Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Cognitive Neuroimaging Laboratory, Research Service (151), VA San Diego Healthcare System, San Diego, CA, USA.
Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2021 Nov;28(6):812-828. doi: 10.1080/13825585.2020.1828804. Epub 2020 Oct 6.
Visuospatial working memory (WM) impairments in Parkinson's disease (PD) are more prominent and evolve earlier than verbal WM deficits, suggesting some differences in underlying pathology. WM is regulated by dopaminergic neurotransmission in the prefrontal cortex, but the effect of dopamine on specific processes supporting visuospatial WM are not well understood. Dopamine therapeutic effects on different WM processes may also differ given the heterogeneity of cognitive changes in PD. The present study examined the effect of dopamine therapy on memory load and distraction during visuospatial WM. Exploratory analyses evaluated whether individual differences in medication effects were associated with a gene, catechol-O-methyltransferase (COMT), which regulates prefrontal cortex dopamine levels. Cognitively normal PD participants (n = 28) and controls (n = 25) performed a visuospatial WM task, which manipulated memory load and the presence/absence of distractors. PD participants performed the task and medication. PD COMT groups were comprised of Met homozygote (lower COMT activity) and heterozygote and Val homozygote carriers (higher COMT activity, Het/Val). The results showed that handling higher memory loads and suppressing distraction were impaired in PD , but not medication. Medication improved distraction resistance in Met, but not Het/Val group. COMT did not modulate medication effects on memory load. These findings demonstrate that dopaminergic therapy restores visuospatial WM processes in patients without cognitive impairment and suggest that COMT variants may partly explain the mixed effects of medication on specific processes governed by distinct brain systems. Future investigations into gene-modulated effects of medication could lead to individualized strategies for treating cognitive decline.
帕金森病（PD）患者的视空间工作记忆（WM）损伤比言语 WM 缺陷更为明显且更早出现，提示其潜在病理存在差异。WM 受前额叶皮质多巴胺能神经传递的调节，但多巴胺对支持视空间 WM 的特定过程的影响尚未得到很好的理解。鉴于 PD 患者认知变化的异质性，多巴胺对不同 WM 过程的治疗效果也可能不同。本研究探讨了多巴胺治疗对视空间 WM 记忆负荷和分心的影响。探索性分析评估了药物效应的个体差异是否与一种调节前额叶皮质多巴胺水平的基因，儿茶酚-O-甲基转移酶（COMT）有关。认知正常的 PD 参与者（n=28）和对照组（n=25）完成了一项视空间 WM 任务，该任务可改变记忆负荷和是否存在分心物。PD 参与者在 和 药物作用下完成了该任务。PD COMT 组由 Met 纯合子（较低的 COMT 活性）和杂合子和 Val 纯合子携带者（较高的 COMT 活性，Het/Val）组成。结果表明，PD 患者在处理较高的记忆负荷和抑制分心方面存在障碍，但在 药物作用下则没有。Met 组的药物治疗改善了对分心的抵抗，但在 Het/Val 组则没有。COMT 并未调节药物对记忆负荷的影响。这些发现表明，多巴胺能治疗可以恢复无认知障碍的 PD 患者的视空间 WM 过程，并表明 COMT 变体可能部分解释了药物对特定受不同大脑系统控制的过程的混合影响。对药物基因调节作用的进一步研究可能会导致针对认知衰退的个体化治疗策略。
