Magnetic Resonance Spectroscopy Biomarkers of Neurodegeneration

描述（由申请人提供）：该项目的长期目标是建立对进行性神经变性及其逆转敏感的非侵入性磁共振波谱（MRS）生物标志物。为了以高灵敏度和特异性完成此工作，使用了高场扫描仪（3特斯拉或更高）。第一个周期的应用重点是遗传性脊髓小脑共济失调（SCAs），它提供了理想的神经退行性疾病模型，因为它们的诊断可以在遗传学上得到证实，患者群体具有很好的特征，并且它们提供了忠实地再现人类疾病病理和表型的转基因小鼠模型，使临床前和临床试验之间的发现能够转化。此外，SCAs的各种治疗方法目前正在进入管道，它们在临床试验中的测试可能会从客观替代标记物中受益匪浅。在这方面，最近成立的SCA联盟将提供在临床试验中利用该技术的机会，因为每个参与站点都有高场扫描仪。最近的研究表明：1)高电场能够从SCA患者和SCA1型（SCA1）转基因小鼠模型中获得小脑神经化学谱，具有良好的可重复性；2) SCA1、SCA2和sc6可以通过神经化学特征来区分；3)在SCA1患者中，MRS生物标志物的改变与疾病严重程度呈横断面相关性，在SCA1小鼠中，与病理呈纵向相关性；4)在抑制转基因表达的条件SCA1小鼠模型中，MRS生物标志物的改变部分或完全逆转。研究建议进一步验证质子MRS （1H MRS）作为临床前和临床试验的结果测量。具体目的是：目的1)确定是否可以通过1H MRS通过测量5年以上早期-中度SCA1患者的小脑和脑干神经化学谱来监测疾病进展。目的2)确定反映SCA2、SCA3和SCA6患者疾病严重程度的1H MRS生物标志物，并通过横断面比较SCA1、SCA2、SCA3和SCA6早期中期患者相对于健康对照组的神经化学差异来确定MRS生物标志物是否具有疾病特异性。目的3)通过同时评估条件SCA1小鼠小脑中的神经化学水平、ataxin-1 mRNA水平和病理，确定1H MRS测量的神经化学水平是否准确反映了转基因表达完全和部分抑制后神经退行性变的恢复程度。

DESCRIPTION (provided by applicant): The long-term goal of this project is to establish non-invasive magnetic resonance spectroscopy (MRS) biomarkers that are sensitive to progressive neurodegeneration and its reversal. To accomplish this with high sensitivity and specificity, high field scanners (3 tesla and higher) are utilized. The focus of the application in this first cycle is hereditary spinocerebellar ataxias (SCAs), which provide the ideal neurodegenerative disease model because their diagnoses can be genetically confirmed, the patient populations are well characterized and they offer transgenic mouse models that faithfully reproduce the pathology and phenotype of the human disease enabling translation of findings between pre-clinical and clinical trials. Furthermore, various treatments are currently entering the pipeline for SCAs and their testing in clinical trials may benefit immensely from objective surrogate markers. In this respect, a recently established SCA Consortium will provide the opportunity to utilize the technology in clinical trials because high field scanners are available at each participating site. Recent work demonstrated that 1) high fields enable acquisition of cerebellar neurochemical profiles from patients with SCAs and transgenic mouse models of SCA type 1 (SCA1) with excellent reproducibility; 2) SCA1, SCA2 and SCA6 can be distinguished by neurochemical signatures; 3) alterations in MRS biomarkers correlate cross-sectionally with disease severity in patients with SCA1 and longitudinally with pathology in SCA1 mice and 4) alterations in MRS biomarkers are partially-to-completely reversed in a conditional SCA1 mouse model upon suppression of transgene expression. Studies are proposed to further validate proton MRS (1H MRS) as an outcome measure in pre-clinical and clinical trials. The specific aims are: Aim # 1) To determine if disease progression can be monitored by 1H MRS by measuring cerebellar and brainstem neurochemical profiles longitudinally over 5 years in early- moderate stage patients with SCA1. Aim # 2) To identify the 1H MRS biomarkers that reflect disease severity in patients with SCA2, SCA3 and SCA6 and to determine if MRS biomarkers are disease specific by a cross- sectional comparison of neurochemical differences in early-moderate stage patients with SCA1, SCA2, SCA3 and SCA6 relative to healthy controls. Aim # 3) To determine if neurochemical levels measured by 1H MRS accurately reflect the extent of recovery from neurodegeneration following complete and partial suppression of transgene expression by evaluating neurochemical levels, mRNA levels of ataxin-1 and pathology simultaneously in the cerebella of conditional SCA1 mice. PUBLIC HEALTH RELEVANCE: This work intends to establish non-invasive, quantitative imaging measures of biochemical and cellular alterations in neurodegenerative diseases. Such measures can eventually be used in the clinic for early disease detection, which will facilitate application of treatments to delay the onset of these diseases, and for monitoring disease progression and treatment response. Successful application of such treatments is expected to reduce the burden caused by these diseases on individuals, their families and society.