Exploring the genetic etiology across the continuum of the general psychopathology factor: a Swedish population-based family and twin study.

Psychiatric comorbidity can be accounted for by a latent general psychopathology factor (p factor), which quantifies the variance that is shared to varying degrees by every dimension of psychopathology. It is unclear whether the entire continuum of the p factor shares the same genetic origin. We investigated whether mild, moderate, and extreme elevations on the p factor shared the same genetic etiology by, first, examining the linearity of the association between p factors across siblings (N = 580,891 pairs). Second, we estimated the group heritability in a twin sample (N = 17,170 pairs), which involves testing whether the same genetic variants influence both extreme and normal variations in the p factor. In both samples, the p factor was based on 10 register-based psychiatric diagnoses. Results showed that the association between siblings' p factors appeared linear, even into the extreme range. Likewise, the twin group heritabilities ranged from 0.42 to 0.45 (95% CI: 0.33-0.57) depending on the thresholds defining the probands (2-3.33 SD beyond the mean; >2 SD beyond the mean; >4.33 SD beyond the mean; and >5.33 SD beyond the mean), and these estimates were highly similar to the estimated individual differences heritability (0.41, 95% CI: 0.39-0.43), indicating that scores above and below these thresholds shared a common genetic origin. Together, these results suggest that the entire continuum of the p factor shares the same genetic origin, with common genetic variants likely playing an important role. This implies, first, genetic risk factors for the aspect that is shared between all forms of psychopathology (i.e., genetic risk factors for the p factor) might be generalizable between population-based cohorts with a higher prevalence of milder cases, and clinical samples with a preponderance of more severe cases. Second, prioritizing low-cost genome-wide association studies capable of identifying common genetic variants, rather than expensive whole genome sequencing that can identify rare variants, may increase the efficiency when studying the genetic architecture of the p factor.

Is it time to discard the Diagnostic and Statistical Manual of Mental Disorders (DSM) in psycho-oncology?

The conceptual basis of psychopathology within cancer survivorship is critical, as the chosen conceptualisation informs assessment and explanatory models, as well as interventions and supportive care approaches. The validity of a chosen conceptualisation of psychopathology is therefore paramount for ensuring cancer survivors receive high-quality and efficacious care and support that can be iteratively improved via coordinated research efforts. In this paper, we discuss the traditional diagnostic approach to conceptualising psychopathology within cancer care, including the diagnostic system the 'Diagnostic and Statistical Manual of Mental Disorders' (DSM) [1], and the significant issues it presents within cancer survivorship. We detail and discuss how an alternate conceptualisation of psychopathology may enhance both research and practice within psycho-oncology. We ultimately pose, and provide our perspective, on the question "Is it Time to Discard the DSM in Psycho-Oncology?"

Automating the analysis of facial emotion expression dynamics: A computational framework and application in psychotic disorders.

Facial emotion expressions play a central role in interpersonal interactions; these displays are used to predict and influence the behavior of others. Despite their importance, quantifying and analyzing the dynamics of brief facial emotion expressions remains an understudied methodological challenge. Here, we present a method that leverages machine learning and network modeling to assess the dynamics of facial expressions. Using video recordings of clinical interviews, we demonstrate the utility of this approach in a sample of 96 people diagnosed with psychotic disorders and 116 never-psychotic adults. Participants diagnosed with schizophrenia tended to move from neutral expressions to uncommon expressions (e.g., fear, surprise), whereas participants diagnosed with other psychoses (e.g., mood disorders with psychosis) moved toward expressions of sadness. This method has broad applications to the study of normal and altered expressions of emotion and can be integrated with telemedicine to improve psychiatric assessment and treatment.

The Prospective Predictive Power of Parent-Reported Personality Traits and Facets in First-Onset Depression in Adolescent Girls.

