Terrie Moffitt - US grants

Several studies have examined the cognitive functions, as revealed by neuropsychological tests, of juvenile delinquents. While suggestive that delinquents may suffer from some cognitive deficits, this literature is troubled by methodological shortcomings: highly selected incarcerated or adjudicated subjects, small N's, cross-sectional design, and posthoc choice of neuropsychological tests for research. The proposed project is designed to evaluate the possibility that some patterns of neuropsychological deficit are predictive of delinquent behavior, while avoiding most of the problems characteristic of earlier research. A battery of neuropsychological tests (selected for broad coverage of a variety of cerebral functions) and the Elliott Self-Report Delinquency Interview Schedule will be administered to an unselected birth cohort of 1,000 13 year old children who are the subjects of the Dunedin Multidisciplinary Child Development Study. The Dunedin Multidisciplinary Health and Development Research Unit of the University of Otago Medical School, Dunedin, New Zealand, has studied this cohort longitudinally for 13 years, collecting and analysing data concerning the subjects' perinatal, health, psychological, educational, familial and social statuses biannually since the subjects' births. Valuable prospective data exist for the subjects, which will be used by this project to investigate possible etiological factors (e.g. birth complications or childhood head injury) for any neuropsychological deficits found to predict delinquent involvement. Existing school and family variables (e.g. learning problems, maternal attitudes toward child rearing, or social class) will be examined as possible mediating factors in any neuropsychological deficity/delinquency relationships found. The Dunedin Research Unit plans to follow up the cohort at ages 15, 17 and probably into adulthood. Neuropsychological data collected during the proposed project will then become prospective data useful for predicting a variety of deviant outcomes, including future delinquency and criminal behavior. Knowledge of delinquency-related patterns of brain dysfunction may provide information useful toward several goals: (1) Increased understanding of etiological factors in delinquency, (2) Identification of specific delinquency-related patterns of cognitive deficit which may be targeted for preventive intervention, and (3) Addition to the growing list of markers for early identification of children at risk for developing seriously delinquent lifestyles.

Several studies have examined the cognitive functions, as revealed by neuropsychological tests, of juvenile delinquents. While suggestive that delinquents may suffer from some cognitive deficits, this literature is troubled by methodological shortcomings: highly selected incarcerated or adjudicated subjects, small N's, cross-sectional design, and posthoc choice of neuropsychological tests for research. The proposed project is designed to evaluate the possibility that some patterns of neuropsychological deficit are predictive of delinquent behavior, while avoiding most of the problems characteristic of earlier research. A battery of neuropsychological tests (selected for broad coverage of a variety of cerebral functions) and the Elliott Self-Report Delinquency Interview Schedule will be administered to an unselected birth cohort of 1,000 13 year old children who are the subjects of the Dunedin Multidisciplinary Child Development Study. The Dunedin Multidisciplinary Health and Development Research Unit of the University of Otago Medical School, Dunedin, New Zealand, has studied this cohort longitudinally for 13 years, collecting and analysing data concerning the subjects' perinatal, health, psychological, educational, familial and social statuses biannually since the subjects' births. Valuable prospective data exist for the subjects, which will be used by this project to investigate possible etiological factors (e.g. birth complications or childhood head injury) for any neuropsychological deficits found to predict delinquent involvement. Existing school and family variables (e.g. learning problems, maternal attitudes toward child rearing, or social class) will be examined as possible mediating factors in any neuropsychological deficity/delinquency relationships found. The Dunedin Research Unit plans to follow up the cohort at ages 15, 17 and probably into adulthood. Neuropsychological data collected during the proposed project will then become prospective data useful for predicting a variety of deviant outcomes, including future delinquency and criminal behavior. Knowledge of delinquency-related patterns of brain dysfunction may provide information useful toward several goals: (1) Increased understanding of etiological factors in delinquency, (2) Identification of specific delinquency-related patterns of cognitive deficit which may be targeted for preventive intervention, and (3) Addition to the growing list of markers for early identification of children at risk for developing seriously delinquent lifestyles.

