Kehagia Angie A, Housden Charlotte R, Regenthal Ralf, Barker Roger A, Müller Ulrich, Rowe James, Sahakian Barbara J, Robbins Trevor W
1 Department of Neuroimaging, Institute of Psychiatry, King's College London, London SE5 8AF, UK
2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK3 Cambridge Cognition Limited, Cambridge, UK4 Department of Psychiatry, University of Cambridge, Cambridge, UK.
Brain. 2014 Jul;137(Pt 7):1986-97. doi: 10.1093/brain/awu117. Epub 2014 Jun 3.
Noradrenergic dysfunction may play a significant role in cognition in Parkinson's disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson's disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P = 0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R(2) = 0.23, F(1,16) = 5.83, P = 0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R(2) = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P = 0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson's disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder.
由于蓝斑核的早期退化，去甲肾上腺素能功能障碍可能在帕金森病的认知方面发挥重要作用。来自患者和动物研究的越来越多的证据表明，去甲肾上腺素在帕金森病执行功能障碍综合征的多巴胺不敏感方面发挥作用，但迄今为止，去甲肾上腺素能增强的直接影响尚未得到研究。我们的目的是直接研究这些影响，重点关注反应抑制和决策过程中的冲动性。为此，我们采用双盲、随机、安慰剂对照设计，对25例帕金森病患者（12名女性/13名男性；64.4±6.9岁）给予40毫克托莫西汀，一种选择性去甲肾上腺素再摄取抑制剂。患者完成了一系列广泛的神经心理学测试，涉及反应抑制、决策、注意力、计划和言语短期记忆。托莫西汀提高了停止信号任务的停止准确性[F(1,19)=4.51，P=0.047]，并降低了反射冲动性[F(1,9)=7.86，P=0.02]以及赌博情境下的冒险行为[F(1,9)=9.2，P=0.01]。该药物还根据其测量的血浆浓度对表现产生影响：它降低了信息采样期间的反射冲动性[调整后R(2)=0.23，F(1,16)=5.83，P=0.03]，并改善了剑桥单触长袜测试中的问题解决能力[调整后R(2)=0.29，F(1,17)=8.34，P=0.01]。它还增强了持续注意力期间的目标敏感性[F(1,9)=5.33，P=0.046]。这项探索性研究的结果为未来关于托莫西汀对帕金森病影响的研究中的具体预测奠定了基础，并支持了这样一种假设，即针对去甲肾上腺素能功能障碍可能代表了治疗该疾病中一些认知和行为缺陷的新的平行途径。
