Biomarkers for diseases with TDP-43 pathology

The discovery that aggregated transactive response DNA-binding protein 43 kDa (TDP-43) is the major component of pathological ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) caused seminal progress in the unveiling of the genetic bases and molecular characteristics of these now so-called TDP-43 proteinopathies. Substantial increase in the knowledge of clinic-pathological coherencies, especially for FTLD variants, could be made in the last decade, but also revealed a considerable complexity of TDP-43 pathology and often a poor correlation of clinical and molecular disease characteristics. To date, an underlying TDP-43 pathology can be predicted only for patients with mutations in the genes C9orf72 and GRN, but is dependent on neuropathological verification in patients without family history, which represent the majority of cases. As etiology-specific therapies for neurodegenerative proteinopathies are emerging, methods to forecast TDP-43 pathology at patients' lifetime are highly required. Here, we review the current status of research pursued to identify specific indicators to predict or exclude TDP-43 pathology in the ALS-FTLD spectrum disorders and findings on candidates for prognosis and monitoring of disease progression in TDP-43 proteinopathies with a focus on TDP-43 with its pathological forms, neurochemical and imaging biomarkers.