Acta Neuropathol (2010) 120:33–41 Introduction Frontotemporal lobar degeneration (FTLD) describes a group of diseases characterised by bilateral, often asym- metric, atrophy of the frontal and anterior temporal lobes. Frontotemporal dementia (FTD), also termed behavioural variant FTD (bvFTD), is the most common clinical mani- festation, but FTLD can also cause the language disorders progressive non-ﬂuent aphasia (PNFA) and semantic dementia (SD), collectively known as primary progressive aphasia (PPA). The clinical presentation is related to the distribution of pathology in the frontal and temporal lobes. Despite gross pathological similarities, FTLD comprises a clinically, genetically, and neuropathologically heteroge- neous collection of disorders. A family history of a similar disease has been reported in 25–40% of FTLD cases [6, 44, 50], although this estimate is much lower in some populations [17]. FTLD- causing mutations have been found in the microtubule- associated protein tau (MAPT) [16], progranulin (GRN) [1, 7] and charged multivesicular body protein 2B (CHMP2B) genes [49]. Mutations in valosin-containing protein (VCP) cause inclusion body myopathy and Paget disease of bone with frontotemporal dementia, in which 20–100% of patients can develop FTD [10, 53, 56]. GRN mutations account for approximately 10% of FTLD cases [2, 7–9] and MAPT up to 10% depending on the population studied [15, 41, 48]; while mutations in CHMP2B are a much rarer cause of FTLD, having been reported in one Danish family termed frontotemporal dementia linked to chromosome 3 (FTD-3) [25, 49, 52] and one unrelated Belgian familial FTLD patient [54]. Up to 40% of FTLD cases, including all MAPT mutation cases, have tau pathology [48] (FTLD-tau); while over 50% have neuronal inclusions, which are immunoreactive for ubiquitin in the absence of abnormal tau, a-synuclein, or amyloid deposition [20]. In the majority of tau-negative cases, the major ubiquitinated protein is the TAR DNA- binding protein 43 (TDP-43) [11, 39], and these are designated FTLD-TDP [30]. FTLD-TDP can be further classiﬁed into neuropathological subtypes depending on the distribution, morphology and precise cellular location of inclusions [28, 45]. Recent studies report that 6–20% of tau-negative FTLD cases have ubiquitinated inclusions which are TDP-43 negative [12, 21, 29, 42]. Ubiquitin positive, tau and TDP- 43 negative cases include those with neuronal intermediate ﬁlament- and a-internexin-positive inclusions [5, 19], termed NIFID, and basophilic inclusion body disease (BIBD) [35, 58]. Distinct from these are a subset of FTLD cases termed atypical FTLD-U (aFTLD-U), which do not have intermediate ﬁlament positive or basophilic inclu- sions, but are characterised by unusual curved or twisted 35 neuronal intranuclear ubiquitin positive inclusions, as well as cytoplasmic inclusions [29, 42]. The recent ﬁnding of FUS (fused in sarcoma) protein pathology in aFTLD-U cases [37] and subsequently in NIFID and BIBD cases [34, 38] has led to further reorganisation of FTLD classi- ﬁcation [31]: aFTLD-U, NIFID and BIBD are now considered three distinct subtypes of FTLD-FUS, the col- lective term for FTLD cases with FUS pathology. Cases with ubiquitinated inclusions that are negative for tau, TDP-43 and FUS are termed FTLD-UPS [30]; this includes FTLD cases caused by CHMP2B mutations [13, 14]. FUS pathology was ﬁrst described in familial ALS cases following the discovery of causative mutations in the FUS gene [23, 55]. FUS is a multifunctional DNA- and RNA- binding protein, sharing functional homology with TDP-43 [24]. FUS pathology has also been found in polyglutamine expansion diseases including Huntington’s disease, sug- gesting a broad spectrum of FUS proteinopathies [34, 38, 57]. However, FUS pathology was not found in FTD-3, a major subtype of FTLD-UPS [14]. A minority of cases do not have tau, TDP-43, FUS or ubiquitinated inclusions and these have been termed FTLD with no inclusions (FTLD-ni, previously dementia lacking distinctive histopathology, or DLDH) [30]. Increasingly sensitive immunostaining protocols have led to most FTLD- ni cases being reclassiﬁed [20, 26, 32]; however, a small group remain negative for characterised inclusions despite the use of updated ubiquitin immunohistochemistry. Here, we report, through a major international collabo- ration, the ﬁrst comprehensive collection of the aFTLD-U subtype of FTLD-FUS and describe their clinical and demographic features. Materials and methods Cases A total of 37 cases with ubiquitin-positive but tau- and TDP-43-negative inclusions were evaluated from 12 aca- demic research centres. In each centre, clinical information was acquired from case notes by a neurologist with expertise in neurodegenerative diseases. Standard neuro- logical and cognitive assessments were used to ascertain the presence of behavioural, cognitive and motor abnor- malities. All centres followed consensus clinical criteria for FTLD diagnosis [33, 36], and were asked to supply pre- senting symptoms for each patient and the ﬁnal clinical diagnosis that had been rendered by the evaluating neu- rologist. These data were collated and then reviewed by an expert in FTLD (K.A.J.) to ensure consistency in diagnosis among the different centres. BIBD and NIFID cases were speciﬁcally excluded in order to focus on a speciﬁc subtype 123