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Aims Frontotemporal lobar degeneration ( FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP-43 negative but immunoreactive for p62 and dipeptide repeat proteins ( DPR), these being generated by a non- ATG RAN translation of the expanded region of the gene. Methods Twenty-two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP-43, p62 and DPR. The extent of TDP-43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease. Results Three Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP-43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP-43 pathology was significantly less. Conclusion Widespread accumulation of DPR within nerve cells may occur much earlier than that of TDP-43 in patients with FTLD bearing expansion in C9ORF72. [ABSTRACT FROM AUTHOR]

Introduction Frontotemporal lobar degeneration ( FTLD) is classified mainly into FTLD-tau and FTLD- TDP according to the protein present within inclusion bodies. While such a classification implies only a single type of protein should be present, recent studies have demonstrated dual tau and TDP-43 proteinopathy can occur, particularly in inherited FTLD. Methods We therefore investigated 33 patients with FTLD-tau (including 9 with MAPT mutation) for TDP-43 pathological changes, and 45 patients with FTLD- TDP (including 12 with hexanucleotide expansion in C9ORF72 and 12 with GRN mutation), and 23 patients with motor neurone disease (3 with hexanucleotide expansion in C9ORF72), for tauopathy. Results TDP-43 pathological changes, of the kind seen in many elderly individuals with Alzheimer's disease, were seen in only two FTLD-tau cases - a 70-year-old male with exon 10 + 13 mutation in MAPT, and a 73-year-old female with corticobasal degeneration. Such changes were considered to be secondary and probably reflective of advanced age. Conversely, there was generally only scant tau pathology, usually only within hippocampus and/or entorhinal cortex, in most patients with FTLD- TDP or MND. The extent of tau pathology in FTLD- TDP and MND, as with amyloid β protein, may relate to increased age and possession of Apolipoprotein ε4 allele. Conclusion We find no predilection or predisposition towards an accompanying TDP-43 pathology in patients with FTLD-tau, irrespective of presence or absence of MAPT mutation, or that genetic changes associated with FTLD- TDP predispose towards excessive tauopathy. Where the two processes coexist, this is limited and probably causatively independent of each other. [ABSTRACT FROM AUTHOR]