Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis
Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis
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DOI：
10.1001/archneur.65.5.636
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发表时间：
2008-05-01
影响因子：
--
通讯作者：
Trojanowski, John Q.
中科院分区：
文献类型：
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作者：
Geser, Felix;Brandmeir, Nicholas J.;Trojanowski, John Q.
背景：最近，病理性43 - kDa反式激活反应序列DNA结合蛋白（TDP - 43）被确定为肌萎缩侧索硬化症（ALS）以及伴或不伴运动神经元疾病的额颞叶变性伴泛素化包涵体中的主要致病蛋白，但ALS中TDP - 43病理的分布可能比先前描述的更为广泛。
目的：确定临床确诊和尸检确诊为ALS的患者中枢神经系统中TDP - 43病理的程度。
设计：对ALS患者进行免疫组织化学全中枢神经系统扫描，以寻找病理性TDP - 43的证据。
地点：一个学术医疗中心。
参与者：我们纳入了31例临床和病理确诊的ALS患者以及8例对照参与者。
主要观察指标：免疫组织化学和双标记免疫荧光法评估TDP - 43病理的频率和严重程度。
结果：除了上、下运动神经元的典型受累外，ALS患者中枢神经系统的多个区域存在神经元和神经胶质的TDP - 43病理，包括黑质 - 纹状体系统、新皮质和异生皮质区域以及小脑，但在对照组中未发现。
结论：这些发现表明，ALS并非仅选择性影响锥体运动系统，而是一种多系统神经退行性TDP - 43蛋白病。
Background: Pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) has been identified recently as the major disease protein in amyotrophic lateral sclerosis (ALS), and in frontotemporal lobar degeneration with ubiquitinated inclusions, with or without motor neuron disease, but the distribution of TDP-43 pathology in ALS may be more widespread than previously described.Objective: To determine the extent of TDP-43 pathology in the central nervous systems of patients with clinically confirmed and autopsy confirmed diagnoses of ALS.Design: Performance of an immunohistochemical whole central nervous system scan for evidence of pathological TDP-43 in ALS patients.Setting: An academic medical center.Participants: We included 31 patients with clinically and pathologically confirmed ALS and 8 control participants.Main Outcome Measures: Immunohistochemistry and double-labeling immunofluorescence to assess the frequency and severity of TDP-43 pathology.Results: In addition to the stereotypical involvement of upper and lower motor neurons, neuronal and glial TDP-43 pathology was present in multiple areas of the central nervous systems of ALS patients, including in the nigro-striatal system, the neocortical and allocortical areas, and the cerebellum, but not in those of the controls.Conclusions: These findings suggest that ALS does not selectively affect only the pyramidal motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy.