How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases.

Repeat expansions in C9orf72 gene are the main genetic cause of frontotemporal dementia, amyotrophic lateral sclerosis and related phenotypes. With the advent of disease-modifying treatments, the presymptomatic disease phase is getting increasing interest as an ideal time window in which innovant therapeutic approaches could be administered. Recommendations issued from international study groups distinguish between a preclinical disease stage, during which lesions accumulate in absence of any symptoms or signs, and a prodromal stage, marked by the appearance the first subtle cognitive, behavioral, psychiatric and motor signs, before the full-blown disease. This paper summarizes the current definitions and criteria for these stages, in particular focusing on how fluid-based, neuroimaging and cognitive biomarkers can be useful to monitor disease trajectory across the presymptomatic phase, as well as to detect the earliest signs of clinical conversion. Continuous advances in the knowledge of C9orf72 pathophysiology, and the integration of biomarkers in the clinical evaluation of mutation carriers will allow a better diagnostic definition of C9orf72 disease spectrum from the earliest stages, with relevant impact on the possibility of disease prevention.

Genetic forms of frontotemporal lobar degeneration: Current diagnostic approach and new directions in therapeutic strategies.

Recent advances in the genetics of neurodegenerative diseases have substantially improved our knowledge about the genetic causes of frontotemporal lobar degeneration (FTLD). Three major genes, namely progranulin (GRN), C9orf72 and MAPT, as well as several less common genes, are responsible for the majority of familial cases and for a significant proportion of sporadic forms, including FTLD with or without associated amyotrophic lateral sclerosis and some rarer clinical presentations. Plasma progranulin dosage and next-generation sequencing are currently available tools which allow the detection of a genetic cause in a more rapid and efficient way. This has important consequences for clinical practice and genetic counseling for patients and families. The ongoing investigations on some therapeutic candidates targeting different biological pathways involved in the most frequent genetic forms of FTLD, as well as a better understanding of the early pathophysiological modifications occurring during the presymptomatic phase of the disease could hopefully contribute to develop effective disease-modifying therapies. The identification of a causal mutation in a family is of outmost importance indeed to propose to presymptomatic carriers their inclusion in clinical trials with the aim to prevent or delay the onset of disease.

Ferritin heavy chain (FHC) is up-regulated in papillomavirus-associated urothelial tumours of the urinary bladder in cattle.

The up-regulation of ferritin heavy chain (FHC) is reported in six papillary and in four invasive urothelial tumours of the urinary bladder of cattle grazing on mountain pastures rich in bracken fern. All tumours contained sequence of bovine papillomavirus type-2 (BPV-2) as determined by polymerase chain reaction (PCR) analyses and validated by direct sequencing of the amplified products. The oncoprotein E5 was also detected in these tumours by immunoprecipitation and by immunofluorescence and laser scanning confocal microscopy. Expression of FHC was evaluated by western blot analysis, reverse transcriptase (RT) PCR, real-time RT-PCR and immunohistochemistry. The oligonucleotide sequence of the bovine ferritin amplicons was identical to that of human ferritin. Nuclear overexpression of p65, an important component of nuclear factor kappaB (NF-kappaB) transcription factors, was also observed. These findings suggest that FHC up-regulation may be mediated by activation of NF-kappaB and that in turn this may be related to the resistance of bovine papillomavirus type-2 (BPV-2) infected urothelial cells to apoptosis.