TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord
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- 作者：Johannes Brettschneider (2)
Kimihito Arai (6) (7)
Kelly Del Tredici (1)
Jon B. Toledo (2)
John L. Robinson (2)
Edward B. Lee (2)
Satoshi Kuwabara (7)
Kazumoto Shibuya (7)
David J. Irwin (2) (3)
Lubin Fang (1)
Vivianna M. Van Deerlin (2) (3)
Lauren Elman (4)
Leo McCluskey (4)
Albert C. Ludolph (5)
Virginia M.-Y. Lee (2) (3)
Heiko Braak (1)
John Q. Trojanowski (2) (3) - 关键词：Amyotrophic lateral sclerosis ; Neurodegeneration ; Oligodendroglia ; Onuf’s nucleus ; Spinal cord ; TDP ; 43
- 刊名：Acta Neuropathologica
- 出版年：2014
- 出版时间：September 2014
- 年：2014
- 卷：128
- 期：3
- 页码：423-437
- 全文大小：4,096 KB
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Kimihito Arai (6) (7)
Kelly Del Tredici (1)
Jon B. Toledo (2)
John L. Robinson (2)
Edward B. Lee (2)
Satoshi Kuwabara (7)
Kazumoto Shibuya (7)
David J. Irwin (2) (3)
Lubin Fang (1)
Vivianna M. Van Deerlin (2) (3)
Lauren Elman (4)
Leo McCluskey (4)
Albert C. Ludolph (5)
Virginia M.-Y. Lee (2) (3)
Heiko Braak (1)
John Q. Trojanowski (2) (3)
2. Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA, 19104, USA
6. Chiba-East Hospital, Nitona-cho 673, Chuo-ku, Chiba, 260-8712, Japan
7. Department of Neurology, Chiba University School of Medicine, Chiba, Japan
1. Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, 89081, Ulm, Germany
3. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA, 19104, USA
4. Department of Neurology, University of Pennsylvania School of Medicine, 3 W Gates, 3400 Spruce Street, Philadelphia, PA, 19104, USA
5. Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany - ISSN：1432-0533
文摘
We examined the phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) inclusions as well as neuronal loss in full-length spinal cords and five selected regions of the central nervous system from 36 patients with amyotrophic lateral sclerosis (ALS) and 10 age-matched normal controls. The most severe neuronal loss and pTDP-43 lesions were seen in lamina IX motor nuclei columns 4, 6, and 8 of lower cervical segments and in columns 9-1 of lumbosacral segments. Severity of pTDP-43 pathology and neuronal loss correlated closely with gray and white matter oligodendroglial involvement and was linked to onset of disease, with severe involvement of columns 4, 6, and 8 of upper extremity onset cases and severe involvement of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuronal loss were observed in stage 4 cases and sometimes included Onuf’s nucleus. Notably, three cases displayed pTDP-43 aggregates in the midbrain oculomotor nucleus, which we had not seen previously even in cases with advanced (i.e., stage 4) pathology. pTDP-43 aggregates were observed in neurons of Clarke’s column in 30.6?% of cases but rarely in the intermediolateral nucleus (IML). Gray matter oligodendroglial pTDP-43 inclusions were present in areas devoid of neuronal pTDP-43 aggregates and neuronal loss. Taken together, our findings indicate that (1) the dorsolateral motor nuclei columns of the cervical and lumbosacral anterior horn may be the earliest foci of pTDP-43 pathology in the spinal cord, (2) gray matter oligodendroglial involvement is an early event in the ALS disease process that possibly heralds subsequent involvement of neurons by pTDP-43 pathology, and (3) in some very advanced cases, there is oculomotor nucleus involvement, which may constitute an additional neuropathological stage (designated here as stage 5) of pTDP-43 pathology in ALS.