Magnetic Resonance Spectroscopy Biomarkers of Neurodegeneration

描述（由申请人提供）：本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实现这一点，使用了高场扫描仪（3特斯拉和更高）。第一个周期的应用重点是遗传性脊髓小脑共济失调（SCA），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，患者群体得到了很好的表征，并且它们提供了转基因小鼠模型，这些模型忠实地再现了人类疾病的病理学和表型，从而能够在临床前和临床试验之间转换结果。此外，各种治疗方法目前正在进入SCA的管道，并且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，因为每个参与研究的研究中心都有高场扫描仪。 近年来的研究表明：1）高场强可获得SCA患者和SCA 1型转基因小鼠（SCA 1）的小脑神经化学谱，具有良好的重复性; 2）SCA 1、SCA 2和SCA 6可通过神经化学特征区分; 3）MRS生物标志物的改变与交叉相关。与SCA 1患者的疾病严重程度部分相关，与SCA 1小鼠的病理学纵向相关，以及4）MRS生物标志物的改变部分相关。在条件性SCA 1小鼠模型中，当抑制转基因表达时，其完全逆转。 建议进行研究以进一步验证质子MRS（1H MRS）作为临床前和临床试验中的结局指标。具体目标是：目的#1）通过在5年内纵向测量SCA 1早期-中期患者的小脑和脑干神经化学谱，确定是否可以通过1H MRS监测疾病进展。目的#2）鉴定反映SCA 2、SCA 3和SCA 6患者疾病严重程度的1H MRS生物标志物，并通过SCA 1、SCA 2、SCA 3和SCA 6早期-中度患者相对于健康对照的神经化学差异的横断面比较来确定MRS生物标志物是否是疾病特异性的。目的#3）通过同时评估条件性SCA 1小鼠小脑中的神经化学水平、共济失调蛋白-1的mRNA水平和病理学，确定通过1H MRS测量的神经化学水平是否准确地反映转基因表达完全和部分抑制后神经变性的恢复程度。 公共卫生相关性：这项工作旨在建立非侵入性，定量成像措施的生化和细胞的变化，神经退行性疾病。这些措施最终可用于临床早期疾病检测，这将有助于应用治疗方法来延迟这些疾病的发作，并用于监测疾病进展和治疗反应。成功应用这些治疗方法有望减轻这些疾病对个人、家庭和社会造成的负担。

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.