Spectrum of Cognitive Impairment in Korean ALS Patients without Known Genetic Mutations

BackgroundCognitive impairment is associated with a negative prognosis in amyotrophic lateral sclerosis (ALS), as well as with clinical specificity. We investigate neuropsychological function in ALS patients without known genetic mutations in a Korean tertiary clinic.MethodsThree hundred and eighteen patients were enrolled in a prospective longitudinal cohort from September 2008 to February 2012. At the time of diagnosis of sporadic ALS, we carried out genetic and comprehensive neuropsychological tests on all patients, and collected demographic and clinical characteristics. Six cognitive domains, namely executive function, attention, language, calculation, visuospatial function and memory were evaluated. ANOVA and t-tests were used to assess differences in clinical characteristics and neuropsychological parameters between sporadic ALS patients. The Kaplan-Meier method and Cox proportional hazard model were used for survival analysis.ResultsOne hundred and sixty-six patients were categorized into five subtypes: normal cognition (ALS pure), cognitive impairment (ALSci), behavioral impairment (ALSbi), frontotemporal dementia (ALS-FTD), and other types of dementia. Seventy patients (70/166, 42.2%) were cognitively or behaviorally impaired. Among the impaired patients, eight (8/166, 4.8%) had FTD-type dementia and one (1/166, 0.6%) was Alzheimer's disease-type. The ALS patients with cognitive impairment (ALSci) and with FTD (ALS-FTD) were more severely impaired in executive function, attention, language and memory than the cognitively intact ALS patients (ALS pure). In a survival analysis, ALSci (β = 1.925, p = 0.025) and ALS-FTD groups (β = 4.150, p = 0.019) tended to have shorter survival than the ALS pure group.ConclusionsAbout half of ALS patients without known genetic variation have cognitive or behavioral impairment. ALS patients with cognitive abnormalities, especially FTD, have a poorer prognosis than those without cognitive impairment. In neuropsychological profiling, executive tasks were effective in identifying cognitive impairment in the ALS patients. It would be useful for clinicians to classify ALS according to neuropsychological profiles, and screen for subtle cognitive impairment.

背景：认知损害与肌萎缩侧索硬化症（amyotrophic lateral sclerosis, ALS）不良预后及临床表型特异性密切相关。本研究于韩国某三级诊疗中心开展，旨在探究无已知遗传突变的ALS患者的神经心理学功能特征。

方法：本研究为前瞻性纵向队列研究，于2008年9月至2012年2月期间纳入318例患者。在确诊散发性ALS时，我们对所有患者开展遗传学检测及全面神经心理学评估，并收集其人口学与临床特征信息。本研究评估了6项认知领域：执行功能、注意力、语言功能、计算能力、视空间功能及记忆功能。采用方差分析（analysis of variance, ANOVA）与t检验比较散发性ALS患者的临床特征与神经心理学参数差异；采用卡普兰-迈耶法（Kaplan-Meier）与考克斯比例风险模型（Cox proportional hazard model）进行生存分析。

结果：166例患者被分为5个亚型：认知正常型单纯ALS（ALS pure）、认知损害型ALS（ALSci）、行为损害型ALS（ALSbi）、额颞叶痴呆合并ALS（ALS-FTD）及其他类型痴呆。其中70例（70/166，42.2%）存在认知或行为损害。在损害人群中，8例（8/166，4.8%）为额颞叶痴呆（frontotemporal dementia, FTD）型，1例（1/166，0.6%）为阿尔茨海默病型。与认知正常的单纯ALS患者相比，认知损害型ALS（ALSci）及ALS-FTD患者的执行功能、注意力、语言功能及记忆损害程度更为严重。生存分析结果显示，认知损害型ALS组（β=1.925，P=0.025）与ALS-FTD组（β=4.150，P=0.019）的生存时长均短于认知正常型单纯ALS组。

结论：约半数无已知遗传变异的ALS患者存在认知或行为损害。伴认知异常的ALS患者（尤其是合并额颞叶痴呆者）预后较认知正常者更差。神经心理学评估中，执行功能任务可有效识别ALS患者的认知损害。临床医师可依据神经心理学表型对ALS进行分型，并筛查潜在的认知损害。