Irina Esterlis, Ph.D. - US grants

DESCRIPTION (provided by applicant): Over the past three decades there has been a strong focus in the field of addiction towards the development of vaccines for the prevention and treatment of tobacco smoking (nicotine dependence). Based on preclinical studies in rodents, the presumed mechanism of action is that the antibodies produced by vaccination, bind to nicotine and decrease the rate and the amount of nicotine that is able to cross the blood brain barrier and occupy nicotinic acetylcholine receptors (nAChR) in the mesocorticolimbic reward pathway. In the present study, we propose to validate this mechanism in living human smokers. Specifically, we will image brain 22 nAChR using the nicotinic agonist [123I]5 IA 85380 ([123I]5 IA) and single photon emission computed tomography (SPECT) to determine the amount of nicotine occupancy of brain 22 nAChR after an IV nicotine challenge in smokers before and after vaccination with the NicVax vaccine. We hypothesize that after vaccination, the amount of nicotine occupying 22 nAChR will be reduced by at least 50%. If confirmed, this reduction in the amount of nicotine occupying nAChR will explain why, vaccinated individuals will be less likely to become addicted if they smoke, and current smokers will not experience the same satisfaction from smoking.

DESCRIPTION (provided by applicant): Bipolar disorder is a chronic, severe and devastating illness which exerts a crippling personal and financial toll on the individual, family and wider society. The main burden of illness in bipolar disorder is in the depressive pole i.e. bipolar depression. There are currently few effective, well-validated treatments for bipolar depression. It is clear that there is an urgent need for novel molecular targets and subsequently treatments in the pharmacotherapy of bipolar depression. One such target is the nicotinic acetylcholinergic receptor system which has been postulated to play a role in the pathophysiology of bipolar disorder. A number of recent studies implicate this system in the causation of bipolar disorder and it warrants justified attention. Until recently this system was not amenable to study in man due to logistical reasons including the lack of availability of appropriate ligands. The development of a novel single photon emission tomography (SPECT) nicotinic acetylcholinergic receptor (nAChR) radioligand now allows us to examine an important aspect of this receptor system;[unreadable]2 subunit containing nicotinic acetylcholinergic receptors. These receptors are widespread in the brain and are assumed to play a key role in the system especially due to their location in mood regulating circuits. Our primary aim is therefore to determine [unreadable]2 subunit containing nAChRs availability in patients with bipolar disorder, who are currently depressed and compare them with healthy control subjects. We propose a SPECT study of [unreadable]2 subunit containing nAChRs in patients with bipolar depression to determine whether there is a dysfunction of this key element. We will study 18 patients with bipolar depression and 18 age-matched healthy control subjects. All subjects will have one MRI scan and one SPECT scan with the SPECT radioligand [123I]5-I-A-85380 to quantify [unreadable]2 subunit containing nicotinic acetylcholinergic receptors in brain regions involved in mood regulating circuits. Based on previous studies and our preliminary data showing significant deficits of this system in unipolar and bipolar depression, we hypothesize that there will be a decrease in [unreadable]2 subunit containing nAChRs in patients with bipolar depression compared with healthy control subjects. The results of this study will allow us to determine if this molecular target is worth pursuing in a larger sample. PUBLIC HEALTH RELEVANCE: It is clear that there is an urgent need for the development of novel therapeutic targets to better treat bipolar depression as there are currently few effective, well-validated treatments for bipolar depression. This study will validate one particular receptor system, the nicotinic acetylcholine receptor, as potentially having a central role in the causation of bipolar depression. If this proves successful then it would be possible to develop newer antidepressant drugs to better treat patients with bipolar depression. [unreadable]

