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

Abstract Background In recent years, the seed amplification assay (SAA) has enabled the identification of pathological TDP-43 in the cerebrospinal fluid (CSF) and olfactory mucosa (OM) of patients with genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we investigated the seeding activity of TDP-43 in OM samples collected from patients with sporadic ALS. Methods OM samples were collected from patients with (a) sporadic motor neuron diseases (MND), including spinal ALS ( n = 35), bulbar ALS ( n = 18), primary lateral sclerosis ( n = 10), and facial onset sensory and motor neuronopathy ( n = 2); (b) genetic MND, including carriers of C9orf72 exp ( n = 6), TARDBP ( n = 4), SQSTM1 ( n = 3), C9orf72 exp + SQSTM1 ( n = 1), OPTN ( n = 1), GLE1 ( n = 1), FUS ( n = 1) and SOD1 ( n = 4) mutations; (c) other neurodegenerative disorders (OND), including Alzheimer’s disease ( n = 3), dementia with Lewy bodies ( n = 8) and multiple system atrophy ( n = 6); and (d) control subjects ( n = 22). All samples were subjected to SAA analysis for TDP-43 (TDP-43_SAA). Plasmatic levels of TDP-43 and neurofilament-light chain (NfL) were also assessed in a selected number of patients. Results TDP-43_SAA was positive in 29/65 patients with sporadic MND, 9/21 patients with genetic MND, 6/17 OND patients and 3/22 controls. Surprisingly, one presymptomatic individual also tested positive. As expected, OM of genetic non-TDP-43-related MND tested negative. Interestingly, fluorescence values from non-MND samples that tested positive were consistently and significantly lower than those obtained with sporadic and genetic MND. Furthermore, among TDP-43-positive samples, the lag phase observed in MND patients was significantly longer than that in non-MND patients. Plasma TDP-43 levels were significantly higher in sporadic MND patients compared to controls and decreased as the disease progressed. Similarly, plasma NfL levels were higher in both sporadic and genetic MND patients and positively correlated with disease progression rate (ΔFS). No significant correlations were detected between TDP-43_SAA findings and the biological, clinical, or neuropsychological parameters considered. Conclusions The OM of a subset of patients with sporadic MND can trigger seeding activity for TDP-43, as previously observed in genetic MND. Thus, TDP-43_SAA analysis of OM can improve the clinical characterization of ALS across different phenotypes and enhance our understanding of these diseases. Finally, plasma TDP-43 could serve as a potential biomarker for monitoring disease progression. However, further research is needed to confirm and expand these findings.