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.

抽象的暴食症 (BED) 是一种常见且令人衰弱的饮食失调症 [1-6]。 BED 的神经生物学将有助于 BED 神经生物学的多项研究开发工作。集中于将前额皮质（PFC）-岛叶-纹状体结构识别为主要区域，并且然而，在理解神经生物学基础方面存在显着差距。 PFC-岛叶-纹状体在微观结构水平上的改变（即突触可塑性或突触密度）。尽管目前存在差距，但临床前和临床文献表明，神经生物学方面存在显着的差异物质使用障碍 (SUD) 和 BED 之间的重叠，例如类似领域的改变 [25, 26]，类似临床特征（例如强迫性食物或药物摄入）[27-29]，以及潜在的常见药理学干预措施（例如，赖右苯丙胺、托吡酯和芬特明治疗可卡因使用障碍和暴食症）[30-38]。临床前研究表明某些药物制剂（包括兴奋剂）能够产生微量额叶-岛叶-纹状体结构的结构变化以及突触之间的关联 PFC 锥体细胞的密度/树突分支和工作记忆、逆转学习和行为在临床水平上，我们的团队开发了一种新型放射性示踪剂 11C-UCB-J，用于成像。使用正电子发射断层扫描（PET）测量活人大脑中的突触密度[55-58]。探索/发育 (PA-21-235) R21 旨在首次测量 PFC 中的突触密度，未接受药物治疗的 BED 受试者 (N =18) 的岛叶皮质和腹侧纹状体，与健康人相比对照（HC；N = 18），使用 11C-UCB-J PET 参与者将接受单次 11C-UCB-J PET 扫描。门诊患者和 HC 数据将从之前和正在进行的研究中获得，BED 参与者也将完成。基于研究领域标准 (RDoC) 正价的认知和行为评估认知系统以及暴食严重程度评估和饮食调查问卷。四个先验 PFC 区域（即前扣带皮层、腹内侧 PFC、 BED 中的背外侧 PFC 和外侧眶额皮质）、岛叶皮质和腹侧纹状体与 HC 受试者相比，我们的白质区域（例如半卵圆中心）也没有变化。在探索性目标中，我们还将探索：1) 11C-UCB-J PET 结果与 BED 严重程度之间的相关性以及行为/认知功能的测量，2）BED 和 BED 之间突触密度的差异 2a) CUD 和 2b) 先前和正在进行的研究中的肥胖 (OB) 和瘦组以及 3) 全脑差异使用一般线性模型 (GLM) 和独立成分分析 (ICA) If 来比较 BED 和 HC 组之间的差异。获得资助后，这将是第一个检查 BED 阳性成人体内突触密度的转化研究。结果可以为未来关于生物标志物开发的研究以及阐明其机制的研究提供信息治疗作用和突触密度变化的纵向性质。