Michael Lyons - US grants

Clinicians and researchers have sought to describe and define a personality type that shares some characteristics of schizophrenia as stable personality traits and shares a common genetic substrate. DSM-III consolidated these efforts by including Schizotypal Personality Disorder (SPD). Much work on SPD has focused on the association of various symptoms with the diagnosis. The proposed study will determine if cognitive and psychophysiological measures related to schizophrenia support the validity of SPD and evaluate the discriminative validity of the individual criteria. Because there is some evidence that SPD may identify a heterogeneous group, the study will also test a putative distinction between two types of SPD, one genetically related to schizophrenia (familial SPD) and another that is not (clinical SPD). The study will also serve as a field trial for proposed DSM-IV criteria. There will be two SPD subgroups with 30 in each subgroup: (1) first- degree relatives of schizophrenic probands (FSPDs); and (2) outpatient SPDs without schizophrenic relatives (CSPDs). There will be four non-SPD comparison groups (n=30 in each): (1) non-SPD first-degree relatives of schizophrenic probands; (2) non-SPD first-degree relatives of non- schizophrenic psychotic probands; (3) outpatients with non-SPD personality disorders; (4) outpatients and relatives with borderline personality disorders at the Brockton V.A. and an outpatient clinic at McLean Hospital. Groups will be compared on symptomatology and vulnerability markers (Smooth Pursuit Eye Movement, Wisconsin Card Sorting Test, Continuous Performance Test, Span of Apprehension, Visual Verbal Test, and Verbal and Nonverbal Cancellation Test). Some comparisons will contrast the entire SPD sample (n=60) to the entire comparison sample (n=120), while other comparisons will compare SPD subgroups (i.e., CSPDs and FSPDs) to one another and to specific non-SPD comparison groups. The inclusion of "endophenotypes", such as psychophysiological and neuropsychological functions, that may be associated with schizophrenia, but be causally "closer" to the genotype, may help explicate the relationship of SPD, or some subset of SPD, to schizophrenia.

The Harvard Twin Study, using data collected from the Vietnam Era Twin (VET) Registry, demonstrated that vulnerability to alcohol abuse is significantly genetically influenced. The next step is to identify biological and psychological factors that mediate this genetic influence and characterize their mechanism(s). This application is a revision of our previous application. Although the high-risk design proposed in our original application could provide a great deal of information, we have concluded that a full twin design, using both members from twin pairs, will yield considerably more information. The adoption of a traditional twin design has eliminated a number of problems identified in our earlier proposal. We believe that our revised application with additional vulnerability indicators and a full twin design dramatically expands the scope of the project without dramatically expanding the cost. We will now be able to address the genetic and environmental determinants of vulnerability and will include several new and highly interesting domains. We will randomly select 400 twin pairs from among 1356 twin pairs interviewed in our previous study who did not serve in Vietnam during the war. The prevalence of alcohol abuse and dependence in our sample is high enough to provide good power using a random sample. Participants will be evaluated using putative vulnerability indicators, selected from the following domains: a) neuropsychological functioning; b) psychophysiological functioning; c) psychopathology; and d) personality and behavior. Data will be gathered from 200 MZ and 200 DZ twin pairs. Twins will be transported to participating sites at Boston, St. Louis; or Davis, CA to be evaluated with a full personality, psychological, psychophysiological, and neuropsychological protocol. The specific aims of the proposed study are: 1) to determine which of the putative vulnerability indicators are associated with alcohol abuse within individuals; 2) to determine the extent to which identified vulnerability indicators are influenced by genetic factors, environmental experiences shared by twins, and non-shared environmental experiences; 3) to determine the extent to which identified vulnerability indicators and alcohol abuse correlate because of genetic and/or environmental factors that influence both; 4) to distinguish alcohol abuse consequences from alcohol abuse vulnerability; and 5) to replicate and validate findings on definitions of alcoholism that may identify subtypes of alcohol abuse that are due primarily to genetic influences and subtypes that are due primarily to environmental influences (in conjunction with intramural researchers at NIDA).

