Detection of TDP-43 seeding activity in the olfactory mucosa from patients with frontotemporal dementia
Elena Fontana1, Matilde Bongianni1, Alberto Benussi2,3
1Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
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.
Insights
TAR DNA-binding protein 43 (TDP-43) seeding activity was detected in olfactory mucosa of FTLD-TDP patients using TDP-43 seeding amplification assay. This assay shows promise for diagnosing and monitoring frontotemporal lobar degeneration with TDP-43 pathology in living individuals.
Area of Science:
- Neuroscience
- Neuropathology
- Biomarker Discovery
Background:
- Frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) is a neurodegenerative disease characterized by abnormal TDP-43 protein aggregation.
- Detecting TDP-43 pathology in living patients is challenging, limiting early diagnosis and treatment monitoring.
Purpose of the Study:
- To assess the feasibility of detecting TAR DNA-binding protein 43 (TDP-43) seeding activity and aggregates in the olfactory mucosa of FTLD-TDP patients.
- To evaluate the utility of the TDP-43 seeding amplification assay (TDP43-SAA) for diagnosing FTLD-TDP in olfactory mucosa samples.
Main Methods:
- Optimized TDP43-SAA using post mortem brain samples from FTLD-TDP, tauopathy, and control cases.
- Collected olfactory mucosa samples from FTLD-TDP patients, healthy controls, and patients with MAPT mutations.
- Analyzed samples using TDP43-SAA and immunocytochemistry for phosphorylated TDP-43.
Main Results:
- TDP43-SAA accurately distinguished between cases with and without TDP-43 neuropathology.
- TDP-43 seeding activity was detected in the olfactory mucosa of 82.4% of FTLD-TDP patients, while 86.7% of controls tested negative.
- Cytoplasmic deposits of phosphorylated TDP-43 were observed in olfactory neural cells of TDP43-SAA positive samples.
Conclusions:
- TDP-43 aggregates are detectable in the olfactory mucosa of FTLD-TDP patients.
- TDP43-SAA is a promising tool for identifying and monitoring FTLD-TDP in living individuals through olfactory mucosa analysis.
