Detection of TDP-43 seeding activity in the olfactory mucosa from patients with frontotemporal dementia

Alzheimers Dement. 2024 Feb;20(2):1156-1165. doi: 10.1002/alz.13541. Epub 2023 Oct 31.

Abstract

Introduction: We assessed TAR DNA-binding protein 43 (TDP-43) seeding activity and aggregates detection in olfactory mucosa of patients with frontotemporal lobar degeneration with TDP-43-immunoreactive pathology (FTLD-TDP) by TDP-43 seeding amplification assay (TDP43-SAA) and immunocytochemical analysis.

Methods: The TDP43-SAA was optimized using frontal cortex samples from 16 post mortem cases with FTLD-TDP, FTLD with tau inclusions, and controls. Subsequently, olfactory mucosa samples were collected from 17 patients with FTLD-TDP, 15 healthy controls, and three patients carrying MAPT variants.

Results: TDP43-SAA discriminated with 100% accuracy post mortem cases presenting or lacking TDP-43 neuropathology. TDP-43 seeding activity was detectable in the olfactory mucosa, and 82.4% of patients with FTLD-TDP tested positive, whereas 86.7% of controls tested negative (P < 0.001). Two out of three patients with MAPT mutations tested negative. In TDP43-SAA positive samples, cytoplasmatic deposits of phosphorylated TDP-43 in the olfactory neural cells were detected.

Discussion: TDP-43 aggregates can be detectable in olfactory mucosa, suggesting that TDP43-SAA might be useful for identifying and monitoring FTLD-TDP in living patients.

Keywords: TAR DNA-binding protein 43; frontotemporal dementia; frontotemporal lobar degeneration; olfactory mucosa; seeding; seeding amplification assays.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Frontal Lobe / metabolism
  • Frontotemporal Dementia* / genetics
  • Frontotemporal Lobar Degeneration* / genetics
  • Frontotemporal Lobar Degeneration* / pathology
  • Humans
  • Neurons / metabolism
  • tau Proteins / genetics
  • tau Proteins / metabolism

Substances

  • tau Proteins
  • DNA-Binding Proteins