DESCRIPTION (provided by applicant): This K01 application proposes support essential for Dr. Esterlis' career development as she transitions to an independent investigator in neuroreceptor imaging of mood and comorbid substance use disorders. The proposed career award plan is designed to further her scientific development as an expert neuroimager, with increased expertise in mood disorders and mood-substance disorder comorbidity, including the conduct of two unique receptor imaging studies. Dr. Esterlis' career development plan focuses on rigorous training in methods of single photon emission computerized tomography (SPECT) and positron emission tomography (PET) brain imaging, including noise- correction techniques and quantitative skills, and application of these techniques to the neuroimaging of biological basis of mood disorders. Training will include an integration of individual meetings with mentors and collaborators in the Departments of Psychiatry and Radiology, intramural and extramural didactics, presentations at scientific meetings and manuscript and grant submissions. The scientific focus of the proposed project is the investigation of a novel mechanism that may be involved in the pathophysiology of bipolar disorder (BD) and comorbid tobacco dependence. Tobacco dependence is three times as prevalent in BD as compared to general population, however, the reasoning behind this comorbidity is not well understood nor are there well-established efficacious treatments for smoking cessation or associated depression symptoms in BD. Thus, there is an urgent need for investigation of new molecular mechanisms for pharmacotherapeutic targets. Emerging evidence implicates the nicotinic acetylcholine receptor (nAChR) system in the pathophysiology of BD and its mood and cognitive symptoms. Thus, we propose an innovative study of the relationship between tobacco smoking and mood and cognitive dysfunction in BD, which may be mediated by the 22 subunit of the nAChR system. Nonsmokers (n=20) and smokers (n=20) with BD and matched controls will participate in a [123I]5-IA-85380 SPECT scan to determine 22-nAChR availability. Mood and cognitive assessments will be administered to smokers before smoking cessation, after 24h smoking cessation, and again on SPECT scan day, and at corresponding times to nonsmokers. Differences in the magnitude and distribution of the 22-nAChR in BD versus controls will be measured, as well as in BD smokers versus nonsmokers. Relationships to mood and cognitive symptoms will be assessed. {{{Furthermore, proposed career training project will provide data on the distribution of the metabotropic glumatamatergic system (mGluR5) in the same BD subjects and will enable a unique investigation of a multi-receptor involvement in BD.

? DESCRIPTION (provided by applicant): There is a critical need for the correct diagnosis and treatment of depression in bipolar disorder - I (BD-Dep). BD is a devastating illness with a lifetime prevalence of 1%, and depression is the most common and most frequent presenting episode type, and is associated with a high risk of suicide. No marker has been identified that distinguishes the depression of BD from that of major depressive disorder (MDD-Dep). Individuals with BD may receive treatments designed for MDD that may have negative consequences, and currently available treatments for BD-Dep are limited in effectiveness and can have adverse effects. These factors highlight the critical importance of identifying a new mechanism that distinguishes BD-Dep from MDD-Dep and that could serve as a target for novel treatment strategies for BD- Dep. Convergent functional magnetic resonance imaging (fMRI) evidence supports a central role in BD for the ventral prefrontal cortex (vPFC), an important region for regulation of emotions and impulses, which are significantly impaired in individuals with BD. Evidence suggests particular abnormalities of responses in the vPFC, and in its regulation of limbic structures such as the amygdala, during the processing of positive emotional stimuli in BD, not evident in MDD. Recent evidence points to glutamatergic system abnormalities in the vPFC specific to BD, with magnetic resonance spectroscopy studies showing different glutamate levels in BD-Dep than in MDD-Dep. Postmortem research supports the specific involvement of PFC metabotropic glutamatergic receptors (mGluR5) in BD-Dep. Our exciting new pilot data from in vivo measurement of mGluR5 using positron emission tomography (PET) provide preliminary evidence for vPFC mGluR5 involvement in BD-Dep, but not MDD-Dep, supporting mGluR5 as a biomarker to help differentiate and diagnose BD-Dep and as a potential novel treatment target. Moreover, we observed associations between the PET and fMRI findings, as well as relationships of those measures to deficits in executive control and impulse regulation. We propose a multidisciplinary PET, fMRI and behavioral study comparing 40 individuals with BD- Dep to 40 with MDD-Dep and 40 healthy comparison (HC) individuals to identify differences in vPFC mGluR5 levels and determine whether they may underlie functional differences between BD-Dep and MDD-Dep, and serve as a biomarker to differentiate them. It is hypothesized that vPFC mGluR5 will be lower in the BD-Dep group, as compared to the MDD-Dep and HC groups. It is also hypothesized that vPFC functional activation and connectivity during processing of positive emotional faces will be reduced in BD-Dep group, as compared to MDD-Dep and HC groups. Finally, it is hypothesized that the lower mGluR5 availability in BD-Dep will be significantly associated with the vPFC dysfunction, as well as behaviors reflecting impaired vPFC system regulation. These results may lead to a breakthrough in characterization and differentiation of BD-Dep from MDD-Dep, as well as to the development of more specifically targeted and efficacious treatments for BD-Dep.

