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Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson's disease and dementia with Lewy bodies
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Brockmann, K. (author)
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Quadalti, C. (author)
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Lerche, S. (author)
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Rossi, M. (author)
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Wurster, I. (author)
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Baiardi, S. (author)
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Roeben, B. (author)
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Mammana, A. (author)
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Zimmermann, M. (author)
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Hauser, A. K. (author)
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Deuschle, C. (author)
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Schulte, C. (author)
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Waniek, K. (author)
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Lachmann, I. (author)
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- Sjödin, Simon (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Brinkmalm, Ann (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Blennow, Kaj, 1958 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Zetterberg, Henrik, 1973 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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Gasser, T. (author)
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Parchi, P. (author)
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(creator_code:org_t)
- 2021-10-30
- 2021
- English.
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In: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 9:1
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https://actaneurocom...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Subject headings
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- The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (alpha-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 alpha-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 alpha-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC alpha-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive alpha-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 alpha-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between alpha-Syn seeding activity and reduced CSF levels of proteins linked to alpha-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF. These findings highlight the value of alpha-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting alpha-Syn.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- alpha-Syn seeding
- RT-QuIC
- CSF
- PD
- GBA
- Parkin
- disorder
- glucocerebrosidase
- neuropathology
- diagnosis
- scale
- mmse
- moca
- Neurosciences & Neurology
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Brockmann, K.
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Quadalti, C.
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Lerche, S.
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Rossi, M.
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Wurster, I.
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Baiardi, S.
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show more...
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Roeben, B.
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Mammana, A.
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Zimmermann, M.
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Hauser, A. K.
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Deuschle, C.
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Schulte, C.
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Waniek, K.
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Lachmann, I.
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Sjödin, Simon
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Brinkmalm, Ann
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Blennow, Kaj, 19 ...
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Zetterberg, Henr ...
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Gasser, T.
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Parchi, P.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Acta Neuropathol ...
- By the university
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University of Gothenburg