Williams-Gray Caroline H, Hampshire Adam, Barker Roger A, Owen Adrian M
Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK.
Brain. 2008 Feb;131(Pt 2):397-408. doi: 10.1093/brain/awm313. Epub 2008 Jan 4.
Cognitive deficits occur even in the earliest stages of Parkinson's disease. Some such deficits are known to relate to dysfunction in dopaminergic frontostriatal networks, and may be influenced by a common functional polymorphism (val(158)met) within the catechol O-methyltransferase (COMT) gene. Abnormal attentional shifting behaviour is an important and well-recognized cognitive problem in PD, but nonetheless its precise cognitive and neural basis remains unclear. Here we explored this impairment in an fMRI study employing a recently developed cognitive task designed to fractionate components of attentional control. We investigated the impact of the COMT val(158)met genotype and dopaminergic medication on both patterns of behaviour and associated brain activation in 29 medicated patients with early PD. Genotype had a critical impact on task strategy: whilst patients with high activity COMT genotypes (val/val) adopted a typical approach of preferentially shifting attention within rather than between dimensions, those with low activity genotypes (met/met) failed to adopt such a strategy, suggesting an inability to form an attentional 'set'. Moreover, this behaviour was associated with significant underactivation across the frontoparietal attentional network. Furthermore, we demonstrated an interactive effect of COMT genotype and dopaminergic medication on task performance and BOLD response. Hence we have shown for the first time that attentional control in PD is critically determined by genetic and pharmacological influences on dopaminergic activity in frontoparietal networks. This has important implications for understanding the neurobiological basis of attentional control, and highlights the risk of medication-induced cognitive dysfunction in certain genotypic groups of PD patients, which may ultimately impact on clinical practice.
认知缺陷甚至在帕金森病的最早阶段就会出现。已知一些此类缺陷与多巴胺能额纹状体网络功能障碍有关，并且可能受儿茶酚-O-甲基转移酶（COMT）基因内一种常见的功能多态性（val(158)met）影响。异常的注意力转移行为是帕金森病中一个重要且公认的认知问题，但其确切的认知和神经基础仍不清楚。在此，我们在一项功能磁共振成像（fMRI）研究中探讨了这种损害，该研究采用了一项最近开发的认知任务，旨在区分注意力控制的各个组成部分。我们调查了COMT val(158)met基因型和多巴胺能药物对29例早期帕金森病服药患者的行为模式和相关脑激活的影响。基因型对任务策略有至关重要的影响：具有高活性COMT基因型（val/val）的患者采用了一种典型方法，即优先在维度内而非维度间转移注意力，而具有低活性基因型（met/met）的患者未能采用这种策略，这表明他们无法形成注意力“定势”。此外，这种行为与额顶叶注意力网络的显著激活不足有关。此外，我们证明了COMT基因型和多巴胺能药物对任务表现和血氧水平依赖（BOLD）反应具有交互作用。因此，我们首次表明，帕金森病中的注意力控制关键取决于对额顶叶网络中多巴胺能活动的遗传和药理学影响。这对于理解注意力控制的神经生物学基础具有重要意义，并凸显了某些基因型帕金森病患者中药物诱导的认知功能障碍风险，这可能最终影响临床实践。
