A 11C-UCB-J PET Study of Synaptic Density in Binge Eating Disorder (BED)

暴食症 (BED) 突触密度的 11C-UCB-J PET 研究

基本信息

批准号：
10673376
负责人：
GUSTAVO Adolfo ANGARITA
金额：
$ 25.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-02 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673376
关键词：
Abstinence Adult Affect Age Anterior Area Axon Behavior Therapy Behavior assessment Behavioral Binge Eating Binge eating disorder Biological Markers Body Weight decreased Body mass index Brain Clinical Cocaine use disorder Cognitive Control Groups Corpus striatum structure DSM-V Data Dendritic Spines Development Diagnosis Eating Eating Disorders Ethnic Origin Food Frequencies Funding Future Gender Glycoproteins Hospitals Human Image Impulsivity In Vitro Individual Insula of Reil Intake International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10)Intervention Label Lateral Linear Models Link Literature Measures Medial Methodology Modality Modeling Morbidity - disease rate Nature Neurobiology Neurocognitive Neuronal Plasticity Neurons Obesity Outcome Outpatients Participant Persons Pharmaceutical Preparations Phentermine Positive Valence Positron-Emission Tomography Prefrontal Cortex Primates Property Pyramidal Cells Questionnaires Race Research Research Domain Criteria Reversal Learning Severities Short-Term Memory Specificity Stimulant Structure Substance Use Disorder Symptoms Synapses Synaptic plasticity Synaptophysin Techniques Testing Thinness Time Tracer Ventral Striatum Vertebral column Vyvanse behavior measurement biomarker development cingulate cortex clinical translation clinically relevant cocaine use cognitive function cognitive system cognitive testing density effective intervention effective therapy first-in-human flexibility imaging properties improved in vivo independent component analysis interest intervention effect neuroimaging novel off-label use patient population pharmacologic pre-clinical preclinical study presynaptic radiotracer receptor therapy development tool topiramate translational study uptake white matter

项目摘要

Abstract Binge eating disorder (BED) is a common and debilitating eating disorder [1-6]. An improved understanding of the neurobiology of BED will aid treatment development efforts. Multiple studies on the neurobiology of BED converge on the identification of the prefrontal cortex (PFC)-insular-striatal structures as prime regions and circuits [7-24]. However, there is a significant gap when it comes to understanding neurobiological underpinnings of PFC-insular-striatal alterations at a micro-architectural level (i.e., synaptic plasticity or synaptic density). Notwithstanding current gaps, preclinical and clinical literature suggests there is significant neurobiological overlap between substance use disorders (SUDs) and BED, such as alterations in similar areas [25, 26], similar clinical features (e.g., compulsive food or drug intake) [27-29], and potential common pharmacological interventions (e.g., lisdexamfetamine, topiramate, and phentermine for cocaine use disorder and BED) [30-38]. Preclinical studies show the capacity of certain pharmacological agents, including stimulants, to produce micro- architectural changes in fronto-insular-striatal structures as well as an association between synaptic density/dendritic branching in pyramidal cells of the PFC and working memory, reversal learning, and behavioral flexibility [39-54]. At a clinical level, our group has developed a novel radiotracer, 11C-UCB-J, for imaging synaptic density in the living human brain using positron-emission tomography (PET) [55-58]. Thus, the current exploratory/developmental (PA-21-235) R21 aims to measure for the first time synaptic density in the PFC, insular cortex, and ventral striatum of unmedicated BED subjects (N =18), as compared to Healthy Controls (HCs; N =18), using 11C-UCB-J PET. BED participants will undergo single 11C-UCB-J PET scans as outpatients and HC data will be obtained from previous and ongoing studies. BED participants will also complete cognitive and behavioral assessments based on Research Domain Criteria (RDoC) positive valence and cognitive systems as well as assessments of BED severity and eating questionnaires. We hypothesize that synaptic density will be decreased in four a priori PFC areas (i.e., anterior cingulate cortex, ventromedial PFC, dorsolateral PFC, and lateral orbitofrontal cortex), in the insular cortex, and in the ventral striatum in BED as compared to HC subjects. We also hypothesize no changes in white matter regions such as centrum semiovale. In exploratory aims, we also will explore: 1) correlations between 11C-UCB-J PET outcomes and BED severity as well as measures of behavioral/cognitive functioning, 2) differences in synaptic density between BED and 2a) CUD and 2b) obese (OB) and lean groups from previous and ongoing studies and 3) whole-brain differences between BED and HC groups using general linear model (GLM) and independent component analysis (ICA). If funded, this will be the first translational study examining synaptic density in vivo in adults with BED. Positive results could inform future studies on biomarker’s development as well as studies elucidating mechanisms of action of treatments and longitudinal natures of changes in synaptic density.

抽象的暴饮暴食（BED）是一种常见且令人衰弱的饮食失调障碍[1-6]。对床的神经生物学将有助于治疗开发工作。关于床神经生物学的多次研究将前额叶皮层（PFC） - 纹状体结构作为主要区域和电路[7-24]。但是，在理解神经生物学基础方面存在很大的差距在微体系构型水平（即突触可塑性或合成密度）处的PFC-单相纹状体变化的。尽管当前差距，临床前和临床文献都表明存在明显的神经生物学物质使用障碍（SUD）和床之间的重叠，例如类似区域的改变[25，26]，相似临床特征（例如，强迫食品或药物摄入量）[27-29]和潜在的常见药物干预措施（例如，用于可卡因障碍和床的lisdexamfemine，topramate和苯甲胺）[30-38]。临床前研究表明，某些药物（包括兴奋剂）的能力产生微型额额 - 纹状体结构的建筑变化以及突触之间的关联 PFC的锥体细胞和工作记忆，反向学习和行为的密度/树突分支灵活性[39-54]。在临床水平上，我们的小组开发了一种新型的放射性示踪剂11C-UCB-J，用于成像使用正电子发射断层扫描（PET）[55-58]的活体大脑中的突触密度。那，电流探索/发育（PA-21-235）R21旨在测量PFC中首次突触密度，与健康相比使用11C-UCB-J PET，对照（HCS; n = 18）。床参与者将接受单个11C-UCB-J PET扫描从以前的研究和正在进行的研究中获得门诊病人和HC数据。床参与者也将完成基于研究领域标准（RDOC）的正价和行为评估的认知和行为评估认知系统以及床严重程度和进食问卷的评估。我们假设这一点突触密度将在四个先验的PFC区域（即前扣带回皮层，腹侧PFC，外托PFC和外侧眶额皮质），在岛状皮质中，在床中的腹侧纹状体中与HC受试者相比。我们还假设白质区域（例如Centrum半竞争）没有变化。在探索性目的中，我们还将探索：1）11C-UCB-J PET结果与床严重程度之间的相关性以及对行为/认知功能的测量，2）床和之间突触密度的差异 2a）cud和2b）肥胖（OB）和正在进行的研究的精益群体以及3）全脑差异使用通用线性模型（GLM）和独立组件分析（ICA）之间的床和HC组之间。如果资助后，这将是第一项转化研究，研究了成人床的体内突触密度。积极的结果可以为未来的有关生物标志物发展的研究以及阐明的机制研究突触密度变化的治疗和纵向性质的作用。