Biomarkers for diseases with TDP-43 pathology

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Abstract

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.

Section snippets

Diseases with TDP-43 pathology

The identification of hyper-phosphorylated and ubiquitinated TDP-43 as major component of aggregates forming the neuropathological hallmark of about 50% of FTLD cases and of 97% of ALS cases (Arai et al., 2006; Mackenzie et al., 2007; Maekawa et al., 2009; Neumann et al., 2006) initialized the research for biomarkers enabling for the detection of TDP-43 pathology in vivo, which is a prerequisite for etiology-specific treatment. Until now, there is no biomarker available that reliably indicates

TDP-43 pathology subtypes

Four histopathological subtypes of inclusions can be distinguished in TDP-43 proteinopathies using ubiquitin and TDP-43 antibodies, and recently a fifth subtype was published (Davidson et al., 2007; Lee et al., 2017; Mackenzie et al., 2006; Mackenzie et al., 2011; Sampathu et al., 2006). Types A and B are characterized by neuronal cytoplasmic inclusions (NCIs) located in superficial cortical layers and for type B also in deeper layers. In type A, additionally short dystrophic neurites (DNs)

Need for biomarkers for TDP-43 pathology/focus of review

To date, there is no biomarker available indicative of TDP-43 pathology at patients' lifetime. As the knowledge of the underlying pathology is a prerequisite of etiology-specific treatment, intensive research is going on to either establish methods for the detection of disease-associated TDP-43 or to identify neurochemical and imaging biomarkers reflecting the underlying pathology.

Here, we review the current status of research about biomarkers for TDP-43 proteinopathies with a focus on TDP-43

TDP-43 structure and function

For the first time the TDP-43 was first isolated in 1995 as a novel transcriptional inactivator of the HIV-1 gene expression by binding to the TAR element (Ou et al., 1995). In addition to transcriptional regulation, TDP-43 also plays a role in splicing regulation and mRNA stability (Buratti and Baralle, 2008). The 414 amino acid protein which belongs to the family of heterogeneous ribonuclear proteins has two RNA recognition motifs (RRM) with the preference to bind TG and UG nucleic acids (Kuo

Immuno-based techniques

Frequently used TDP-43 detection methods are antibody-based techniques. A systematic review of existing antibodies and ELISA for TDP-43 was published in 2015 (Goossens et al., 2015). The most commonly used ELISA to quantify TDP-43 in body fluids (Foulds et al., 2008; Foulds et al., 2009; Hosokawa et al., 2014; Kasai et al., 2009; Kuiperij et al., 2010; Noto et al., 2011; Verstraete et al., 2012) includes a monoclonal capture antibody (2E2-D3, Abnova) that targets within amino acids 205–222. For

Plasma and blood-derived cells

Several studies have analyzed TDP-43 in blood, since blood can be rapidly acquired in a minimally invasive manner and therefore is the preferential source for follow-up measurements. Studies that quantified TDP-43 in plasma and blood-derived cells are summarized in Table 1.

In 2008, TDP-43 was measured in plasma of FTD and AD patients for the first time (Foulds et al., 2008). Elevated TDP-43 plasma levels were detected in 46% FTD and 22% AD patients, conforming to the known proportions of TDP-43

TDP-43-unrelated fluid biomarkers

Until today, CSF biomarkers are not included in the diagnostic criteria for ALS or FTLD subgroups. The AD core biomarkers Aβ42, t-tau, and p-tau, can help to differentiate between AD and FTLD-TDP, especially in early disease stage. Furthermore, they might be useful in the differential diagnosis of FTLD subgroups. Beyond, biomarkers of neurodegeneration or neuronal dysfunction, especially neurofilaments, may assist diagnosis and were proposed to figure as biomarkers for severity of the disease

Imaging biomarkers

Structural and functional imaging is used with the aim to describe differences between TDP-43 and other proteinopathies, mostly via correlation with clinical pictures, which obviously constitutes shortcomings of most studies. The cortical atrophy pattern for FTD subtypes is well defined (Lindberg et al., 2009), and a diagnosis of probable FTD requires MRI or positron emission tomography (PET) findings of frontal and/or anterior temporal atrophy or hypometabolism for bvFTD (Rascovsky et al., 2011

Future directions

Improvements in the precision of the description of pathological TDP-43 subtypes in relation to clinical phenotypes have been accompanied in recent times by achievements in the detailed characterization of the molecular properties and the reliable detection of pathological TDP-43. Neurochemical marker profiles as well as imaging modalities are increasingly examined with regard to the correlation to the clinical diagnosis, to disease progression and prognosis. Also the prediction of an

Acknowledgements

This study was supported by the JPND project (Prefontals), the BMBF (FTLD consortium), the EU (Fair-park II), the Baden-Württemberg Foundation, the Thierry Latran Foundation, the ALS Association and the Boehringer Ingelheim Ulm University Bio Center (BIU). For discussion and critical reading we thank Prof M. Schöll (Gothenburg).

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      Hyper-phosphorylated and ubiquitinated TDP-43 is the major component of inclusions found in ALS and some variants of FTLD [134]. The normal function of TDP-43 is to regulate gene transcription in nucleus, whereas the pathological states are marked by the TDP-43 redistribution and aggregate formation in cytoplasmic space [134]. Currently there are no TDP-43 imaging agents available.

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