Metabolic evaluation of genetic and environmental contributors to Alzheimer’s disease

Understanding the effect of the environment on human health has benefited from progress made in measuring the exposome. High resolution mass spectrometry (HRMS) has made it possible to measure small molecules across a large dynamic range, allowing researchers to study the role of low abundance environmental toxicants in causing human disease, including examining their effects on biochemistry. Alzheimer’s disease is the most prevalent neurodegenerative disease in the world. While aging is the largest risk factor of the disease, evidence of risk factors for dementias show that lifestyle choices and the environment may modify disease onset and alter the projected prevalence. Observational epidemiological studies have linked exposure to the persistent pesticide dichlorodiphenytrichloroethane (DDT) with increased risk of Alzheimer’s disease (AD). In Chapter 2, using an aging cohort based in Washington Heights and Inwood in Northern Manhattan, I investigated systemic biochemical changes associated with Alzheimer’s disease (AD). Small molecules in plasma were measured in 59 AD cases and 60 healthy participants of African American, Caribbean Hispanic, and non-Hispanic white ancestry using untargeted liquid-chromatography–based ultra-high-resolution mass spectrometry. Metabolite differences between AD and healthy, the different ethnic groups and apolipoprotein E gene (APOE) ε allele status were analyzed. Untargeted network analysis identified pathways enriched by AD-associated metabolites. Then, in Chapter 3, using the genetically tractable nematode model Caenorhabditis elegans, I investigated whether DDT can exacerbate AD-related pathology. DDT is a persistent organic pollutant which, despite its ban in 1972, can be detected in the blood of most people in the U.S. I investigated whether DDT can exacerbate AD-related pathology using a transgenic C. elegans strain that expresses a mutant tau protein fragment that is prone to aggregation, as well as a mutant strain expressing a non-aggregating form of tau protein. DDT restricted the growth in all strains; however, the restriction was more severe in the aggregating tau transgenic strain. Further, I found that DDT exacerbates the inhibitory effects of aggregating tau protein on basal mitochondrial respiration, and increases the amount of time the worms spent curled/coiled. High-resolution metabolomics in the whole worm suggests that DDT reduces levels of several amino acids but increases levels of uric acid and adenosylselenohomocysteine. Surprisingly, developmental exposure to DDT blunts the lifespan reduction caused by aggregating tau protein suggesting a mitohormetic effect of the “double-hit” from DDT and aggregating tau protein or an antagonistic effect which could ultimately turn on lifespan extension pathways. Our data suggest that exposure to DDT likely exacerbates the mitochondrial inhibitory effects of aggregating tau protein in C. elegans. DDT may mimic some of the mitochondrial inhibitory effects induced by increased tau protein aggregation, suggesting that the genetic and environmental insult converge on a common mitochondrial inhibitory pathway, which has been associated with AD in several other studies. Finally, in Chapter 4, I determined changes in global metabolism associated with aggregating tau protein in both C. elegans and humans. We performed high-resolution metabolomic analysis on cerebrospinal fluid (CSF) and plasma obtained from patients of AD and mild cognitive impairment, and cognitively normal controls. Using a transgenic strain of C. elegans which expresses aggregating tau protein in all neurons, I studied the effect of aggregating tau protein on metabolism using high-resolution metabolomic analysis in the whole worm. In the population study, I found >300 features associated (p 900 features altered. Pathway enrichment suggested alterations in glycerophospholipid, fatty acid and amino acid metabolism pathways. To determine which metabolic features are altered in both species, I analyzed annotated features for overlap. Five metabolites were concordant between human plasma and C. elegans, and four concordant between human CSF and C. elegans. Thus, in this analysis I provide evidence in support of using C. elegans to study changes in global metabolism associated with Alzheimer’s disease. In conclusion, using liquid and gas-based chromatography coupled with high-resolution mass spectrometry, we can measure levels of endogenous and exogenously derived small molecules in different biological matrices. By using the appropriate study design, we can identify candidate molecules and biochemical pathways associated with environmental exposures or disease in human populations. These candidates can be followed up by exposing an appropriate C. elegans strain: transgenic strains, mutant strains, or strains that are susceptible to RNAi based knockdown. Given their short life cycle and being amenable to high-throughput behavioral assays, they can readily provide functional and molecular readouts of the perturbation. The findings can provide leads for relevant policy around environmental exposures, understanding mechanisms of toxicity and disease, and identifying potential therapeutic targets