Certain personality traits and facets are well-known risk factors that predict first-onset depression during adolescence. However, prior research predominantly relied on self-reported data, which has limitations as a source of personality information. Reports from close informants have the potential to increase the predictive power of personality on first-onsets of depression in adolescents. With easy access to adolescents' behaviors across settings and time, parents may provide important additional information about their children's personality. The same personality trait(s) and facet(s) rated by selves (mean age 14.4 years old) and biological parents at baseline were used to prospectively predict depression onsets among 442 adolescent girls during a 72-month follow-up. First, bivariate logistic regression was used to examine whether parent-reported personality measures predicted adolescent girls' depression onsets; then multivariate logistic regression was used to test whether parent reports provided additional predictive power above and beyond self-reports of same trait or facet. Parent-reported personality traits and facets predicted adolescents' depression onsets, similar to findings using self-reported data. After controlling for the corresponding self-report measures, parent-reported higher openness (at the trait level) and higher depressivity (at the facet-level) incrementally predicted first-onset of depression in the sample. Findings demonstrated additional variance contributed by parent-reported personality measures and validated a multi-informant approach in using personality to prospectively predict onsets of depression in adolescent girls.

Psychosis superspectrum II: neurobiology, treatment, and implications.

Alternatives to traditional categorical diagnoses have been proposed to improve the validity and utility of psychiatric nosology. This paper continues the companion review of an alternative model, the psychosis superspectrum of the Hierarchical Taxonomy of Psychopathology (HiTOP). The superspectrum model aims to describe psychosis-related psychopathology according to data on distributions and associations among signs and symptoms. The superspectrum includes psychoticism and detachment spectra as well as narrow subdimensions within them. Auxiliary domains of cognitive deficit and functional impairment complete the psychopathology profile. The current paper reviews evidence on this model from neurobiology, treatment response, clinical utility, and measure development. Neurobiology research suggests that psychopathology included in the superspectrum shows similar patterns of neural alterations. Treatment response often mirrors the hierarchy of the superspectrum with some treatments being efficacious for psychoticism, others for detachment, and others for a specific subdimension. Compared to traditional diagnostic systems, the quantitative nosology shows an approximately 2-fold increase in reliability, explanatory power, and prognostic accuracy. Clinicians consistently report that the quantitative nosology has more utility than traditional diagnoses, but studies of patients with frank psychosis are currently lacking. Validated measures are available to implement the superspectrum model in practice. The dimensional conceptualization of psychosis-related psychopathology has implications for research, clinical practice, and public health programs. For example, it encourages use of the cohort study design (rather than case-control), transdiagnostic treatment strategies, and selective prevention based on subclinical symptoms. These approaches are already used in the field, and the superspectrum provides further impetus and guidance for their implementation. Existing knowledge on this model is substantial, but significant gaps remain. We identify outstanding questions and propose testable hypotheses to guide further research. Overall, we predict that the more informative, reliable, and valid characterization of psychopathology offered by the superspectrum model will facilitate progress in research and clinical care.

Psychosis superspectrum I: Nosology, etiology, and lifespan development.

This review describes the Hierarchical Taxonomy of Psychopathology (HiTOP) model of psychosis-related psychopathology, the psychosis superspectrum. The HiTOP psychosis superspectrum was developed to address shortcomings of traditional diagnoses for psychotic disorders and related conditions including low reliability, arbitrary boundaries between psychopathology and normality, high symptom co-occurrence, and heterogeneity within diagnostic categories. The psychosis superspectrum is a transdiagnostic dimensional model comprising two spectra-psychoticism and detachment-which are in turn broken down into fourteen narrow components, and two auxiliary domains-cognition and functional impairment. The structure of the spectra and their components are shown to parallel the genetic structure of psychosis and related traits. Psychoticism and detachment have distinct patterns of association with urbanicity, migrant and ethnic minority status, childhood adversity, and cannabis use. The superspectrum also provides a useful model for describing the emergence and course of psychosis, as components of the superspectrum are relatively stable over time. Changes in psychoticism predict the onset of psychosis-related psychopathology, whereas changes in detachment and cognition define later course. Implications of the superspectrum for genetic, socio-environmental, and longitudinal research are discussed. A companion review focuses on neurobiology, treatment response, and clinical utility of the superspectrum, and future research directions.

Developmental pathway for first onset of depressive disorders in females: from adolescence to emerging adulthood.

