Brain anatomical imaging and neurocognition in pediatric kidney disease (BRAIN KID)

项目摘要 儿童慢性肾脏病(PCKD)最常见的原因是肾脏和尿路的先天性异常；因此，意味着终生疾病。即使患有轻度CKD的儿童也有患上特定于注意力调节、学习成绩低下和执行功能的神经认知障碍的风险[1-3]。神经认知缺陷对生活质量有广泛的影响，因为它们导致成年CKD人群较低的高中毕业率和长期就业不足[4]。PCKD的认知并发症被认为是异常的“肾-脑轴”的后遗症，肾脏损伤和相关的疾病后遗症可能对大脑产生负面影响，导致pCKD进展过程中认知损害的风险增加[5-7]。然而，在pCKD的背景下，我们对发育中的大脑的理解存在着严重的差距。因此，这项建议的首要目标是使用MRI和认知/行为评估来量化患有轻度到中度(早期)CKD的pCKD参与者与未受影响的对照组之间的大脑结构和功能差异。据我们所知，这是世界上第一个使用磁共振成像(MRI)定量评估早期pCKD患儿大脑的建议。我们实验室的初步数据是惊人的，表明与健康同龄人相比，患有先天性、非肾小球原因的CKD儿童的大脑结构存在显著差异(特别是在小脑内)。小脑体积减少和肾功能受损之间似乎有直接关系。此外，较低的小脑灰质体积似乎可以预测CKD儿童在特定于执行功能的神经认知任务中的表现。我们的实验数据显示，pCKD患儿的静息状态连接异常，CKD儿童的小脑(齿状核)和额叶皮质之间的连接不足。我们将研究疾病负担对轻/中度CKD儿童神经发育的“剂量”影响。了解pCKD进展和严重程度对发育中大脑的影响将有助于提高对疾病进展对儿童神经发育结果的作用的认识，并为整个CKD生命周期的患者护理提供新的方法。

Project Summary Pediatric chronic kidney disease (pCKD) is most commonly due to congenital anomalies of the kidney and urinary tract; thus, meaning a lifetime of disease. Children with even mild CKD are at risk for neurocognitive difficulties specific to attention regulation, academic underachievement, and executive function [1-3]. Neurocognitive deficits have broad implication on quality of life, as they contribute to poorer high school graduation rates and long-term underemployment in the adult CKD population [4]. The cognitive complications of pCKD are thought to represent sequelae of an aberrant “kidney-brain axis” whereby kidney impairment and associated disease sequelae may negatively impact the brain, leading to increased risk of cognitive impairment in the course of pCKD progression [5-7]. However, there is a critical gap in our understanding of the developing brain in the context of pCKD. Thus, the overarching goal of this proposal is to quantify structural and functional brain differences using MRI and cognitive/behavioral assessments in pCKD participants with mild to moderate (early) CKD compared to unaffected controls. To our knowledge, this proposal is the first in the world to quantitatively evaluate the brain in young children with early stage pCKD due to a focused disease etiology using magnetic resonance imaging (MRI). Preliminary data from our laboratory are striking and demonstrate robust structural brain differences (particularly within the cerebellum) in children with congenital, non-glomerular causes of CKD compared to healthy peers. There appears to be a direct relationship between decreased cerebellum volume and impaired kidney function. Furthermore, lower cerebellum gray matter volume appears to predict performance on neurocognitive tasks specific to executive function in children with CKD. Our pilot data demonstrate abnormal resting state connectivity in pCKD whereby children with CKD show hypo-connectivity between the cerebellum (dentate nucleus) and the frontal cortices. We will investigate a “dosage” effect of disease burden on neurodevelopment in children with mild/moderate CKD. Understanding the influence of pCKD progression and severity on the developing brain will allow enhanced awareness of the role of disease progression on neurodevelopmental outcomes in childhood and inform new approaches to patient care across the CKD lifespan.