Cited by 187Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsAmyloidosis: Diagnosis, Treatment, Outcomes

Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions

Nishihira, Yasushi, Tan, Chun-Feng, Onodera, Osamu, Toyoshima, Yasuko, Yamada, Mitsunori, Morita, Takashi, Nishizawa, Masatoyo, Kakita, Akiyoshi +1 more·2008·Acta Neuropathologica

Abstract

A nuclear protein, 43-kDa TAR DNA-binding protein (TDP-43), was recently identified as a component of the ubiquitinated inclusions (UIs) in frontotemporal lobar degeneration (FTLD-U) and sporadic amyotrophic lateral sclerosis (SALS). In the present study using immunohistochemistry, we examined various regions of the nervous system in a series of 35 SALS cases using a polyclonal antibody against TDP-43. Seven of the 35 cases had disease durations of more than 10 years with artificial respiratory support (ARS; duration: 69-156 months). In all cases, TDP-43-immunoreactive (ir) neuronal and glial cytoplasmic inclusions (NCIs and GCIs) were found together in many regions, including the histologically affected lower motor neuron nuclei. Cluster analysis of the distribution pattern of TDP-43-ir NCIs for cases without ARS (n = 28) identified two types (type 1, n = 16; type 2, n = 12). Type 2 was distinguished from type 1 by the presence of TDP-43-ir NCIs in the frontotemporal cortex, hippocampal formation, neostriatum and substantia nigra, and was significantly associated with dementia. Eleven of the 28 cases showed UIs in the hippocampal dentate granule cells, all of which had type-2 distribution pattern. Cases with ARS (n = 7) were also classified into the same types (type 1, n = 5; type 2, n = 2). Cases having type-1 distribution pattern (n = 21) showed no evident neuronal loss in most of the non-motor neuron nuclei where TDP-43-ir NCIs were present, whereas cases having type-2 distribution pattern (n = 14) often showed evident neuronal loss in the frontotemporal cortices, amygdaloid nuclei and substantia nigra. These findings indicate that SALS is a multisystem degenerative disease widely affecting both neurons and glial cells with a heterogeneous pattern of TDP-43-ir NCI distribution (SALS showing type-2 distribution pattern being closely linked to FTLD-U), and that long-term survival supported by a respirator has no apparent influence on the TDP-43 neuronal distribution pattern.

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Crossref · 10.1007/s00401-008-0385-z

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Authors
Nishihira, Y., Tan, C.-F., Onodera, O., Toyoshima, Y., Yamada, M., Morita, T., Nishizawa, M., Kakita, A., & Takahashi, H.
Affiliations
  • Brain Research Institute, Niigata University (JP)
  • Shinrakuen Hospital (JP)
Corresponding author
Takahashi, Hitoshi
Venue
Acta Neuropathologica
Published
2008-05-15
Volume
116
Issue
2
Pages
169-182
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
OpenAlex
W2009160206
Cited by
187
References
51
Citations by year
2026: 3 · 2025: 6 · 2024: 7 · 2023: 14 · 2022: 12 · 2021: 9 · 2020: 13 · 2019: 14 · 2018: 6 · 2017: 8 · 2016: 9 · 2015: 11 · 2014: 5 · 2013: 12 · 2012: 9
FWCI
10.24
Type
journal article
Language
en
Open access
closed
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
Keywords
amyotrophic lateral sclerosis, TDP-43, neuronal cytoplasmic inclusions, glial cytoplasmic inclusions, ubiquitinated inclusions, frontotemporal lobar degeneration, dementia, lower motor neurons, substantia nigra, disease heterogeneity, neuronal loss
MeSH terms
Amyotrophic Lateral Sclerosis, Brain, Inclusion Bodies, DNA-Binding Proteins, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Neuroglia, Neurons, Respiration, Artificial, Spinal Cord, Cluster Analysis, Ubiquitin, Microscopy, Electron, Transmission

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