BACKGROUND: Although risk markers for depressive disorders (DD) are dynamic, especially during adolescence, few studies have examined how change in risk levels during adolescence predict DD onset during transition to adulthood. We compared two competing hypotheses of the dynamic effects of risk. The risk escalation hypothesis posits that worsening of risk predicts DD onset beyond risk level. The chronic risk hypothesis posits that persistently elevated risk level, rather than risk change, predicts DD onset. METHODS: Our sample included 393 girls (baseline age 13.5-15.5 years) from the adolescent development of emotions and personality traits project. Participants underwent five diagnostic interviews and assessments of risk markers for DD at 9-month intervals and were re-interviewed at a 6-year follow-up. We focused on 17 well-established risk markers. For each risk marker, we examined the prospective effects of risk level and change on first DD onset at wave six, estimated by growth curve modeling using data from the first five waves. RESULTS: For 13 of the 17 depression risk markers, elevated levels of risk during adolescence, but not change in risk, predicted first DD onset during transition to adulthood, supporting the chronic risk hypothesis. Minimal evidence was found for the risk escalation hypothesis. CONCLUSIONS: Participants who had a first DD onset during transition to adulthood have exhibited elevated levels of risk throughout adolescence. Researchers and practitioners should administer multiple assessments and focus on persistently elevated levels of risk to identify individuals who are most likely to develop DD and to provide targeted DD prevention.

Effects of Daily Posttraumatic Stress Disorder Symptoms on Heart Rate Variability.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is common, debilitating, and associated with an increased risk of health problems, including cardiovascular disease. PTSD is related to poor autonomic function indicated by reduced heart rate variability (HRV). However, very little work has tested the timescale or direction of these effects, given that most evidence comes from cross-sectional studies. Documentation of when effects occur and in what direction can shed light on mechanisms of cardiovascular disease risk and inform treatment. The present study of 169 World Trade Center responders, oversampled for PTSD, tested how daily PTSD symptoms were associated with autonomic function as reflected through HRV. METHODS: Participants ( N = 169) completed surveys of PTSD symptoms three times a day at 5-hour intervals for 4 days while also wearing ambulatory monitors to record electrocardiograms to derive HRV (i.e., mean absolute value of successive differences between beat-to-beat intervals). RESULTS: HRV did not predict PTSD symptoms. However, PTSD symptoms during a 5-hour interval predicted reduced HRV at the next 5-hour interval ( ß = -0.09, 95% confidence interval = -0.16 to -0.02, p = .008). Results held adjusting for baseline age, current heart problems, and current PTSD diagnosis. CONCLUSIONS: Findings underscore growing awareness that PTSD symptoms are not static. Even their short-term fluctuations may affect cardiovascular functioning, which could have more severe impacts if disruption accumulates over time. Research is needed to determine if momentary interventions can halt increases in PTSD symptoms or mitigate their impact on cardiovascular health.

Principles and procedures for revising the hierarchical taxonomy of psychopathology.

Quantitative, empirical approaches to establishing the structure of psychopathology hold promise to improve on traditional psychiatric classification systems. The Hierarchical Taxonomy of Psychopathology (HiTOP) is a framework that summarizes the substantial and growing body of quantitative evidence on the structure of psychopathology. To achieve its aims, HiTOP must incorporate emerging research in a systematic, ongoing fashion. In this article, we describe the historical context and grounding of the principles and procedures for revising the HiTOP framework. Informed by strengths and shortcomings of previous classification systems, the proposed revisions protocol is a formalized system focused around three pillars: (a) prioritizing systematic evaluation of quantitative evidence by a set of transparent criteria and processes, (b) balancing stability with flexibility, and (c) promoting inclusion over gatekeeping in all aspects of the process. We detail how the revisions protocol will be applied in practice, including the scientific and administrative aspects of the process. Additionally, we describe areas of the HiTOP structure that will be a focus of early revisions and outline challenges for the revisions protocol moving forward. The proposed revisions protocol is designed to ensure that the HiTOP framework reflects the current state of scientific knowledge on the structure of psychopathology and fulfils its potential to advance clinical research and practice. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Do general and specific factors of preschool psychopathology predict preadolescent outcomes? A transdiagnostic hierarchical approach.

