Differential diagnosis of amyotrophic lateral sclerosis from Guillain–Barré syndrome by quantitative determination of TDP-43 in cerebrospinal fluid

Abstract

The aim of this study was to investigate whether an increased level of TAR DNA-binding protein 43 (TDP-43) in the cerebrospinal fluid (CSF) could be a biomarker for amyotrophic lateral sclerosis (ALS) and facilitate differential diagnosis of ALS from peripheral motor neuropathy. TDP-43 is the major constituent of neuronal and glial inclusions that neuropathologically characterize both ALS and tau-negative frontotemporal lobar degeneration. Recent discoveries of various missense mutations in the TDP-43 gene in familial ALS indicate a pivotal role of the aberrant accumulation of TDP-43 in neurodegeneration. Increased TDP-43 in the CSF could be a hallmark of ALS and other TDP-43 proteinopathy. Sandwich enzyme-linked immunosorbent assay (ELISA) was established to measure the concentration of TDP-43 in biological fluids. Culture supernatants of cells transfected with various TDP-43 constructs were used to confirm that the ELISA detected TDP-43. TDP-43 in the culture supernatant of TDP-43 transfected cells was detected by immunoprecipitation with subsequent immunoblotting and concentrations were successfully measured by sandwich ELISA. We then measured TDP-43 concentrations in the CSF of patients with ALS and Guillain–Barré syndrome (GBS). TDP-43 concentrations in CSF were significantly higher in ALS than in GBS (p = 0.016). The sensitivity of the diagnostic test was 71.4% and the specificity was 84.6%. Quantitative determination of TDP-43 concentrations in the CSF by sandwich ELISA is a potential laboratory test for differentiating ALS from peripheral motor neuropathies such as GBS.

KEYWORDS: :

• TDP-43
• cerebrospinal fluid (CSF)
• amyotrophic lateral sclerosis (ALS)
• ELISA
• culture supernatant
• Guillain–Barré syndrome (GBS)

Acknowledgements

The authors would like to thank Ms. Erika Arakawa for technical assistance. They would also like to thank Drs. William Campbell, Catherine Campbell, and Edith G. McGeer for editing of the manuscript.