22.09.2022
Linking the phenotype of SNCA Triplication with PET-MRI imaging pattern and alpha-synuclein CSF seeding, Wurster et al., 2022
Kurzfassung
In dieser Studie wurde ein Patient mit einem seltenen Gendefekt, der zu Parkinson und damit verbundener Demenz führt, untersucht. Zusätzlich zur standardmäßigen neuroradiologischen Beurteilung der MRT-Bilder des Gehirns wurde mit der Software von AIRAmed eine objektive Analyse des Hirnvolumens des Patienten durchgeführt. Die dadurch ermittelten quantitativen Werte stimmten mit der neuroradiologischen Einschätzung überein und lieferten die Möglichkeit zum Vergleich mit Kontrolldaten von über 8000 gesunden Menschen, was einen neuen Ansatz in der Erforschung von neurodegenerativen Erkrankungen darstellt.
Published in
NPJ Parkinsons Disease
Autoren
I. Wurster, C. Quadalti, M. Rossi, A. Hauser, C. Deuschle, C. Schulte, K. Waniek, I. Lachmann, C. la Fougere, K. Doppler, T. Gasser, B. Bender, P. Parchi, K. Brockmann
Abstract
Lewy-body pathology with aggregation of abnormal conformations of the protein alpha-synuclein (α-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 α-Syn-related profiles in patient-derived biomaterial. We identified a family with a SNCA triplication and assessed the index patient for CSF α-Syn seeding capacity and levels of total α-Syn along with other neurodegenerative CSF markers (Aβ1-42, 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 α-Syn pathology. Additionally, skin biopsies with staining for phospho-α-Syn were done. To assess cerebral glucose metabolism and brain atrophy combined positron emission tomography and magnetic resonance imaging ([18F]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 α-Syn were threefold higher and RT-QuIC showed remarkable α-Syn seeding activity in all kinetic categories in the SNCATriplication 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 α-Syn protein lead to PD and PD dementia and show a striking CSF α-Syn seeding profile, thus substantiating the role of RT-QuIC as a specific in vivo biomarker of α-Syn brain pathology.