Background Cognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72 repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic factors impact these changes. Methods Participants with MND were recruited through the Phenotype-Genotype-Biomarker study. Every 3–6 months, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was used to assess amyotrophic lateral sclerosis (ALS) specific (executive functioning, verbal fluency, language) and ALS non-specific (memory, visuospatial) functions. Informants reported on behaviour symptoms via semi-structured interview. Results Participants with neuropsychological data at ≥3 visits were included (n=237, mean age=59, 60% male), of which 18 (8%) were C9ORF72 positive. Baseline cognitive impairment was apparent in 18 (8%), typically in ALS specific domains, and associated with lower education, but not C9ORF72 status. Cognition, on average, remained stable over time, with two exceptions: (1) C9ORF72 carriers declined in all ECAS domains, (2) 8%–9% of participants with baseline cognitive impairment further declined, primarily in the ALS non-specific domain, which was associated with less education. Behavioural symptoms were uncommon. Conclusions In this study, cognitive dysfunction was less common than previously reported and remained stable over time for most. However, cognition declines longitudinally in a small subset, which is not entirely related to C9ORF72 status. Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations. Data are available upon reasonable request. Data that supports the findings of this study are available upon reasonable request from the corresponding author (MB).

中文翻译：

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运动神经元疾病认知和行为变化的时间过程

背景 运动神经元疾病 (MND) 患者可能会出现认知和行为功能障碍，一些研究表明与 C9ORF72 重复扩增有关。然而，人们对它们的发生和进展知之甚少。我们探讨了认知和行为如何随时间变化，以及人口、临床和遗传因素是否影响这些变化。方法 通过表型-基因型-生物标志物研究招募 MND 参与者。每 3-6 个月，使用爱丁堡认知和行为 ALS 筛查 (ECAS) 评估肌萎缩侧索硬化症 (ALS) 特异性（执行功能、言语流畅性、语言）和 ALS 非特异性（记忆、视觉空间）功能。线人通过半结构化访谈报告行为症状。结果 纳入≥3 次就诊时具有神经心理学数据的参与者（n=237，平均年龄=59，60% 男性），其中 18 名（8%）C9ORF72 阳性。18 名患者 (8%) 的基线认知障碍很明显，通常发生在 ALS 特定领域，并且与较低教育程度相关，但与 C9ORF72 状态无关。平均而言，认知能力随着时间的推移保持稳定，但有两个例外：(1) C9ORF72 携带者在所有 ECAS 领域均下降，(2) 8%–9% 的基线认知障碍参与者进一步下降，主要是在 ALS 非特定领域，这与教育程度较低有关。行为症状并不常见。结论 在这项研究中，认知功能障碍比之前报道的要少见，并且大多数人的认知功能障碍随着时间的推移保持稳定。然而，一小部分人的认知能力纵向下降，这与 C9ORF72 状态并不完全相关。我们的研究结果对 MND 认知障碍发生的时间提出了疑问，以及它是否出现在早期临床表现疾病期间，甚至出现在运动表现之前。数据可根据合理要求提供。支持本研究结果的数据可根据通讯作者 (MB) 的合理要求提供。