Non-Invasive Imaging of Neurological Glycogen Storage Disease

项目总结/摘要 Lafora病（LD）是一种致命的常染色体隐性遗传神经退行性疾病，表现为癫痫， 儿童晚期或青春期，随后迅速出现认知能力下降、痴呆，并在10年内死亡。 年发病率。目前，没有治疗方法，抗癫痫药物仅在早期阶段有益。LD是 其特征在于称为Lafora小体（LB）的糖原样聚集体的细胞内积累， 发生在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，目前还没有 使用生物标志物来非侵入性地评估LD进展和/或治疗功效。我们最近报道了一部小说 一种利用脂肪族之间的核Overhauser效应（NOE）非侵入性地成像糖原的方法， 和糖原中的羟基质子，它们可以用标准的MRI设备检测到。使用这个glycoNOE 方法，我们成功地表明，肝糖原的变化可以动态测量高， 时间和空间分辨率重要的是，glycoNOE对比度与 糖原浓度 这项资助的目的是建立一个定量的MRI测试，用于报告LB负荷和治疗效果， 肌肉和大脑的非侵入性治疗为了实现这一点，我们将利用LD小鼠作为我们的模型系统，我们已经 （1a）建立用于检测骨骼肌中LB的稳健的glycoNOE MRI方案 肌肉，（1b）校准肌肉中的glycoNOE MRI作为糖原浓度的函数，（2a）开发一种 用于报告脑中LB的基于glycoNOE MRI的定量测试，（2b）小鼠中LD的纵向研究 （3a）利用glycoNOE MRI监测治疗干预后LD小鼠中的LB水平， (3b)评估治疗后LB的再蓄积。 这些目标将产生一种非侵入性的方法，用于成像大脑和肌肉中的糖原变化， 空间分辨率该提案中开发的方法将立即转化为标准的人类 核磁共振扫描仪。这项技术将适用于所有糖原累积病，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目标至关重要。 导致诊断和监测治疗LD和更广泛的GSD患者人群。

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.