There is a growing focus upon CNS factors in antisocial behavior. As yet, this area of research is unguided by theory, but several studies have reported that delinquents evidence a variety of cognitive deficits, as assessed by neuropsychological tests. This literature is troubled by methodological shortcomings: small N's, cross-sectional design, bias from highly-selected incarcerated or referred subjects, post-hoc choice of tests for research use, and failure to demonstrate the specificity of the deficits to delinquency, rather than to ADD or reading disability. This project was designed to evaluate the possibility that some specific patterns of cognitive deficit are predictive of delinquent behavior, while using self-reported delinquent behavior, a large unselected cohort, and a research battery of tests to avoid most of the problems characteristic of earlier research. The birth cohort studied comprises the 1037 subjects of the longitudinal Dunedin (New Zealand) Multidisciplinary Health and Development Study. Neurological, health, educational, psychological, social and family data have been collected for the cohort since birth. The project's first three years, supported by a NIH New Investigator Award, consisted of data collection when the subjects were 13 years old, and has produced six papers to date. Analyses are yielding evidence that patterns of neuropsychological deficit do exist which relate to self-report early adolescent delinquent behavior. The proposed project is a follow-up, designed to collect self-report delinquency data at age 15 and police records of official delinquency at ages 15, 16, and 17. The ultimate aim of the project is to test the efficacy of neuropsychological variables, in concert with other pertinent variables, for discriminating nondeliquents, minor delinquents who desist early on, and delinquents who go on to develop serious and recidivistic juvenile offense careers. Knowledge of delinquency-related patterns of cognitive dysfunction may provide information useful toward goals of: (1) Increased understanding of the etiology of delinquency, (2) Identification of specific delinquency-related patterns of deficit which may be targeted for preventive intervention, (3) Addition to the growing list of warning signs for early identification of children at risk for developing seriously delinquent lifestyles, and (4) Provision of information in support of theory construction.

This project is designed to examine closely the relationships between four phenomena that contribute risk for delinquent behavior: (1)childhood Conduct Disorder (CD), (2)Attention-Deficit Disorder with Hyperactivity(ADD-H), (3)neuropsychological deficits, and (4)family factors (demographic disadvantage, parental criminality, family disruption and instability, child-rearing and communication styles). The conceptual emphasis is on understanding the influence of these factors on the developmental course of persistent serious delinquent behavior. ADD+CD comorbidity has recently been identified as a strong predictor of later recidivistic criminal offending. The PI's previous research into neuropsychological status and self-reported delinquency has shown that cases with early histories of ADD-H and CD may also show marked deficits in auditory memory and verbal cognitive abilities, and that the delinquent acts of this sub-group are especially aggressive. The proposed research suggests a neuropsychological study of the 500 members of the 4th grade cohort currently being studied longitudinally by the Pittsburgh Youth Study. One-half of the subjects were selected as high risk for delinquency because of symptoms of ADD-H & CD. The PYS is collecting detailed family, mental health, and self-report delinquency data at 6-monthly intervals for the cohort from 1987 through 1991, and those data would be made available for our analysis. The proposed research would conduct neuropsychological assessments of the subjects in 1990 when they are 12 & 13 years old, by administering performance measures of language, visual-motor integration, memory, sustained attention, abstract reasoning, and cognitive/behavioral disinhibition. We hypothesize that (1)knowledge of cognitive deficit and childhood behavior problems can add to our ability to prospectively discriminate persistent/serious delinquents, and (2)neuropsychological strengths may help to protect children from delinquency, despite a criminogenic family social environment. Goals of the research are to analyze the specific cognitive deficit patterns shown by some delinquents in greater depth than has been possible in the past, to focus upon subgroups of delinquents defined developmentally by childhood behavior disorder, and to closely examine the multifactorial facets of family life that interact with individual risk factors in affecting delinquency. The longitudinal risk design of the PYS is well-suited to supporting these research goals.

