Journal Article

DZNE-2021-01335

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson's disease and dementia with Lewy bodies.

Brockmann, K. (First author)DZNE* ; Quadalti, C. ; Lerche, S.DZNE* ; Rossi, M. ; Wurster, I.DZNE* ; Baiardi, S. ; Röben, B.DZNE* ; Mammana, A. ; Zimmermann, M.DZNE* ; Hauser, A.-K.DZNE* ; Deuschle, C.DZNE* ; Schulte, C.DZNE* ; Waniek, K. ; Lachmann, I. ; Sjödin, S. ; Brinkmalm, A. ; Blennow, K. ; Zetterberg, H. ; Gasser, T.DZNE* ; Parchi, P.

2021
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s40478-021-01276-6

Abstract: The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. 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 GBA, parkin, PINK1, DJ1, and LRRK2. 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 GBA 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 GBA 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 GBA 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.These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.

Keyword(s): Biomarkers: cerebrospinal fluid (MeSH) ; Humans (MeSH) ; Lewy Body Disease: cerebrospinal fluid (MeSH) ; Lewy Body Disease: genetics (MeSH) ; Lewy Body Disease: pathology (MeSH) ; Parkinson Disease: cerebrospinal fluid (MeSH) ; Parkinson Disease: genetics (MeSH) ; Parkinson Disease: pathology (MeSH) ; alpha-Synuclein: cerebrospinal fluid (MeSH) ; CSF ; GBA ; PD ; Parkin ; RT-QuIC ; α-Syn seeding

Note: CC BY

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Core ICRU (Core ICRU)
3. Biobanking Facility Tübingen (Biobanking Facility Tübingen)
4. Parkinson's Disease Genetics (AG Berg)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2021

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