Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration
Because accumulation of α-synuclein (αS) 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...
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| Veröffentlicht in: | Experimental neurology 2008-10, Vol.213 (2), p.315-325 |
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| creator | Mollenhauer, Brit Cullen, Valerie Kahn, Ilana Krastins, Bryan Outeiro, Tiago F. Pepivani, Imelda Ng, Juliana Schulz-Schaeffer, Walter Kretzschmar, Hans A. McLean, Pamela J. Trenkwalder, Claudia Sarracino, David A. VonSattel, Jean-Paul Locascio, Joseph J. El-Agnaf, Omar M.A. Schlossmacher, Michael G. |
| description | Because accumulation of α-synuclein (αS) 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 αS-derived peptides by mass spectrometry. The concentration of αS amounted to |
| doi_str_mv | 10.1016/j.expneurol.2008.06.004 |
| format | Article |
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Following affinity enrichment and trypsin digestion of CSF collected from a neurologically healthy donor, we identified several αS-derived peptides by mass spectrometry. The concentration of αS 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 αS 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 αS concentrations ranged from 0.8 to 16.2 pg/μl. Mean CSF αS 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 αS levels (n=8; mean, 300 pg/μl; p<0.001). Our results unequivocally confirm the presence of αS in adult human CSF. In a first feasibility study employing a novel ELISA, we found relatively low CSF αS concentrations in subjects with parkinsonism linked to synucleinopathy, PD and DLB. In definite prion disease cases, we recorded a marked rise in total CSF αS resulting from rapid cell death. Our results will likely aid future biomarker explorations in neurodegenerative conditions and facilitate target validation studies.</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2008.06.004</identifier><identifier>PMID: 18625222</identifier><identifier>CODEN: EXNEAC</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>Adult ; Aged ; Aged, 80 and over ; alpha-Synuclein - cerebrospinal fluid ; alpha-Synuclein - genetics ; Amino Acid Sequence ; Animals ; Biological and medical sciences ; Biomarker ; Biomarkers - cerebrospinal fluid ; Cells, Cultured ; Cerebrospinal fluid ; Cross-Sectional Studies ; Dementia ; ELISA ; Enzyme-Linked Immunosorbent Assay - methods ; Enzyme-Linked Immunosorbent Assay - standards ; Female ; Humans ; Male ; Mass spectrometry ; Medical sciences ; Mice ; Middle Aged ; Molecular Sequence Data ; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis ; Nerve Degeneration - cerebrospinal fluid ; Nerve Degeneration - genetics ; Nerve Degeneration - pathology ; Neurology ; Parkinsonism ; Rats ; α-synuclein</subject><ispartof>Experimental neurology, 2008-10, Vol.213 (2), p.315-325</ispartof><rights>2008 Elsevier Inc.</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-2978d2fc80d9bb711018caa6c2a9bbf7dd110b67fa152772e99bdc4cc86b3f203</citedby><cites>FETCH-LOGICAL-c430t-2978d2fc80d9bb711018caa6c2a9bbf7dd110b67fa152772e99bdc4cc86b3f203</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0014488608002562$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20696792$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18625222$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mollenhauer, Brit</creatorcontrib><creatorcontrib>Cullen, Valerie</creatorcontrib><creatorcontrib>Kahn, Ilana</creatorcontrib><creatorcontrib>Krastins, Bryan</creatorcontrib><creatorcontrib>Outeiro, Tiago F.</creatorcontrib><creatorcontrib>Pepivani, Imelda</creatorcontrib><creatorcontrib>Ng, Juliana</creatorcontrib><creatorcontrib>Schulz-Schaeffer, Walter</creatorcontrib><creatorcontrib>Kretzschmar, Hans A.</creatorcontrib><creatorcontrib>McLean, Pamela J.</creatorcontrib><creatorcontrib>Trenkwalder, Claudia</creatorcontrib><creatorcontrib>Sarracino, David A.</creatorcontrib><creatorcontrib>VonSattel, Jean-Paul</creatorcontrib><creatorcontrib>Locascio, Joseph J.</creatorcontrib><creatorcontrib>El-Agnaf, Omar M.A.</creatorcontrib><creatorcontrib>Schlossmacher, Michael G.</creatorcontrib><title>Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>Because accumulation of α-synuclein (αS) 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 αS-derived peptides by mass spectrometry. The concentration of αS 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 αS 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 αS concentrations ranged from 0.8 to 16.2 pg/μl. Mean CSF αS 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 αS levels (n=8; mean, 300 pg/μl; p<0.001). Our results unequivocally confirm the presence of αS in adult human CSF. In a first feasibility study employing a novel ELISA, we found relatively low CSF αS concentrations in subjects with parkinsonism linked to synucleinopathy, PD and DLB. In definite prion disease cases, we recorded a marked rise in total CSF αS resulting from rapid cell death. Our results will likely aid future biomarker explorations in neurodegenerative conditions and facilitate target validation studies.