There is a growing focus upon central nervous system factors in antisocial behavior. Studies have reported that delinquents evidence a variety of cognitive deficits, as assessed by neuropsychological tests, but the literature is troubled by small N's, cross-sectional design, bias from highly-selected incarcerated subjects, post-hoc use of tests for research, and failure to demonstrate the specificity of the deficits to delinquency per se, rather than to other childhood problems that accompany delinquency. This project was designed to ask whether some specific patterns of cognitive deficit are prospectively predictive of delinquent behavior, for the first time using self-reported delinquent behavior (SRD) in a large unselected birth cohort and a theory-based research test battery, in order to avoid problems characteristic of earlier research. The cohort studied comprises the 1037 subjects of the Dunedin (New Zealand) Multidisciplinary Health & Development Study. Neurological, health, educational, psychological, social and family data have been collected for the cohort semiannually since birth. The project's first 3 years, supported by a NIH New Investigator Award, consisted of data collection when the subjects were 13 years old, and has produced 18 papers to date. Analyses are yielding evidence that patterns of neuropsychological deficit do exist that relate differentially to early adolescent SRD. Also, the data suggest that cognitive strengths may protect children from criminogenic environments. We are now collecting SRD at age 15, and lifetime police records through age 17. The project proposed herein is a follow-up designed to collect data on self-report delinquency, attitudes toward crime, neuropsychological function, mental health, drug & alcohol use, socio-familial, education & employment, at age 18. The ultimate aim of the project is to test the efficacy of neuropsychological variables, in concert with other pertinent variables, for discriminating nondelinquents, minor delinquents who desist early on, and delinquents who go on to develop serious and recidivistic juvenile offense careers. Knowledge of delinquency-related patterns of cognitive dysfunction may provide information useful toward several goals: (1) Increased understanding of the etiology of delinquency, (2) Identification of specific patterns of deficit which may be targeted for preventive intervention, (3) Addition to the growing list of warning signs for early identification of children at risk for developing seriously delinquent lifestyles, and (4) Provision of information in support of theory construction.

DESCRIPTION (Adapted from applicant's abstract): The proposed research aims to build knowledge about adult antisocial behavior disorders and violence. Specific hypotheses address: (a) why some young adults persist in antisocial behavior beyond adolescence while others desist, (b) what broad constellation of mental disorders and life problems accompanies adult antisocial behavior, (c) if childhood aggression can lead to adulthood abuse of family members, (d) if bonds to a job or a romantic partner can foster recovery from antisocial behavior, (e) how parental antisocial behavior affects the children of study participants, and (f) if developmental models of male antisocial behavior apply to women, or if female-specific models are needed. The longitudinal Dunedin Multidisciplinary Health and Development Study has traced the development of antisocial behavior among a representative 1972 birth cohort of 1,000 New Zealand men and women from age 3 to 21. Age-26 outcomes will be measured. Analyses will ascertain relations between the sample members' adult antisocial status and variables drawn from extensive data gathered over many years for study members, their parents, their partners, and now their children. The proposed research will generate (a) disconfirming tests of a published developmental theory of antisocial behavior, (b) recommendations for tailoring the timing and content of intervention to fit delinquents' developmental histories, (c) documentation of the full scope of the cost of antisocial behavior to society, (d) information about the co-incidence of adult life problems for coordinating disparate service-delivery systems to young adults, (e) knowledge about links between delinquency and later family violence, which can be used for prevention of partner and child abuse, (f) knowledge of what brings about natural desistence from crime, which can be harnessed to hasten desistence, (g) an understanding of the process that underlies transmission of aggression from parent to child, and (h) a knowledge base on the origins and consequences of problem behaviors among women.

