Abstract
In the search for therapeutic modifiers, frontotemporal dementia (FTD) has traditionally been overshadowed by other conditions such as Alzheimer’s disease (AD). A clinically and pathologically diverse condition, FTD has been galvanized by a number of recent discoveries such as novel genetic variants in familial and sporadic forms of disease and the identification of TAR DNA binding protein of 43 kDa (TDP-43) as the defining constituent of inclusions in more than half of cases. In combination with an ever-expanding knowledge of the function and dysfunction of tau—a protein which is pathologically aggregated in the majority of the remaining cases—there exists a greater understanding of FTD than ever before. These advances may indicate potential approaches for the development of hypothetical therapeutics, but FTD remains highly complex and the roles of tau and TDP-43 in neurodegeneration are still wholly unclear. Here the challenges facing potential therapeutic strategies are discussed, which include sufficiently accurate disease diagnosis and sophisticated technology to deliver effective therapies.
Highlights
Therapeutic and diagnostic challenges for frontotemporal dementiaA clinically and pathologically diverse condition, Frontotemporal dementia (FTD) has been galvanized by a number of recent discoveries such as novel genetic variants in familial and sporadic forms of disease and the identification of TAR DNA binding protein of 43 kDa (TDP-43) as the defining constituent of inclusions in more than half of cases
Frontotemporal dementia (FTD) is the third most common dementia in modern society, rendering it a critical public health issue (Onyike and Diehl-Schmid, 2013)
Tau has long been recognized as the principle component of neurofibrillary tangles (NFTs) in FTD (Joachim et al, 1987) and mutations in the microtubule associated protein tau (MAPT) are responsible for a subset of FTD cases (Hutton et al, 1998; Spillantini et al, 1998; D’Souza et al, 1999), investment in tau therapies has traditionally lagged somewhat due to the focus on proteotoxicity of other aggregated proteins such as amyloid-beta (Aβ) in Alzheimer’s disease (AD; Schneider et al, 2014)
Summary
A clinically and pathologically diverse condition, FTD has been galvanized by a number of recent discoveries such as novel genetic variants in familial and sporadic forms of disease and the identification of TAR DNA binding protein of 43 kDa (TDP-43) as the defining constituent of inclusions in more than half of cases. In combination with an ever-expanding knowledge of the function and dysfunction of tau—a protein which is pathologically aggregated in the majority of the remaining cases—there exists a greater understanding of FTD than ever before. These advances may indicate potential approaches for the development of hypothetical therapeutics, but FTD remains highly complex and the roles of tau and TDP-43 in neurodegeneration are still wholly unclear.
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