Department of Translational Biomedicine and Neurosciences (DiBraiN), University of Bari Aldo Moro, Bari, Italy.
Neurology Unit, ASL Bari, San Paolo Hospital, Bari, Italy.
J Neurol. 2023 Oct;270(10):4868-4875. doi: 10.1007/s00415-023-11827-7. Epub 2023 Jun 20.
Upper motor neuron (UMN) and lower motor neuron (LMN) involvement represent the core clinical features of amyotrophic lateral sclerosis (ALS). Several studies divided patients into prevalent UMN and LMN impairment phenotypes to investigate the association between motor systems impairments and ALS clinical course. However, this distinction was somehow heterogeneous and significantly affected the comparability across studies.
This study aimed to investigate whether patients spontaneously segregate based on the extent of UMN and LMN involvement without a-priori categorization and to identify potential clinical and prognostic features of different clusters.
Eighty-eight consecutive spinal-onset ALS patients were referred to an ALS tertiary center between 2015 and 2022. UMN and LMN burden was assessed with the Penn Upper Motor Neuron scale (PUMNS) and the Devine score, respectively. PUMNS and LMN scores were normalized into 0-1 and analyzed using a two-step cluster analysis and the Euclidean distance measure. The Bayesian Information Criterion was used to determine the cluster number. Demographic and clinical variables were tested for differences among the clusters.
Three distinct clusters emerged at cluster analysis. Patients in "cluster-1" showed moderate UMN and severe LMN involvement, corresponding to the typical ALS phenotype. Patients in "cluster-2" showed mild LMN and severe UMN damage, corresponding to a predominant UMN phenotype, while "cluster-3" patients showed mild UMN and moderate LMN damage, corresponding to a predominant LMN phenotype. Patients in "cluster-1" and "cluster-2" showed a higher prevalence of definite ALS than those in "cluster-3" (61% and 46 vs 9%, p < 0.001). "Cluster-1" patients had a lower median ALSFRS-r score compared to both "cluster-2" and 3 patients (27 vs 40 and 35, < 0.001). "Cluster-1" (HR: 8.5; 95% CI 2.1-35.1 and p = 0.003) and 3 (HR: 3.2; 95% CI 1.1-9.1; p = 0.03) were associated with shorter survival than those in "cluster-2".
Spinal-onset ALS can be categorized into three groups according to LMN and UMN burden. The UMN burden is related to higher diagnostic certainty and broader disease spread, while LMN involvement is associated with higher disease severity and shorter survival.
上运动神经元（UMN）和下运动神经元（LMN）受累是肌萎缩侧索硬化症（ALS）的核心临床特征。几项研究将患者分为显性 UMN 和 LMN 损伤表型，以研究运动系统损伤与 ALS 临床病程之间的关系。然而，这种区分有些混杂，严重影响了研究间的可比性。
本研究旨在探讨患者是否可以在没有预先分类的情况下，根据 UMN 和 LMN 受累的程度自发分组，并确定不同簇的潜在临床和预后特征。
2015 年至 2022 年间，88 例连续的脊髓起病 ALS 患者被转诊至 ALS 三级中心。UMN 和 LMN 负担分别用 Penn 上运动神经元量表（PUMNS）和 Devine 评分评估。PUMNS 和 LMN 评分归一化为 0-1，并使用两步聚类分析和欧几里得距离测量进行分析。贝叶斯信息准则用于确定聚类数。对不同簇之间的人口统计学和临床变量进行差异检验。
聚类分析产生了三个不同的簇。“簇 1”患者表现为中重度 UMN 和重度 LMN 受累，与典型的 ALS 表型相对应。“簇 2”患者表现为轻度 LMN 和重度 UMN 损伤，与主要 UMN 表型相对应，而“簇 3”患者表现为轻度 UMN 和中度 LMN 损伤，与主要 LMN 表型相对应。“簇 1”和“簇 2”患者的明确 ALS 患病率高于“簇 3”（61%和 46%比 9%，p<0.001）。与“簇 2”和“簇 3”相比，“簇 1”患者的 ALSFRS-r 中位数评分较低（27 分比 40 分和 35 分，均 p<0.001）。“簇 1”（HR：8.5；95%CI 2.1-35.1 和 p=0.003）和 3（HR：3.2；95%CI 1.1-9.1；p=0.03）与生存时间较短相关。
脊髓起病 ALS 可根据 LMN 和 UMN 负担分为三组。UMN 负担与更高的诊断确定性和更广泛的疾病传播有关，而 LMN 受累与更高的疾病严重程度和更短的生存时间有关。