DESCRIPTION (provided by applicant): We propose to conduct a longitudinal study to investigate ways in which genes and environmental factors contribute to cognitive and adaptive aging, and how the relative influence of genes and environmental factors may change over time. We will study the now middle-aged subjects from the Vietnam Era Twin Registry who we have been studying for the past 12 years. We will study 360 pairs of twins at age 51 years and 360 pairs at age 56, for a total sample of 720 twin pairs (Our colleagues at the U. C. -Davis are concurrently submitting a grant application that parallels ours. In our application we are requesting funding to collect data from 360 pairs in our lab in Boston and in our colleagues' application, they are requesting funding to collect data from the other 360 pairs at their lab in Sacramento. The two applications comprise an integrated project.) Based on a broad, conceptual model of cognitive and adaptive aging, our Specific Aims are: 1) To characterize normative age-related changes in individual cognitive, health, and personality variables using the classical twin method (univariate approaches); 2) To explicate the bases of patterns of inter-relationships seen within the cognitive domain and between cognitive and non-cognitive variables using bivariate, multivariate, and longitudinal approaches; and 3) To characterize risk factors for change in cognitive and adaptive functioning during mid- and later-life using a co-twin control approach. We propose to address developmental issues by means of: 1) cross-sectional data from the twin cohorts; 2) cognitive and personality data collected previously from this sample; and 3) future longitudinal/cohort sequential data In contemporary data collection we will include genotyping for APOE, personality traits and characteristics that have implications for later life cognitive functioning and well-being (attachment, coping styles, positive and negative emotionality, constraint, resiliency), sensory functioning, and physical functioning. Cognitive assessment will consist of an extensive neuropsychological test battery with particular emphasis on working memory and frontal-executive function, episodic memory, and processing speed. This project will shed light on the dynamic interplay of biological and psychosocial environmental factors that create age-associated changes in health, cognition, and personality. Beginning the project in midlife is particularly advantageous for studying adult aging, enabling us to assess subjects who are in the "prime of life" at baseline, yet relatively close to the time when age-associated changes are likely to become more prominent.

[unreadable] DESCRIPTION (provided by applicant): This proposal will allow the Principal Investigator (PI) to develop as an independent investigator with a novel focus on emergency department (ED) screening and surveillance of HIV infection, and factors related to HIV infection. The ED represents a new frontier for public health intervention, presenting opportunities to monitor infectious diseases of public health importance, to increase penetration of at-risk populations with screening and intervention programs, and to reduce health disparities. Maximizing these opportunities requires trained clinical researchers. The PI, an Assistant Professor of Emergency Medicine, will complete a Masters in Public Health and advanced epidemiology and biostatistics courses as part of an individualized curriculum designed by his mentors. Research projects will allow for practical experience, application of knowledge gained, and generation of preliminary data for future NIH funding. Specific aims are: 1) to develop skills in clinical research methodology, epidemiology, and biostatistics to become an independent and fully funded clinical researcher; 2) to evaluate HIV screening in an urban ED in a city with low HIV seroprevalence (<1%) by comparing a targeted HIV screening strategy (testing offered to those perceived to be at-risk) to: a) concurrently obtained ED seroprevalence estimates, b) routine screening (testing offered to all regardless of risk), and c) targeted screening in community health centers. These aims are complementary to the career development of the PI and provide a unique opportunity to positively impact the HIV epidemic. The PI will attain the skills of a clinical researcher under the direct supervision of a multi-disciplinary group of highly qualified mentors. His prior research experience demonstrates a dedication to ED-based HIV prevention research and the ability to coordinate multi-disciplinary collaboration. By capitalizing on current collaborative and mentoring relationships as well as institutional strengths, the PI will develop an evidence- based public health program that can reach a population that is notoriously difficult to penetrate. The quintessential contribution of this research will be to not only help mitigate the HIV epidemic, but to provide evidence for the utility of ED-based screening and surveillance for infectious diseases of national public health importance. