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, mildmoderate 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 ≤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 ≤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 ≤40 years, negative family history, bvFTD and caudate atrophy on MRI.

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Keywords FUS, Frontotemporal lobar degeneration (FTLD), TAR DNA binding protein, TDP-43, Ubiquitin, adult, article, brain atrophy, caudate nucleus, clinical article, dementia, female, frontotemporal, fused in sarcoma, human, immunohistochemistry, male, neuroimaging, neurologic examination, nuclear magnetic resonance imaging, onset age, p62, priority journal, protein p62, sarcoma, ubiquitin
Persistent URL dx.doi.org/10.1007/s00415-009-5404-z, hdl.handle.net/1765/20736
Citation
Seelaar, H, Klijnsma, K.Y, de Koning, I, van der Lugt, A, Chiu, W.Z, Azmani, A, … van Swieten, J.C. (2010). Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration. Journal of Neurology: official journal of the European Neurological Society, 257(5), 747–753. doi:10.1007/s00415-009-5404-z