Soto Isabel, Nejtek Vicki A, Siderovski David P, Salvatore Michael F
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States.
Front Neurosci. 2024 May 16;18:1390215. doi: 10.3389/fnins.2024.1390215. eCollection 2024.
Cognitive decline in Parkinson's disease (PD) is a critical premotor sign that may occur in approximately 40% of PD patients up to 10 years prior to clinical recognition and diagnosis. Delineating the mechanisms and specific behavioral signs of cognitive decline associated with PD prior to motor impairment is a critical unmet need. Rodent PD models that have an impairment in a cognitive phenotype for a time period sufficiently long enough prior to motor decline can be useful to establish viable candidate mechanisms. Arguably, the methods used to evaluate cognitive decline in rodent models should emulate methods used in the assessment of humans to optimize translation. Premotor cognitive decline in human PD can potentially be examined in the genetically altered PINK1 rat model, which exhibits a protracted onset of motor decline in most studies. To increase translation to cognitive assessment in human PD, we used a modified non-water multiple T-maze, which assesses attention, cognitive flexibility, and working memory similarly to the Trail Making Test (TMT) in humans. Similar to the deficiencies revealed in TMT test outcomes in human PD, 4-month-old PINK1 rats made more errors and took longer to complete the maze, despite a hyperkinetic phenotype, compared to wild-type rats. Thus, we have identified a potential methodological tool with cross-species translation to evaluate executive functioning in an established PD rat model.
帕金森病(PD)中的认知衰退是一种关键的运动前体征,在临床识别和诊断前约10年,可能发生在约40%的PD患者中。在运动功能受损之前,明确与PD相关的认知衰退的机制和特定行为体征是一个尚未满足的关键需求。在运动衰退之前,在足够长的时间段内具有认知表型损伤的啮齿动物PD模型,对于建立可行的候选机制可能是有用的。可以说,用于评估啮齿动物模型中认知衰退的方法应该模仿人类评估中使用的方法,以优化转化。在基因改变的PINK1大鼠模型中,可能会检测到人类PD中的运动前认知衰退,在大多数研究中,该模型表现出运动衰退的延迟发作。为了增加对人类PD认知评估的转化,我们使用了一种改良的非水多重T迷宫,它评估注意力、认知灵活性和工作记忆的方式与人类的连线测验(TMT)类似。与人类PD中TMT测试结果显示的缺陷相似,尽管具有运动亢进表型,但4个月大的PINK1大鼠与野生型大鼠相比,犯的错误更多,完成迷宫所需的时间更长。因此,我们已经确定了一种具有跨物种转化潜力的方法学工具,用于评估已建立的PD大鼠模型中的执行功能。