In vivo monitoring of recovery from neurodegeneration in conditional transgenic SCA1 mice.
In vivo monitoring of recovery from neurodegeneration in conditional transgenic SCA1 mice.
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DOI：
10.1016/j.expneurol.2011.09.021
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发表时间：
2011-12
影响因子：
5.3
通讯作者：
Clark, H. Brent
中科院分区：
文献类型：
--
作者：
Oez, Guelin;Vollmers, Manda L.;Nelson, Christopher D.;Shanley, Ryan;Eberly, Lynn E.;Orr, Harry T.;Clark, H. Brent
神经退行性疾病的临床试验迫切需要可靠、客观的神经元功能和病理标志物，以直接评估脑内神经保护治疗的效果。在这里，我们利用具有良好特征的脊髓小脑共济失调1型（SCA1）条件小鼠模型，评估了高场质子磁共振波谱（1H MRS）监测神经变性逆转的敏感性，其中小脑病理和共济失调表型通过给予多西环素是可逆的。早期组6 - 12周龄的小鼠和中期组12 - 24周龄的小鼠分别喂食含有强力霉素的食物抑制转基因表达。在治疗前后以9.4特斯拉(T)测量治疗和未治疗的条件小鼠的小脑神经化学谱，并与野生型（WT）对照以及组织学测量（原发性裂缝分子层厚度和整体病理严重程度评分）进行比较。治疗小鼠的n -乙酰天冬氨酸（NAA）和肌醇浓度在早期和中期均趋于正常化至WT水平。NAA-to-myo-inositol比值在治疗组和未治疗组的SCA1小鼠之间存在显著差异，并且在早期和中期表现出部分逆转WT值，与组织学测量一致。牛磺酸和总肌酸水平分别在早期和中期治疗组完全正常化。在早期组中，MRS标记物是治疗反应的一种更敏感的测量，而不是来自相同兴趣量的组织学测量。NAA、肌醇和牛磺酸水平与所有组的组织学指标均显著相关。这些数据表明，MRS标志物可靠地检测神经病理的恢复，并暗示MRS测量的神经化学水平准确反映治疗效果。因此，这项研究为验证MRS生物标志物作为潜在的替代标志物来评估SCA1临床前和临床试验中的治疗方法迈出了重要的一步。
Reliable and objective markers of neuronal function and pathology that can directly assess the effects of neuroprotective treatments in the brain are urgently needed for clinical trials in neurodegenerative diseases. Here we assessed the sensitivity of high field proton magnetic resonance spectroscopy (1H MRS) to monitor reversal of neurodegeneration by taking advantage of a well characterized conditional mouse model of spinocerebellar ataxia type 1 (SCA1), where the cerebellar pathology and ataxic phenotype are reversible by doxycycline administration. Transgene expression was suppressed by feeding the mice with chow that contains doxycycline from 6 – 12 weeks of age in an early stage group and from 12 – 24 weeks in a mid-stage group. Cerebellar neurochemical profiles of treated and untreated conditional mice were measured at 9.4 tesla (T) before and after treatment and compared to those of wild type (WT) controls, as well as to histology measures (molecular layer thickness in the primary fissure and a global pathological severity score). Concentrations of N-acetylaspartate (NAA) and myo-inositol in the treated mice trended towards normalization to WT levels in both the early and mid-stage groups. The NAA-to-myo-inositol ratio was significantly different between the treated vs. untreated SCA1 mice and demonstrated partial reversal to WT values both at early and mid-stage, consistent with the histological measures. Taurine and total creatine levels were completely normalized in early and mid-stage treatment groups, respectively. The MRS markers were a more sensitive measure of treatment response than the histological measures from the same volume-of-interest in the early stage group. NAA, myo-inositol and taurine levels were significantly correlated with the histology measures in data combined from all groups. These data demonstrate that MRS markers reliably detect rescue from neuronal pathology and imply that the neurochemical levels measured by MRS accurately reflect treatment efficacy. Therefore this study presents an important step in validating MRS biomarkers as potential surrogate markers to evaluate therapeutics in pre-clinical and clinical trials in SCA1.
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影响因子：
2.2
作者：
Garwood, M;DelaBarre, L
通讯作者：
DelaBarre, L
影响因子：
9.9
作者：
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6.1
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3.3
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Tkac, Ivan
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2.9
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BRAND, A;RICHTERLANDSBERG, C;LEIBFRITZ, D
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