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The Vietnam Era Twin Study of Aging (VETSA) study provides a unique opportunity to examine genetic and environmental influences on early cognitive change and associated risk factors. In VETSA 2, we propose our first 5-6 year follow-up of a large, age-homogenous sample that was middle-aged (50s) at baseline. Longitudinal studies of cognitive aging have employed cohort-sequential designs with age-heterogeneous samples that are usually weighted toward older subjects. There is solid evidence of change in midlife to early old age, but because mean change does tend to be modest, increased ability to examine individual differences is key. While no single design can provide all the answers, our novel design does enhance the ability to study differences in within-individual change patterns. By focusing on midlife, our design also has increased potential to identify early predictors of cognitive decline. Moreover, we are including an objective measure of allocation of cognitive effort that will be an important indicator, even in the absence of performance changes. We will follow 720 middle-aged twin pairs (1440 individuals) 5-6 years after collection of baseline neurocognitive, biomedical, and psychosocial data. Mean age at our VETSA 2 follow-up will be 60 (57-66). Applications from 2 Principal Investigators (Kremen, UCSD; Lyons, Boston Univ.) comprise a single integrated project. Our focus is to characterize genetic and environmental influences on early age-related changes in cognitive effort and performance (Aims 1, 2), and to examine major factors that mediate or moderate those changes: APOE [Aim 3]; other biomedical risks [Aim 4]; lifestyle/psychosocial factors [Aim 5]). Aims are: 1) Characterize genetic and environmental influences on cognitive change over time (and specific component processes driving change); 2) Investigate cognitive efficiency (i.e., ratio of performance to effortful resource allocation [based on task-evoked pupillary responses]) as a key cognitive aging process; 3) Examine the relationship of APOE genotype to changes in cognitive function over time; 4) Elucidate biomedical risk factors related to cognition and identify specific health risk factors that best predict cognitive aging (with multivariate genetic models not previously used); 5) Examine lifestyle and psychosocial factors related to cognitive aging. We will obtain comprehensive assessments in multiple domains, utilize a novel approach that integrates the twin method with experimental/neuroscience approaches of parsing cognitive component processes, and use a cost-effective psychophysiological method (pupillometry) to measure cognitive effort.

DESCRIPTION (provided by applicant): Early HIV diagnosis is critical for prevention of new HIV infections. Diagnosed patients can limit further transmission and receive medical care that reduces infectivity. Two effective approaches are "population-based screening" and "transmission network targeting." In healthcare settings, population-based screening is emphasized as a means to test all persons in a defined population, but the vast majority of tests will be negative. In public health and HIV care settings, targeting of transmission networks by testing exposed partners or peer-recruited social contacts is emphasized. This efficiently identifies undiagnosed individuals with fewer negative tests, but misses others not known to be network members. Scarce resources prevent full implementation of either approach, yet partial implementation of multiple complementary and intersecting strategies might be more effective and feasible than full implementation of any one strategy. Demonstrating the implementation and outcomes of such a multi-component screening approach could lead to coordinated allocation of resources on a system-wide basis for maximal impact. The goal of this innovative implementation research proposal is to test whether combinations of screening methods improve the early detection of undiagnosed HIV. We will use population-based screening to identify infected or at-risk patients and then target the transmission networks rendered accessible by those patients. Our emergency department (ED) HIV screening program identifies patients who are: 1) HIV negative but high-risk, 2) known to be HIV positive and engaging in high-risk behavior, and 3) newly diagnosed in the ED as HIV positive. Patients will be asked to provide access to transmission networks. We will then implement an array of multi-component transmission network targeting "packages" in three complementary settings: the ED itself, our HIV treatment center, and our local health department. Package components will focus on: companions present with patients when care is delivered, peer-referral for testing, and health department partner notification. Our specific aims are to measure changes in: 1) number newly diagnosed as a proportion of total tests, and 2) early diagnosis as indicated by median initial CD4 count, that result when we augment an existing population-based ED screening program with comprehensive system-wide transmission network targeting. We will directly characterize the interrelatedness of package components and their capacity to augment one another. By integrating complementary strategies within and across settings, we will inform health policy, promote translation of screening to practice, and demonstrate a means to improve early diagnosis of HIV. PUBLIC HEALTH RELEVANCE: Earlier diagnosis of HIV is critical for prevention. We have effective strategies, but implementation is incomplete. Translation of population-based screening and transmission network targeting in both public health and healthcare settings could be accelerated by a better understanding of the beneficial outcomes of available strategies relative to one another. The fundamental contribution of this study will be to measure the impact of an integrated system-wide approach using the combination of population-based screening and transmission network targeting in public health and healthcare settings.