Between ages 18 and 24, the prevalence of criminal offending decreases sharply. It is commonly believed that delinquents become desisters because of the developmental transitions of young adulthood: marriage, a new family, and employment. However, there are few empirical descriptions of this process. At the same time that the majority of delinquents abandon crime for more pro-social lifestyles, a smaller number of individuals continue their crime careers into young adulthood and beyond. These persisters are thought to have high offense rates and to be often violent. It is not known why criminal persisters are exempt from the taming influence of adult transitions that presumably help others to desist. Criminological theories, preoccupied with the origins of antisocial behavior, fail to account for the marked divergence in the lifecourses of delinquents during young adulthood, one of the most robust facts known about crime. The proposed program of research offers innovations in theory and empirical research. We propose to follow up at age 21 the 1,000 members of the Dunedin New Zealand Multidisciplinary Health and Developmental Longitudinal Study, and their new spouses and children. The sample is a representative birth cohort of males and females whose antisocial behavior has been previously studied at ages 3, 5, 7, 9, 11, 13, 15, and 18. To complement the existing data base of social, psychological, and biological variables on this cohort, we shall collect new data on: self-reported, peer-reported and official crime, mental disorder, substance use, sexual & reproductive behavior, and intra-familial antisocial behavior toward spouses and children. These outcomes will be related to new data on the timing and quality of young adult transitions: education, work, finances, cohabitation and marriage, child-bearing, parenting, social networks, residence change, and illness and disability. The research will be the first to describe the natural history of antisocial behavior in the same individuals, male and female, from infancy to adulthood. The collection and analysis of data in this program of research are guided by a new theory developed during the first 6 years of NIMH support. The theory is both developmental and taxonomic in nature. It proposes two distinct types of antisocial involvement: "Life-Course Persistent Antisocial Behavior" and "Adolescence-Limited Delinquency". I have argued that the two types differ in etiology, developmental course, demographic distribution, prognosis for intervention, and in the classification of their behavior as either pathological or adaptive. The follow up of the NZ sample at age 21 will allow tests of a set of point predictions generated from the theory. By linking criminal desistence and criminal persistence to life history data from birth to young adulthood, the proposed research aspires to make some advances in research design and theory-testing, and to yield findings that are of practical relevance for intervention policy.

DESCRIPTION (Adapted from applicant's abstract): The proposed research aims to build a knowledge base about partner violence among young adults, the peak risk group. Specific hypotheses address: (a) developmental pathways from childhood into partner-violence, (b) changes in proximal, contextual circumstances that precipitate incidents of partner violence, (c) relations between partner violence and mental disorders, (d) typological comparisons of partner-violence perpetrators, (e) effects of exposure to parental violence on the children of study participants, and (f) a comparison of findings across sites in two countries. Perpetration and victimization will be measured for both men and women in the longitudinal Dunedin Multidisciplinary Health and Development Study, which follows a representative 1972 birth cohort of 1,000 New Zealand men and women to age 26. Findings will be replicated and extended by measuring men s perpetration and victimization in the longitudinal Pittsburgh Youth Study, which follows a high-risk 7th grade cohort of 500 Black and White urban American men to age 24. Analyses will ascertain relations between the sample members partner violence and independent variables drawn from extensive longitudinal data gathered over many years for these two cohorts, their parents, and their children. The proposed research is expected to contribute: (1) a knowledge base for a developmental theory of the etiology of men s violence against women partners, (2) recommendations for the timing and content of primary preventions and therapeutic interventions, (3) information about contextual factors that may control perpetrators behavior and reduce victims risk, (4) information about how mental health professionals can screen male patients for their risk for perpetration, and (5) information about protective factors that can help children exposed to parental violence. By comparing results across genders, races, and sites in two different nations, the investigators aim to document which findings about young partner violence are robust enough to inform theory, practice, and policy.

