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Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration
Abstract
Because accumulation of alpha-synuclein (alphaS) in the brain is a hallmark of Parkinson disease (PD) and related disorders, we examined its occurrence in human cerebrospinal fluid (CSF). Following affinity enrichment and trypsin digestion of CSF collected from a neurologically healthy donor, we identified several alphaS-derived peptides by mass spectrometry. The concentration of alphaS amounted to <0.001% of the CSF proteome. We then built, validated and optimized a sandwich-type, enzyme-linked immunoadsorbent assay (ELISA) to measure total alphaS levels in unconcentrated CSF. In a cross-sectional study of 100 living donors, we examined cell-free CSF samples from subjects clinically diagnosed with advanced PD, dementia with Lewy bodies (DLB), Alzheimer disease (AD), and a group of non-neurodegenerative disease controls (NCO). In these four groups the CSF alphaS concentrations ranged from 0.8 to 16.2 pg/microl. Mean CSF alphaS values were lower in donors with a primary synucleinopathy (PD, DLB: n=57) than in the other two groups (AD, NCO: n=35; p=0.025). By contrast, living Creutzfeldt-Jakob disease patients showed markedly elevated CSF alphaS levels (n=8; mean, 300 pg/microl; p<0.001). Our results unequivocally confirm the presence of alphaS in adult human CSF. In a first feasibility study employing a novel ELISA, we found relatively low CSF alphaS concentrations in subjects with parkinsonism linked to synucleinopathy, PD and DLB. In definite prion disease cases, we recorded a marked rise in total CSF alphaS resulting from rapid cell death. Our results will likely aid future biomarker explorations in neurodegenerative conditions and facilitate target validation studies.
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“numerous studies have documented unaltered or slightly increased CSF αSyn levels in patients with MCI and AD [27, 80–82, 86, 90, 91, 93, 94].”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [82]
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Self-citation
Metadata
- Authors
- Mollenhauer, B., Cullen, V., Kahn, I., Krastins, B., Outeiro, T. F., Pepivani, I., Ng, J., Schulz-Schaeffer, W., Kretzschmar, H. A., McLean, P. J., Trenkwalder, C., Sarracino, D. A., VonSattel, J.-P., Locascio, J. J., El-Agnaf, O. M. A., & Schlossmacher, M. G.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Ottawa (CA)
- Ludwig-Maximilians-Universität München (DE)
- Paracelsus Elena Klinik Kassel (DE)
- Columbia University (US)
- Corresponding author
- Schlossmacher, Michael G.
- ORCID
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 213
- Issue
- 2
- Pages
- 315-325
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2003260773
- Cited by
- 382
- References
- 68
- Citations by year
- 2026: 6 · 2025: 18 · 2024: 8 · 2023: 9 · 2022: 22 · 2021: 16 · 2020: 25 · 2019: 19 · 2018: 16 · 2017: 17 · 2016: 20 · 2015: 25 · 2014: 32 · 2013: 26 · 2012: 30
- FWCI
- 19.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (P50NS038375, 5P50-NS038375)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, cerebrospinal fluid, Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, Creutzfeldt-Jakob disease, synucleinopathies, cell-free biomarkers, ELISA quantification, neurodegeneration, prion disease, cell death
- MeSH terms
- Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Animals, Cells, Cultured, Cross-Sectional Studies, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Nerve Degeneration, Biomarkers, Mice, Rats, alpha-Synuclein
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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