Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification 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 inclusions (FTLD-U), 37 of whom were ascertained in Manchester UK and 23 in Newcastle-Upon-Tyne, UK. There were three distinct histological patterns according 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 intraneuronal 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 histological type 3 (25 patients, 42%), UBQ intraneuronal cytoplasmic 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 influence of histological type on clinical phenotype was highly significant with type 1 histology being associated clinically with cases of frontotemporal dementia (FTD) or progressive non-fluent aphasia (PNFA), type 2 histology with semantic dementia (SD), and type 3 histology with FTD, or FTD and motor neurone disease (MND).

Fig. 1

Type 1 histology: In patient #1 there are numerous, UBQ immunoreactive neurites and intraneuronal cytoplasmic inclusions within layer II of the cerebral cortex (a) though UBQ cytoplasmic inclusions within granule cells of the dentate gyrus were relatively few (b). Neuronal intranuclear inclusions (NII) of a “cat’s eye” or “lentiform” appearance were also seen in pyramidal cells of layer II of cerebral cortex in this patient (c). Only in a single patient (patient #2) was a single NII seen within hippocampus dentate gyrus granule cells (d), and in another patient (patient #3) NII were seen within pyramidal cells in area CA4/5 of hippocampus (e). Immunoperoxidase-haematoxylin, ×20 (a), ×40 (b–e) microscope magnification

Fig. 2

Type 2 histology: In patients #22 and #19, there are numerous UBQ neurites predominantly, or exclusively, present within layer II of the cerebral cortex with few or no intraneuronal cytoplasmic inclusions (a and c, respectively). UBQ cytoplasmic inclusions within granule cells of the dentate gyrus were also numerous in patient #22 (b), but were less common in patient #19 (d) Immunoperoxidase-haematoxylin, ×20 (a, c), ×40 (b, d) microscope magnification

Fig. 3

Type 3 histology: In patient #28 with type 3a histology, UBQ neuronal cytoplasmic inclusions are predominantly, or exclusively, present within the brain with only relatively few UBQ neurites being present (a). UBQ inclusions were also sometimes numerous within granule cells of the dentate gyrus numerous (b). In patient #32 there were few neuronal UBQ cytoplasmic inclusions and neurites within the cerebral cortex (c), though UBQ cytoplasmic inclusions were widespread within granule cells of the hippocampus dentate gyrus (d). Immunoperoxidase-haematoxylin, ×20 (a,c), ×40 (b,d) microscope magnification