DESCRIPTION (provided by applicant): Objective: The proposed research aims to build knowledge about four behavior disorders: depression, schizophreniform, antisocial, and substance abuse disorders. In all four disorders, developmental subtypes have been proposed as a way forward to carve up the heterogeneity now hindering scientific understanding. We will study heterogeneity within each disorder over the first three decades of life, by analyzing variation in onset (early versus later) and subsequent course (persistent, recurrent, or limited). We aim to ascertain the existence, discriminant validity, and implications of developmental subgroups within disorders. Methods: The Dunedin Study has traced the development of a representative 1972 birth cohort of 1,000 New Zealand men and women at birth and ages 3, 5, 7, 9, 11, 13, 15, 18, 21, and 26. New data will be gathered at age 31. Psychiatric data from childhood to age 31 will be analyzed to identify developmental subgroups within each disorder. Hypotheses address: (a) different childhood risk factors and family psychiatric histories for developmental subgroups, (b) different adult outcomes in work life, family life, and physical health for developmental subgroups, (c) proximal life events that precipitate adult-onset disorder, (d) temporal comorbid sequences in which one type of disorder reliably leads to another, and (f) whether findings apply to men and women, or if sex-specific models are needed. Implications for diagnosis: Findings will improve the current DSM classification system by enabling clinicians to use developmental history to know more about a disorder's probable etiology and prognosis. Implications for prevention: Findings will (a) yield recommendations for tailoring interventions to fit developmental subtypes, (b) clarify the relative importance of preventing onset versus recurrence, (c) identify factors posing pervasive risk for many disorders as top prevention priorities, (d) point to common sequences of disorders, which suggest that treatment of disorder A may prevent disorder B. Implications for genetic and neuroscience research: Findings will characterize psychiatric phenotypes more precisely, and show which subtypes have familial and neuro-developmental correlates.

DESCRIPTION (provided by applicant): We propose to test the novel hypothesis that a persistent history of psychiatric disorder might accelerate individuals' risk of progression toward age-related disease. Specifically, the hypothesis is that people who suffer chronic or recurrent psychiatric disorders during early adulthood will, already by age 38, show cognitive decline and abnormal status on sub-clinical biomarkers that are known to be prognostic early warning signs for late-life diseases, frailty and disability. Rather than focus on psychiatric disorders as an outcome, we study psychiatric disorders as a potentially preventable `exposure' that may accelerate aging. METHOD: We will test this hypothesis in the context of the Dunedin Study, a longitudinal study from birth to age 38 of a representative birth cohort of men and women (N=1037). A unique design feature is that baseline physical health and baseline neuropsychological assessments were carried out from birth to age 13, prior to the onset of most psychiatric disorders. To our knowledge, no other study of the health consequences of psychiatric disorder has these prospective baseline data, which are essential to test whether health and neuropsychological functions have deteriorated in individuals with persistent psychiatric disorder. Cohort members' psychiatric histories of recurrent Depression, recurrent Anxiety, chronic Schizophrenia-syndrome, persistent Alcohol Dependence, and persistent Cannabis Dependence will be defined using data from repeated assessments across 20 intervening years in this longitudinal study. Here we propose to assess the cohort again at age 38, for new data collection. We will assess sensitive outcome measures of sub-clinical health status that are known predictors of age-related diseases in later life: neuropsychological tests of memory and executive functions, the metabolic syndrome, immunological biomarkers, and shortened telomere length. These markers were chosen because they show meaningful variation among people in their late 30's and are known early warning signs for dementia, cardiovascular disease and diabetes. INNOVATION AND SIGNIFICANCE: Life expectancy is growing longer and longer. Policy makers and citizens are concerned that our extra years of life should be healthy, productive, and enjoyable, not extra years of disease and disability. The hope of preventing age-related diseases and of increasing health expectancy requires research to identify candidate risk targets that can be treated successfully, in early- to-middle adulthood. If the hypothesis that psychiatric disorder accelerates the sub-clinical progression toward age-related disease were shown to be true by our proposed research, this would imply that age- related disease could be reduced by successfully treating psychiatric disorders early in life.

