Imaging heterogeneous TDP-43 neuropathologies

A diverse range of human neurodegenerative diseases with severe clinical phenotypes are associated with accumulation of the transactive response DNA binding protein 43 kDa (TDP-43).

TDP-43 is an RNA and DNA binding protein, and is associated with a number of cellular functions, including RNA processing, RNA transport, DNA damage repair, synaptic plasticity and organellar homeostasis.The heterogeneity of TDP-43 neuropathologies is a rapidly expanding area of research.

One of the major clinical limitations in understanding and diagnosing TDP-43-related diseases is the lack of suitable PET tracers for imaging TDP-43 accumulation in vivo.

We will address this clinical need by: a) better characterizing the diverse forms of TDP-43 that accumulate in different diseases and b) developing potential PET ligands that discriminate between different forms of TDP-43.Our team has already mastered a number of methodologies that would allow us to succeed in these important goals.

Crucially, we have already identified tool compounds to develop into prospective candidate TDP-43 PET tracers.

These tool compounds will be applied to biochemically and structurally defined forms of TDP-43 and tested for their ability to bind to TDP-43 in model systems and postmortem human brain samples. The best of these agents will be screened in vivo to identify one or more clinical candidates for TDP-43 PET imaging.

Our studies will then culminate with a human TDP-43 PET imaging trial in familial FTLD subjects.