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

亨廷顿病(HD)是一种主要由CAG引起的遗传性、致命性神经退行性疾病 亨廷顿(HTT)基因的扩增。HD优先累及基底节--尤其是纹状体 但也会影响到其他大脑区域，目前还没有治愈或改善疾病的治疗方法。因为它的收益- 作用机制、降低突变型HTT的策略是有史以来最有希望的疾病修饰疗法。 大多数方法目前针对的是清单HD，当临床结果可以用来评估 有效性。然而，由于发病时几乎50%的纹状体体积已经丢失，因此 最好在纹状体体积大量丧失之前的显性前期开始治疗。一个未被满足的人 挑战是如何在没有临床症状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，功能性的 大脑的变化可以比运动发作早很多年。神经血管的异常 我们和其他人在预清单和早期HD中报告了这一情况。我们已经报告了显著改变的微动脉CBV (CBVa)在未发现纹状体萎缩的先兆HD脑中。我们最近发现这一点发生了变化 在HD小鼠模型中，CBVa发生在纹状体萎缩之前，CRISPR/Cas9介导的mHTT 降压可使先证型HD小鼠的CBVa恢复。总体而言，这些数据表明， 神经血管改变可能是显性前HD有价值的生物标志物。CBV与大脑有很强的关联性 新陈代谢和脑代谢异常越来越被认为是早期的神经病理 高清活动。我们发现先兆HD患者的大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 早期发病，可能是HD的另一个早期生物标志物。此外，最近(重新)发现的 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，纹状体萎缩之前，这个系统的元素受损。 HD小鼠mHTT聚集。这个项目的目标是确定早期的大脑功能变化。 在HD临床前研究中通过结合多模式先进的MRI措施对治疗做出快速反应 并开发可翻译为HD临床试验的敏感生物标记物，特别是在显性前期。 目的1.我们将验证突变的HTT损害大脑代谢和改变神经血管的假说 HD小鼠脑萎缩和行为缺陷前的反应性。目标2.我们将评估Glymphatic 通过测量HD小鼠的淋巴流动动力学和血脑屏障通透性来实现其功能。目标3.我们将确定 代谢、血管和淋巴核磁共振测量可以在多大程度上监测预显性疾病的影响 CRISPR/Cas9介导的HTT下降对HD小鼠的明显治疗作用。

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.