Reward processing in genetic frontotemporal dementia and mood disorders

摘要 额颞叶痴呆（FTD）是一种常见的神经退行性疾病的早期年龄发作的痴呆。 个性、社会和情感功能的变化是FTD行为变体（bvFTD）的特征， 由于与精神疾病的症状有部分重叠， 重度抑郁症（MDD）或双相情感障碍（BPAD）。延迟接受正确的诊断 对这些患者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C9 orf 72）之一的显性突变。通过研究最早期的行为 携带这些FTD突变之一的个体的变化，我们可以确定区分情绪的特征， FTD引起的疾病。奖励处理涉及到确定个人觉得愉快和愿意做什么 追求或工作。bvFTD中的许多症状反映了奖励处理的变化，包括 食物、性、酒精、金钱和社会认可的动机。已证实bvFTD患者 对别人认为消极或厌恶的事情特别不敏感。拟议的研究将 比较伴有遗传性FTD的症状前患者和那些伴有情绪障碍的患者的奖励处理。我们 将研究60例症状前遗传性FTD患者，60例相同家族的基因阴性成员，40例 bvFTD患者、MDD患者40例、BPAD患者40例，并将其与60例健康对照进行比较。中央 这个建议的假设是，奖励处理在bvFTD之间的特征方式不同，甚至在其 早期阶段，以及情绪障碍，反映了这些疾病的脆弱解剖学。在目标1中， 我们将使用一种方法， 一系列以实验室为基础的范例，在此期间，我们将记录患者的反应，并测量他们的 自主神经系统对奖赏刺激的反应。在目标2中，我们将评估以下疾病的诊断准确性： 目标1中区分早期bvFTD与情绪障碍的奖励措施和分类方法。 在目标3中，我们将患者的奖励任务表现与他们的情绪和行为的严重程度相关联。 症状，并将通过结构和功能成像识别神经解剖相关性。结果 的拟定研究将通过客观的、基于实验室的措施改善bvFTD的早期诊断， 导致更好的临床护理和促进临床试验;建议以奖励为基础的目标， 治疗和基于奖励的行为测量，以应用于FTD动物模型。它还将扩大 理解奖励行为及其在精神疾病中的解剖学相关性， 靶向治疗。

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.