BACKGROUND: Preschool psychiatric symptoms significantly increase the risk for long-term negative outcomes. Transdiagnostic hierarchical approaches that capture general ('p') and specific psychopathology dimensions are promising for understanding risk and predicting outcomes, but their predictive utility in young children is not well established. We delineated a hierarchical structure of preschool psychopathology dimensions and tested their ability to predict psychiatric disorders and functional impairment in preadolescence. METHODS: Data for 1253 preschool children (mean age = 4.17, s.d. = 0.81) were drawn from three longitudinal studies using a similar methodology (one community sample, two psychopathology-enriched samples) and followed up into preadolescence, yielding a large and diverse sample. Exploratory factor models derived a hierarchical structure of general and specific factors using symptoms from the Preschool Age Psychiatric Assessment interview. Longitudinal analyses examined the prospective associations of preschool p and specific factors with preadolescent psychiatric disorders and functional impairment. RESULTS: A hierarchical dimensional structure with a p factor at the top and up to six specific factors (distress, fear, separation anxiety, social anxiety, inattention-hyperactivity, oppositionality) emerged at preschool age. The p factor predicted all preadolescent disorders (ΔR2 = 0.04-0.15) and functional impairment (ΔR2 = 0.01-0.07) to a significantly greater extent than preschool psychiatric diagnoses and functioning. Specific dimensions provided additional predictive power for the majority of preadolescent outcomes (disorders: ΔR2 = 0.06-0.15; functional impairment: ΔR2 = 0.05-0.12). CONCLUSIONS: Both general and specific dimensions of preschool psychopathology are useful for predicting clinical and functional outcomes almost a decade later. These findings highlight the value of transdiagnostic dimensions for predicting prognosis and as potential targets for early intervention and prevention.

Examining the relationship between genetic risk for depression and youth episodic stress exposure.

BACKGROUND: Offspring of depressed mothers have elevated risk of developing depression because they are exposed to greater stress. While generally assumed that youth's increased exposure to stress is due to the environmental effects of living with a depressed parent, youth's genes may influence stress exposure through gene-environment correlations (rGEs). To understand the relationship between risk for depression and stress, we examined the effects of polygenic risk for depression on youth stress exposure. METHODS: We examined the relations of a polygenic risk score (PRS) for depression (DEP-PRS), as well as PRSs for 5 other disorders, with youth stress exposure. Data were from a longitudinal study of a community sample of youth and their parents (n = 377) focusing on data collected at youth's aged 12 and 15 assessments. RESULTS: Elevated youth DEP-PRS was robustly associated with increased dependent stress, particularly interpersonal events. Exploratory analyses indicated that findings were driven by major stress and were not moderated by maternal nor paternal history of depression, and of the 5 additional PRSs tested, only elevated genetic liability for bipolar I was associated with increased dependent stress-particularly non-interpersonal events. LIMITATIONS: Like other PRS studies, we focused on those of European ancestry thus, generalizability of findings is limited. CONCLUSION: Polygenic risk contributes to youth experiencing stressful life events which are dependent on their behavior. This rGE appears to be specific to genetic risk for mood disorders.

Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies.

Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical 'splitting' and 'lumping' approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come.

Preonset predictors of chronic-intermittent depression from early adolescence to early adulthood.

Individuals with prolonged or frequent episodes account for a disproportionate share of the burden of depression. However, there are surprisingly few data on whether individuals at risk for developing chronic-intermittent depression (CID) as opposed to briefer, infrequent depressive episodes (time-limited depression [TLD]) can be distinguished before their first depressive episode. We followed a community sample of 465 never-depressed females on five occasions from age 14 to 20 years and examined whether 18 preonset clinical and psychosocial variables prospectively predicted CID. The CID group accounted for 40% of depressed cases but 84% of the cumulative time depressed in the sample. Participants with CID (n = 60) exhibited significantly higher preonset levels of 16 of the 18 risk factors than the never-depressed group (n = 315). The TLD group (n = 90) had significantly higher preonset levels of nine risk factors than never-depressed participants. Finally, the CID group had significantly higher levels of nine risk factors than the TLD group, five of which were similar in TLD and never-depressed participants. These findings indicate that differences between CID and TLD are evident before onset and suggest that the liability to CID may be both greater than, and somewhat different from, the liability to TLD. Moreover, they suggest that individuals at risk for a malignant course of depression can be targeted for prevention and early intervention. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Abnormal neurophysiological sensitivity to rewards in depression is moderated by sex and age in middle adulthood.

