Robert H. Pietrzak - US grants

DESCRIPTION (provided by applicant): The worker response to the World Trade Center (WTC) attacks was unprecedented in scope, involving tens of thousands of traditional and non-traditional responders in rescue, recovery, and clean-up efforts. Posttraumatic stress disorder (PTSD) arising in response to equally unprecedented traumatic exposures, and characterized by disabling intrusive memories of the disaster, repeated nightmares, avoidance of disaster reminders, increased fear of another attack, disrupted sleep and other symptoms, is both highly prevalent (about 14%) and persistent in WTC responders, even over a decade after 9/11. The proposed study aims to fill a major gap in our understanding of the development of this disabling condition by conducting a multi-level assessment of vulnerability to PTSD in a diverse sample of 500 professional (i.e., police) and non-traditional (i.e., construction workers) WTC responders recruited from a large responder cohort followed prospectively at the WTC Medical Monitoring and Treatment Program (WTC- MMTP) at the Mount Sinai School of Medicine. We have previously identified four distinct trajectories of PTSD symptoms over time in this cohort of over 10,000 responders: chronic PTSD, delayed-onset PTSD, recovering and resistant trajectories. In this project we will study 500 WTC responders (125 selected from each of the four trajectories) to identify a range of exposure, psychological and biological factors that distinguis responders in the four trajectories. This assessment will include in-person psychiatric, medical, cognitive and psychosocial evaluations, as well as collection of blood and urine samples for testing. Testing will include (1) measurement of cortisol and its metabolites in urine; (2) measurement of cortisol and adrenocorticotropin hormone (ACTH) levels in blood before and after administration of a steroid, dexamethasone (dexamethasone suppression test); (3) measurement of the inhibition of lysozyme synthesis in blood cells by dexamethasone, and index of glucocorticoid receptor sensitivity in blood cells; (4) the identification of gene variant associated with increased risk for PTSD; (5) measurement of the expression levels of two different genes previously found to be associated with risk for PTSD -the gene coding for the glucocorticoid receptor (GR) and the gene coding for FKBP5, a modulator of GR sensitivity-; and (6) measurement of methylation levels of the GR and FKBP5 genes (a mechanism by which environmental influences such as traumatic experiences can modify genetic effects). The goal of the study is to further the field's understanding of PTSD risk and protective factors in disaster responders with varying degrees of preparedness and training in disaster response. Findings on risk factors can be used to improve future prevention and treatment strategies, while findings on protective factors can be applied to bolster resilience in rescue and recovery workers prior to trauma exposure.

Project Summary A significant proportion of World Trade Center (WTC) rescue and recovery workers continue to suffer from clinically significant WTC-related PTSD symptoms more than a decade after the 9/11/01 attacks. While cognitive behavioral therapy (CBT) is the most effective and empirically supported of currently available treatments for PTSD, the provision of this treatment to WTC workers is often limited by geographical distance, reduced availability of expertly trained therapists, and stigma associated with seeking formal mental health treatment in this population. Thus, there is an imperative need for treatment approaches that enhance access to CBT while preserving the effectiveness of key aspects of this treatment, such as therapeutic alliance. Internet-based CBT is an emerging treatment for PTSD that has demonstrated high treatment adherence, therapeutic alliance, and large magnitude reductions in PTSD symptoms in initial studies of other trauma survivor populations. If shown to be effective in WTC workers, Internet-based CBT (IBCBT) has the potential to reach many symptomatic workers who have encountered obstacles to mental health treatment. We propose to conduct a randomized controlled trial of Internet-based, therapist-assisted, CBT in WTC rescue and recovery workers with clinically significant WTC-related PTSD symptoms, compared to a control intervention of Internet- based, therapist-assisted supportive counseling. We plan to achieve a sample size of n = 90 study completers, n = 45 randomized to each treatment condition. To the best of our knowledge, the proposed RCT will be the first to evaluate the efficacy of IBCBT in this population, and one of the first to compare IBCBT for PTSD symptoms to an active control condition. We will additionally evaluate the efficacy of this intervention in enhancing functioning, quality of life, and posttraumatic growth in this population. A separable but complementary aim of the proposed study is to evaluate: (A) baseline genetic and epigenetic predictors of treatment response and (B) the capacity of Internet-based psychotherapy to induce changes in epigenetic regulation of genes implicated in risk for PTSD. For this aim, we will collect saliva samples pre- and post-treatment, to conduct genotyping studies of genes previously associated with PTSD in trauma-exposed samples, and measure methylation levels in a subset of those genes that is thought to operate in peripheral tissue, including NR3C1, FKBP5, 5-HTTLPR and BDNF. Gene expression validation studies will be conducted on genes with significant genetic and/or epigenetic findings. We will additionally bank samples for future genome-wide assays and include our data in meta-analyses conducted by the Psychiatric Genomics Consortium PTSD working group. Results will have the potential to identify objective biomarkers of Internet- based CBT treatment response, as well as to inform treatment matching and advance understanding of biological mechanisms of Internet-based psychotherapy among symptomatic WTC and other disaster responders.

