Modeling Cerebral Microbleeds and Striatal Brain Iron in Adult Congenital Heart Disease in Relationship to Differential Genetic Risk for Alzheimer Disease

新出现的数据表明，先天性心脏病(CHD)成年幸存者人数的飙升， 患认知衰退和早发性痴呆症的风险增加。其他重要风险的作用 痴呆症的因素，包括脑微出血的存在，脑铁水平升高，以及 载脂蛋白E(APOE)在成人冠心病中的基因分型尚不清楚。ApoE-ε4等位基因频率为14% 在大约25%的美国人口中存在，并与阿尔茨海默病风险增加有关。 我们的总体假设是，脑内微出血和脑铁水平升高可预测不良 成年冠心病患者的神经认知结果和加速的老年前期(早发)痴呆风险 关系受载脂蛋白E基因的调节。在NHLBI资助的儿童心脏目前的辅助RO1中 网络(PHN)思维研究，我们正在测量获得性脑损伤和多模式神经成像生物标记物 利用18-30岁之间的患者队列的神经认知测试，并利用 为母公司PHN Minds研究建立的基础设施已经到位。关于这个问题的研究还很有限 CHD对这些相关神经影像生物标志物的长期影响[脑微出血测量 用静息功能成像(BOLD)测量磁化率加权成像(SWI)和纹状体脑铁] 已经利用大规模痴呆症高危人群(阿尔茨海默病)详细开发了 神经成像倡议(ADNI)。我们在成年CHD患者中的初步数据表明， 与阿尔茨海默病重叠，包括青年冠心病患者的高患病率(&gt；50%) SWI成像显示皮质和皮质下微出血。这项管理的目标是 补充内容是将神经成像生物标记物的描述扩展到深度特征化特征 这些脑微出血(使用定量SWI)和纹状体脑铁的严格定量(使用 休息大胆的想象)。Minds父母研究还包括一个广泛的NIH工具箱 神经认知/神经行为测试组件。我们最终将能够利用广泛的母公司 Minds研究生物样本的收集/分析，其中不仅包括DNA，还包括ApoE基因分型 DATA和其他血管应激和弹性基因型别。我们对这项行政管理的具体目标 补充：具体目标#1：脑微出血：量化大脑多维特征 使用SWI成像进行微出血。将采用先进的神经信息学技术，包括空间 形态测量学和机器学习技术。我们将脑内微出血的特征与 神经认知结果(主要)、心血管相关患者/医疗因素数据(次要)、未来载脂蛋白E 基因分型(探索性)。具体目标2：纹状体脑铁测量：利用现有思维 使用静息状态BOLD成像对纹状体脑铁进行定量的神经成像方案。与特征的相关性 脑部微出血、神经认知结果和未来脑部队列中的载脂蛋白E基因型也将是 已执行。我们建议对当前RO1拨款进行行政补充的结果将有助于 脑微出血、纹状体脑铁和载脂蛋白E基因分型的相互作用 通过利用NHLBI资助的PHN Minds研究，异常可以引起认知-行为表型。 通过描绘和确定哪些成年冠心病患者在以下年龄最有可能出现认知能力下降/痴呆 可能的较早时间点将使我们能够采取预防可改变的风险因素。反过来， 我们建议的行政补充的结果将有助于了解载脂蛋白Eε4基因型之间的关系 脑微出血和纹状体脑铁的表达可能是明显认知障碍的先兆 阿尔茨海默病要早几十年。早期发现这些脑部改变具有内在的价值 不仅是预测，而且不仅是预防治疗疗法的发展和评估 冠心病相关的痴呆症，但也有阿尔茨海默病，可能在青壮年时期使用。

Emerging data suggests that the soaring population of adult survivors of congenital heart disease (CHD), are at increased risk of developing cognitive decline and early-onset dementia. The role of other important risk factors for dementia, including the presence of cerebral microbleed, elevated brain iron levels, and apolipoprotein E (APOE) genotype in adult CHD is unknown. With an allele frequency of 14%, APOE-ε4 is present in approximately 25% of the US population and associated with increased risk of Alzheimer’s Disease. Our overall hypothesis the presence of cerebral microbleeds and elevated brain iron levels predict poor neurocognitive outcomes and accelerating presenile (early onset) dementia risk in adult CHD and that this relationship is moderated by APOE genotype. In the current ancillary Ro1 to the NHLBI-funded Pediatric Heart Network (PHN) MINDS study, we are measuring acquired brain injury and multi-modal neuroimaging biomarkers leveraging the neurocognitive testing of the patient cohort between 18-30 years of age and utilizing the well- established infrastructure already in place for the parent PHN MINDS study. There is limited research about the long-term impact of CHD on these relevant neuroimaging biomarkers [cerebral microbleeds measures with susceptibility weighted imaging (SWI) and striatal brain iron measured with resting functional imaging (BOLD)] that have been developed in detail utilizing large-scale dementia risk populations (Alzheimer’s Disease Neuroimaging Initiatives- ADNI). Our preliminary data in adult CHD MINDS patients demonstrate findings that overlap with Alzheimer’s disease which includes a high prevalence (>50%) of young adult CHD patients with cortical and subcortical microbleeds as identified with SWI imaging. The goal of this administrative supplement is to expand the delineation of neuroimaging biomarkers to deeply characterized features of these cerebral microbleeds (using quantitative SWI) and rigorously quantitate striatal brain iron (using resting BOLD imaging). The MINDS parent study also includes an extensive NIH-Tool Box neurocognitive/neurobehavioral testing battery. We will eventually be able to leverage the extensive parent MINDS study biological specimen collection/analysis which includes not only DNA, but also ApoE genotyping data and other vascular stress and resilience genotypes. Our specific aims for this administrative supplement are: Specific Aim #1: Cerebral Microbleeds: Quantitate multi-dimensional features of cerebral microbleeds using SWI imaging. Advanced neuroinformatic techniques will be employed including spatial morphometry and machine learning techniques. We will correlate features of cerebral microbleeds with neurocognitive outcomes (primary), cardiovascular related patient/medical factors data (secondary), future ApoE genotyping (exploratory). Specific Aim #2: Striatal Brain Iron Measurement: Leverage the current MINDS neuroimaging protocol to quantitate striatal brain iron using resting state BOLD imaging. Correlation with features of cerebral microbleeds, neurocognitive outcomes and future ApoE genotype in the MINDS cohort will also be performed. The results from our proposed administrative supplement to our current Ro1 grant will help to elucidate the way interactions between cerebral microbleeds, striatal brain iron and APOE genotyping abnormalities give rise to cognitive-behavioral phenotypes by leveraging the NHLBI-funded PHN MINDS study. By delineating and identifying which adult CHD patients are mostly likely at risk for cognitive decline/dementia at the earlier time point possible will allow us to employ prevention of modifiable risk factors. Reciprocally, the results from our proposed administrative supplement will help inform the relationship between APOE ε4 genotype expression and cerebral microbleeds and striatal brain iron which may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these brain alterations holds inherent value for not only prognostication, but also the development and evaluation of preventive treatment therapies for not only CHD- related dementia, but also Alzheimer disease, possibly employed during the young adult period.