DESCRIPTION (provided by applicant): The candidate in this K25 application has a background in theoretical physics and computer science. The long term career goal of this candidate is to combine rigorous training in the field of bioscience with his quantitative and computer skills in order to accelerate the late-stage drug development process for the treatment of tuberculosis (TB). The immediate goal is to develop improved computational methods and tools to determine new optimal combination therapies for TB in the preclinical stage of development. This Career Development Award is requested to support a research and training program that includes intensive coursework, mentored readings, attendance at workshops, meetings and seminars, and a research plan that provides for a well-founded understanding of the host-drug-pathogen interactions for the treatment of TB. The candidate will be supported by the Department of Microbiology, Immunology and Pathology at Colorado State University (CSU). The mentors and collaborators for this proposal include faculty from the Mycobacteria Research Laboratories (MRL), the Department of Environmental & Radiological Health Sciences, Chemical & Biological Engineering, and the Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences. CSU is a leader in infectious disease research, and the MRL, with their 19 faculty and over 100 full-time staff, is the worlds largest group focused on mycobacterial research, providing an ideal environment to be introduced to the field of TB research, and for the success of this project. In order to provide guidance for clinical trial testing of new drug regimens for TB, there is a clear need for an efficient method to determine optimal combination regimens in the preclinical stage of development. While conventional pharmacokinetic/pharmacodynamic (PK/PD) methods have proven useful for the determination of optimal single drug antimicrobial regimens, they are data intensive and have limited utility for a systematic and thorough evaluation of the 3- and 4-drug regimens required to treat TB. The objective and goal of this research plan is therefore to develop and demonstrate the use of a computational framework which provides optimal combination drug dosage regimens for treatment of Mycobacterium tuberculosis infection in mice. The proposed framework is a novel integration of physiologically based mathematical modeling, Bayesian inference, targeted experimental studies, and a rigorous method for dose optimization. The specific aims of this proposal are to: (1) develop the computational framework for host-drug-pathogen interactions and drug dose optimization in mouse TB infection models, and (2) demonstrate the use of the computational framework for the determination of an optimal multidrug regimen in mouse TB infection models. While we seek to establish the feasibility of the proposal using current front-line anti-TB drugs (isoniazid, rifampin, pyrazinamide), the ultimate aim of this project is the application of the methodology to the newer anti-TB drugs in order to render predictions of optimal regimens for testing in clinical trials.

