Magnetic Resonance Spectroscopy Biomarkers of Neurodegeneration

磁共振波谱学神经退行性变的生物标志物

基本信息

批准号：
8535224
负责人：
Gulin Oz
金额：
$ 31.28万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8535224
关键词：
Affect Ataxia Biochemical Biological Markers Brain Stem Brain region Cerebellum Choline Clinic Clinical Clinical Research Clinical Trials Creatine Data Detection Diagnosis Disease Disease Progression Disease model Family Functional disorder Future Genetic Glutamates Goals Histology Image Individual Inherited Inositol Investigation LY6E gene Light MJD1 protein Magnetic Resonance Spectroscopy Measurement Measures Messenger RNA Modeling Monitor Motor Movement Disorders Mus Mutation N-acetylaspartate Nerve Degeneration Neurodegenerative Disorders Neurons Onset of illness Outcome Measure Pathology Patients Phenotype Protons Recovery Relative (related person)Reproducibility Research Infrastructure Residual state Resolution Resource Sharing Sensitivity and Specificity Severity of illness Site Societies Specificity Spinocerebellar Ataxias Staging Surrogate Markers Technology Testing Transgenic Mice Transgenic Organisms Translations Type 1 Spinocerebellar Ataxia Work ataxin-1 clinical application human disease innovation magnetic field medical schools mouse model neurochemistry neuron loss patient population pre-clinical progressive neurodegeneration public health relevance response transgene expression treatment effect treatment response

项目摘要

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.

描述（由申请人提供）：该项目的长期目标是建立对渐进神经变性及其逆转敏感的非侵入性磁共振光谱（MRS）生物标志物。为了以高灵敏度和特异性来实现这一目标，使用了高场扫描仪（3特斯拉及更高）。在第一个周期中，应用的重点是遗传性脊髓脑性共济失调（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得到遗传确认，患者人群的特征很好，并且它们提供了转基因小鼠模型，这些模型可忠实地重现人类疾病的病理和表型，从而在人类疾病中进行发现，从而在临床和临床上进行临床试验。此外，目前正在各种治疗方法进入SCA的管道，其在临床试验中的测试可能会受益于客观替代标记。在这方面，最近建立的SCA联盟将为在临床试验中使用该技术提供机会，因为每个参与站点都有高现场扫描仪。最近的工作表明，1）高场能够从SCAS和SCA 1型SCA和转基因小鼠模型（SCA1）的患者中获取小脑神经化学特征，具有出色的可重复性； 2）SCA1，SCA2和SCA6可以通过神经化学特征来区分； 3）生物标志物MRS生物标志物的改变与SCA1患者的疾病严重程度在SCA1小鼠中与病理纵向的疾病严重程度相关，4）MRS生物标志物的改变在有条件的SCA1小鼠模型中，在抑制转基因表达的情况下，在条件SCA1小鼠模型中部分反转。提出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果度量。具体目的是：目标＃1）确定疾病进展是否可以通过1H MRS来监测1H MRS，通过在SCA1的早期阶段患者中测量5年的小脑和脑干神经化学特征。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，并确定MRS生物标志物是否是特定于疾病的疾病。目的＃3）确定通过1H MRS测量的神经化学水平是否准确地反映了通过评估神经化学水平，actaxin-1的mRNA水平和病理学的mRNA水平，同时在条件SCA1小鼠的小脑中同时评估ataxin-1和病理学的mRNA水平，从而准确反映了神经变性的程度。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改变的非侵入性定量成像测量。这些措施最终可以在诊所中用于早期疾病检测，这将有助于治疗以延迟这些疾病的发作，并监测疾病进展和治疗反应。预计成功应用这种治疗将减轻这些疾病对个人，家人和社会的负担。