Magnetic Resonance Spectroscopy Biomarkers of Neurodegeneration

描述(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)生物标记物。为了实现高灵敏度和高特异度，使用了高场扫描仪(3特斯拉及以上)。第一个周期的应用重点是遗传性脊髓小脑性共济失调(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从基因上得到确认，患者群体特征良好，并且它们提供的转基因小鼠模型能够忠实地再现人类疾病的病理和表型，从而能够在临床前和临床试验之间转换研究结果。此外，各种治疗方法目前正在进入SCA的流水线中，它们在临床试验中的测试可能会从客观的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使用该技术的机会，因为每个参与地点都有高场扫描仪。最近的工作证明，1)高场能够以良好的重复性获得SCA患者和SCA 1型(SCA1)转基因小鼠模型的小脑神经化学图谱；2)可以通过神经化学特征区分SCA1、SCA2和SCA6；3)MRS生物标记物的变化与SCA1患者的疾病严重程度和SCA1小鼠的病理纵向相关；4)在有条件的SCA1小鼠模型中，转基因表达受到抑制后，MRS生物标记物的变化可部分或完全逆转。建议在临床前和临床试验中进一步验证质子磁共振波谱(1HMRS)作为结果衡量标准的有效性。具体目标是：目的1)通过纵向测量早、中期SCA1患者5年来的小脑和脑干神经化学特征，确定1H MRS是否可以监测疾病的进展。目的#2)通过横断面比较早、中期SCA1、SCA2、SCA3和SCA6患者与健康对照组的神经化学差异，确定反映SCA2、SCA3和SCA6患者病情严重程度的1H MRS生物标志物是否具有疾病特异性。目的#3)通过同时评估条件性SCA1小鼠小脑的神经化学水平、ataxin-1的mRNA水平和病理变化，确定1HMRS测量的神经化学水平是否准确地反映了完全和部分抑制转基因表达后神经退行性变的恢复程度。 公共卫生相关性：这项工作旨在建立神经退行性疾病中生化和细胞变化的非侵入性、定量成像测量方法。这些措施最终可以在临床上用于早期发现疾病，这将有助于应用治疗方法来推迟这些疾病的发病，并用于监测疾病的进展和治疗反应。这些治疗的成功应用有望减轻这些疾病对个人、其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.