Assay Development for the Measurement of Pathological TDP-43

The refinement of biomarkers is a key strategy for elucidating the pathogenesis of neurodegenerative diseases and for developing sensitive measures of disease activity and progression. In addition to their diagnostic value, biomarker assays provide a reliable and sensitive means to test drug efficacy and, ultimately, help determine the best course of action for patients once treatments become available. We hypothesize that the presence of TDP-43-positive inclusions in ALS, FTLD-U and other TDP-43 proteinopathies such as Alzheimer's disease, suggests that TDP-43 levels in cerebrospinal fluid (CSF), and potentially in plasma or serum, may parallel TDP-43 brain pathology. Indeed, TDP-43 can be detected in human plasma [1, 2] and CSF [3, 4] and levels are reportedly elevated in cases of ALS, FTLD and AD [1-4], though wide variations among individuals are observed. Nonetheless, we believe that the sensitivity and usefulness of TDP-43 as a biomarker may be improved by developing Enzyme-Linked Immunosorbent Assays (ELISAs) that detect pathological forms of TDP-43, such as phosphorylated TDP-43 and C-terminal TDP-43 fragments. At present, data on longitudinal levels of TDP-43 in biological fluids of ALS or FTLD-U patients is not available. Thus, we aim to develop sensitive ELISAs for the measurement of phosphorylated and truncated TDP-43 to determine if pathologically modified TDP-43 in CSF, plasma or serum is a suitable surrogate marker of disease activity and progression.

References cites on this page:

  1. Foulds, P., et al., TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer's disease and frontotemporal lobar degeneration. Acta Neuropathol, 2008. 116(2): p. 141-6.
  2. Foulds, P.G., et al., Plasma phosphorylated-TDP-43 protein levels correlate with brain pathology in frontotemporal lobar degeneration. Acta Neuropathol, 2009. 13: p. 13.
  3. Steinacker, P., et al., TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol, 2008. 65(11): p. 1481-7.
  4. Kasai, T., et al., Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathol, 2008. 7: p. 7.