Acta Neuropathol (2006) 112:539–549 DOI 10.1007/s00401-006-0138-9ORIGINAL PAPER Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classiWcation and relation to clinical phenotype

Abstract We have investigated the extent and pattern of immunostaining for ubiquitin protein (UBQ) in 60 patients with frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclu-sions (FTLD-U), 37 of whom were ascertained in Manchester UK and 23 in Newcastle-Upon-Tyne, UK. There were three distinct histological patterns accord-ing to the form and distribution of the UBQ pathology. Histological type 1 was present in 19 patients (32%) and characterised by the presence of a moderate number, or numerous, UBQ immunoreactive neurites and intran-euronal cytoplasmic inclusions within layer II of the frontal and temporal cerebral cortex, and cytoplasmic inclusions within granule cells of the dentate gyrus; neuronal intranuclear inclusions (NII) of a “cat’s eye” or “lentiform ” appearance were present in 17 of these patients. In histological type 2 (16 patients, 27%), UBQ neurites were predominantly, or exclusively, present with few intraneuronal cytoplasmic inclusions within layer II of the cerebral cortex, while in histologi-cal type 3 (25 patients, 42%), UBQ intraneuronal cyto-plasmic inclusions either within the cortical layer II or in the granule cells of the dentate gyrus, with few or no UBQ neurites, were seen. In neither of these latter two groups were NII present. The inXuence of histological type on clinical phenotype was highly signiWcant with type 1 histology being associated clinically with cases of frontotemporal dementia (FTD) or progressive non-Xuent aphasia (PNFA), type 2 histology with semantic dementia (SD), and type 3 histology with FTD, or FTD and motor neurone disease (MND)