Cognitive reserve as a modulator of cognitive decline and of behavioral symptoms in patients with amyotrophic lateral sclerosis

Introduction: Amyotrophic lateral sclerosis (ALS) has heterogeneous manifestations ranging from motor neuron degeneration to cognitive and behavioral impairment. This study aims to clarify the interactions between cognition and behavioral symptoms with relevant disease predictors and with cognitive reserve (CR), quantified through education, physical activity, and occupation proxies. Methods: A prospective sample of 162 ALS patients and 61 controls were evaluated with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (dependent variable), a Cognitive Reserve Index questionnaire (CRIq) and demographic data (age and sex), and, for patients, clinical variables: disease duration, site of onset, the ALS Functional Rating Scale (ALSFRS), forced vital capacity (FVC), and gene mutation chromosome 9 open reading frame 72 (C9orf72) (independent variables). Multiple regression and mediation analyses were performed to predict cognitive and behavioral symptoms. Results: For the ALS group, the statistical model explained 38.8% of variance in ECAS total (p < 0.001), 59.4% of executive functions (p < 0.001), and 55% of behavioral symptoms (p < 0.001). For controls, it accounted for 52.8% of variance in ECAS total (p < 0.001). Interaction effects and mediation analysis showed CR is an ECAS total modulator, with a differential effect within groups (p < 0.001). Verbal fluency was the single best cognitive score to differentiate patients from controls (p = 0.004), and the gene mutation C9orf72 was found to be a behavioral symptom’ predictor in patients (p = 0.009). Conclusion: This study supports the proposed concept that CR acts as a cognitive modulator in ALS patients and healthy individuals. Moreover, CR also modulates behavioral manifestations in ALS.

引言：肌萎缩侧索硬化症（Amyotrophic lateral sclerosis, ALS）的临床表现具有异质性，可从运动神经元退变进展至认知与行为功能受损。本研究旨在阐明认知与行为症状与相关疾病预测因子，以及通过教育、体力活动和职业替代指标量化的认知储备（Cognitive Reserve, CR）之间的相互作用。
研究方法：本研究纳入162例ALS患者与61名健康对照者作为前瞻性队列。评估工具包括作为因变量的爱丁堡认知与行为ALS筛查量表（Edinburgh Cognitive and Behavioral ALS Screen, ECAS）、认知储备指数问卷（Cognitive Reserve Index questionnaire, CRIq），以及人口学数据（年龄与性别）；针对患者队列，额外收集临床变量：疾病病程、起病部位、ALS功能评定量表（ALS Functional Rating Scale, ALSFRS）评分、用力肺活量（forced vital capacity, FVC）以及9号染色体开放阅读框72（chromosome 9 open reading frame 72, C9orf72）基因突变情况，以上均作为自变量。本研究采用多元回归与中介分析方法，对认知与行为症状进行预测。
研究结果：针对ALS患者组，统计模型可解释ECAS总分38.8%的变异量（p < 0.001）、执行功能59.4%的变异量（p < 0.001）以及行为症状55%的变异量（p < 0.001）；针对健康对照组，模型可解释ECAS总分52.8%的变异量（p < 0.001）。交互效应与中介分析显示，认知储备是ECAS总分的调节因子，在两组中均存在差异化效应（p < 0.001）。言语流畅性是区分患者与对照者的最佳单项认知评分指标（p = 0.004），而C9orf72基因突变被证实为ALS患者行为症状的预测因子（p = 0.009）。
研究结论：本研究支持此前提出的认知储备可作为ALS患者与健康个体的认知调节因子这一概念。此外，认知储备同样可调控ALS患者的行为症状表现。