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Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration

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Abstract

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) can typically be categorized into one of four distinct histopathologic patterns of TDP-43 pathology, types A to D. The strength of this histopathologic classification lies in the association between FTLD-TDP subtypes and various clinical and genetic features of disease. Seven cases of FTLD-TDP were identified here which were difficult to classify based on existing pathologic criteria. Distinct features common to these cases included TDP-43 aggregates over a wide neuroanatomic distribution comprised of granulofilamentous neuronal inclusions, abundant grains, and oligodendroglial inclusions. TDP-43 aggregates were phosphorylated and associated with loss of normal nuclear TDP-43 protein (nuclear clearance) but were negative for ubiquitin. Biochemical analysis confirmed the presence of insoluble and phosphorylated TDP-43 and also revealed a distinct pattern of TDP-43 C-terminal fragments relative to other FTLD-TDP subtypes. Finally, these cases were uniformly associated with a very rapid clinical course culminating in death within ~3 years of disease onset. We suggest that these cases may represent a unique clinicopathologic subtype of FTLD-TDP which we provisionally call “type E.” The immature appearance of TDP-43 aggregates, widespread distribution, uniform biochemical profile and rapid clinical course highlights the clinical and pathologic variability within FTLD-TDP, and raises the possibility that type E neuropathology is the sequelae of a particularly virulent strain of TDP-43 proteinopathy.

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Acknowledgements

EBL is supported by a Clinical Scientist Development Award from the Doris Duke Chartiable Foundation, and by the National Institutes of Health (R01NS095793 and R21NS097749). Additional support for this study includes National Institutes of Health Grants P30AG10124 and P01AG017586. We thank Maia A. Yoshida for her scientific illustration, and our patients and their families who made this research possible. We thank Manuela Neumann and Elisabeth Kremmer for providing the phosphorylation-specific TDP-43 antibody 1D3.

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Correspondence to Edward B. Lee.

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Lee, E.B., Porta, S., Michael Baer, G. et al. Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol 134, 65–78 (2017). https://doi.org/10.1007/s00401-017-1679-9

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