TSPO-PET imaging using [18F]PBR06 is a potential translatable biomarker for treatment response in Huntington's disease: preclinical evidence with the p75NTR ligand LM11A-31.
TSPO-PET imaging using [18F]PBR06 is a potential translatable biomarker for treatment response in Huntington's disease: preclinical evidence with the p75NTR ligand LM11A-31.
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DOI：
10.1093/hmg/ddy202
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发表时间：
2018-08-15
影响因子：
3.5
通讯作者：
Longo FM
中科院分区：
文献类型：
--
作者：
Simmons DA;James ML;Belichenko NP;Semaan S;Condon C;Kuan J;Shuhendler AJ;Miao Z;Chin FT;Longo FM
亨廷顿氏病（HD）是一种无法治愈的遗传性神经退行性疾病。HD治疗的发展将受益于一种非侵入性可翻译的生物标志物，以跟踪疾病进展和治疗反应。一个潜在的生物标志物是使用正电子发射断层扫描（PET）成像和转运蛋白18 kDa （TSPO）放射性示踪剂来检测小胶质细胞激活，这是HD发病的关键因素。TSPO-PET在HD小鼠模型中识别小胶质细胞激活的能力（对于可翻译的生物标志物或HD患者或小鼠的治疗效果至关重要）尚不清楚。因此，本研究评估了利用PET成像与TSPO示踪剂[18F]PBR06在两种HD小鼠模型中检测活化的小胶质细胞的可行性，并监测对LM11A-31治疗的反应，LM11A-31是一种已知可减少HD小鼠神经炎症的p75NTR配体。[18F]PBR06-PET检测到R6/2小鼠在疾病晚期纹状体、皮质和海马的小胶质细胞活化，值得注意的是，在早期和中期有症状的BACHD小鼠中也是如此。R6/2和BACHD小鼠口服LM11A-31后[18F]， PBR06-PET发现LM11A-31对两种HD小鼠模型的神经炎症均有减轻作用。[18F]PBR06-PET信号的空间分布与离体脑放射自显影相似，与小胶质细胞激活标志物相关：IBA-1和TSPO免疫染色/印迹升高，纹状体细胞因子IL-6和TNFα水平升高。这些结果表明[18F]PBR06-PET是一种有用的HD小鼠治疗效果的替代标记物，具有很高的潜力作为临床前和临床HD试验的可翻译生物标志物。
Huntington’s disease (HD) is an inherited neurodegenerative disorder that has no cure. HD therapeutic development would benefit from a non-invasive translatable biomarker to track disease progression and treatment response. A potential biomarker is using positron emission tomography (PET) imaging with a translocator protein 18 kDa (TSPO) radiotracer to detect microglial activation, a key contributor to HD pathogenesis. The ability of TSPO–PET to identify microglial activation in HD mouse models, essential for a translatable biomarker, or therapeutic efficacy in HD patients or mice is unknown. Thus, this study assessed the feasibility of utilizing PET imaging with the TSPO tracer, [18F]PBR06, to detect activated microglia in two HD mouse models and to monitor response to treatment with LM11A-31, a p75NTR ligand known to reduce neuroinflammation in HD mice. [18F]PBR06-PET detected microglial activation in striatum, cortex and hippocampus of vehicle-treated R6/2 mice at a late disease stage and, notably, also in early and mid-stage symptomatic BACHD mice. After oral administration of LM11A-31 to R6/2 and BACHD mice, [18F]PBR06-PET discerned the reductive effects of LM11A-31 on neuroinflammation in both HD mouse models. [18F]PBR06-PET signal had a spatial distribution similar to ex vivo brain autoradiography and correlated with microglial activation markers: increased IBA-1 and TSPO immunostaining/blotting and striatal levels of cytokines IL-6 and TNFα. These results suggest that [18F]PBR06-PET is a useful surrogate marker of therapeutic efficacy in HD mice with high potential as a translatable biomarker for preclinical and clinical HD trials.
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影响因子：
5.6
作者：
Dupont AC;Largeau B;Santiago Ribeiro MJ;Guilloteau D;Tronel C;Arlicot N
通讯作者：
Arlicot N
影响因子：
16.8
作者：
Crotti A;Glass CK
通讯作者：
Glass CK
影响因子：
7.3
作者：
Briard E;Zoghbi SS;Siméon FG;Imaizumi M;Gourley JP;Shetty HU;Lu S;Fujita M;Innis RB;Pike VW
通讯作者：
Pike VW
影响因子：
2.9
作者：
BOURDIOL, F;TOULMOND, S;SCATTON, B
通讯作者：
SCATTON, B
DOI：
10.1007/s00259-010-1622-y
发表时间：
2011-02
影响因子：
9.1
作者：
Dickstein, Leah P.;Zoghbi, Sami S.;Fujimura, Yota;Imaizumi, Masao;Zhang, Yi;Pike, Victor W.;Innis, Robert B.;Fujita, Masahiro
通讯作者：
Fujita, Masahiro