Imaging brain glucose uptake by onVDMP MRI in Huntington's Disease

亨廷顿病(HD)是最常见的遗传性神经退行性疾病，由扩张性 亨廷顿基因中的DNA三核苷酸CAG。先天性巨结肠症的临床诊断是基于存在 运动障碍。然而，从微妙到显著的大脑功能变化可以早于运动- 基于起效。鉴于基因测试的可用性，有可能确定哪些受试者会患上 在出现运动症状之前的疾病。这为发现潜力提供了一个独特的机会 生物标志物，对促进疾病修饰的发展具有不容置疑的价值 治疗。到目前为止，已经证实的HD的神经保护策略仍然难以捉摸，尽管已经有了快速的 其发病机制的研究进展。问题的一部分是，大多数临床试验 试图在退变过程已经推进时进行干预，即使在大多数情况下也是困难的 有效的治疗以证明任何益处。因此，在前清单期间敏感生物标记物的可用性 阶段对于确定开始治疗的最佳时间以及可靠地评估是至关重要的 临床试验中的疗效。大脑是一个需要能量的器官，它的重量约占全身的2%，但 在静息状态下消耗约20%的总葡萄糖。早期葡萄糖代谢低下的有力证据 在高清大脑中已有报道。先显性HD患者的葡萄糖低代谢是否代表 不可逆转的损伤或它是否预测了大脑结构的变化仍是未知的。体内葡萄糖摄取 对大脑的评估主要使用2-[18F]氟-2-脱氧-D-葡萄糖正电子发射断层扫描。 葡萄糖化学交换饱和转移磁共振成像是一种新近发展起来的技术，它可以 使用纯质子核磁共振扫描仪检测生理相关浓度的未标记葡萄糖 需要额外的硬件。这种新方法可以检测到低浓度的葡萄糖 通过羟基和水之间的质子化学交换。然而，该事件的敏感性 由于这些羟基质子的快速交换率(&gt；3000赫兹)，传统的葡糖CEST磁共振成像是有限的。 为了提高这种质子的标记效率，我们最近开发了一种开共振变量 延迟多脉冲(OnVDMP)MRI序列。我们的初步数据显示了一个令人兴奋的发现，即 这项技术可以灵敏地区分HD小鼠脑中葡萄糖的摄取和清除情况。 R21的目的是确定在VDMP MRI上测量葡萄糖摄取是否可以作为 用于描述HD早期疾病进展和评估治疗反应的敏感生物标志物 老鼠。在目标1中，我们将确定HD小鼠脑内葡萄糖摄取和清除的时空动力学 并确定葡萄糖摄取和清除受损是否随着疾病和早产儿的进展而进展 根据高分辨率核磁共振的测量，可以预测选择性脑萎缩。在目标2中，我们将评估 促进淋巴功能将改善HD小鼠脑内葡萄糖的摄取和清除。

Huntington's disease (HD) is the most common inherited neurodegenerative disorder caused by an expanded DNA trinucleotide CAG in the Huntingtin gene. The clinical diagnosis of HD is based on the presence of movement disorders. However, subtle-to-prominent brain functional changes can precede by years the motor- based onset. Given the availability of a genetic testing, it is possible to identify which subjects will develop the disease before motor symptoms are present. This provides a unique opportunity to identify potential biomarkers, which would be of unquestionable value for promoting the development of disease-modifying therapies. To date, proven neuroprotective strategies for HD remain elusive although there has been a rapid progress in understanding of the pathogenesis. Part of the problem is that most of the clinical trials have attempted intervening when the degenerative process is already advanced making it difficult even for the most effective therapy to demonstrate any benefit. Thus, availability of sensitive biomarkers during the premanifest phase is critical for determining an optimal time to initiate the treatment, as well as for reliably evaluating efficacy in clinical trials. The brain is an energy-demanding organ that weighs ~2% of the whole body but consumes ~20% of total body glucose in the resting state. Strong evidence of early glucose hypometabolism in the HD brain has been reported. Whether glucose hypometabolism in premanifest HD represents an irreversible damage or whether it predicts the brain structural changes remains unknown. Glucose uptake in brain has been assessed mostly using 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography. Glucose chemical exchange saturation transfer (glucoCEST) MRI is a recently developed technique that can detect unlabeled glucose at physiologically relevant concentrations using proton-only MRI scanners without the requirement of additional hardware. This new method allows the detection of low concentration glucose through the chemical exchange of protons between hydroxyl groups and water. However, the sensitivity of the conventional glucoCEST MRI is limited due to the fast-exchange rates of these hydroxyl protons (>3000 Hz). In order to improve the labeling efficiency of such protons, we recently developed an on-resonance variable delay multiple pulse (onVDMP) MRI sequence. Our preliminary data show an exciting discovery, namely that this technique is sensitive to differentiate the glucose uptake and clearance in HD mouse brain from controls. The objective of this R21 is to determine whether onVDMP MRI measures of glucose uptake can serve as sensitive biomarkers for characterizing early disease progression and assessing response to treatment in HD mice. In Aim 1, we will identify spatiotemporal dynamics of glucose uptake and clearance in HD mouse brain and to determine whether impaired glucose uptake and clearance progresses with disease and predates and predicts selective brain atrophy, as measured by high-resolution MRI. In Aim 2, we will assess whether facilitating glymphatic function will improve glucose uptake and clearance in the HD mouse brain.