Genetic Influences on Frontotemporal Connectivity in Bipolar Disorder

描述（由申请人提供）：这项R01更新提出了多模态磁共振成像（MRI）研究在患有和不患有双相情感障碍（BD）的青少年和成人中与年龄相关的额颞叶（FT）连接模式的差异以及影响它们的遗传因素。尽管双相障碍给个人、家庭和社区带来了严重的痛苦，并且与之相关的自杀率很高，但双相障碍发展及其有效治疗的生物学机制仍不清楚。目前，虽然不正确的治疗会对预后产生不利影响，并且许多双相障碍患者会出现难治性症状，但没有生物标志物来诊断双相障碍或指导谁可能从特定的治疗中受益。了解特定的遗传倾向如何导致特定的大脑差异，以提高检测，针对那些最有可能受益的生物进行靶向治疗，并发现新的机制，以开发新的治疗方法，这是至关重要的。该领域面临的主要挑战还包括，由于未知的原因，双相障碍的表现在生命周期中存在差异，限制了适应生命阶段的检测和治疗能力。我们的研究项目的进展包括确定了一个FT神经系统，该系统在双相障碍中起着中心作用，支持情绪处理。重要的是，该系统随着寿命的变化而变化。我们目前的工作支持双相障碍患者和健康对照（HC）个体在青春期晚期/成年早期出现显著差异的FT灰质的进行性差异，并暗示神经营养基因（如脑源性神经营养因子，BDNF）与神经发育差异有关。提供FT神经系统内连接的白质（WM）与BD的关系越来越密切。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中，FT WM结构完整性增加，然后减少。我们的初步数据还支持青少年和成年双相障碍患者WM的不同模式，导致双相障碍患者WM的结构完整性下降，与HC个体相比，下降的峰值出现在40年代早期。这提出了重要的可能性窗口，以防止发育进展的WM异常的双相障碍进入成年期。此外，数据表明与WM发育相关的基因神经调节蛋白1 （NRG1）影响BD中FT - WM的完整性。因此，在这项更新中，我们计划扩展我们对BD中FT神经系统的研究，使用多模态MRI研究DTI的WM，并使用功能MRI方法研究FT功能连接。在一个更大的样本中（包括150名新青少年和成年BD患者和150名hc患者），这将允许对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。该项目的长期目标是根据患者的遗传背景和生命阶段，提高对双相障碍患者的针对性治疗能力，并开发更有效的检测、治疗和预防策略。

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.