feedback loop. These atoms are combined in multiple ways with slight variations to form a group of related activities referred to as game mechanics. These activities will be mapped to education standards to introduce or reinforce various STEM+C concepts. This project uses design-based research methodology to iteratively develop and refine the activities through meaningfully integrating feedback from educational stakeholders, including teachers and students. Key outcomes from this research include changes in students' interest, attitudes, beliefs, and self-efficacy in STEM+C, engagement in collaborative open-ended solution making, and achievement in related computing and mathematics concepts. This research will help broaden interest in computing to a more diverse pool of students.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Project Summary The nasal cavity is constantly exposed to airborne particles, some of which are potentially damaging to the respiratory tract. Noxious particles are trapped in the mucosal layer and are expelled through mucociliary clearance. Some particles trigger a local, protective inflammatory response through stimulation of solitary chemosensory cells that results in activation of peptidergic nerve fibers. Solitary chemosensory cells respond to numerous airborne irritants through receptors on their apical microvillar processes. The range of substances these cells are known to detect include bitter substances, homoserine lactones excreted by bacteria, and some odorous irritants. While these cells are generally protective, chronic stimulation could contribute to the etiology of airway disorders including chronic rhinosinusitis and conductive smell loss. The current proposal seeks to leverage innovative technologies to explore how this single population of cells is able to detect a wide variety of airborne irritants. First, single cell RNA-sequencing will be used to examine the heterogeneity of solitary chemosensory cells. The types of chemoreceptors on individual cells will be investigated and statistical methods will be used to cluster certain populations of cells based on the transcripts they contain. These results will help define specific signaling mechanisms by which certain stimuli could activate different classes of solitary chemosensory cells and signal to the nervous system or surrounding tissue. In the second part of this proposal, the distribution and innervation of solitary chemosensory cells in the entire nasal cavity will be explored using optical clearing methods and light sheet microscopy. The use of light sheet microscopy on optically cleared tissues prevents the need to physically section tissue samples for immunocytochemistry. By combining these methods, three dimensional reconstructions of large volumes of tissues can be generated to ascertain accurate spatial information. Specifically, subpopulations of solitary chemosensory cells and nerve fibers will be visualized using antibodies or RNA-probes. These experiments will address whether certain populations of solitary chemosensory cells are spatially segregated in the nasal cavity and whether certain populations are more or less likely to be innervated by peptidergic nerve fibers. The results from this study will be beneficial to chemosensory and respiratory system scientists. Currently, solitary chemosensory cells are usually referred to as a homogenous population of chemosensors in the nasal cavity that trigger inflammatory responses through a single mechanism; however, the results from this study will reshape current knowledge of solitary chemosensory cells by defining subtypes and examining their distribution patterns within the nose. These results will give insight to ways that specific stimuli could activate certain classes of solitary chemosensory cells and communicate this information to the nervous system or surrounding tissues.

Systems of polynomial equations are ubiquitous in mathematics, and related fields such as physics, cryptography, and other sciences. When such a system describes a one-dimensional object, the corresponding geometric object is known as an algebraic curve. Broadly speaking, this project studies the geometry of algebraic curves, both individually and as they vary in families. One specific question this project investigates is the concept of interpolation: When can a certain type of curve be passed through a general collection of points? In other words, one can draw a line through any two points in the plane and draw a circle through any three points in the plane, unless those three points lie on a line. More generally, the PI will consider what happens for other types of curves in higher-dimensional spaces, assuming again that the points do not lie in any special configurations. This project also includes training for undergraduate students. <br/><br/>The project considers various questions for the investigation of the structure of the equations of general curves. For example, in what degrees are they generated? What is the Betti table of a general divisor on such a curve? The PI will also investigate certain natural vector bundles on curves that control their deformation theory --- the restricted tangent bundle and the normal bundle --- and study how they break down into stable vector bundles, which are the atomic building blocks of all vector bundles. Finally, the PI will study the geometry of moduli spaces of curves, focusing on their integral intersection theory.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.