Project Summary Nearly 9 in 10 Americans will be exposed to trauma in their lifetime and 1 in 10 will develop post-traumatic stress disorder (PTSD), which is characterized by elevated threat (e.g., intrusions, anxious arousal), loss (e.g., anhedonia, negative affect) and neurocognitive (e.g., verbal learning, attention) symptoms. Individuals with PTSD have elevated rates of physical health conditions, as well as functional impairment, with loss symptoms in particular contributing to decreased quality of life. The immune system is responsible for maintaining health, which includes mounting a response to physical (e.g., virus, injury) and psychological (e.g., stress) insults, as well as modulating the progression of neurodegenerative disorders such as Alzheimer?s disease. All of these - physical health conditions, psychological distress, and neurodegenerative disorders - are more prevalent in individuals with than without PTSD. There are peripheral immune system abnormalities in PTSD; however, no known study has evaluated the role of the neuroimmune system in PTSD. In the healthy immune system, the response of the central nervous system to an insult or damage is mediated by the activation of microglia, which carry out repair functions. However, excessive activation can lead to neuronal dysfunction and damage through the release of inflammatory cytokines and stress hormones, and may contribute to neurodegeneration, such as that found in individuals with PTSD. When microglia are activated, there is a robust increase in the expression of translocator protein (TSPO). Positron emission tomography (PET) radiotracers such as [11C]PBR28, which bind to TSPO, can therefore be used to measure levels of activated microglia in vivo. In addition to measuring levels of activated microglia in individuals with PTSD (vs. controls), we can also challenge the immune system by administering E. Coli lipopolysaccharide (LPS), a potent immune activator and measure increases in activated microglia within subject. We have recently demonstrated robust LPS- induced increases in activated microglia, and concomitant increases in peripheral inflammatory cytokines, and associated mood, anxiety, and neurocognitive symptoms in humans. In the proposed study, we will systematically evaluate the relationship between ?neuroinflammation?, as assessed with [11C]PBR28 and PET, and the expression of threat, loss, and neurocognitive symptoms in 80 trauma-exposed individuals presenting with the full dimensional spectrum of PTSD symptoms. Specifically, we will (1) determine whether individuals with PTSD have higher levels of activated microglia compared to trauma-exposed controls; (2) use a novel neuroimmune ?stress test? to determine whether individuals with PTSD have a dysfunctional neuroimmune response to systemic administration of LPS; and (3) determine the role of activated microglia in mediating the relationship between peripheral inflammatory markers (e.g., TNF-?), and trauma-related symptoms to discover potential biomarkers of PTSD. Results of this study will yield insight into novel, mechanism-based, and treatable neuroimmune mechanisms implicated in PTSD and related syndromes.

