No 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 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 nonXuent aphasia (PNFA), type 2 histology with semantic dementia (SD), and type 3 histology with FTD, or FTD and motor neurone disease (MND).

We have investigated the extent and pattern of immunostaining for the TAR DNA-binding protein, TDP-43, in 37 patients with frontotemporal lobar degeneration with ubiquitin (UBQ) pathology (FTLD-U). We confirm that TDP-43 protein is a component of the UBQ immunoreactive (UBQ-ir) neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII) and neurites of the cerebral cortex and hippocampus in FTLD-U. We further show that the same three histological patterns, previously identified by us according to the form, number and distribution of the UBQ-ir NCI, NII and neurites are equivalently present in TDP-43 immunohistochemistry. TDP-43 immunoreactive (TDP-43-ir) NCI with rounded, spicular or skein-type appearance were seen in motor neurones of the trigeminal or facial cranial nerve nuclei in one patient with frontotemporal dementia (FTD) and in the spinal cord in three patients with FTD + motor neurone disease (MND). In patients with MND alone, TDP-43-ir NCI are common in anterior horn cells of the spinal cord, and occasionally seen in neurones of the hypoglossus nucleus. We show that TDP-43-ir NCI are also present within neurones in the superior and inferior olives in FTLD-U, and in some patients with MND. Although TDP-43 is normally seen as a nuclear protein, nuclear TDP-ir was not observed in neurones of the cerebral cortex, brainstem and spinal cord in FTLD-U or MND when NCI were present. We conclude that the UBQ-ir lesions of FTLD and MND are defined by the presence of TDP-43, and that these disorders can be subsumed into a single disease entity under the umbrella of TDP-43 proteinopathy.