Abstract

TDP-43 was recently identified as the major disease protein in neuronal inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). TDP-43 is not only linked to disease mechanisms in FTLD-U, but it is also the most robust marker for the specific detection of neuronal inclusions in FTLD-U. In this study, we describe additional TDP-43 pathology in the white matter as a characteristic feature in a series of 38 FTLD-U cases including 3 cases with mutations in the progranulin gene. White matter pathology was most abundant in frontal and temporal lobes, but it was also detectable in brainstem and spinal cord. Based on morphology and double-labeling experiments, white matter cells with TDP-43-positive inclusions most likely represent oligodendrocytes. Biochemically, hyperphosphorylated and truncated TDP-43 was detectable in insoluble brain extracts from affected white matter regions in FTLD-U, similar to the biochemical signature observed in FTLD-U gray matter. Taken together, these results expand the spectrum of TDP-43 pathology in FTLD-U, suggesting that white matter pathology might contribute to the neurodegenerative process and clinical symptoms in FTLD-U.