Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-L-deprenyl using whole hemisphere autoradiography
Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-L-deprenyl using whole hemisphere autoradiography
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DOI：
10.1016/j.neuint.2010.10.013
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发表时间：
2011-01-01
影响因子：
4.2
通讯作者：
Halldin, Christer
中科院分区：
文献类型：
--
作者：
Gulyas, Balazs;Pavlova, Elena;Halldin, Christer
在人脑中，单氨基氧化酶-B酶或MAO-B在星形胶质细胞中高度丰富。由于星形胶质细胞活性以及因此MAO-B酶的活性在神经炎症过程中上调，因此丙炔苯丙胺的放射性标记类似物可用作神经炎症和神经变性（包括阿尔茨海默病）中的成像生物标志物。在本研究中，[C-11]-L-丙炔苯丙胺，L-丙炔苯丙胺或司来吉兰（R）的PET放射性配体形式，一种选择性不可逆MAO-B抑制剂，用于人脑切片的全半球放射自显影实验，以测试放射性配体与人脑组织中MAO-B酶的结合，着眼于探索放射性配体作为人类PET研究中分子成像生物标志物的适用性，特别是关于反应性星形胶质细胞增生的诊断检测。检查了从阿尔茨海默病患者和年龄匹配的对照受试者获得的全半球脑切片。在对照组大脑中，[C-11]-L-丙炔苯丙胺的结合在海马、基底神经节、丘脑、黑质、外侧膝状体、丘脑核和室周灰质中最高。在阿尔茨海默氏症的大脑中，颞叶和白色物质中观察到显著更高的结合。此外，在Alzheimer脑中，海马、颞叶和白色物质中的结合与Braak分期呈负相关。在Braak I-II中观察到最高结合，而随着Braak等级的增加而降低。阿尔茨海默氏症大脑中区域结合的增加与激活的星形胶质细胞数量增加的存在相一致，正如相邻脑切片中GFAP的相关免疫组织化学研究所证明的那样。丙炔苯丙胺本身以及MAO-B拮抗剂雷沙吉兰确实有效地阻断了放射性配体的结合，而MAO-A拮抗剂吡吲哚不影响它。对PBR系统具有高亲和力的化合物也不阻断放射性配体的结合，这为[C-11]-L-丙炔苯丙胺对MAO-B酶的特异性提供了证据。总之，目前的观察结果表明，[C-11]-L-丙炔苯丙胺可能是一个有前途的和选择性的成像生物标志物增加MAO-B活性在人脑中，因此可以作为一个前瞻性的PET示踪剂靶向神经炎症和神经变性。(C)2010爱思唯尔有限公司版权所有。
In the human brain the monoaminooxidase-B enzyme or MAO-B is highly abundant in astrocytes. As astrocyte activity and, consequently, the activity of the MAO-B enzyme, is up-regulated in neuroinflammatory processes, radiolabelled analogues of deprenyl may serve as an imaging biomarker in neuroinflammation and neurodegeneration, including Alzheimer's disease. In the present study [C-11]-L-deprenyl, the PET radioligand version of L-deprenyl or selegiline (R), a selective irreversible MAO-B inhibitor was used in whole hemisphere autoradiographic experiments in human brain sections in order to test the radioligand's binding to the MAO-B enzyme in human brain tissue, with an eye on exploring the radioligand's applicability as a molecular imaging biomarker in human PET studies, with special regard to diagnostic detection of reactive astrogliosis. Whole hemisphere brain sections obtained from Alzheimer patients and from age matched control subjects were examined. In control brains the binding of [C-11]-L-deprenyl was the highest in the hippocampus, in the basal ganglia, the thalamus, the substantia nigra, the corpus geniculatum laterale, the nucleus accumbens and the periventricular grey matter. In Alzheimer brains significantly higher binding was observed in the temporal lobes and the white matter. Furthermore, in the Alzheimer brains in the hippocampus, temporal lobe and white matter the binding negatively correlated with Braak stages. The highest binding was observed in Braak I-II, whereas it decreased with increasing Braak grades. The increased regional binding in Alzheimer brains coincided with the presence of an increased number of activated astrocytes, as demonstrated by correlative immunohistochemical studies with GFAP in adjacent brain slices. Deprenyl itself as well as the MAO-B antagonist rasagiline did effectively block the binding of the radioligand, whereas the MAO-A antagonist pirlindole did not affect it. Compounds with high affinity for the PBR system did not block the radioligand binding either, providing evidence for the specificity of [C-11]-L-deprenyl for the MAO-B enzyme. In conclusion, the present observations indicate that [C-11]-L-deprenyl may be a promising and selective imaging biomarker of increased MAO-B activity in the human brain and can therefore serve as a prospective PET tracer targeting neuroinflammation and neurodegeneration. (C) 2010 Elsevier Ltd. All rights reserved.