? DESCRIPTION (provided by applicant): This application responds to a call for research on the mid-life reversibility of early-established bio-behavioral risk factors (RFA-AG-14-006). Population aging increases the public-health burden of age-related conditions, such as cardiovascular disease, type 2 diabetes, and dementia. It is now known that the pathogenesis of such age- related diseases involves gradually accumulating damage to organ systems, beginning in the first half of the life course, particularly in people exposed to early-life adversty. It is also known that age-related diseases and early mortality are portended by a variety of adverse experiences in early life. Although these facts imply that it is desirable to prevent early life adversities, adversity cannot be fully prevented (and it is too late to prevent early- life adversity for the baby-boomer generation). Therefore there is growing interest in interventions for midlife adults, to reverse the damage done by early-life adversity. This interest lends new scientific significance to existing studies that have followed cohorts from childhood to midlife, because they can provide an evidence base to inform and speed the development of novel intervention strategies. The RFA extends a call for such studies. We propose to undertake data analyses in one such study, the NIA-funded Dunedin Multidisciplinary Health & Development Study, a longitudinal birth-cohort study of both problematic and positive processes of lifelong development. Our data resource comprises in-clinic assessments at birth and ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, and most recently 38 years, with 95% retention as the cohort enters midlife. The data combine demographic/economic surveys, clinical-quality health assessments, a bio-bank, genome-wide SNP data, and administrative-record linkage. First, we will generate outcome measures to detect individual differences in decline of biomarkers for organ systems in the general population at early midlife, the stage when future reversibility interventions will be applied. Second, we will compare the performance of retrospective versus prospective measures of early-life adversity. Future reversibility interventions will have to rely on midlife participants' retrospective reports of adversity, so there is a need to know how well this is going to work. Third, we will test how the connection between early-life adversity and midlife aging relates to polygenic genetic risk and family history of age-related diseases. Will genotype or family history influence responsiveness to reversibility interventions? Fourth, we will identify potentially reversible behavioral and social factors that mediate the connection from early-life adversity to midlife biological aging. Findings are expected to support the design of future randomized clinical trials of midlife interventions intended to reverse the effects of early-life adversity, prevent age-related diseases, and enhance wellbeing in late life.

? DESCRIPTION (provided by applicant): Declining fertility rates, aging of the baby-boomers, and increasing life expectancy are leading to population aging. As the population ages, this increases the public-health burden of age-related conditions, such as cardiovascular disease, type 2 diabetes, and dementia. Treating un-prevented diseases in late life has proven costly and ineffective. It is now known that potentially preventable risk exposures and physiological causes of age-related disease emerge in childhood. This recognition lends new scientific significance to studies that have followed cohorts from childhood. It is also now known that the pathogenesis of age-related diseases involves gradually accumulating decline in organ systems, beginning in the first half of the life course. Consequently, new interventions aiming to prevent age-related diseases will have to be applied to individuals while they are yet young, before they reach midlife. Translation of basic-science geronotology discoveries into interventions for young humans is lacking because virtually nothing is known about the process of biological aging during the first half of the life course. This prompts our proposal to study the pace of biological aging from the twenties forward. We will use the Dunedin Multidisciplinary Health & Development Study, a longitudinal study of a birth cohort now entering its fifth decade. This study combines methods of demographic/economic surveys, clinical- quality health assessments, biobanking, and linkage to nationwide administrative records (health, welfare, finances). We propose to administer a full-day data-collection protocol to the 1004 living members of the birth cohort. To assess each cohort member's pace of biological aging we will: (a) measure biomarkers across multiple organ systems, and (b) statistically model correlated change in these biomarkers assessed at ages 26, 32, 38, and 45 years. We will describe individual variation in the pace of aging, plus its developmental origins, genomic signatures, functional consequences, and economic costs. We will identify attributes that set apart individuals whose bodies are months or years younger than their chronological age. The proposed work will improve knowledge by generating findings to support future interventions to slow aging, prevent age-related disease, and improve the quality of longer lives.

