Soltész Fruzsina, Suckling John, Lawrence Phil, Tait Roger, Ooi Cinly, Bentley Graham, Dodds Chris M, Miller Sam R, Wille David R, Byrne Misha, McHugh Simon M, Bellgrove Mark A, Croft Rodney J, Lu Bai, Bullmore Edward T, Nathan Pradeep J
Clinical Unit Cambridge, GlaxoSmithKline, Cambridge, United Kingdom.
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, United Kingdom.
PLoS One. 2014 Apr 23;9(4):e95558. doi: 10.1371/journal.pone.0095558. eCollection 2014.
Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such "synaptogenic" therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.
越来越多的证据表明，突触功能障碍是神经退行性疾病的核心病理生理特征。脑源性神经营养因子（BDNF）是关键的突触生成分子，通过调节BDNF信号传导来靶向突触修复已被认为是一种潜在的药物发现策略。这种“突触生成”疗法的发展取决于是否有BDNF敏感的突触功能标记物，这些标记物可作为生物标志物，用于检测人体中的靶点参与情况或药物疗效。在此，我们利用BDNF Val66Met基因多态性来研究该多态性和基因负荷（即Met等位基因负荷）对突触活动的电生理（EEG）标记物及其结构（MRI）相关性的影响。60名健康成年人被前瞻性地纳入三个基因组（Val/Val、Val/Met、Met/Met）。作为一项更大规模研究的一部分，受试者还接受了功能磁共振成像（fMRI）、经颅直流电刺激/重复经颅磁刺激（tDCS/TMS）和认知评估。总体而言，一些通过MRI测量的突触活动和脑结构的EEG标记物是该多态性最敏感的标记物。Met携带者在侧翼任务（ERN）期间测量时，在负责错误处理的神经网络中表现出振荡活动和同步性降低；在静息状态下慢波活动增加。没有证据表明Met负荷对EEG测量有影响，并且该多态性对失匹配负波（MMN）和P300没有影响。Met携带者在前扣带回和（左侧）前额叶皮质的灰质体积也减少。此外，前扣带回灰质体积以及侧翼任务期间的EEG振荡功率预测了随后的行为适应性，表明在与错误处理和监测相关的脑结构、功能和行为之间存在BDNF依赖性联系。这些发现表明，诸如ERN和静息EEG等EEG标记物可在早期临床开发中用作BDNF敏感的功能标记物，以检测人体中突触修复疗法的靶点参与情况或药物相关疗效。
