Takeda Takahiro, Iijima Mutsumi, Uchihara Toshiki, Ohashi Takashi, Seilhean Danielle, Duyckaerts Charles, Uchiyama Shinichiro
From the Department of Neurology, Tokyo Women's Medical University (TT, MI, SU); Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science (TT, TU); Department of Neurology, Tokyo Women's Medical University Yachiyo Medical Center, Tokyo, Japan (TO); and Raymond Escourolle Laboratory of Neuropathology, Université Pierre et Marie Curie, Assistance Publique-Hôpitaux de Paris, La Salpêtrière Hospital, Paris, France (TT, DS, CD).
J Neuropathol Exp Neurol. 2015 Jun;74(6):547-56. doi: 10.1097/NEN.0000000000000198.
Odor impairment and its relationship with TAR DNA-binding protein 43 (TDP-43) pathology in patients with amyotrophic lateral sclerosis (ALS) have not been fully elucidated. We performed the odor stick identification test for Japanese (OSIT-J) in 18 ALS patients and in 18 controls. The score was significantly decreased (6.6 ± 2.7) in the patients versus the controls (9.2 ± 2.4) (U = 77.0, p = 0.007). This decrement of the OSIT-J score paralleled the cognitive decline. We then studied samples from a series of 42 postmortem ALS cases. Quantitative analyses demonstrated that TDP-43-positive inclusions were most frequent in the hippocampus and least abundant in the olfactory bulb and were of intermediate density in the primary olfactory cortex. This centrifugal gradient suggests that TDP-43 pathology starts in the hippocampus, spreads into the primary olfactory center, and finally reaches the olfactory bulb. TDP-43, tau, and α-synuclein accumulations appeared to be independent. These observations suggest that impaired odor discrimination in ALS patients may be related to TDP-43-positive lesions affecting predominantly secondary olfactory centers (especially the hippocampus) in contrast to decreased odor sensitivity in Parkinson disease in which α-synuclein pathology mainly involves the peripheral region (i.e., olfactory bulb). We suggest that detectable odor impairments in ALS patients are useful for predicting the presence of TDP-43 pathology in the extramotor system.
肌萎缩侧索硬化症（ALS）患者的嗅觉损害及其与TAR DNA结合蛋白43（TDP - 43）病理学的关系尚未完全阐明。我们对18例ALS患者和18例对照者进行了日语嗅觉棒识别测试（OSIT - J）。患者的得分（6.6±2.7）与对照者（9.2±2.4）相比显著降低（U = 77.0，p = 0.007）。OSIT - J得分的这种下降与认知能力下降平行。然后，我们研究了42例ALS死后病例的样本。定量分析表明，TDP - 43阳性包涵体在海马体中最常见，在嗅球中最少，在初级嗅觉皮层中密度居中。这种离心梯度表明TDP - 43病理学始于海马体，扩散到初级嗅觉中枢，最后到达嗅球。TDP - 43、tau和α - 突触核蛋白的积累似乎是独立的。这些观察结果表明，与帕金森病中α - 突触核蛋白病理学主要累及外周区域（即嗅球）导致嗅觉敏感性降低相反，ALS患者嗅觉辨别受损可能与主要影响次级嗅觉中枢（尤其是海马体）的TDP - 43阳性病变有关。我们认为，ALS患者可检测到的嗅觉损害有助于预测运动外系统中TDP - 43病理学的存在。