A candidate pathophysiological process in major depressive disorder is diminished neural reactivity to reward delivery, which is theorized to give rise to anhedonia. Reduced amplitude in the reward positivity (RewP), which captures initial reward evaluation, has been linked to current symptoms of depression among child, adolescent, and young adult samples. However, the developmental trajectory of this association is incomplete, with relatively few studies in middle and older adulthood. Further, emerging evidence in the literature also suggests that this association may be linked to female sex-specific processes, but no studies to date have directly contrasted the effect of sex on the depression-RewP association. The current study sought to address these gaps by testing how sex and age may moderate the depression-RewP association within a mature adult community sample. Symptoms of depression were evaluated using a survey and a clinical interview, and the RewP was elicited using a simple guessing task. There was a three-way interaction between depression symptom severity, age, and sex in predicting RewP amplitude. This was driven by younger (late 30's to early 40's) female-sexed people such that for this group, elevated symptoms of depression were associated with blunting of the RewP. This association tapered around age 50. This effect was specific to clinician-rated rather than self-reported depressive symptom severity. This pattern of effects suggests that among female-sexed people, developmental processes continue to shape the association between reward responsiveness and depression throughout middle adulthood.

General v. specific vulnerabilities: polygenic risk scores and higher-order psychopathology dimensions in the Adolescent Brain Cognitive Development (ABCD) Study.

BACKGROUND: Polygenic risk scores (PRSs) capture genetic vulnerability to psychiatric conditions. However, PRSs are often associated with multiple mental health problems in children, complicating their use in research and clinical practice. The current study is the first to systematically test which PRSs associate broadly with all forms of childhood psychopathology, and which PRSs are more specific to one or a handful of forms of psychopathology. METHODS: The sample consisted of 4717 unrelated children (mean age = 9.92, s.d. = 0.62; 47.1% female; all European ancestry). Psychopathology was conceptualized hierarchically as empirically derived general factor (p-factor) and five specific factors: externalizing, internalizing, neurodevelopmental, somatoform, and detachment. Partial correlations explored associations between psychopathology factors and 22 psychopathology-related PRSs. Regressions tested which level of the psychopathology hierarchy was most strongly associated with each PRS. RESULTS: Thirteen PRSs were significantly associated with the general factor, most prominently Chronic Multisite Pain-PRS (r = 0.098), ADHD-PRS (r = 0.079), and Depression-PRS (r = 0.078). After adjusting for the general factor, Depression-PRS, Neuroticism-PRS, PTSD-PRS, Insomnia-PRS, Chronic Back Pain-PRS, and Autism-PRS were not associated with lower order factors. Conversely, several externalizing PRSs, including Adventurousness-PRS and Disinhibition-PRS, remained associated with the externalizing factor (|r| = 0.040-0.058). The ADHD-PRS remained uniquely associated with the neurodevelopmental factor (r = 062). CONCLUSIONS: PRSs developed to predict vulnerability to emotional difficulties and chronic pain generally captured genetic risk for all forms of childhood psychopathology. PRSs developed to predict vulnerability to externalizing difficulties, e.g. disinhibition, tended to be more specific in predicting behavioral problems. The results may inform translation of existing PRSs to pediatric research and future clinical practice.

Longitudinal Stability and Interrelations of Tonic and Phasic Irritability in Adolescent Girls.

Irritability is a transdiagnostic feature and a common mental health problem in adolescence. Prior studies indicate that irritability is composed of two correlated but separable dimensions, tonic irritability (i.e., irritable mood) and phasic irritability (i.e., temper outbursts), which are respectively associated with internalizing and externalizing outcomes. However, little is known about the stability and interrelations of tonic and phasic irritability. The current study examined the longitudinal interplay between tonic and phasic irritability during adolescence. A community sample of 544 girls (age 13.5-15.5 years) was assessed at 5 waves (over 3 years, in 9-month intervals). A random-intercept cross-lagged panel model was used to examine the within-person stability and longitudinal interrelations of tonic and phasic irritability. Pseudo-indicator models were used to help analyze all available data. Results suggest that tonic and phasic irritability had distinct patterns of development and co-development. Between individuals, tonic and phasic irritability showed moderate rank-order stability and high concurrent correlations. Within individuals, phasic irritability was found to positively predict both tonic and phasic irritability at the subsequent wave, whereas tonic irritability did not predict later phasic irritability and showed weaker within-person stability. These results suggest that increased or decreased phasic irritability in adolescent girls may signify continued increase or decrease in both tonic and phasic irritability. The study was among the first to demonstrate the discriminant validity of tonic and phasic irritability from a developmental perspective.

Candidate biomarkers in psychiatric disorders: state of the field.

The field of psychiatry is hampered by a lack of robust, reliable and valid biomarkers that can aid in objectively diagnosing patients and providing individualized treatment recommendations. Here we review and critically evaluate the evidence for the most promising biomarkers in the psychiatric neuroscience literature for autism spectrum disorder, schizophrenia, anxiety disorders and post-traumatic stress disorder, major depression and bipolar disorder, and substance use disorders. Candidate biomarkers reviewed include various neuroimaging, genetic, molecular and peripheral assays, for the purposes of determining susceptibility or presence of illness, and predicting treatment response or safety. This review highlights a critical gap in the biomarker validation process. An enormous societal investment over the past 50 years has identified numerous candidate biomarkers. However, to date, the overwhelming majority of these measures have not been proven sufficiently reliable, valid and useful to be adopted clinically. It is time to consider whether strategic investments might break this impasse, focusing on a limited number of promising candidates to advance through a process of definitive testing for a specific indication. Some promising candidates for definitive testing include the N170 signal, an event-related brain potential measured using electroencephalography, for subgroup identification within autism spectrum disorder; striatal resting-state functional magnetic resonance imaging (fMRI) measures, such as the striatal connectivity index (SCI) and the functional striatal abnormalities (FSA) index, for prediction of treatment response in schizophrenia; error-related negativity (ERN), an electrophysiological index, for prediction of first onset of generalized anxiety disorder, and resting-state and structural brain connectomic measures for prediction of treatment response in social anxiety disorder. Alternate forms of classification may be useful for conceptualizing and testing potential biomarkers. Collaborative efforts allowing the inclusion of biosystems beyond genetics and neuroimaging are needed, and online remote acquisition of selected measures in a naturalistic setting using mobile health tools may significantly advance the field. Setting specific benchmarks for well-defined target application, along with development of appropriate funding and partnership mechanisms, would also be crucial. Finally, it should never be forgotten that, for a biomarker to be actionable, it will need to be clinically predictive at the individual level and viable in clinical settings.

Glial suppression and post-traumatic stress disorder: A cross-sectional study of 1,520 world trade center responders.

Background: Chronically re-experiencing the memory of a traumatic event might cause a glial response. This study examined whether glial activation would be associated with PTSD in a study of responders present after the 9/11 World Trade Center attacks without comorbid cerebrovascular disease. Methods: Plasma was retrieved from 1,520 WTC responders and stored for a cross-sectional sample of responders of varying levels of exposure and PTSD. Plasma levels (pg/ml) of glial fibrillary acidic protein (GFAP) were assayed. Because stroke and other cerebrovascular diseases cause distributional shifts in GFAP levels, multivariable-adjusted finite mixture models analyzed GFAP distributions in responders with and without possible cerebrovascular disease. Results: Responders were aged 56.3 years and primarily male; 11.07% (n = 154) had chronic PTSD. Older age was associated with increased GFAP, whereas higher body mass was associated with decreased GFAP. Multivariable-adjusted finite mixture models revealed that severe re-experiencing trauma from 9/11 was associated with lower GFAP (B = -0.558, p = 0.003). Conclusion: This study presents evidence of reduced plasma GFAP levels among WTC responders with PTSD. Results suggest re-experiencing traumatic events might cause glial suppression.

Daily Sleep-Stress Reactivity and Functional Impairment in World Trade Center Responders.

