Non-Invasive Imaging of Neurological Glycogen Storage Disease

神经糖原累积病的无创成像

• 批准号: 10598109
• 负责人: Nirbhay Narayan Yadav
• 金额: $ 41.53万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598109
• 关键词: Adolescence; Affect; Aftercare; Age; Animal Diseases; Animals; Antibodies; Anticonvulsants; Astrocytes; Automobile Driving; Behavioral; Biochemical; Biological Markers; Biological Models; Brain; Calibration; Cells; Cessation of life; Childhood; Clinical; Cognitive; Cytoplasm; Data; Dementia; Detection; Deterioration; Diagnosis; Disease; Disease Progression; Enzymes; Epilepsy; Equipment; Etiology; Euthanasia; Feedback; Funding; Genes; Glucose; Glycogen; Glycogen Storage Disease; Grant; Human; Hydroxyl Radical; Imaging Device; Imaging Techniques; Label; Lafora Disease; Liver; Liver Glycogen; Longitudinal Studies; Magnetic Resonance Imaging; Magnetism; Maps; Measures; Methods; Monitor; Mus; Muscle; Mutation; Neurodegenerative Disorders; Neurons; Noise; Nuclear; Organ; Phosphoric Monoester Hydrolases; Physiologic pulse; Predisposition; Protocols documentation; Protons; Publishing; Reporting; Resolution; Signal Transduction; Skeletal Muscle; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Techniques; Technology; Testing; Therapeutic Intervention; Tissues; Translations; Treatment Efficacy; United States National Institutes of Health; Water; Work; autosome; brain metabolism; computerized data processing; design; imaging approach; imaging modality; in vivo; instrumentation; molecular imaging; mouse model; neuroimaging; non-invasive imaging; nonhuman primate; novel strategies; patient population; radio frequency; soft tissue; solute; stem; therapy development; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT Lafora disease (LD) is a fatal, autosomal recessive, neurodegenerative disorder that presents as epilepsy in late childhood or adolescence and is followed rapidly by cognitive deterioration, dementia, and death within 10 years of onset. Currently, there is no treatment and anti-seizure drugs are only beneficial in early stages. LD is characterized by the intracellular accumulation of glycogen-like aggregates called Lafora bodies (LBs) that occur in cells from most tissues, thus LD is also a glycogen storage disease (GSD). Although multiple labs are defining LD cellular and behavioral disease sequela as well as developing therapies, there is currently no biomarker to assess LD progression and/or treatment efficacy non-invasively. We recently reported a novel approach for imaging glycogen non-invasively using the nuclear Overhauser effect (NOE) between aliphatic and hydroxyl protons in glycogen that can be detected with standard MRI equipment. Using this glycoNOE approach, we successfully showed that changes in liver glycogen could be measured dynamically with high temporal and spatial resolution. Importantly, there was a linear correlation between glycoNOE contrast and glycogen concentration. The objective of this grant is to establish a quantitative MRI test for reporting LB load and treatment efficacy in muscle and brain non-invasively. To achieve this, we will utilize LD mice as our model system, and we have set the following specific aims (1a) Establish a robust glycoNOE MRI protocol for detecting LBs in skeletal muscle, (1b) Calibrate glycoNOE MRI in muscle as a function of concentration of glycogen, (2a) Develop a glycoNOE MRI-based quantitative test for reporting LBs in the brain, (2b) Longitudinal study of LD in mice using glycoNOE, (3a) Utilize glycoNOE MRI to monitor LB levels in LD mice after a therapeutic intervention, (3b) Assess the re-accumulation of LBs after treatment. These aims will result a non-invasive method for imaging glycogen changes in the brain and muscle with high spatial resolution. The methods developed in this proposal will be immediately translatable to standard human MRI scanners. This technology will be applicable to all glycogen storage diseases, which affect about 1 in 15,000 and thus expand the scope beyond LD. The proposed aims are critical to enable translation of these results into diagnosing and monitoring of treatments for LD and the broader GSD patient population.

项目摘要/摘要 Lafora病（LD）是一种致命的，常染色体隐性的神经退行性疾病，呈现为癫痫 童年或青春期晚期，紧随其后的是认知恶化，痴呆和死亡，在10之内 发病多年。目前，没有治疗，抗塞氏菌药物仅在早期才有益。 LD是 以糖原样聚集体的细胞内积累为特征，称为Lafora身体（LBS） 出现在大多数组织中的细胞中，因此LD也是糖原储存疾病（GSD）。虽然多个实验室是 定义LD细胞和行为疾病后遗症以及开发疗法，目前没有 生物标志物可无创地评估LD进展和/或治疗功效。我们最近报道了一本小说 使用脂肪族之间的核过度大冲突效应（NOE）非侵入性成像糖原的方法 糖原中可以使用标准MRI设备检测的糖原中的羟基质子。使用此甘康 方法，我们成功地表明，肝糖原的变化可以动态测量 时间和空间分辨率。重要的是，GlyConoe对比与 糖原浓度。 该赠款的目的是建立定量MRI测试，以报告LB负载和治疗功效 肌肉和大脑无创。为了实现这一目标，我们将利用LD小鼠作为我们的模型系统，我们有 设置以下特定目的（1A）建立可检测骨骼中LBS的强大甘康MRI协议 肌肉，（1B）在肌肉中校准糖基MRI与糖原浓度的关系，（2a）发展 基于GlyConoe MRI的定量测试，用于报告大脑中LB的LBS，（2B）LD的纵向研究小鼠的纵向研究 （3A）使用甘康（GlyConoe （3B）评估治疗后LB的重新蓄能。 这些目的将导致一种非侵入性方法，用于成像大脑和肌肉的糖原变化 空间分辨率。本提案中开发的方法将立即转换为标准人 MRI扫描仪。该技术将适用于所有糖原储存疾病，影响约1个 15,000，从而将范围扩大到LD之外。提出的目标对于使这些翻译至关重要 结果诊断和监测LD和更广泛的GSD患者人群的治疗方法。