Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration.
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.
Seelaar
Harro
H
Department of Neurology, Erasmus MC, University Medical Center Rotterdam, Room Hs 611, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Klijnsma
Kirsten Y
KY
de Koning
Inge
I
van der Lugt
Aad
A
Chiu
Wang Zheng
WZ
Azmani
Asma
A
Rozemuller
Annemieke J M
AJ
van Swieten
John C
JC
D000328:Adult; D017668:Age of Onset; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002421:Caudate Nucleus / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000453:epidemiology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D034702:RNA-Binding Protein FUS / Q000378:metabolism*; D012720:Severity of Illness Index; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism*
D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; D025801:Ubiquitin