LAUSR

The relatively recently coined terms, frontotemporal dementia (FTD) and frontotemporal lobar degeneration (FTLD), are the result of over a century-long development of the concept of circumscribed cerebral atrophy, in which involvement of the frontal and temporal lobes is associated with a characteristic spectrum of clinical presentations. This process was triggered by the seminal work of the neuropsychiatrist Arnold Pick, who headed a group of neuroscientists in Prague with considerable contributions to research in dementias [1–3]. In 1892, Pick described the unusual case of his patient August H who presented with a progressive speech disorder and who at post-mortem, was confirmed to have severe frontotemporal atrophy [4]. The subsequent documentation of increasing numbers of cases with this type of brain atrophy with or without the classical microscopic features of Pick’s disease, such as the argyrophilic Pick bodies, led to the emergence of an allencompassing concept of Pick’s disease [5]. Such understanding of Pick’s disease, however, was rejected in view of discoveries made in the past two decades, which has highlighted the diversity of the molecular and genetic mechanisms underlying FTDs [6–16]. FTLD is now used as an overarching pathological term for the description of a heterogeneous group of neurodegenerative diseases, which are linked together by a relatively selective involvement of the frontal and/ or temporal lobes. The accumulation of one of two pathologically altered, inclusion-forming proteins is associated with the vast majority of the FTLD cases. The TAR DNA-binding protein 43 (TDP-43) forms inclusions in the largest disease subgroup, FTLD-TDP [13], while the microtubule-binding protein tau is the disease protein in the second largest subgroup, FTLDtau (for a review see [17]). The fused in sarcoma protein (FUS) is implicated only in a small number of cases (FTLD-FUS or FTLD-FET) [18,19]. A remarkable feature of FTLDs is that at least one-third of the cases are familial, showing an autosomal dominant mode of inheritance with the majority of the familial cases being due to a mutation in one of three genes: MAPT, GRN and C9orf72. The characteristic topographical distributions of the pathology determine the clinical repertoire, for which the FTD term is now used. FTDs primarily manifest as one of a number of language disorders (variants of primary progressive aphasia or PPA) or as FTD characterised by altered behaviour (behavioural variant FTD or bvFTD). Some cases also show evidence of motor neurone disease or an atypical parkinsonian disorder. The public health significance of this group of dementias is underpinned by epidemiological data indicating that in the presenile age group with disease onset <65 years, FTDs are the second most common dementias after Alzheimer’s disease. In view of their significance, this year’s special issue of Neuropathology and Applied Neurobiology is entirely dedicated to FTLDs. As the 2015 special issue of this journal dealt with tauopathies, several of which are part of the FTLD-tau spectrum, the articles of the current issue focus on the ‘non-tau’ diseases. Our aim was to provide the reader with a comprehensive, up-to-date overview of several important aspects of this fast-moving field and, accordingly, the five reviews presented in this issue cover a wide range of relevant topics. The first article by Convery, Mead and Rohrer [20], gives an update on the main clinical aspects, genetics and neuroimaging features of FTDs. The two tables summarising the diagnostic criteria of bvFTD and the main clinical features of the PPA syndromes will provide additional help for understanding the diverse clinical presentations by the non-clinician reader of this article. The second review by Neumann and Mackenzie [21] provides most up-to-date information relevant for understanding the complexity of the morphological changes and neuropathological diagnosis of the ‘nontau’ FTLDs. The authors also discuss the molecular classification of FTLDs and highlight the relevant underlying molecular processes. A significant part of this review is dealing with genetic FTLDs, which also discusses in considerable detail the molecular basis of the characteristic p62/ubiquitin-positive, TDP-43-negative inclusions in FTLD-TDP due to C9orf72 mutations. The article dedicates a long section to discussing