Journal
ACTA NEUROPATHOLOGICA
Volume 115, Issue 1, Pages 123-131Publisher
SPRINGER
DOI: 10.1007/s00401-007-0315-5
Keywords
TDP-43; frontotemporal dementia; frontotemporal lobar degeneration; motor neuron disease
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Funding
- NHLBI NIH HHS [HL071483] Funding Source: Medline
- NIA NIH HHS [AG10124, AG17586] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T35HL071483] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG017586, P30AG010124] Funding Source: NIH RePORTER
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Recently, TDP-43, a 43 kDa nuclear TAR DNA-binding protein, was identified as the major disease protein in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), FTLD-U with motor neuron disease (FTLD-MND), and amyotrophic lateral sclerosis. To date, TDP-43 pathology in sporadic FTLD-MND has been reported only in select central nervous system areas. However, this distribution of lesions is insufficient to explain all clinical signs of FTLD-MND and the extent of TDP-43 pathology, throughout the brain, remains unknown. Therefore, as a pilot study, we performed an immunohistochemical whole brain scan of two cases diagnosed clinically as FTLD-MND and two control subjects. We found evidence of both neuronal and glial TDP-43 pathology in multiple brain areas including the nigro-striatal system, neo- and allocortical brain areas, with varying frequency, morphology, and degree, and nowhere in control tissue. The finding of a distinct cytopathological profile consisting of a cell nucleus devoid of endogenous TDP-43 staining coupled with diffuse/granular cytoplasmic staining (pre-inclusion) was prominent in a couple of brain areas. These pre-inclusions were not or only weakly ubiquitin-immunoreactive. While the findings of severe involvement of extracortical or extrapyramidal areas are strongly suggestive for FTLD-MND being a TDP-43 multisystem proteinopathy rather than a disease predominantly affecting the cortex and spinal cord, more detailed clinicopathological studies of larger cohorts are needed to fully elucidate the distribution and severity of pathological TDP-43 in this disease.
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