Abstract
Frontotemporal lobar degeneration (FTLD) with TDP-43-immunoreactive inclusions (FTLD–TDP) is a neurodegenerative disease associated with clinical, genetic, and neuropathological heterogeneity. An association between TDP-43, FTLD and amyotrophic lateral sclerosis (ALS) was first described in 2006. However, a century before immunohistochemistry existed, atypical dementias displaying behavioral, language and/or pyramidal symptoms and showing non-specific FTLD with superficial cortical neuronal loss, gliosis and spongiosis were often confused with Alzheimer’s or Pick’s disease. Initially this pathology was termed dementia lacking distinctive histopathology (DLDH), but this was later renamed when ubiquitinated inclusions originally found in ALS were also discovered in (DLDH), thus warranting a recategorization as FTLD-U (ubiquitin). Finally, the ubiquitinated protein was identified as TDP-43, which aggregates in cortical, subcortical, limbic and brainstem neurons and glial cells. The topography and morphology of TDP-43 inclusions associate with specific clinical syndromes and genetic mutations which implies different pathomechanisms that are yet to be discovered; hence, the TDP-43 journey has actually just begun. In this review, we describe how FTLD–TDP was established and defined clinically and neuropathologically throughout the past century.
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Acknowledgements
We are grateful to Ms. Lea Dacy, Department of Neurology, Mayo Clinic, Rochester for her assistance. We also wish to thank the Mayo Clinic Libraries for providing materials for the literature review.
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This study was funded by the National Institutes of Health grants R01 AG037491 and RF1 NS120992.
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AFC performed the literature search and prepared the original draft. KAJ had the idea for the article and critically revised the manuscript.
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Carlos, A.F., Josephs, K.A. Frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43): its journey of more than 100 years. J Neurol 269, 4030–4054 (2022). https://doi.org/10.1007/s00415-022-11073-3
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DOI: https://doi.org/10.1007/s00415-022-11073-3