Alteration of the in vivo nicotinic receptor density in ADNFLE patients:: a PET study
Alteration of the in vivo nicotinic receptor density in ADNFLE patients:: a PET study
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DOI：
10.1093/brain/awl156
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发表时间：
2006-08-01
期刊：
影响因子：
14.5
通讯作者：
Bottlaender, M.
中科院分区：
文献类型：
--
作者：
Picard, F.;Bruel, D.;Bottlaender, M.
烟碱乙酰胆碱受体（nAChR）参与额叶癫痫的家族性形式，常染色体显性夜间额叶癫痫（ADNFLE）。在几个ADNFLE家族中，在nAChR α 4或β 2亚基中鉴定出突变，它们共同构成主要的大脑nAChR。使用体外表达系统的电生理评估表明突变受体的功能获得。然而，它们导致局灶性癫痫发病的确切机制仍然不清楚，特别是因为已知α 4 β 2 nAChR广泛分布在整个大脑中。使用[F-18]-F-A-85380（一种α 4 β 2 nAChR的高亲和力激动剂）进行的PET研究可以确定健康志愿者和ADNFLE患者中nAChR的区域分布和密度，从而为研究分子缺陷的某些体内后果提供了独特的机会。我们使用PET和[F-18]-F-A-85380评估了8名携带nAChR突变的非吸烟ADNFLE患者（来自5个家族）和7名年龄匹配的非吸烟健康志愿者的nAChR分布。分布容积（Vd）的参数图像生成为组织与血浆放射性的比值。这些图像显示，与健康志愿者相比，患者大脑中的nAChR密度模式存在明显差异。ADNFLE患者中脑、脑桥和小脑的Vd值较对照组显著增加（12 ~ 21%，P < 0.05）。然后使用统计参数映射（SPM）来更好地分析细微的区域差异。该分析证实了患者和对照组之间存在明显的区域差异：患者的上丘脑、腹侧中脑和小脑的nAChR密度增加，但右背外侧前额叶区域的nAChR密度降低。在接受额外[F-18]-氟脱氧葡萄糖（FDG）PET实验的5例患者中，在右侧眶额皮质的邻近区域观察到代谢减退。尽管已知这些受体分布在整个大脑皮层，但在前额叶皮层区域nAChR密度降低的证明与涉及额叶的局灶性癫痫一致。我们还建议，中脑nAChR密度增加参与ADNFLE的病理生理通过脑干胆碱能系统的作用，在觉醒。
Nicotinic acetylcholine receptors (nAChRs) are involved in a familial form of frontal lobe epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In several ADNFLE families, mutations were identified in the nAChR alpha 4 or beta 2 subunit, which together compose the main cerebral nAChR. Electrophysiological assessment using in vitro expression systems indicated a gain of function of the mutant receptors. However the precise mechanisms by which they contribute to the pathogenesis of a focal epilepsy remain obscure, especially since alpha 4 beta 2 nAChRs are known to be widely distributed within the entire brain. PET study using [F-18]-F-A-85380, a high affinity agonist at the alpha 4 beta 2 nAChRs, allows the determination of the regional distribution and density of the nAChRs in healthy volunteers and in ADNFLE patients, thus offering a unique opportunity to investigate some in vivo consequences of the molecular defect. We have assessed nAChR distribution in eight non-smoking ADNFLE patients (from five families) bearing an identified mutation in nAChRs and in seven age-matched non-smoking healthy volunteers using PET and [F-18]-F-A-85380. Parametric images of volume of distribution (Vd) were generated as the ratio of tissue to plasma radioactivities. The images showed a clear difference in the pattern of the nAChR density in the brains of the patients compared to the healthy volunteers. Vd values revealed a significant increase (between 12 and 21%, P < 0.05) in the ADNFLE patients in the mesencephalon, the pons and the cerebellum when compared to control subjects. Statistical parametric mapping (SPM) was then used to better analyse subtle regional differences. This analysis confirmed clear regional differences between patients and controls: patients had increased nAChR density in the epithalamus, ventral mesencephalon and cerebellum, but decreased nAChR density in the right dorsolateral prefrontal region. In five patients who underwent an additional [F-18]-fluorodeoxyglucose (FDG) PET experiment, hypometabolism was observed in the neighbouring area of the right orbitofrontal cortex. The demonstration of a regional nAChR density decrease in the prefrontal cortex, despite the known distribution of these receptors throughout the cerebral cortex, is consistent with a focal epilepsy involving the frontal lobe. We also propose that the nAChR density increase in mesencephalon is involved in the pathophysiology of ADNFLE through the role of brainstem ascending cholinergic systems in arousal.