DETECTION OF α- SYNUCLEIN AND TDP-43 IN THE SKIN AND OLFACTORY MUCOSA OF A PATIENT WITH IDIOPATHIC PARKINSON’S DISEASE CARRYING THE Thr272fs GRN MUTATION

Objectives: Seed amplification assays (SAA) for TDP-43 (TDP-43_SAA) has recently been used to detect misfolded TDP-43 in olfactory mucosa (OM) and CSF of patients with genetic FTD, including carriers of GRN mutations. This assay is also highly sensitive and specific in detecting α-synuclein in OM in synucleinopathies (αSyn_SAA). Parkinsonism can be a clinical phenotype of GRN mutations, representing an atypical phenotype at onset or coincident association. Here, we report a patient with idiopathic Parkinson's disease and prodromal FTD, carrying the GRN Thr272Serfs*10 mutation, in whom we suspect the coexistence of mixed α-synuclein and TDP-43 pathology. Materials and Methods: The patient underwent longitudinal clinical and neuropsychological evaluations, MRI, DaTSCAN SPECT and MIBG myocardial scintigraphy before OM and skin collection. OM underwent TDP-43_SAA and αSyn_SAA analyses, while the skin was subjected to immunohistochemical staining to assess the presence of phosphorylated α-synuclein (p-syn) and TDP-43 deposits. Results: At the age of 59, the patient developed right upper limb rigidity, followed by hypomimia, axial rigidity, camptocormia and bradykinesia. DaTSCAN SPECT showed dopaminergic deficit and myocardial MIBG uptake was reduced. The patient was highly responsive to L-dopa therapy and diagnosed with idiopathic PD. He later developed mild behavioral disorders and attentional-executive deficits, consistent with prodromal FTD. As the family history was positive for FTD, a genetic analysis was performed, which revealed a p.T272Serfs*10 mutation in the GRN gene. Both α-synuclein and TDP-43 seeding activities were detected in the OM. In skin samples, p-syn and TDP43 deposits were found in dermal fibroblast and macrophages. Some TDP43+ dermal cells were also in close contact with nerve bundles. Discussion: The positivity of MIBG scintigraphy and the response to L-dopa suggests the presence of synucleinopathy, making an atypical disease onset less probable. Interesting, seeding activity was detected for both TDP-43 and α-synuclein in OM suggesting the potential co-occurrence of a mixed pathology. Findings obtained in skin samples confirmed these data, and more intriguingly, the detection of both TDP-43 and p-syn deposits expressed in dermal cells suggests a peculiar neuropathological pattern. Conclusions: Our results suggest the presence of a coexisting pathology in our patient. These assays could potentially be used in FTD patients with PD phenotype to disclose the nature of the neuropathological process.