The many ways to frontotemporal degeneration and beyond

Abstract

Background: Frontotemporal degeneration (FTD) is the most common cause of dementia after Alzheimer's disease. To date, it has been addressed with intensive and intense research.

Objective: To report on the most recent findings in the biology of FTD.

Methods: Review of FTD literature.

Results: FTD presents with many phenotypes that span from prefrontal syndromes to lower motor neuron disease passing through temporal, parietal and extrapyramidal syndromes. FTD includes the frontotemporal lobar atrophies clinically characterised by abnormal behaviour, progressive aphasia or semantic dementia, as well as corticobasal degeneration, progressive supranuclear palsy, progressive subcortical gliosis and FTD with motor neuron disease. The molecular classification of FTD can be traced following the immunocytochemical properties of the material accumulated in neuroectodermic cells. This procedure allows the separation of FTD with tau-positive inclusions from FTD with ubiquitin-positive inclusions, and from FTD with inclusions negative for both. Genetically, seven loci (chromosomes 3p, 9q and 17q24, one locus each; 9p and 17q21, two loci each) and four genes (MAPT, PRGN, VCP, CHMP2B) have been identified. Proteins involved are tau, progranulin, VCP, CHMP2B, Progranulin TDP43, ubiquitin and the intermediate neurofilament system. Neurodegeneration is most likely due to changes in cytoskeletal structure and in ubiquitin-dependent protein degradation activity.