Linking the phenotype of SNCA Triplication with PET-MRI imaging pattern and alpha-synuclein CSF seeding

Lewy-body pathology with aggregation of abnormal conformations of the protein alpha-synuclein (alpha-Syn) represent the histopathological hallmarks of Parkinson's disease (PD). Genetic prototypes such as PD due to mutations in the alpha-synuclein gene (SNCA) offer the opportunity to evaluate alpha-Syn-related profiles in patient-derived biomaterial. We identified a family with a SNCA triplication and assessed the index patient for CSF alpha-Syn seeding capacity and levels of total alpha-Syn along with other neurodegenerative CSF markers (A beta(1-42), total-Tau, phospho-Tau, NFL). As no published CSF data in patients with SNCA triplication are available, we descriptively compared his CSF profiles to those of sporadic PD patients and PD patients with GBA mutations as these are also specifically associated with prominent alpha-Syn pathology. Additionally, skin biopsies with staining for phospho-alpha-Syn were done. To assess cerebral glucose metabolism and brain atrophy combined positron emission tomography and magnetic resonance imaging ([F-18]FDG-PET/MRI) was performed. Age at onset was 24 years and motor impairment was accompanied by prominent non-motor symptoms with early development of dementia, depression, REM sleep behavior disorder, hyposmia, and dysautonomia. Correspondingly, PET-MRI showed hypometabolism and atrophy in frontal, temporoparietal and occipital regions. CSF levels of total alpha-Syn were threefold higher and RT-QuIC showed remarkable alpha-Syn seeding activity in all kinetic categories in the SNCA(Triplication) patient compared to patients with GBA mutations. Our results are consistent with findings that not only mutant forms but also overexpression of the wild-type alpha-Syn protein lead to PD and PD dementia and show a striking CSF alpha-Syn seeding profile, thus substantiating the role of RT-QuIC as a specific in vivo biomarker of alpha-Syn brain pathology.

Automated summary

A family with SNCA triplication was identified, with the patient showing early onset, motor impairment, prominent non-motor symptoms, significantly elevated CSF α-Syn levels, and remarkable alpha-Syn seeding activity. PET-MRI revealed hypometabolism and atrophy in the brain, supporting the association between overexpression of α-Syn and PD.