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

Isabel Wurster; Corinne Quadalti; Marcello Rossi; Ann-Kathrin Hauser; Christian Deuschle; Claudia Schulte; Katharina Waniek; Ingolf Lachmann; Christian la Fougere; Kathrin Doppler; Thomas Gasser; Benjamin Bender; Piero Parchi; Kathrin Brockmann

doi:10.1038/s41531-022-00379-8

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

NPJ Parkinsons Dis. 2022 Sep 15;8(1):117. doi: 10.1038/s41531-022-00379-8.

Authors

Isabel Wurster^{1

2}, Corinne Quadalti^{3

4}, Marcello Rossi^{3

4}, Ann-Kathrin Hauser^{1

2}, Christian Deuschle^{1

2}, Claudia Schulte^{1

2}, Katharina Waniek⁵, Ingolf Lachmann⁵, Christian la Fougere⁶, Kathrin Doppler⁷, Thomas Gasser^{1

2}, Benjamin Bender⁸, Piero Parchi^{3

4}, Kathrin Brockmann^{9

10}

Affiliations

¹ Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
² German Center for Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany.
³ IRCCS, Istituto Delle Scienze Neurologiche di Bologna, Bologna, Italy.
⁴ Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
⁵ Roboscreen GmbH, Leipzig, Germany.
⁶ Department of Nuclear Medicine and Clinical Molecular Imaging, University of Tuebingen, Tuebingen, Germany.
⁷ Department of Neurology, University Hospital of Wuerzburg, Wuerzburg, Germany.
⁸ Center of Neuroradiology, University of Tuebingen, Tuebingen, Germany.
⁹ Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. [email protected].
¹⁰ German Center for Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany. [email protected].

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 (Aβ_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 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 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 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.