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TDP-43 Variants of Frontotemporal Lobar Degeneration

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Abstract

It has been only 5 years since the identification of TDP-43 as the major protein component of the ubiquitinated inclusions in FTLD-U. At that time, there were approximately a dozen papers about TDP-43; today, a “TDP-43” search reveals almost 600 papers. It is now clear that the majority of FTLD cases containing tau- and alpha-synuclein-negative, ubiquitin-positive inclusions (FTLD-U) are FTLD-TDP. The spectrum of TDP-43 proteinopathies includes FTLD-TDP with or without ALS, with or without mutations in GRN, VCP, or TARDBP, with or without chromosome 9p linkage, and sporadic and non-SOD1 familial ALS with or without FTLD-TDP. There are four sub-types of FTLD-TDP, and these correlate with specific clinical and genetic profiles. Sub-types are determined by the presence, predominance, and distribution of the various TDP-43 immunopositive insoluble aggregates—neuronal cytoplasmic inclusions, neuronal intranuclear inclusions, and dystrophic neurites. In this paper, FTLD-TDP pathologic sub-types will be described, and examples of each sub-type will be shown, and implications for future research will be discussed.

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Acknowledgments

We would like to gratefully acknowledge the NU CNADC directed by Dr. M-Marcel Mesulam, the NU Lois Insolia ALS Center directed by Dr. Teepu Siddique, Manjari Mishra, and Katherine Gasho for histological and immunohistochemical expertise, the UT Southwestern ADC for the FTLD-TDP type 4 case, and, most importantly, the generous patients and families without whom these studies would not be possible. This study is supported in part by NIH grant AG13854

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  1. Department of Pathology and Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Eileen H. Bigio

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  1. Eileen H. Bigio
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Correspondence to Eileen H. Bigio.

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This work was presented at the 7th International FTD Conference in Indianapolis, IN, USA on October 6, 2010.

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Bigio, E.H. TDP-43 Variants of Frontotemporal Lobar Degeneration. J Mol Neurosci 45, 390–401 (2011). https://doi.org/10.1007/s12031-011-9545-z

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