Acute Stress Attenuates Cognitive Flexibility in Males Only: An fNIRS Examination

Cognitive processes that afford us the ability to control thoughts and achieve goal-directed behavior are known as executive functions. Empirical evidence in the past few years has demonstrated that executive functions can be influenced by acute stress. The impact of acute stress on cognitive flexibility, a key aspect of executive functions, has received little attention in the literature. We present the results of two experiments conducted to examine the effect of acute stress on cognitive flexibility. Acute stress was induced using the cold pressor task. Cognitive flexibility was assessed using the Wisconsin Card Sorting Test (WCST). Across both experiments acute stress had an attenuating effect on task switching on the WCST. Our findings also indicate that this effect was moderated by the participant’s gender. In Study 1, we observed that following stress exposure male participants in the stress condition made more perseverative errors than participants in the control group. In Study 2, we examined the bilateral hemodynamics in the prefrontal cortex (PFC) during acute stress induction using functional near infrared spectroscopy (fNIRS). Our analysis indicated that functional oxyHb signals fluctuated with greater amplitude than systemic components for participants in the stress group relative to those in the control group. In addition, oxyHb levels post stress induction were correlated with performance on the WCST for the male participants in the stress group only. Concordant with previous reports, our findings indicate that acute stress impacts cognitive flexibility in males and females differentially. Our work also demonstrates the feasibility of using fNIRS as a practical and objective technique for the examination of hemodynamics in the PFC during acute stress

High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage

In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome

Emotion regulation strategies modulate the effect of adverse childhood experiences on perceived chronic stress with implications for cognitive flexibility.

Exposure to early life adversity is associated with chronic stress and a range of stress-related health problems in adulthood. Since chronic stress debilitates activity in the prefrontal cortex (pFC), maladaptive regulatory strategies in response to stress have been proposed as one explanation for the impact of early life adversity on health outcomes in adulthood. We conducted a study to examine the impact of adverse childhood experiences (ACEs) on cognitive flexibility, a key executive function implicated in activity in the pFC, in a sample of adults (N = 486). Additionally, we investigated whether perceptions of chronic stress in adulthood would mediate the influence of ACEs on cognitive flexibility. However, stress is a subjective experience, and emotion regulation strategies can attenuate the stress response. So, we also examined if individual differences in emotion regulation strategies would modulate the relationship between ACEs and chronic stress. Our results demonstrate that early life adversity, as characterized by ACEs, is associated with decreased cognitive flexibility in adulthood. Additionally, number of ACEs was positively correlated with perceived stress, which in turn was negatively correlated with cognitive flexibility. But, individual differences in the habitual use of emotion regulation strategies moderated the influence of ACEs on chronic stress. Specifically, habitual use of cognitive reappraisal attenuated the stress levels whereas habitual use of expressive suppression exacerbated stress levels. Overall, our study highlights the importance of examining emotion regulation in individuals who have experienced early life adversity

Cognitive flexibility and perceived threat from COVID-19 mediate the relationship between childhood maltreatment and state anxiety.

Converging empirical evidence indicates that exposure to adversity in childhood is associated with increased vulnerability to mental health problems in adulthood. As early life adversity has the potential to alter an individual's appraisal of threat, we hypothesized that individuals exposed to adversity in childhood may also exhibit increased threat from environmental stressors, which in turn may impact their state anxiety levels. We examined the relations between adverse childhood experiences, assessed using the Adverse Childhood Experiences Scale (ACEs), perceived threat from COVID-19, and state anxiety in a sample of adults. Additionally, flexibility is implicated in adaptive coping with life's stressors so we also assessed participants' cognitive flexibility. Parallel mediation regression analyses revealed that both perceived threat from COVID-19 and flexibility in the appraisal of challenges mediated the influence of maltreatment, but not household dysfunction, on state anxiety. Our data indicate that experience with early life adversity in the form of maltreatment is associated with increased perceived threat from COVID-19, which results in higher anxiety levels for the individual. In contrast, childhood maltreatment is associated with reduced flexibility in appraising challenges, which in turn mediates the relationship between maltreatment and anxiety. The findings of this study adds to the limited literature on the impact of early life adversity on cognitive flexibility and highlights the psychological toll of COVID-19 on individuals who have been exposed to adverse childhood experiences

