Fig. 3. A proposed neuropathological explanation for the found patterns of α-syn distribution.

a In the brain-first subtype, α-syn pathology could initiate in the amygdala (a) and spread retrogradely to the olfactory bulb (OB), explaining a negative finding in both skin biopsy and nasal brushing in the earliest stage of brain-first PD (in our study only one PD patient was allocated to this group; notably the nasal brushing could be a false negative due to pronounced inhibitory effect in this sample). Alternatively, the initial site could be olfactory epithelium. In this case, the absence of α-syn seeding in the nasal brushing would mean a false-negative result. b Presence of α-syn seeding in the nasal brushing but not in the skin corresponds to a brain-first PD before pathology spreads caudally. c, d In the body-first PD, which would include all iRBD patients and a proportion of PD patients, α-syn seeding can be detected in the skin with or without the involvement of olfactory epithelium. The number of PD patients in group C was probably overestimated, as likely more PD patients would have demonstrated α-syn seeding in the nasal brushings if sampled bilaterally. e If the pathology is present in both skin and olfactory epithelium in PD, the initial site of α-syn pathology can no longer be determined. SN substantia nigra, LC locus coeruleus.