Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration

Abstract

Frontotemporal lobar degeneration (FTLD) is a clinically, genetically and pathologically heterogeneous disorder. Within FTLD with ubiquitin-positive inclusions (FTLD-U), a new pathological subtype named FTLD-FUS was recently found with fused in sarcoma (FUS) positive, TDP-43-negative inclusions, and striking atrophy of the caudate nucleus. The aim of this study was to determine the frequency of FTLD-FUS in our pathological FTLD series, and to describe the clinical, neuroimaging and neuropathological features of FTLD-FUS, especially caudate atrophy. Demographic and clinical data collected prospectively from 387 patients with frontotemporal dementia (FTD) yielded 74 brain specimens. Immunostaining was carried out using a panel of antibodies, including AT-8, ubiquitin, p62, FUS, and TDP-43. Cortical and caudate atrophy on MRI (n = 136) was rated as normal, mild-moderate or severe. Of the 37 FTLD-U cases, 33 were reclassified as FTLD-TDP and four (0.11, 95%: 0.00-0.21) as FTLD-FUS, with ubiquitin and FUS-positive, p62 and TDP-43-negative neuronal intranuclear inclusions (NII). All four FTLD-FUS cases had a negative family history, behavioural variant FTD (bvFTD), and three had an age at onset <or=40 years. MRI revealed mild-moderate or severe caudate atrophy in all, with a mean duration from onset till MRI of 63 months (range 16-119 months). In our total clinical FTD cohort, we found 11 patients (0.03; 95% CI: 0.01-0.05) with bvFTD, negative family history, and age at onset <or=40 years. Caudate atrophy was present in 10 out of 136 MRIs, and included all four FUS-cases. The newly identified FTLD-FUS has a frequency of 11% in FTLD-U, and an estimated frequency of three percent in our clinical FTD cohort. The existence of this pathological subtype can be predicted with reasonable certainty by age at onset <or=40 years, negative family history, bvFTD and caudate atrophy on MRI.

Fig. 1

MRI scans of FTLD-FUS cases. a Patient 1 with severe atrophy (PD-weighted MR image). b Patient 2 with severe atrophy (PD-weighted MR image). c Patient 3 with mild-moderate atrophy (FLAIR MR image). d Patient 4 with severe atrophy (T1-weighted MR image)

Fig. 2

Immunohistochemistry of the FTLD-FUS cases. Ubiquitin-positive neuronal intranuclear inclusions (NII) in the granular cells of the dentate gyrus, which are worm-like (a). Only the ubiquitin-positive neuronal cytoplasmatic inclusions (NCI) stained positive with p62 (b); NII did not. TDP-43-immunohistochemistry stained only normal nuclei, and stained neither ubiquitin-positive NCI nor NII (c). NCI as well as NII stained positive with FUS antibody (d). Scale bar 50 μm