Biomarkers of Neurological Injury and Recovery in Urea Cycle Disorders

尿素循环障碍神经损伤和恢复的生物标志物

基本信息

批准号：
8916161
负责人：
Andrea Lynne Gropman
金额：
$ 10.01万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8916161
关键词：
Acute Affect Age Ammonia Anisotropy Argininosuccinate lyase deficiency Atrophic Attention Berry Biochemical Biochemical Markers Biochemistry Biological Markers Brain Brain Injuries Brain Pathology Brain region Cell Death Cells Chronic Chronic Brain Damage Chronology Citrulline Citrullinemia Clinical Clinical Research Cognitive Coma Data Defect Development Diet Diffusion Magnetic Resonance Imaging Disease Distal Doctor of Philosophy Edema Ensure Exhibits Female Functional disorder Glutamine Hyperammonemia Impaired cognition Injury Inositol Lead Lesion Longitudinal Studies Magnetic Resonance Imaging Measures Metabolic Methodology Methods Morbidity - disease rate Nervous System Trauma Neurocognitive Neurocognitive Deficit Neuropsychological Tests Nitrogen Ornithine Ornithine carbamoyltransferase deficiency Outcome Patients Performance Pharmaceutical Preparations Plasma Process Rare Diseases Recording of previous events Resolution Secondary to Short-Term Memory Structural defect Test Result Time Toxic effect adverse outcome cytotoxic executive function gray matter multidisciplinary neurocognitive test neuroimaging neurological recovery neuroprotection neuropsychiatry neuropsychological neurotoxic novel novel strategies spectroscopic imaging urea cycle white matter

项目摘要

In proximal urea cycle disorders (UCD), particularlyornithine transcarbamylase deficiency (OTCD), hyperammonemia (HA) causes increased brain glutamine (Gin) which perturbation is thoughtto be at the core of the neurological injury. In contrast, in distal UCD such as citrullinemia(argininosuccinatesynthetase deficiency; (ASSD) and argininosuccinicaciduria(argininosuccinatelyase deficiency); (ASLD) cognitive impairment and neuropsychiatric disease are common even in the absence of acute HA. As a consequence, both citrulline and argininosuccinate (ASA) or their metabolic products have been implicated as neurotoxic. In this project we will use state-of- the-art neuroimaging and neuropsychological methods to investigate whether patients with OTCD have chronically elevated brain Gin and reduced myo-inositol (ml) levels that correlate with regional brain structural abnormalities and neurocognitive dysfunction. We will further investigate whether during an acute episode of HA elevated brain Gin and decreased ml levels correlate with the magnitude of cytotoxic edema and whether a Gln/ml ratio threshold can be identified at which the cytotoxic edema is followed by cell loss. Finally, will investigate whether regions of brain damage in ASSD and/or ASLD are distinct from those in OTCD and compare brain Gin levels in ASSD and ASLD in the absence of HA to those in OTCD. We will also seek to determine if brain citrulline and ASA can be identified in the brains of patients with distal UCD and whether they correlate with brain abnormalities seen in MRI and neuropsychological testing. This project will elucidate the chronology of brain pathology both in acute hyperammonemia and chronic UCD and whether, proximal and distal UCD differ in their pathophysiology of brain damage.

在近端尿素周期疾病（UCD）中，特别是洋他氨酸经氨基甲基酶缺乏（OTCD），高症血症（HA）会导致脑谷氨酰胺（GIN）增加，这些脑谷氨酰胺（GIN）被认为是神经系统损伤的核心。相反，在远端UCD中，例如柠檬丁素血症（Argininosonoccinatesynthetase deative;（ASSD）和Argininosuccinicaciduria（Argininoscinationalase酶缺乏症）；（ASLD）认知障碍和神经疾病疾病都是常见的，甚至是伴有毒性的毒气，也是危机的疾病。（ASA）或它们的代谢产物已被与神经毒性有关。大脑杜松子酒和降低的ML水平与细胞毒性水肿的幅度相关，以及是否可以鉴定出细胞毒性水肿之后的GLN/ML比阈值，最终会研究ASSD和/或ASLD中的脑损伤区域是否与OTCD和ASL中的ASSL中的区别不同。我们还将寻求确定在远端UCD患者的大脑中是否可以鉴定出脑柑桔和ASA，以及它们是否与MRI和神经心理学测试中的脑异常相关。该项目将阐明急性高症和慢性UCD中脑病理学的年代学，以及UCD近端和远端UCD在其脑损伤的病理生理学方面是否有所不同。