PROJECT SUMMARY: Bipolar disorder (BD) can cause a great deal of suffering for individuals with the disorder and their families due to the acute mood episodes that also include a high risk of suicide, and the cognitive difficulties that can contribute to disability and impair prognosis. Unfortunately, the mechanisms underlying the acute mood episodes and the vulnerability to the switch between mood states, as well as cognitive dysfunction in the disorder, are not known, and current medications are often ineffective in treating mood episodes and cognitive difficulties. In order to provide more effective treatments for the mood episodes and cognitive difficulties in BD, and potentially prevent or reduce the onset or severity of acute episodes, it is necessary to elucidate the molecular mechanisms that underlie these features of the disorder. Preclinical and clinical evidence implicates the glutamatergic neurotransmitter system in BD, including data from magnetic resonance spectroscopy (MRS) studies showing altered levels of glutamate in depression or mania as compared to control group and positron emission tomography (PET) data from our group implicating the metabotropic glutamatergic receptors (mGluR5) in depressed and elevated mood states of BD. Unfortunately, most of the preclinical and clinical data come from studies of individuals with BD in the depressed mood state, and data during elevated mood state is sparse, limiting our understanding of the glutamatergic involvement in BD, and specifically its role in affective cycling. Thus, we propose an innovative study to examine glutamate neurotransmission (i.e., glutamate-glutamine cycling) in the prefrontal region of individuals with BD who are in depressed mood state or elevated mood state, and compare to healthy controls. State of the art isotopic 13C- MRS imaging with 13C-glucose methods will be used to measure glutamate neurotransmission in individuals with BD in depressed and elevated (manic/hypomanic) mood states and compare to those in healthy control individuals. The relationships between glutamate neurotransmission and glutamate levels will be correlated with measures of depressive and elevated mood symptoms, as well as with measures of PFC-related executive cognitive control of behavior. It is hypothesized that glutamate neurotransmission will be decreased in depression (and corresponding to higher glutamate levels during BD depression) but increased in elevated mood states (corresponding to lower glutamate levels during BD mania). We also hypothesize that the degree of abnormalities in the glutamate neurotransmission will be associated with the severity of mood symptoms and cognitive difficulties. These multidisciplinary results could lead to breakthrough in elucidating a process that may be important in the pathophysiology of BD, and one that can serve as a target for novel approaches for improved detection, treatment and prevention of BD.

