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

• 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
• 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

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.

摘要 暴食症（BED）是一种常见的使人衰弱的饮食失调症[1-6]。更好地理解 BED的神经生物学将有助于治疗开发工作。关于BED神经生物学的多项研究 集中于前额叶皮层（PFC）-岛-纹状体结构作为主要区域的识别， 电路[7-24]。然而，在理解神经生物学基础方面， PFC-岛叶-纹状体在微结构水平的改变（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， 物质使用障碍（SUD）和BED之间的重叠，例如相似区域的改变[25，26]， 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（例如，利右苯丙胺、托吡酯和芬特明治疗可卡因使用障碍和BED）[30-38]。 临床前研究表明，某些药物，包括兴奋剂，产生微- 额-岛-纹状体结构的结构变化以及突触 PFC和工作记忆的锥体细胞中的密度/树突状分支，逆转学习和行为 灵活性[39-54]。在临床水平上，我们的小组已经开发了一种新的放射性示踪剂，11 C-UCB-J，用于成像 使用正电子发射断层扫描（PET）[55-58]在活体人脑中的突触密度。因此电流 探索性/发育性（PA-21-235）R21旨在首次测量PFC中的突触密度， 未用药的BED受试者（N =18）的岛叶皮质和腹侧纹状体，与健康受试者相比 对照（HC; N =18），使用11 C-UCB-J PET。BED受试者将接受单次11 C-UCB-J PET扫描， 将从既往和正在进行的研究中获得门诊患者和HC数据。BED参与者还将完成 基于研究领域标准（RDoC）的认知和行为评估阳性效价， 认知系统以及对BED严重程度和饮食问卷的评估。我们假设 突触密度将在四个先验PFC区域中降低（即，前扣带皮层，腹内侧PFC， 背外侧PFC和外侧眶额皮质）、岛叶皮质和BED的腹侧纹状体中， 与HC主题相比。我们还假设半卵圆中心等白色区无变化。 在探索性目的中，我们还将探索：1）11 C-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 2a）CUD和2b）来自先前和正在进行的研究的肥胖（OB）和瘦型组和3）全脑差异 采用一般线性模型（GLM）和独立成分分析（伊卡）分析BED组和HC组之间的差异。如果 这将是第一个在BED成人体内检查突触密度的转化研究。积极 结果可以为未来生物标志物的发展以及阐明 治疗的作用和突触密度变化的纵向性质。