Advanced MRI biomarkers in HD mouse models translatable to humans: nature history and response to therapeutics

亨廷顿病（HD）是一种由CAG引起的显性遗传性、致死性神经退行性疾病 亨廷顿蛋白（HTT）基因。HD优先累及基底神经节-尤其是纹状体- 而且还影响其他大脑区域，目前还没有治愈或改善疾病的治疗方法。因为它的收益- 功能机制，降低突变HTT的策略有望成为有史以来第一个疾病修饰疗法。 当临床结果可用于评价HD时，大多数方法目前针对的是显性HD。 有效性然而，由于发病时纹状体体积几乎损失了50%， 优选在纹状体体积大量损失之前的表现前期开始治疗。未满足的 挑战是如何在没有临床症状作为结果的情况下可靠地评估治疗效果 措施HD的临床诊断是基于运动障碍的存在。然而，功能 大脑的变化可以在运动开始之前许多年。神经血管异常 我们和其他人在预清单和早期HD中报告了这一点。我们曾报道小动脉CBV显著改变 （CBVa）在表现前HD大脑中，当纹状体萎缩检测不到时。我们最近发现， 在HD小鼠模型中，CBVa发生在纹状体萎缩之前，并且CRISPR/Cas9介导的mHTT 降低表现前HD小鼠中恢复的CBVa。总的来说，这些数据表明， 神经血管改变可能是预显HD的有价值的生物标志物。CBV与脑强耦合 脑代谢异常越来越多地被认为是早期神经病理学 HD事件我们发现，在前驱HD患者中，脑代谢对视觉刺激的反应受损 患者，与CAG年龄乘积（CAP）评分相关，支持代谢紊乱发生在 早期致病阶段，可能是HD的另一个早期生物标志物。此外，最近（重新）发现 脑淋巴管和脑脊液淋巴引流系统说明了脑废物的重要清除 系统我们的初步数据暗示，损害的元素，这一系统之前，纹状体萎缩 和mHTT聚集。这个项目的目的是识别早期脑功能变化 在HD临床前研究中，通过结合多模式先进MRI措施， 并开发可转化为HD临床试验的敏感生物标志物，特别是在预表现期。 目标1.我们将检验突变HTT损害脑代谢和改变神经血管的假设。 脑萎缩和行为缺陷之前的反应性。目标二。我们将评估glymphatic 通过测量HD小鼠中的淋巴流动动力学和BBB渗透性来观察功能。目标3.我们将确定 代谢、血管和淋巴MRI测量可以监测预显效应的程度 并且表现出用CRISPR/Cas9介导的HTT降低治疗HD小鼠。

Huntington’s disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene. HD preferentially involves the basal ganglia- especially the striatum- but also affects other brain regions and has no cure or disease-modifying treatment yet. Because of its gain-of- function mechanism, strategies to lower mutant HTT are promising as first-ever disease-modifying therapies. Most approaches are currently targeted at manifest HD when clinical outcomes can be used to evaluate the effectiveness. However, as almost 50% of striatal volume has been lost at the time of onset, it would be preferable to begin treatment in the premanifest period before massive loss of striatal volumes. An unmet challenge is how to reliably evaluate therapeutic efficacy in the absence of clinical symptoms as outcome measures. The clinical diagnosis of HD is based on the presence of movement disorders. However, functional changes in the brain can precede motor onset by many years. Neurovascular abnormalities have been reported in premanifest and early HD by us and others. We have reported significantly altered arteriolar CBV (CBVa) in premanifest HD brains, when striatal atrophy was undetectable. We recently found that altered CBVa occurred prior to striatal atrophy in an HD mouse model and that CRISPR/Cas9-mediated mHTT lowering restored CBVa in premanifest HD mice. Collectively, these data suggest reliable measures of neurovascular changes might be valuable biomarkers in premanifest HD. CBV is strongly coupled with brain metabolism, and cerebral metabolic abnormalities are increasingly considered as early neuropathological events in HD. We found impaired response of cerebral metabolism to visual stimulation in premanifest HD patients, correlating with the CAG-Age product (CAP) score, supporting that metabolic disturbances occur at early pathogenic stage and may be another early biomarker for HD. In addition, the recent (re)discovery of brain lymphatic vessels and CSF-lymphatic drainage system illustrates an important brain waste clearance system. Our preliminary data implicate that impairment of elements of this system precedes striatal atrophy and mHTT aggregation in HD mice. The objective of this project is to identify early brain functional changes that rapidly respond to treatment in HD preclinical study by incorporating multimodal advanced MRI measures and to develop sensitive biomarkers translatable to HD clinical trials, particularly in the premanifest period. Aim 1. We will test the hypothesis that mutant HTT impairs cerebral metabolism and alters neurovascular responsivity prior to brain atrophy and behavioral deficits in HD mice. Aim 2. We will assess glymphatic function by measuring lymphatic flow dynamics and BBB permeability in HD mice. Aim 3. We will determine the extent to which metabolic, vascular, and lymphatic MRI measures can monitor the effects of premanifest and manifest treatment of HD mice with CRISPR/Cas9-mediated HTT lowering.