Reward processing in genetic frontotemporal dementia and mood disorders

遗传性额颞叶痴呆和情绪障碍的奖励处理

基本信息

批准号：
10338052
负责人：
DAVID C PERRY
金额：
$ 80.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338052
关键词：
Affect Affective Age of Onset Alcohols Amygdaloid structure Anatomy Animal Model Anterior Arousal Atrophic Autonomic nervous system Behavior Behavioral Behavioral Symptoms Bipolar Disorder C9ORF72 Caregivers Characteristics Classification Climacteric Clinical Trials Dementia Diagnosis Disease Disease Marker Early Diagnosis Elderly Elements Emotional Emotions Evaluation Family Family member Fatigue Food Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional Imaging Functional disorder Galvanic Skin Response Genes Genetic Goals Health Services Accessibility Heart Rate Hypersensitivity Impaired cognition Individual Inherited Insula of Reil Laboratories Lead Link Major Depressive Disorder Measures Mental disorders Methods Mood Disorders Moods Motivation Mutation National Institute of Mental Health Negative Valence Nerve Degeneration Neuroanatomy Nucleus Accumbens Onset of illness Patient Care Patients Personality Phenotype Prognosis Psychiatric Diagnosis Psychophysiology Punishment Reporting Research Research Domain Criteria Rewards Series Services Severities Site Social Functioning Specialist Stimulus Symptoms Task Performances Testing Work autosomal dominant mutation base behavior change behavioral variant frontotemporal dementia cingulate cortex classification algorithm clinical care diagnostic accuracy diagnostic criteria disease-causing mutation emotional functioning emotional symptom functional disability improved member mood symptom neuropsychiatry patient response psychiatric symptom reward processing sex social social contact targeted treatment therapeutic target white matter

项目摘要

ABSTRACT Frontotemporal dementia (FTD) is a common neurodegenerative cause of an early age-of-onset dementia. Changes in personality, social, and emotional function characterize the behavioral variant of FTD (bvFTD) and since there is partial overlap with the symptoms of psychiatric illness patients often receive early diagnoses of major depressive disorder (MDD) or bipolar illness (BPAD). A delay in receiving the correct diagnosis negatively impacts the care these patients receive. 10-40% of FTD is inherited, most commonly by autosomal dominant mutations in one of three genes (MAPT, GRN, and C9orf72). By studying the earliest behavior changes in individuals who carry one of these FTD mutations we can identify features that distinguish mood disorders from FTD. Reward processing involves a determination of what an individual finds pleasant and will pursue or work for. Many of the symptoms in bvFTD reflect a shift in reward processing, including changes in motivation for food, sex, alcohol, money, and social approval. Patients with bvFTD have been shown to be particularly insensitive to things that others would find negative or aversive. The proposed research will compare reward processing in presymptomatic patients with genetic FTD and those with mood disorders. We will study 60 patients with presymptomatic genetic FTD, 60 gene negative members of the same families, 40 patients with bvFTD, 40 with MDD, 40 with BPAD, and will compare them with 60 healthy controls. The central hypothesis of this proposal is that reward processing differs in characteristic ways between bvFTD, even in its early stages, and mood disorders in a way that reflects the vulnerable anatomy of these disorders. In Aim 1 we will identify differences in reward processing abnormalities that distinguish bvFTD from mood disorders using a series of laboratory-based paradigms during which we will record patient responses and measure their autonomic nervous system reactivity to rewarding stimuli. In Aim 2 we will assess the diagnostic accuracy of the reward measures and classification approach from Aim 1 in separating early bvFTD from mood disorders. In Aim 3 we will correlate patients' reward task performance with the severity of their mood and behavioral symptoms and will identify the neuroanatomic correlates through structural and functional imaging. The results of the proposed research will improve early diagnosis of bvFTD through objective, laboratory based measures, resulting in better clinical care and facilitation of clinical trials; suggest reward-based targets for symptomatic therapies and reward-based measures of behavior to apply in FTD animal models. It will also expand the understanding of reward behaviors and their anatomic correlates in psychiatric illness, allowing for more targeted therapies.

抽象的额颞叶痴呆（FTD）是早期发病痴呆的常见神经退行性原因。人格、社交和情感功能的变化是 FTD (bvFTD) 行为变异的特征由于与精神疾病的症状有部分重叠，患者通常会得到以下早期诊断：重度抑郁症 (MDD) 或双相情感障碍 (BPAD)。延迟获得正确诊断对这些患者接受的护理产生负面影响。 10-40% 的 FTD 是遗传的，最常见的是常染色体遗传三个基因（MAPT、GRN 和 C9orf72）之一的显性突变。通过研究最早的行为携带这些 FTD 突变之一的个体发生变化，我们可以识别区分情绪的特征 FTD 引起的疾病。奖励处理涉及确定个人感到愉快和愿意的事情追求或为之工作。 bvFTD 的许多症状反映了奖励处理的转变，包括食物、性、酒精、金钱和社会认可的动机。 bvFTD 患者已被证明对别人认为消极或厌恶的事情特别不敏感。拟议的研究将比较患有遗传性 FTD 的症状前患者和患有情绪障碍的患者的奖励处理。我们将研究60名症状前遗传性FTD患者，其中60名基因阴性的同一家庭成员，40名患有 bvFTD 的患者、40 名 MDD 患者、40 名 BPAD 患者，并将他们与 60 名健康对照进行比较。中央该提案的假设是，bvFTD 之间的奖励处理在特征方式上有所不同，即使在其早期阶段和情绪障碍在某种程度上反映了这些疾病的脆弱解剖结构。在目标 1 中，我们将使用以下方法识别奖励处理异常的差异，从而将 bvFTD 与情绪障碍区分开来：一系列基于实验室的范例，在此期间我们将记录患者的反应并测量他们的反应自主神经系统对奖励刺激的反应。在目标 2 中，我们将评估诊断的准确性目标 1 中的奖励措施和分类方法用于区分早期 bvFTD 和情绪障碍。在目标 3 中，我们将患者的奖励任务表现与其情绪和行为的严重程度相关联症状并通过结构和功能成像识别神经解剖学相关性。结果拟议研究的一部分将通过客观的、基于实验室的措施改善 bvFTD 的早期诊断，带来更好的临床护理和临床试验的便利；针对症状提出基于奖励的目标适用于 FTD 动物模型的疗法和基于奖励的行为测量。它还将扩大了解奖励行为及其在精神疾病中的解剖学相关性，从而允许更多靶向治疗。