Genetic Influences on Frontotemporal Connectivity in Bipolar Disorder

描述(申请人提供)：此R01更新建议多模式磁共振成像(MRI)研究青少年和成人额颞叶(FT)连接的年龄相关模式的差异，有或没有双相情感障碍(BD)以及影响他们的遗传因素。尽管BD对个人、其家庭和社区造成了严重的后果，自杀率也很高，但BD发展及其有效治疗的生物学机制仍不清楚。目前，还没有生物标志物来诊断BD或指导谁可能从特定的治疗中受益，尽管不正确的治疗会对预后产生不利影响，许多BD患者会出现顽固的症状。关键是要了解特定的遗传倾向是如何导致特定的大脑差异的，以改进检测，根据他们的生物学将治疗瞄准那些最有可能受益的人，并发现新的机制来瞄准新的治疗开发。该领域的主要挑战还包括因不明原因而在寿命上存在差异的BD的陈述，限制了适应生命阶段的检测和治疗的能力。我们研究项目的进展包括识别出在BD中以情绪处理为中心的FT神经系统。重要的是，这个系统在生命周期内会发生变化。我们目前的工作支持BD患者和健康对照(HC)个体之间FT灰质的渐进性差异，这些差异在青春期晚期/成年期早期出现显著差异，并暗示神经营养基因(例如脑源性神经营养因子，BDNF)与神经发育差异有关。白质(WM)在这个FT神经系统内提供联系，越来越多地与BD有关。在朝着我们的新目标前进的过程中，随着对WM的新关注，初步的弥散张量成像(DTI)分析表明，健康个体的WM发育模式的特征是在生命的第四个十年期间，FT WM的结构完整性增加，然后减少。我们的初步数据也支持青少年和成人BD患者WM的不同模式，导致BD患者WM结构完整性的下降，与HC患者相比，在第四个十年的早期下降达到峰值。这增加了WINDOWS预防BD中WM异常发展到成年的重要可能性。此外，这些数据还暗示了一个与白质发育相关的基因，即神经调节蛋白1(NRG1)，在BD中影响FT-WM的完整性。因此，在这次更新中，我们计划使用多模式MRI来扩展我们对BD中FT神经系统的研究，以研究DTI的WM以及与功能MRI方法相关联的FT功能连接，在更大的样本中(包括150名患有BD的青少年和成人以及150名HC)，将允许对NRG1和其他相关基因的年龄相关模式和影响的差异进行建模。该计划致力于提高根据BD患者的遗传背景和寿命点更具体地治疗BD患者的能力，并开发更有效的检测、治疗和预防策略。 公共卫生相关性：双相情感障碍(BD)对全世界数百万患有这种疾病的人、他们的家庭和社区造成无法估量的痛苦，是自杀的主要原因；然而，其原因仍不清楚，现有的治疗方法效果有限。通过对从青春期到成年期的BD患者进行脑扫描和遗传学联合研究，我们建议从我们正在进行的工作中获得令人兴奋的新线索，展示BD从青春期到成年期的大脑回路差异，并识别与这一进程相关的基因。这项研究可能会带来阻止BD疾病进展的新方法，提高检测BD的能力，并根据患者的遗传背景和寿命点更具体地治疗BD患者，并有朝一日预防这种疾病。

DESCRIPTION (provided by applicant): This R01 renewal proposes multimodality magnetic resonance imaging (MRI) study of differences in age-related patterns of frontotemporal (FT) connectivity in adolescents and adults with and without bipolar disorder (BD) and the genetic factors that influence them. Despite severe consequences of BD in suffering for individuals, their families and communities, and the high associated rate of suicide, the biological mechanisms that underlie the development of BD and its effective treatment remain unclear. Currently, there is no biological marker to diagnose BD or to guide who might benefit from a specific treatment, though incorrect treatment can adversely affect prognosis and many with BD suffer from refractory symptoms. It is critical to understand how specific genetic predispositions lead to specific brain differences to improve detection, target treatments to those most likely to benefit based on their biology and discover new mechanisms to target for novel treatment development. Major challenges for the field also include presentations of BD that differ over the lifespan for reasons not understood, limiting ability to adapt detection and treatments for life phases. Progress of our research program includes identification of a FT neural system that subserves emotional processing as central in BD. Importantly, this system changes over the lifespan. Our current work supports progressive differences in FT gray matter between those with BD and healthy comparison (HC) individuals that emerge as significantly divergent in late adolescence/early adulthood and implicates neurotrophic genes (e.g. brain-derived neurotrophic factor, BDNF) in the neurodevelopmental differences. The white matter (WM) providing the connections within this FT neural system is increasingly implicated in BD. In progress towards our new aims, with a new focus on WM, preliminary diffusion tensor imaging (DTI) analyses suggest patterns of WM development in healthy individuals are characterized by increases in structural integrity of FT WM through the 4th decade of life, followed by decreases. Our preliminary data also support a divergent pattern for WM in adolescents and adults with BD that results in decreases in the structural integrity of WM in BD, with a peak in the decreases compared to HC individuals in the early 4th decade. This raises the important possibility of windows to prevent developmental progression of WM abnormalities in BD into adulthood. Moreover, the data implicate a gene associated with WM development, neuregulin 1 (NRG1), in influencing FT WM integrity in BD. In this renewal we therefore plan to extend our study of the FT neural system in BD using multimodality MRI to study WM with DTI, and associated FT functional connectivity with functional MRI methods, in a larger sample (including 150 new adolescents and adults with BD and 150 HCs) that will permit modeling of differences in age-related patterns and effects of NRG1 and other implicated genes. This program is devoted to a long-term goal of enhancing ability to treat individuals with BD more specifically, based on their genetic background and point in their lifespan, and development of more effective detection, treatment and prevention strategies. PUBLIC HEALTH RELEVANCE: Bipolar Disorder (BD) causes immeasurable suffering for the millions of individuals worldwide with the disorder, their families, and their communities, and it is a leading cause of suicide; yet, its causes remain unknown and existing treatments are limited in effectiveness. Using combined brain scanning and genetics study in individuals with BD from adolescence through adulthood, we propose to build on exciting new leads from our ongoing work that show brain circuitry differences in BD that progress through adolescence into adulthood and identify genes that are related to this progression. This research could lead to new ways to halt illness progression in BD, enhance ability to detect BD and to treat individuals with it more specifically, based upon their genetic background and point in their lifespan, and someday prevent the disorder.