PROJECT SUMMARY Elucidating the molecular changes that underlie depression and associated symptoms in Bipolar Disorder?I (BD) is critical for diagnostic and therapeutic efficacy. BD is a devastating illness with a lifetime prevalence of 1%. Within BD, depression is the most common and most frequent presenting episode type, and is associated with a high risk of suicide. Unfortunately, currently available pharmacotherapies are not able to provide effective relief to a large portion of individuals with BD, and do not normalize the observed deficits in cognitive functioning in the disorder. Thus, there is a pressing need to identify novel molecular sites, which may prove as treatment targets to reduce the burden of depression and cognitive dysfunction in BD. Significant evidence suggests heightened inflammatory tone in BD, which may contribute to the pathophysiology of the disorder. For example, peripheral markers of inflammation are higher in individuals with BD as compared to controls and individuals with BD have higher prevalence of inflammatory disorders such as heart disease. Furthermore, elevated peripheral inflammatory markers appear to subserve some of the cognitive deficits observed in BD, for which currently there are no targeted treatments. It was previously thought that the brain and peripheral immune system were isolated by the blood-brain-barrier, but we now know that cytokines in the periphery can enter the brain, lead to changes in behavior and initiate a central inflammatory response. In response to signals from the periphery and damaging stimuli, microglial cells become activated and, in their pro-inflammatory state may lead to neuro- and excitotoxicity. Unfortunately, investigation of inflammatory factors in the brains of individuals with BD is limited. However, the existing evidence from postmortem studies and one in vivo imaging study of euthymic individuals with BD supports the hypothesis of elevated neuroinflammatory factors in BD, which can lead to neuronal damage. We propose a novel and critical examination of microglial activation in BD depression using [11C]PBR28 ? a radioligand with high specificity for the Translocator Protein (TSPO), which is upregulated in activated microglia and used as a marker of neuroinflammation. We will scan 15 individuals with BD-Dep and 15 healthy control individuals with to identify whether there is increased neuroinflammation in BD-Dep. We previously showed that [11C]PBR28 is able to detect changes in neuroinflammation following a peripheral immune challenge and is thus an excellent tool to detect neuroinflammation in BD. Importantly, we will address the question of whether the hypothesized increased neuroinflammation in BD is associated with the depressive symptomatology and cognitive deficits in individuals with BD-Dep. We hypothesize that individuals with the greatest degree of neuroinflammation will exhibit more severe depressive symptoms and have the strongest cognitive deficits in executive control, memory, and attention. These results may lead to a breakthrough in the characterization of BD-Dep and the neurobiological basis of its symptoms, which may benefit from treatments with anti-inflammatory agents.

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.

PROJECT SUMMARY: Bipolar disorder (BD) is associated with a suicide attempt rate of up to 50% and completion rate of up to 20%, making prevention and treatment of suicidal behavior in BD one of the most critical challenges that Psychiatry faces. Women with BD have much higher rate of suicide attempts (SA) than men, and completion rates are on the rise. The RDoC Suicide Task Force revealed several endophenotypes that may distinguish attempters versus non-attempters including reward responsiveness and response inhibition. Further, evidence from fMRI studies indicates that attempters and non-attempters have different brain responses to reward and inhibition tasks. Alterations have been observed in the dlPFC and OFC, and these are also the brain regions highly associated with the suicide-related endophenotypes. Unfortunately, the molecular mechanisms underlying suicidal behavior are not well elucidated and current medications are often ineffective in reducing the rates of suicide completion. In order to provide more effective treatments for the highly prevalent suicidal behavior in BD, it is necessary to elucidate the molecular mechanisms that underlie its associated features, so that they can be targeted with new treatments in men and women with BD. We have exciting new preliminary evidence supporting the involvement of cortical metabotropic glutamatergic receptors (mGluR5s) in suicidal behavior. mGluR5 aid in regulation of other glutamatergic receptors, neurotransmission and synaptic plasticity, which are all critical to healthy mood regulation and cognitive processes. Modulation of mGluR5 was shown to play a role in reward processing and impulsivity, and mGluR5 associated genes and proteins have been implicated in suicide specifically. Our novel in vivo data suggest that higher dlPFC and OFC mGluR5 availability may be a trait marker of suicidal behavior in BD and may therefore aid with the identification of patients at higher risk for completed suicide. We built upon this knowledge and developed an innovative multidisciplinary approach to studying this novel mechanism in suicidal behavior. State of the art positron emission tomography (PET) methods will be used to measure prefrontal cortical mGluR5 levels in groups of individuals with BD who have and have not attempted suicide in the past. The relationships between mGluR5 levels and suicide-related endophenotypes will be assessed. Importantly, we will examine the role of sex in the association between severity of dysregulation in mGluR5 and suicide related endophenotypes, with the hypothesis that women will exhibit a greater extent of dysregulation in mGluR5 as compared to men. Further, we hypothesize that individuals in the BD attempt group will have the greatest dysregulation in mGluR5, and that this will be associated with greatest deficits in the related endophenotypes. These results may lead to a breakthrough in determining a mechanism that may be important in the pathophysiology of suicidal behavior, and one that can be targeted for critically-needed improved detection, treatment and prevention of suicide in BD and potentially other high-risk disorders.