Young Christina B, Cholerton Brenna, Smith Alena M, Shahid-Besanti Marian, Abdelnour Carla, Mormino Elizabeth C, Hu Shu-Ching, Chung Kathryn A, Peterson Amie, Rosenthal Liana, Pantelyat Alexander, Dawson Ted M, Quinn Joseph, Zabetian Cyrus P, Montine Thomas J, Poston Kathleen L
From the Departments of Neurology and Neurological Sciences (C.B.Y., A.M.S., M.S.-B., C.A., E.C.M., K.L.P.) and (B.C., T.J.M.), Stanford University School of Medicine, CA; Veterans Affairs Puget Sound Health Care System (B.C., S.-C.H., C.P.Z.), Seattle; Department of Neurology (S.-C.H., C.P.Z.), University of Washington School of Medicine, Seattle; Department of Neurology (K.A.C., A. Peterson, J.Q.), Oregon Health and Science University, Portland; Portland Veterans Affairs Health Care System (K.A.C., A. Peterson, J.Q.), Oregon; Department of Neurology (L.R., A. Pantelyat, T.M.D.), Johns Hopkins University School of Medicine, Baltimore, MD.
Neurology. 2024 Jul 23;103(2):e209609. doi: 10.1212/WNL.0000000000209609. Epub 2024 Jun 13.
Executive functioning is one of the first domains to be impaired in Parkinson disease (PD), and the majority of patients with PD eventually develop dementia. Thus, developing a cognitive endpoint measure specifically assessing executive functioning is critical for PD clinical trials. The objective of this study was to develop a cognitive composite measure that is sensitive to decline in executive functioning for use in PD clinical trials.
We used cross-sectional and longitudinal follow-up data from PD participants enrolled in the PD Cognitive Genetics Consortium, a multicenter setting focused on PD. All PD participants with Trail Making Test, Digit Symbol, Letter-Number Sequencing, Semantic Fluency, and Phonemic Fluency neuropsychological data collected from March 2010 to February 2020 were included. Baseline executive functioning data were used to create the Parkinson's Disease Composite of Executive Functioning (PaCEF) through confirmatory factor analysis. We examined the changes in the PaCEF over time, how well baseline PaCEF predicts time to cognitive progression, and the required sample size estimates for PD clinical trials. PaCEF results were compared with the Montreal Cognitive Assessment (MoCA), individual tests forming the PaCEF, and tests of visuospatial, language, and memory functioning.
A total of 841 participants (251 no cognitive impairment [NCI], 480 mild cognitive impairment [MCI], and 110 dementia) with baseline data were included, of which the mean (SD) age was 67.1 (8.9) years and 270 were women (32%). Five hundred forty five PD participants had longitudinal neuropsychological data spanning 9 years (mean [SD] 4.5 [2.2] years) and were included in analyses examining cognitive decline. A 1-factor model of executive functioning with excellent fit (comparative fit index = 0.993, Tucker-Lewis index = 0.989, and root mean square error of approximation = 0.044) was used to calculate the PaCEF. The average annual change in PaCEF ranged from 0.246 points per year for PD-NCI participants who remained cognitively unimpaired to -0.821 points per year for PD-MCI participants who progressed to dementia. For PD-MCI, baseline PaCEF, but not baseline MoCA, significantly predicted time to dementia. Sample size estimates were 69%-73% smaller for PD-NCI trials and 16%-19% smaller for PD-MCI trials when using the PaCEF rather than MoCA as the endpoint.
The PaCEF is a sensitive measure of executive functioning decline in PD and will be especially beneficial for PD clinical trials.
执行功能是帕金森病（PD）中最早受损的领域之一，大多数PD患者最终会发展为痴呆。因此，开发一种专门评估执行功能的认知终点指标对于PD临床试验至关重要。本研究的目的是开发一种对执行功能下降敏感的认知综合指标，用于PD临床试验。
我们使用了来自帕金森病认知遗传学联盟（一个专注于PD的多中心研究）的PD参与者的横断面和纵向随访数据。纳入了所有在2010年3月至2020年2月期间收集了连线测验、数字符号、字母数字排序、语义流畅性和音素流畅性神经心理学数据的PD参与者。使用基线执行功能数据通过验证性因子分析创建帕金森病执行功能综合指标（PaCEF）。我们研究了PaCEF随时间的变化、基线PaCEF对认知进展时间的预测能力以及PD临床试验所需的样本量估计。将PaCEF结果与蒙特利尔认知评估量表（MoCA）、构成PaCEF的各个测试以及视觉空间、语言和记忆功能测试进行比较。
共有841名有基线数据的参与者（251名无认知障碍[NCI]、480名轻度认知障碍[MCI]和110名痴呆患者）被纳入，其中平均（标准差）年龄为67.1（8.9）岁，女性270名（32%）。545名PD参与者有长达9年（平均[标准差]4.5[2.2]年）的纵向神经心理学数据，并被纳入认知下降分析。使用执行功能的单因素模型（拟合优度良好，比较拟合指数 = 0.993，塔克 - 刘易斯指数 = 0.989，近似均方根误差 = 0.044）来计算PaCEF。PaCEF的平均年变化范围从认知未受损的PD - NCI参与者每年0.246分，到进展为痴呆的PD - MCI参与者每年 - 0.821分。对于PD - MCI，基线PaCEF而非基线MoCA能显著预测痴呆发生时间。当使用PaCEF而非MoCA作为终点时，PD - NCI试验的样本量估计减少69% - 73%，PD - MCI试验的样本量估计减少16% - 19%。
PaCEF是PD中执行功能下降的敏感指标，对PD临床试验将特别有益。
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