? DESCRIPTION (provided by applicant): Advances in early identification and treatment of risk factors are likely to be major weapons in the battle against Alzheimer's disease (AD) and age-related cognitive decline, just as they are for cardiovascular disease and cancer. For AD, it is only relatively recently that researchers concluded that a likely reason for treatment ineffectiveness is the fact that the disease process unfolds decades before dementia onset. AD jumped from the 32nd ranked disease for years of life lost in 1990 to 9th in 2010 (largest increase of any disease), and from 17th to 12th for years lived with disability, in contrast to substantial improvements in cardiovascular disease or cancer where early identification and treatment of risk factors are emphasized. With these alarming trends, it is no wonder that there is now an ever stronger push for earlier identification of AD and cognitive impairment. Therefore, our focus is on mild cognitive impairment (MCI), which can be a precursor to AD. A disease process beginning decades before dementia also calls for a focus on midlife and the transition from middle age to early old age. However, this age period remains notably understudied. We propose to collect a third wave of data in the Vietnam Era Twin Study of Aging (VETSA). VETSA has a narrow 10-year age cohort for assessing within-person differences. Data from mean ages 55 and 61 plus wave 3 data at age 67 will provide a 12-year follow-up for early identification of MCI. Aim 1 is to construct a maximally valid MCI definition using a state-of-the-art approach based on longitudinal consistency, proportion of people converting to MCI and reverting to normal, and associations with biomarkers. We will include 3 categories of biomarkers with potential for screening large populations: blood-based (Aß, exosomal p-tau, clusterin, APOE, NT-proBNP, CRP, free testosterone); externally-validated polygenic risk scores for AD and cognitive impairment; and physiological (pupillometry, light reflex, erectile dysfunction, metabolic syndrome). The first 2 categories are new to this proposal. Capitalizing on plasma stored from VETSA 1, we will examine blood-based biomarkers from VETSA 1 and 3. Aim 2 is to develop the first risk index specifically for MCI based on the combination of biomarkers and traditional risk factors that maximizes sensitivity and specificity. Aim 3 is to elucidate the heterogeneity of continuously measured cognitive function and cognitive change, and identify predictors and correlates. In doing so, we will identify different subgroups of change patterns, and differential sensitivity of cognitive change to particular environmental contexts depending on genetic factors. Aim 4 is to determine predictors of cognitive resilience (being high on polygenic or blood-based risk factors but having no cognitive impairment), so that we can be informative about successful cognitive aging as well as decline. We will have 1261 twins with wave 3 data. After completion, we will make the data publicly available for research. Our unique combination of features puts VETSA ahead of curve with respect to its ability to gain knowledge about early identification and modifiable risk factors that can have a profound public health impact.

Project Summary/Abstract Tuberculosis (TB) is a widespread bacterial infectious disease that kills nearly 1.5 million people annually. While effective drug therapy for TB has been available for more than 50 years, there is a substantial number of drug resistant clinical cases that are signi?cantly impacting public health. Drug regimens for TB are designed to limit the emergence of resistance by using multiple drugs concurrently (combination therapy) which greatly increases the time and cost of their development. While the U.S. Food and Drug Administration (FDA), in partnership with the recently formed Critical Path to New TB Drug Regimens (CPTR) initiative, now provides regulatory guidance for developing new drug combinations as a single unit, and while several new anti-TB regimens are in clinical testing under this FDA guidance, there are critical questions about how to establish the optimal dose of each individual drug within these new combination regimens. Dosage regimens for new anti-TB drug combinations are generally based on ?nding an optimal dose for every single drug in the preclinical stage, and through Phase II dose-ranging clinical trials. While tailoring the doses of each individual drug within a drug combination could potentially yield a more effective and better tolerated treatment regimen, the exponential increase in the in vitro methodologies, animal ef?cacy studies, and clinical testing required to identify such doses for combinations of three or more drugs needed for TB would be prohibitively expensive. To address this gap in TB drug development we propose a new approach to dosage regimen design of combination drug therapies that consists of (1) the use of conventional preclinical and clinical measurements to inform a mathematical dose-response model for a speci?ed drug combination in TB patients, (2) the integration of this mathematical model with a biologically inspired genetic algorithm to design dosage regimens in a manner analogous to natural selection, and (3) the empirical evaluation of these optimized regimens in experimental TB-infection models. To establish our approach with a clinically relevant example, we will design optimized dosage regimens for the new anti-TB combination pretomanid + moxi?oxacin + pyrazinamide (PaMZ); a promising and urgently needed treatment option for patients with multidrug resistant (MDR) TB, currently assessed in a Phase II clinical trial. There is a large amount of high quality preclinical and clinical data for this TB drug combination that will provide a sound evidence base to develop our computational framework and to test our conclusions. Successful completion of the proposed aims will establish new methods and tools to better translate preclinical studies to clinical dosage regimen design for future anti-TB combinations. While motivated by the needs of TB drug development, this project includes innovations that apply to the treatment of other diseases such as cancer, human immunode?ciency virus (HIV) infection, and malaria.

