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Brockmann, Kathrin; Quadalti, Corinne; Lerche, Stefanie; Rossi, Marcello; Wurster, Isabel; Baiardi, Simone; Roeben, Benjamin; Mammana, Angela; Zimmermann, Milan; Hauser, Ann-Kathrin; Deuschle, Christian; Schulte, Claudia; Waniek, Katharina; Lachmann, Ingolf; Sjödin, Simon; Brinkmalm, Ann; Blennow, Kaj; Zetterberg, Henrik; Gasser, Thomas; Parchi, Piero

Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies

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  • Media type: E-Article
  • Title: Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies
  • Contributor: Brockmann, Kathrin; Quadalti, Corinne; Lerche, Stefanie; Rossi, Marcello; Wurster, Isabel; Baiardi, Simone; Roeben, Benjamin; Mammana, Angela; Zimmermann, Milan; Hauser, Ann-Kathrin; Deuschle, Christian; Schulte, Claudia; Waniek, Katharina; Lachmann, Ingolf; Sjödin, Simon; Brinkmalm, Ann; Blennow, Kaj; Zetterberg, Henrik; Gasser, Thomas; Parchi, Piero
  • imprint: Springer Science and Business Media LLC, 2021
  • Published in: Acta Neuropathologica Communications
  • Language: English
  • DOI: 10.1186/s40478-021-01276-6
  • ISSN: 2051-5960
  • Keywords: Cellular and Molecular Neuroscience ; Neurology (clinical) ; Pathology and Forensic Medicine
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers <jats:italic>in-vivo</jats:italic>. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in <jats:italic>GBA</jats:italic>, <jats:italic>parkin</jats:italic>, <jats:italic>PINK1</jats:italic>, <jats:italic>DJ1,</jats:italic> and <jats:italic>LRRK2</jats:italic>. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe <jats:italic>GBA</jats:italic> mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe <jats:italic>GBA</jats:italic> mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with <jats:italic>GBA</jats:italic> mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.</jats:p><jats:p>These findings highlight the value of α-Syn seeding activity as an <jats:italic>in-vivo</jats:italic> marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.</jats:p>
  • Access State: Open Access