Home > Publications Database > Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson's disease and dementia with Lewy bodies. > print

001     162639
005     20240722121853.0
024 7 _ |a 10.1186/s40478-021-01276-6
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100 1 _ |a Brockmann, Kathrin
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245 _ _ |a Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson's disease and dementia with Lewy bodies.
260 _ _ |a London
|c 2021
|b Biomed Central
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500 _ _ |a CC BY
520 _ _ |a 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.
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650 _ 7 |a CSF
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650 _ 7 |a GBA
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650 _ 7 |a PD
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650 _ 7 |a Parkin
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650 _ 7 |a RT-QuIC
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650 _ 7 |a α-Syn seeding
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650 _ 2 |a Biomarkers: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Lewy Body Disease: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Lewy Body Disease: genetics
|2 MeSH
650 _ 2 |a Lewy Body Disease: pathology
|2 MeSH
650 _ 2 |a Parkinson Disease: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Parkinson Disease: genetics
|2 MeSH
650 _ 2 |a Parkinson Disease: pathology
|2 MeSH
650 _ 2 |a alpha-Synuclein: cerebrospinal fluid
|2 MeSH
700 1 _ |a Quadalti, Corinne
|b 1
700 1 _ |a Lerche, Stefanie
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700 1 _ |a Rossi, Marcello
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700 1 _ |a Wurster, Isabel
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700 1 _ |a Baiardi, Simone
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700 1 _ |a Röben, Benjamin
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700 1 _ |a Mammana, Angela
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700 1 _ |a Zimmermann, Milan
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700 1 _ |a Hauser, Ann-Kathrin
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700 1 _ |a Deuschle, Christian
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700 1 _ |a Schulte, Claudia
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700 1 _ |a Waniek, Katharina
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700 1 _ |a Lachmann, Ingolf
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700 1 _ |a Sjödin, Simon
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700 1 _ |a Brinkmalm, Ann
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700 1 _ |a Blennow, Kaj
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700 1 _ |a Zetterberg, Henrik
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700 1 _ |a Gasser, Thomas
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700 1 _ |a Parchi, Piero
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773 _ _ |a 10.1186/s40478-021-01276-6
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