? DESCRIPTION (provided by applicant): Declining fertility rates, aging of the baby-boomers, and increasing life expectancy are leading to population aging. As the population ages, this increases the public-health impact of age-related conditions, such as cardiovascular disease, type 2 diabetes, and dementia. Treating un-prevented diseases in late life has proven costly and ineffective. Consequently, effective strategies are needed in midlife to prevent age-related diseases and to improve the quality of longer lives. It is now known that potentially preventable risk exposures and physiological causes of age-related disease emerge in childhood. This recognition lends new scientific significance to studies that have followed cohorts from childhood. It is also now known that the pathogenesis of age-related diseases involves gradually accumulating damage to organ systems, beginning in the first half of the life course. Of these organ systems, the central nervous system is integral, prompting our proposal to add neuroimaging to the Dunedin Multidisciplinary Health & Development Study, a longitudinal study of both problematic and positive processes of adult development and aging, in a birth cohort now entering its fifth decade. This study combines methods of demographic/economic surveys, clinical-quality health assessments, biobanking, and linkage to nationwide administrative records (health, welfare, finances). We propose to administer a multimodal MRI protocol to the 1004 living members of the birth cohort. Our proposed neuroimaging protocol will measure individual variation in brain function, structure, and connectivity. We focus on the hubs of four neural circuits and the core behavioral capacities each supports: (1) the amygdala and emotion/threat, (2) the ventral striatum and motivation/reward, (3) the hippocampus and memory, and (4) the dorsolateral prefrontal cortex and executive control. With the resulting midlife neural measures, we propose three primary aims that will generate findings about problematic and successful aging: Aim 1 tests whether prospectively ascertained early- life adversity is linked to midlife neural measures. Aim 2 tests whether neural measures are linked to real-world behaviors (e.g., saving behavior) necessary to prepare for successful aging. Aim 3 tests if neural measures are related to the accelerated pace of biological aging. The proposed work will improve knowledge by generating findings about the neural correlates of age-related diseases and successful healthy aging. These findings are expected to support preventing disease and enhancing preparedness for wellbeing in late life. Beyond the proposed 5-year project, follow-up neuroimaging is envisaged. This project thus brings neuroimaging into three timely and vigorous areas of aging science: the study of early-life programming of lifelong health, the study of midlife preparation for successful aging, and mind-body research linking brain function to physical health.

This R01 application responds to FOA PA-18-061: Marijuana Use In Older Adults. Baby- boomers who began using cannabis as young people, and who have continued cannabis use for years, are now entering later life. The FOA prioritizes new evidence about the current risk status of life-long cannabis users in relation to the aging process, and the aging brain, including potential risk for Alzheimer?s disease and related disorders. How prepared are they for successful aging and a long healthspan in late life? We propose to characterize midlife reserve status of long-term cannabis users in the Dunedin Study, a cohort of 1037 infants born in one city in 1972-73 and studied to age 45 in 2019, with 94% retention. There have been 8 waves of in-depth clinical cannabis-use interviews from age 13 to age 45, a unique asset for defining the users who are the target of this FOA. Our primary group of interest are the cohort members who have used cannabis weekly-to-daily for the past 3 decades, three-quarters of whom have met cannabis-dependence criteria. We will test whether such long-term cannabis users do or do not show diminished reserve capacities in midlife, including accelerated biological aging. Accelerated aging and diminished reserve pose risk for poor quality of life, brief health span, and early mortality. The project?s novel conceptual framework extends the logic of ?protective cognitive reserve capacities? to a range of other life domains: we will study reserve in tested cognitive abilities, but also reserve in neural structure and connectivity assessed through neuroimaging, physical-health reserve assessed in clinical medical examinations, epigenetic- maintenance reserve assessed as genome-wide DNA methylation, and financial reserves assessed through interviews, credit ratings and tax records. In addition to analyses of continuous dimensional measures, analyses will uniquely be able to compare long-term cannabis users against 5 informative groups: lifelong non-users, midlife recreational users, formerly cannabis-dependent quitters, cannabis-free long-term alcohol-abusers, and cannabis- free long-term tobacco-smokers. For many of the project?s Aims, the Dunedin Study?s prospective repeated measures allow the rare advantage of comparing long-term users against themselves at a younger age, before prolonged cannabis exposure. Innovations are: (1) cannabis-use histories validly defined with 4 decades of prospective assessments, (2) our conceptual framework of ?reserve? for future aging, (3) a comprehensive portrait of participants? reserve status on aging-relevant measures across multiple disciplines, collected in the same individuals.