Environmental Pollutants and Neurodevelopment: Review of Benefits From Closure of a Coal-Burning Power Plant in Tongliang, China

Background . Understanding preventable causes of neurodevelopmental disorders is a public health priority. Polycyclic aromatic hydrocarbons (PAH) from combustion of fossil fuel, lead, and mercury are among known neurodevelopmental toxicants. Method . For the first time, we comprehensively review the findings from a study by the Columbia Center for Children’s Environmental Health and Chinese partners that followed 2 groups of mother-child pairs, one from 2002 and another from 2005, in Tongliang County, China. Pregnant mothers in the 2 cohorts experienced different exposure to PAH because a local coal-burning power plant was shut down in 2004. Investigators assessed change in prenatal PAH exposure, measured using a biomarker (benzo[a]pyrene [BaP]-DNA adducts in cord blood). Developmental quotients were measured using the Gesell Developmental Scales at age 2 and IQ was assessed using the Wechsler Intelligence Scale for Children at age 5. Biologic markers of preclinical response were measured in cord blood: methylation status of long interspersed nuclear elements ( LINE1 ), an indicator of genomic stability, and brain-derived neurotrophic factor (BDNF), a neuronal growth promoter. Analyses accounted for co-exposure to lead and mercury. Results . BaP-DNA adducts were significantly inversely associated with Gesell Developmental Scales scores in the first cohort but not in the second cohort; and levels of BDNF and LINE1 methylation were higher in the second cohort. Conclusion . In this study, reduced exposure to PAH was associated with beneficial effects on neurodevelopment as well as molecular changes related to improved brain development and health. These benefits should encourage further efforts to limit exposure to these toxic pollutants

Gritty or Flexible: Which Is a Better Predictor of Academic Success?

In any classroom, there are clear differences in the ways students learn and respond to challenges. Growth mindset, the belief that intelligence is malleable and can be improved through hard work (Dweck, 2008), has been shown to influence response to challenging problems. Another quality associated with the response to challenges is grit. Grit is defined as the tendency to sustain perseverance and passion for challenging long-term goals (Duckworth & Gross, 2014). Consequently both growth mindset and grit are implicated in problem solving. However, it is unclear whether either one is associated with executive functioning. 61 college-aged students completed the Growth Mindset Questionnaire (Dweck, 2008), a short Grit Scale (Duckworth, Peterson, Matthews, & Kelly, 2007), two Sudoku puzzles (one easy, one hard, with the order counterbalanced), and the Wisconsin Card Sorting Test (WCST, to assess executive functioning). We found that grit was associated with more correct responses and fewer errors on the WCST. When participants completed the easy Sudoku puzzle before the hard Sudoku puzzle, growth mindset was associated with performance on the hard puzzle. When participants completed the hard Sudoku puzzle before the easy Sudoku puzzle, grit was associated with performance on the hard puzzle

Relationship between the Pacific Decadal Oscillation (PDO) and persistent organic pollutants in sympatric Alaskan seabird (Uria aalge and U. lomvia) eggs between 1999 and 2010.

Although climate change occurs alongside other anthropogenic ecosystem impacts, little is known about how sea-surface temperature variability influences the ecotoxicology of persistent organic pollutants (POPs). We analyzed POP contaminant levels, and stable isotopes δ15N and δ13C as measures of trophic position, in eggs collected from the Gulf of Alaska and Bering Sea between 1999 and 2010 from two similar avian species with different trophic positions: common murres (Uria aalge) and thick-billed murres (Uria lomvia). The ebb and flow of the Pacific Decadal Oscillation (PDO), a long-lived El Niño-like pattern of climate variability in the Pacific Ocean, predicted both trophic position and polychlorinated biphenyl (PCB) levels in thick-billed murres, but not in common murres. There was a similar pattern of association of the PDO with organochlorine pesticide levels in thick-billed murres, but not in common murres. The magnitude of association in thick-billed murres of PDO with the level of a specific PCB congener was a function of the number of chlorine groups on the PCB congener. Although this statistical analysis does not account for all factors contributing to climate variation, this contrast between the species suggests that facultative changes in foraging behavior, reflected in trophic position, can determine how POPs flow through and thereby alter ecosystems under climate change