BACKGROUND: How sleep is impacted by stress ("sleep reactivity to stress") and how stress is impacted by sleep ("stress reactivity to sleep") are trait-like characteristics of individuals that predict depression, anxiety, and insomnia. However, pathways between reactivity and functional impairment (e.g., impairment in social relationships and interpersonal functioning) have not been explored, which may be a critical pathway in understanding the link between reactivity and the development of psychological disorders. PURPOSE: We examined associations between reactivity and changes in functional impairment among a cohort of 9/11 World Trade Center responders. METHODS: Data from 452 responders (Mage = 55.22 years; 89.4% male) were collected between 2014 and 2016. Four baseline sleep and stress reactivity indices (i.e., sleep duration and efficiency reactivity to stress; stress reactivity to sleep duration and efficiency) were calculated from 14 days of sleep and stress data using random slopes from multilevel models. Functional impairment was assessed approximately 1 year and 2 years after baseline via semi-structured interviews. Latent change score analyses examined associations between baseline reactivity indices and changes in functional impairment. RESULTS: Greater baseline sleep efficiency reactivity to stress was associated with decreases in functioning (ß = -0.05, p = .039). In addition, greater stress reactivity to sleep duration (ß = -0.08, p = .017) and sleep efficiency (ß = -0.22, p < .001) was associated with lower functioning at timepoint one. CONCLUSION: People who are more reactive to daily fluctuations in stress and sleep have poorer interpersonal relationships and social functioning. Identifying individuals with high reactivity who could benefit from preventative treatment may foster better social integration.

How sleep is impacted by stress ("sleep reactivity to stress") and how stress is impacted by sleep ("stress reactivity to sleep") are trait-like characteristics of individuals that may contribute to an individual's risk of developing of psychological disorders, such as depression, anxiety, and insomnia. It is possible that individuals with high sleep-stress reactivity are more likely to experience long-term functional impairment (e.g., impairment in social relationships and interpersonal functioning)­a predisposing factor for psychological disorders, yet this pathway has not been explored. Therefore, we examined associations between sleep-stress reactivity and changes in functional impairment across a 1-year period in a large sample of 9/11 World Trade Center responders. The study results suggest that 9/11 World Trade Center responders who are more reactive to daily fluctuations in stress and sleep have poorer interpersonal relationships and social functioning. Identifying individuals with high sleep-stress reactivity who could benefit from preventative treatment may foster better social integration.

Plasma amyloid beta 40/42, phosphorylated tau 181, and neurofilament light are associated with cognitive impairment and neuropathological changes among World Trade Center responders: A prospective cohort study of exposures and cognitive aging at midlife.

Introduction: World Trade Center (WTC) responders are experiencing a high risk of mild cognitive impairment (MCI) and dementia, though the etiology remains inadequately characterized. This study investigated whether WTC exposures and chronic post-traumatic stress disorder (PTSD) were correlated with plasma biomarkers characteristic of Alzheimer's disease (AD) neuropathology. Methods: Eligible participants included WTC-exposed individuals with a baseline cognitive assessment and available plasma sample. We examined levels of the amyloid beta (Aß)40/42 ratio, phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL) and associations with a WTC exposures (duration on site ≥15 weeks, dust cloud), the PTSD Symptom Checklist for Diagnostic and Statistical Manual of Mental Disorders, 4th edition PTSD, and classification of amyloid/tau/neurodegeneration (AT[N]) profiles. Multinomial logistic regressions assessed whether biomarkers predicted increased risk of MCI or dementia. Results: Of 1179 eligible responders, 93.0% were male, mean (standard deviation) age 56.6 years (7.8). Aß40/42, p-tau181, and NfL intercorrelated and increased with age. In subgroup analyses of responders with available neuroimaging data (n = 75), Aß40/42 and p-tau181 were further associated with decreased hippocampal volume (Spearman's ρ = -0.3). Overall, 58.08% of responders with dementia had ≥1 elevated biomarker, and 3.45% had elevations across all biomarkers. In total, 248 (21.05%) had MCI and 70 (5.94%) had dementia. Increased risk of dementia was associated with plasma AT(N) profile T+ or A+N+. Exposure on site ≥15 weeks was independently associated with T+ (adjusted risk ratio [aRR] = 1.03 [1.01-1.05], P = 0.009), and T+N+ profile (aRR = 2.34 [1.12-4.87]). The presence of PTSD was independently associated with risk of A+ (aRR = 1.77 [1.11-2.82]). Discussion: WTC exposures and chronic PTSD are associated with plasma biomarkers consistent with neurodegenerative disease.