Non-Invasive Imaging of Neurological Glycogen Storage Disease

神经糖原累积病的无创成像

• 批准号: 10419023
• 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/10419023
• 关键词: Adolescence; Affect; Aftercare; Age; Animal Diseases; Animals; Antibodies; Astrocytes; Automobile Driving; Behavioral; Biochemical; Biological Markers; Biological Models; Brain; Cells; Cessation of life; Childhood; Clinical; Cognitive; Data; Dementia; Detection; Deterioration; Diagnosis; Disease; Disease Progression; Enzymes; Epilepsy; Equipment; Etiology; 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; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Physiologic pulse; Protocols documentation; Protons; Publishing; Reporting; Resolution; Seizures; 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; base; 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.

项目概要/摘要 拉福拉病 (LD) 是一种致命的常染色体隐性遗传性神经退行性疾病，表现为癫痫 儿童晚期或青春期，随后迅速出现认知衰退、痴呆，并在 10 年内死亡 发病年数。目前尚无治疗方法，抗癫痫药物仅在早期有效。 LD 为 其特征是细胞内糖原样聚集体（称为拉福拉体（LB））的积累， 发生于大多数组织的细胞中，因此 LD 也是一种糖原累积病 (GSD)。尽管多个实验室 定义 LD 细胞和行为疾病后遗症以及开发治疗方法，目前尚无 用于非侵入性评估 LD 进展和/或治疗效果的生物标志物。最近我们报道了一本小说 利用脂肪族之间的核奥弗豪瑟效应（NOE）对糖原进行非侵入性成像的方法 糖原中的羟基质子可以用标准 MRI 设备检测到。使用这种 glycoNOE 通过这种方法，我们成功地证明了可以用高浓度动态测量肝糖原的变化 时间和空间分辨率。重要的是，糖基NOE对比和 糖原浓度。 这笔赠款的目的是建立一种定量 MRI 测试，用于报告 LB 负荷和治疗效果 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，并且我们有 设定以下具体目标 (1a) 建立稳健的 gluNOE MRI 协议，用于检测骨骼中的 LB 肌肉，(1b) 校准肌肉中的 gluNOE MRI 作为糖原浓度的函数，(2a) 开发 基于 gluNOE MRI 的定量测试，用于报告大脑中的 LB，(2b) 小鼠 LD 的纵向研究 使用 gluNOE，（3a）利用 gluNOE MRI 监测治疗干预后 LD 小鼠的 LB 水平， (3b) 评估治疗后 LB 的重新积累。 这些目标将产生一种非侵入性方法，以高浓度对大脑和肌肉中的糖原变化进行成像。 空间分辨率。该提案中开发的方法将立即转化为标准人类 核磁共振扫描仪。该技术将适用于所有糖原储存疾病，影响约 1 % 15,000，从而将范围扩大到 LD 之外。拟议的目标对于实现这些内容的翻译至关重要 结果可用于 LD 和更广泛的 GSD 患者群体的诊断和治疗监测。