Browsing by Author "Moffitt, Terrie E"

Exposure to psychosocial stress is a robust predictor of subsequent psychopathology. However, only a portion of individuals with these experiences will develop psychiatric symptoms. The concept of gene-environment interaction (GxE) has provided one theoretical framework for reconciling these observations, but the empirical findings from this literature are mixed and often fail to replicate across studies. This dissertation explores the use of a relatively new approach to measuring the mental-health effects of environmental stress (the “p-factor”), and examines whether this approach has the potential to advance and consolidate studies of gene-environment interaction and psychopathology. First, I present lifetime prevalence data from The Dunedin Multidisciplinary Health and Development Study indicating that mental disorder is near-ubiquitous, consistent with the notion that liability to these conditions is distributed quantitatively throughout the population. Second, I present analyses from the Environmental Risk Longitudinal Twin Study showing that the mental-health effects of victimization exposure (one of the most common and severe types of psychosocial stress) are both non-specific and likely causal. These data suggest that stressful life experiences increase risk of psychopathology largely through effects on general liability. Third, I examine whether victimization’s effects on general psychopathology vary as a function of multiple measures of genetic propensity. Results consistently indicate that they do not, suggesting minimal gene-environment interaction. Implications for future research that seeks to identify the genetic and non-genetic factors that determine vulnerability and resilience to the mental-health effects of environmental stress are discussed.

The global population is aging with projections that the number of people over 60 will more than triple by 2050. While many organ systems are impacted by aging, deterioration of the brain is a particularly debilitating form of age-related disease. Alzheimer's disease and related dementias (ADRD) represent neurodegeneration that results in a loss of the ability to perform everyday tasks, maintain independence, and care for oneself. To date, ADRD interventions targeting older adults have largely proven to be ineffective at limiting morbidity and disability, suggesting that interventions may be failing to slow age-related disease because they are implemented too late in the aging process after decline has taken hold. However, to target ADRD interventions to younger adults we will need surrogate biomarkers that track sub-clinical signs of accelerated brain-aging that has yet to be fully cemented. This dissertation consists of 4 original studies that aim to measure and begin to validate magnetic resonance imaging (MRI)-based surrogate biomarkers for accelerated brain-aging in midlife adults. Each of these studies utilizes the Dunedin Study, a population-representative birth cohort of 1,037 adults, who have been followed longitudinally from birth to the most recent wave of data collection, completed when Study members were 45 years old. In Chapter 1, I found that individual differences in WMH volume, an established marker of dementia risk, cognitive decline, and dementia in older adults, were associated with cognitive decline from childhood to age-45. In Chapter 2, I found that individual differences in brainAGE were also associated with cognitive decline from childhood to age-45. In Chapter 3, I found that a known neurotoxicant, lead, was associated with cognitive decline from childhood to age 45, as well as with several MRI measures at age 45 including hippocampal volume, surface area, fractional anisotropy, and brainAGE. In chapter 4, I found that an accelerated Pace of Aging was associated with a thinner cortex, smaller surface area, lower hippocampal volume, higher WMH volume, and older brainAGE. Together, by triangulating evidence from cognitive aging, neurotoxic exposure, and biological aging, these studies help motivate the critical need for researchers to embrace midlife brain aging as a tool for better understanding the aging brain and dementia risk. I conclude with a discussion of the limitations of this research and opportunities for future research to target midlife brain aging itself as a target for clinical translation.

Many diverse adult diseases, from diabetes to dementia, are increasingly viewed as arising, in part, from early life environmental influences. The so-called Developmental Origins of Health and Disease (DOHaD) research paradigm offers the potential to improve our understanding of the etiology of many hard-to-treat adult diseases by focusing researcher’s attention on the pre and post-natal and early childhood years, where small interventions could pay large dividends later on. Along with great potential, the DOHaD framework offers great challenges, as it is logistically and conceptually difficult to investigate the environmental origins of chronic diseases that may manifest only decades after harmful exposures. This dissertation presents a series of five original studies that sought to answer open empirical questions about the developmental origins of health and disease focusing on early-life factors that influence the health and aging of the brain. Three increasingly broad "levels" of the early life environment are considered across three sequential dissertation chapters: (1) the individual micro-physical level, (2) the family level, and (3) the neighborhood level. At each level this dissertation considers at least one exposure that has relevance to researchers and policy makers, either because, like exposure to neighborhood vegetation / greenery, it may offer a good route for intervention (e.g., the exposure is potentially modifiable) or because, like exposure to the heavy metal lead, it is understood to be more widespread than previously assumed. Studies were conducted using data from two population-representative longitudinal birth cohorts, the New Zealand-based Dunedin Multidisciplinary Health and Development Study (born in 1972-1973) and the United Kingdom-based Environmental Risk Longitudinal Twin Study (born in 1994-1995). Across the five studies, results supported the DOHaD framework and provided new evidence about the long-term consequences of childhood exposure to lead, adversity (e.g., physical and emotional abuse, household dysfunction, etc.), and neighborhood disadvantage. These negative early life events / exposures at the micro-physical, family, and neighborhood-levels associated, across multiple decades, with subtle and diverse poor brain-related outcomes later in life, including diminished cognitive capacity, increased symptoms of psychopathology, altered epigenetic controls, disadvantageous personality styles, and worse physical health. Results collectively reinforce the view that the early life represents a profound window of vulnerability and opportunity, with a lifespan perspective offering great potential for more efficacious public health research, clinical practice, and policy, as the diseases of the adult likely have roots in the life of the child.