Genetic Influences on Frontotemporal Connectivity in Bipolar Disorder

描述（由申请人提供）：本次R 01更新提出了多模态磁共振成像（MRI）研究，旨在研究患有和不患有双相情感障碍（BD）的青少年和成人的额颞（FT）连接的年龄相关模式差异以及影响它们的遗传因素。尽管BD对个人，家庭和社区造成严重后果，以及相关的高自杀率，但BD发展及其有效治疗的生物学机制仍不清楚。目前，没有生物标志物来诊断BD或指导谁可能从特定治疗中受益，尽管不正确的治疗会对预后产生不利影响，许多BD患者患有难治性症状。关键是要了解特定的遗传倾向如何导致特定的大脑差异，以改善检测，靶向治疗那些最有可能受益于他们的生物学和发现新的机制，以针对新的治疗开发。该领域的主要挑战还包括由于不了解的原因而在寿命期间不同的BD的呈现，限制了适应生命阶段的检测和治疗的能力。我们的研究计划的进展包括确定一个FT神经系统，使情绪处理在BD的中央。重要的是，这个系统在生命周期中会发生变化。我们目前的工作支持BD和健康对照（HC）个体之间FT灰质的渐进性差异，这些差异在青春期后期/成年早期出现显著差异，并暗示神经营养基因（例如脑源性神经营养因子，BDNF）在神经发育差异中。白色物质（WM）在FT神经系统内提供连接，越来越多地牵连在BD中。在朝着我们的新目标前进的过程中，随着对WM的新关注，初步的扩散张量成像（DTI）分析表明，健康个体的WM发展模式的特征是在生命的第4个十年中FT WM的结构完整性增加，然后减少。我们的初步数据还支持一个发散的模式，为WM在青少年和成人BD，导致在结构完整性的WM在BD的减少，与HC个人相比，在第4个十年的早期减少的峰值。这提出了重要的可能性窗口，以防止发展进展的WM异常BD进入成年期。此外，这些数据暗示与WM发展相关的基因，神经调节蛋白1（NRG 1），影响BD中FT WM的完整性。因此，在这次更新中，我们计划在更大的样本（包括150名新的青少年和成人BD和150名HC）中，使用多模态MRI扩展我们对BD中FT神经系统的研究，以研究WM与DTI，以及相关的FT功能连接与功能性MRI方法，这将允许建模NRG 1和其他相关基因的年龄相关模式和影响的差异。该计划致力于提高更具体地治疗BD患者的能力的长期目标，基于他们的遗传背景和生命周期，以及开发更有效的检测，治疗和预防策略。 公共卫生相关性：双相情感障碍（BD）给全世界数百万患有这种疾病的人、他们的家庭和他们的社区造成了不可估量的痛苦，它是自杀的主要原因;然而，其原因仍然未知，现有的治疗方法的有效性有限。在从青春期到成年期的BD患者中使用脑扫描和遗传学研究相结合，我们建议从我们正在进行的工作中建立令人兴奋的新线索，这些工作显示了BD中的脑回路差异，这些差异从青春期发展到成年期，并确定了与这种进展相关的基因。这项研究可能会导致新的方法来阻止BD的疾病进展，提高检测BD的能力，并根据他们的遗传背景和生命周期更具体地治疗个体，并有一天预防这种疾病。

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.