Non-Invasive Imaging of Neurological Glycogen Storage Disease

项目摘要/摘要 拉福拉病是一种致命性、常染色体隐性遗传的神经退行性疾病，临床表现为癫痫。 儿童晚期或青春期，紧随其后的是认知能力下降、痴呆症和10%内死亡 发病年限。目前，还没有治疗方法，抗癫痫药物只在早期有效。LD是 以被称为拉福拉小体(LBS)的糖原样聚集体在细胞内积累为特征的 发生在大多数组织的细胞中，因此LD也是一种糖原储存疾病(GSD)。尽管有多个实验室 定义LD细胞和行为疾病后遗症以及开发治疗方法，目前还没有 非侵入性评估LD进展和/或治疗疗效的生物标志物。我们最近报道了一部小说 利用脂肪族之间的核Overhauser效应(NOE)无创成像糖原的方法 和糖原中的羟基质子，可以用标准的磁共振设备检测到。使用这一糖苷 方法，我们成功地证明了肝糖原的变化可以用高密度的 时间和空间分辨率。重要的是，糖基化对比和糖皮质激素之间存在线性相关 糖原浓度。 这笔赠款的目的是建立一种定量的MRI测试，以报告Lb负荷和治疗效果 非侵入性的肌肉和大脑。为了实现这一点，我们将使用LD小鼠作为我们的模型系统，我们有 设定以下具体目标(1a)建立一套可靠的检测骨骼中LBS的GNOE MRI方案 肌肉，(1b)校准肌肉中的糖原MRI作为糖原浓度的函数，(2a)形成 GlyNOE MRI定量检测LBS在脑中的表达，(2b)小鼠LD的纵向研究 使用糖NOE，(3a)使用糖NOE MRI监测治疗干预后LD小鼠的LB值， (3B)评估治疗后LBS的再蓄积。 这些目标将导致一种非侵入性的方法来成像大脑和肌肉中高血糖的糖原变化。 空间分辨率。这项建议中开发的方法将立即可以翻译成标准的人类 核磁共振扫描仪。这项技术将适用于所有糖原储存疾病，这些疾病影响大约1/4。 15,000人，从而将范围扩大到LD以外。建议的目标对于能够翻译这些目标至关重要 结果用于诊断和监测LD和更广泛的GSD患者群体的治疗。

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.