TDP-43 seeding activity in the olfactory mucosa of patients with amyotrophic lateral sclerosis

Background Recent advances in the seed amplification assay (SAA) have enabled the detection of pathological TDP-43 in the cerebrospinal fluid and olfactory mucosa (OM) of patients with genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Objective We aimed to investigate the seeding activity of TDP-43 in OM samples from patients with sporadic ALS. Methods OM samples were collected from patients with: (a) sporadic motor neuron diseases (MND) including spinal ALS (sALS, 35), bulbar ALS (bALS, 18), primary lateral sclerosis (PLS, 10), and facial onset sensory and motor neuronopathy (FOSMN, 2); (b) genetic MND (21); (c) other neurodegenerative disorders (OND), including Alzheimer’s disease (AD, 3), dementia with Lewy bodies (DLB, 8), and multiple system atrophy (MSA, 6); and (d) controls (CTRL, 22). All samples were analyzed using SAA for TDP-43 (TDP-43_SAA). Plasmatic levels of TDP-43 and neurofilament-light (NfL) were also assessed in a subset of patients. Results TDP-43_SAA was positive in 29/65 patients with sporadic MND, 9/21 patients with genetic MND, 6/17 OND, and 3/22 controls. Notably, one presymptomatic individual also tested positive. As expected, OM from genetic non-TDP-43-related MND patients were negative. Fluorescence values from TDP-43-positive non-MND samples were significantly lower than those in positive MND samples. Furthermore, the lag phase in positive MND samples was significantly longer than in non-MND. Plasma TDP-43 levels were significantly higher in sporadic MND compared to controls and decreased as disease progressed. Plasma NfL levels were elevated in both sporadic and genetic MND and positively correlated with disease progression. No significant correlations were found between TDP-43_SAA results and clinical, biological, or neuropsychological parameters. Conclusions This study provides proof-of-concept that TDP-43 seeding can be detected in OM samples from sporadic ALS patients, mirroring findings in genetic ALS. While the sensitivity is currently insufficient for diagnostic use, the distinct kinetic pattern observed in ALS cases raises important questions regarding the role of protein misfolding in the disease. Plasma TDP-43 could serve as a potential biomarker for monitoring disease progression. However, further research is needed to confirm and expand these findings.