Project Summary A significant proportion of World Trade Center (WTC) rescue and recovery workers continue to suffer from clinically significant WTC-related PTSD symptoms more than a decade after the 9/11/01 attacks. While cognitive behavioral therapy (CBT) is the most effective and empirically supported of currently available treatments for PTSD, the provision of this treatment to WTC workers is often limited by geographical distance, reduced availability of expertly trained therapists, and stigma associated with seeking formal mental health treatment in this population. Thus, there is an imperative need for treatment approaches that enhance access to CBT while preserving the effectiveness of key aspects of this treatment, such as therapeutic alliance. Internet-based CBT is an emerging treatment for PTSD that has demonstrated high treatment adherence, therapeutic alliance, and large magnitude reductions in PTSD symptoms in initial studies of other trauma survivor populations. If shown to be effective in WTC workers, Internet-based CBT (IBCBT) has the potential to reach many symptomatic workers who have encountered obstacles to mental health treatment. We propose to conduct a randomized controlled trial of Internet-based, therapist-assisted, CBT in WTC rescue and recovery workers with clinically significant WTC-related PTSD symptoms, compared to a control intervention of Internet- based, therapist-assisted supportive counseling. We plan to achieve a sample size of n = 90 study completers, n = 45 randomized to each treatment condition. To the best of our knowledge, the proposed RCT will be the first to evaluate the efficacy of IBCBT in this population, and one of the first to compare IBCBT for PTSD symptoms to an active control condition. We will additionally evaluate the efficacy of this intervention in enhancing functioning, quality of life, and posttraumatic growth in this population. A separable but complementary aim of the proposed study is to evaluate: (A) baseline genetic and epigenetic predictors of treatment response and (B) the capacity of Internet-based psychotherapy to induce changes in epigenetic regulation of genes implicated in risk for PTSD. For this aim, we will collect saliva samples pre- and post-treatment, to conduct genotyping studies of genes previously associated with PTSD in trauma-exposed samples, and measure methylation levels in a subset of those genes that is thought to operate in peripheral tissue, including NR3C1, FKBP5, 5-HTTLPR and BDNF. Gene expression validation studies will be conducted on genes with significant genetic and/or epigenetic findings. We will additionally bank samples for future genome-wide assays and include our data in meta-analyses conducted by the Psychiatric Genomics Consortium PTSD working group. Results will have the potential to identify objective biomarkers of Internet- based CBT treatment response, as well as to inform treatment matching and advance understanding of biological mechanisms of Internet-based psychotherapy among symptomatic WTC and other disaster responders.

PROJECT SUMMARY: Normal aging slowly affects the brain via alterations in synaptic transmission and plasticity through various processes including changes in dendritic spine morphologies and loss of synaptic proteins. Major depressive disorder (MDD) is the most prevalent and disabling psychiatric disorder worldwide and is associated with reduced synaptic signaling proteins, such as presynaptic neurotransmitter vesicle- associated proteins and postsynaptic structural and functional proteins. Converging evidence from human clinical and postmortem studies, and preclinical work suggests that depression may accelerate brain aging, as evidenced by neuronal atrophy, and reduced synaptic and synaptic vesicle protein densities, and vesicle trafficking and growth, particularly in the hippocampus (HIP) and dorsolateral prefrontal cortex (dlPFC), and may thus represent a prodrome to dementia. In animal and postmortem work, changes in synaptic density have been robustly evaluated via quantification of synaptic vesicle proteins. In vivo quantification of synaptic density in humans was recently made possible with the development of a novel radioligand 11C-UCB-J, which quantifies the density of synaptic vesicle glycoprotein 2A (SV2A), a ubiquitously expressed marker of synaptic density, using positron emission tomography (PET) imaging. In this study, we will conduct the first known in vivo human examination of whether MDD may accelerate synaptic aging over a 25-year span (ages 40-65), as well as how MDD-related changes in synaptic density relate to cognitive functioning and the heterogeneous clinical presentation of this disorder. Our preliminary data from a large normative sample of healthy adults suggest a systematic age-related decline in synaptic density in the HIP and dlPFC, which becomes more pronounced as a function of increasing age. They further reveal a substantially more pronounced decline in synaptic density in the HIP and dlPFC in individuals with MDD compared to age-matched healthy controls. In the proposed study, we will employ a novel accelerated longitudinal design that builds on these initial results by evaluating whether MDD accelerates synaptic aging by examining in vivo changes in synaptic density in the HIP and dlPFC compared to healthy controls across the middle-to-older age spectrum. We will also evaluate how synaptic density in these brain regions relates to the endophenotypic and phenotypic expression of MDD using state-of-the-art objective laboratory, structured clinical interview, and neuropsychological measures. Results of the proposed study will provide the first human in vivo data on the role of MDD as a potential accelerator of synaptic aging, as well as the effect of MDD-related changes in synaptic density on the clinical expression of this multi-faceted disorder. They will also inform pathophysiologic models of how MDD contributes to synaptic aging, and yield new insight into a novel ?upstream? mechanism-based target for therapies designed to mitigate accelerated brain aging and risk for cognitive decline and dementia.