Cykowski Matthew D, Powell Suzanne Z, Peterson Leif E, Appel Joan W, Rivera Andreana L, Takei Hidehiro, Chang Ellen, Appel Stanley H
From the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX (MDC, SZP, ALR, HT); Houston Methodist Neurological Institute, Houston Methodist Hospital, Houston, Texas (SZP, JWA, ALR, HT, SHA); Center for Biostatistics, Houston Methodist Research Institute, Houston, Texas (LP); Stanley H. Appel Department of Neurology, Houston Methodist Hospital, Houston, Texas (JWA, SHA); and Residency Program in the Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California (EC).
J Neuropathol Exp Neurol. 2017 May 1;76(5):402-413. doi: 10.1093/jnen/nlx025.
To determine the significance of TAR DNA binding protein 43 kDa (TDP-43) pathology in amyotrophic lateral sclerosis (ALS), we examined the whole brains and spinal cords of 57 patients (35 men; 22 women; mean age 63.3 years; 15 patients with c9orf72-associated ALS [c9ALS]). TDP-43 pathologic burden was determined relative to symptom onset site, disease duration, progression rate, cognitive status, and c9ALS status. There was a trend for greater TDP-43 pathologic burden in cognitively impaired patients (p = 0.07), though no association with disease duration or progression rate was seen. Shorter disease duration (p = 0.0016), more severe striatal pathology (p = 0.0029), and a trend toward greater whole brain TDP-43 pathology (p = 0.059) were found in c9ALS. Cluster analysis identified "TDP43-limited," "TDP43-moderate," and "TDP43-severe" subgroups. The TDP43-limited group contained more cognitively intact (p = 0.005) and lower extremity onset site (p = 0.019) patients, while other subgroups contained more cognitively impaired patients. We conclude that TDP-43 pathologic burden in ALS is associated with cognitive impairment and c9ALS, but not duration of disease or rate of progression. Further, we demonstrate a subgroup of patients with low TDP-43 burden, lower extremity onset, and intact cognition, which requires further investigation.
为了确定43 kDa的TAR DNA结合蛋白（TDP - 43）病理学在肌萎缩侧索硬化症（ALS）中的意义，我们检查了57例患者（35例男性；22例女性；平均年龄63.3岁；15例与c9orf72相关的ALS [c9ALS]患者）的全脑和脊髓。相对于症状起始部位、疾病持续时间、进展速度、认知状态和c9ALS状态，确定了TDP - 43病理负担。认知受损患者的TDP - 43病理负担有增加趋势（p = 0.07），但未发现与疾病持续时间或进展速度相关。在c9ALS中发现疾病持续时间较短（p = 0.0016）、纹状体病理学更严重（p = 0.0029）以及全脑TDP - 43病理学有增加趋势（p = 0.059）。聚类分析确定了“TDP43 - 局限型”、“TDP43 - 中等型”和“TDP43 - 严重型”亚组。TDP43 - 局限型亚组包含更多认知完整（p = 0.005）和下肢起始部位（p = 0.019）的患者，而其他亚组包含更多认知受损患者。我们得出结论，ALS中的TDP - 43病理负担与认知障碍和c9ALS相关，但与疾病持续时间或进展速度无关。此外，我们证明了存在一个TDP - 43负担低、下肢起始且认知完整的患者亚组，这需要进一步研究。