PROJECT SUMMARY/ABSTRACT This application requests funds to support the 2019 meeting of the American Psychopathological Association (APPA) on the topic of ?Psychopathology and Aging.? The program was designed with the goal of covering the outcomes in late life of the major types of psychopathology. Therefore, there are lectures on anxiety disorders, depression, PTSD, substance use disorders, and neurodevelopmental disorders. There is a session on biological influences on mental health in late life that includes genetics and the relationship of medical disorders to mental health. There is also a lecture on mental health issues as individuals reach the end of their lives. Because of the increasing importance of dementia and related disorders, an entire day is devoted to these topics. The meeting concludes with presentations on two topics that are particularly salient during late life: suicide and bereavement. The goal of the meeting is to provide cutting-edge information about aging and to engage and inform the meeting participants, including speakers, discussants, and audience. The meeting will be held the first Thursday, Friday and Saturday of March 2019.

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most costly and burdensome disease in the U.S. Its public health impact will only grow with the increase of 65-75 year olds in the next decade. The AD process begins 2 or more decades before dementia onset. Identifying individuals during early stages (e.g., mild cognitive impairment ([MCI]) is estimated to result in massive savings. Thus, NIH and Alzheimer's Association consensus statements emphasize early identification. Like cardiovascular disease, focusing on middle age is crucial for earlier identification of risk for cognitive decline, preclinical AD, and MCI. Despite this protracted progression of AD pathology, little is known about its temporal course and relation to cognition in middle age. To address this critical knowledge gap, we propose to collect a fourth wave of data in the Vietnam Era Twin Study of Aging (VETSA). VETSA provides detailed characterization of change throughout midlife. With wave 4, VETSA will cover an 18-year period in our community-dwelling sample. VETSA began with virtually all subjects in their 50s, so we can track shifts from normal cognition to MCI/AD and normal to abnormal biomarker status. We focus on 4 sets of indicators that improve the ability to identify at-risk individuals earlier than in most studies: 1) extensive cognitive testing; 2) plasma AD biomarkers for beta-amyloid (A?), tau, and neurofilament light (NfL); 3) polygenic risk scores; and 4) novel assessments of cognitive processes. Almost all subjects will have been A?- at VETSA 1. Average age at VETSA 4 will be 74, and a meta-analysis indicates that >30% of non- demented adults at age 75 are A?+. Thus, leveraging data from previous waves, the timing is ideal to capture the transition to disease states. We utilize the amyloid-tau-neurodegeneration (ATN) biomarker classification system and examine the proposed A!T!N staging of the AD continuum. Naturally, most research focuses on ATN biomarkers as predictors, but it would be highly advantageous to identify people at risk before reaching pathological A? levels. Thus, Aim1 will examine plasma ATN biomarker trajectories as well as predictors of ATN biomarker accumulation and abnormality. We have biomarker data from VETSA 1 and 3, and will perform assays on VETSA 4 data. Aim 2 models risk and protective factors for cognitive decline, biomarker trajectories, and progression to MCI using genetically-informative analyses that can test causality. With 4 time points, we will use our combination of twin and polygenic risk score data and our extensive health/medical and psychosocial data to elucidate factors accounting for accelerated cognitive decline. In Aim 3, we evaluate 2 novel early risk indicators by: a) extending our work on pupil dilation as a measure of cognitive effort before cognitive performance declines; and b) assessing visual short-term memory binding, an early indicator tested primarily in familial AD families. To increase detection of decline, Aim 4 adds telephone/mailed assessments partway in the funding period. Wave 4 will have N=1000. VETSA's unique features make it a most promising resource for advancing knowledge about early identification, with potential for a profound public health impact.