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>alpha-Synuclein - cerebrospinal fluid</subject><subject>alpha-Synuclein - genetics</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biomarker</subject><subject>Biomarkers - cerebrospinal fluid</subject><subject>Cells, Cultured</subject><subject>Cerebrospinal fluid</subject><subject>Cross-Sectional Studies</subject><subject>Dementia</subject><subject>ELISA</subject><subject>Enzyme-Linked Immunosorbent Assay - methods</subject><subject>Enzyme-Linked Immunosorbent Assay - standards</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Mass spectrometry</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Molecular Sequence Data</subject><subject>Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis</subject><subject>Nerve Degeneration - cerebrospinal fluid</subject><subject>Nerve Degeneration - genetics</subject><subject>Nerve Degeneration - pathology</subject><subject>Neurology</subject><subject>Parkinsonism</subject><subject>Rats</subject><subject>α-synuclein</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1uEzEUhS1ERUPhFcAb2M302jOxx8sotFApEou2a8vjH3A08aS2p5DH6ov0mXB-VJZdWba-c3zPPQh9JlATIOxyXdu_22CnOA41BehqYDVA-wbNCAioaNvAWzQDIG3Vdh07R-9TWgOAaCl_h85Jx-icUjpD0zcfrc74YVIhe-e1yn4MeHR4eXuNn5-qtAuTHqwPuN_hq9XN7QKrYLDzMWWs45hSlYpBEakBpzyZHS7sttjYkBP-4_NvfBjU2F822Hjw_4DOnBqS_Xg6L9D99dXd8ke1-vn9ZrlYVboEyBUVvDPU6Q6M6HtOSvROK8U0VeXuuDHlqWfcKTKnnFMrRG90q3XH-sZRaC7Q16PvNo4Pk01ZbnzSdhhUsOOUJBPztmFt-ypIRNNQwrsC8iN4iB6tk9voNyruJAG5r0au5Us1cl-NBCZLNUX56fTF1G-s-a87dVGALydAJa0GF1XQPr1wFJhgXOy5xZGzZXOP3kaZdFm2tuZQpTSjf3WYf2abs-s</recordid><startdate>20081001</startdate><enddate>20081001</enddate><creator>Mollenhauer, Brit</creator><creator>Cullen, Valerie</creator><creator>Kahn, Ilana</creator><creator>Krastins, Bryan</creator><creator>Outeiro, Tiago F.</creator><creator>Pepivani, Imelda</creator><creator>Ng, Juliana</creator><creator>Schulz-Schaeffer, Walter</creator><creator>Kretzschmar, Hans A.</creator><creator>McLean, Pamela J.</creator><creator>Trenkwalder, Claudia</creator><creator>Sarracino, David A.</creator><creator>VonSattel, Jean-Paul</creator><creator>Locascio, Joseph J.</creator><creator>El-Agnaf, Omar M.A.</creator><creator>Schlossmacher, Michael G.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>20081001</creationdate><title>Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration</title><author>Mollenhauer, Brit ; Cullen, Valerie ; Kahn, Ilana ; Krastins, Bryan ; Outeiro, Tiago F. ; Pepivani, Imelda ; Ng, Juliana ; Schulz-Schaeffer, Walter ; Kretzschmar, Hans A. ; McLean, Pamela J. ; Trenkwalder, Claudia ; Sarracino, David A. ; VonSattel, Jean-Paul ; Locascio, Joseph J. ; El-Agnaf, Omar M.A. ; Schlossmacher, Michael G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-2978d2fc80d9bb711018caa6c2a9bbf7dd110b67fa152772e99bdc4cc86b3f203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>alpha-Synuclein - cerebrospinal fluid</topic><topic>alpha-Synuclein - genetics</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biomarker</topic><topic>Biomarkers - cerebrospinal fluid</topic><topic>Cells, Cultured</topic><topic>Cerebrospinal fluid</topic><topic>Cross-Sectional Studies</topic><topic>Dementia</topic><topic>ELISA</topic><topic>Enzyme-Linked Immunosorbent Assay - methods</topic><topic>Enzyme-Linked Immunosorbent Assay - standards</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Mass spectrometry</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Molecular Sequence Data</topic><topic>Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis</topic><topic>Nerve Degeneration - cerebrospinal fluid</topic><topic>Nerve Degeneration - genetics</topic><topic>Nerve Degeneration - pathology</topic><topic>Neurology</topic><topic>Parkinsonism</topic><topic>Rats</topic><topic>α-synuclein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mollenhauer, Brit</creatorcontrib><creatorcontrib>Cullen, Valerie</creatorcontrib><creatorcontrib>Kahn, Ilana</creatorcontrib><creatorcontrib>Krastins, Bryan</creatorcontrib><creatorcontrib>Outeiro, Tiago F.</creatorcontrib><creatorcontrib>Pepivani, Imelda</creatorcontrib><creatorcontrib>Ng, Juliana</creatorcontrib><creatorcontrib>Schulz-Schaeffer, Walter</creatorcontrib><creatorcontrib>Kretzschmar, Hans A.</creatorcontrib><creatorcontrib>McLean, Pamela J.</creatorcontrib><creatorcontrib>Trenkwalder, Claudia</creatorcontrib><creatorcontrib>Sarracino, David A.</creatorcontrib><creatorcontrib>VonSattel, Jean-Paul</creatorcontrib><creatorcontrib>Locascio, Joseph J.</creatorcontrib><creatorcontrib>El-Agnaf, Omar M.A.</creatorcontrib><creatorcontrib>Schlossmacher, Michael G.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mollenhauer, Brit</au><au>Cullen, Valerie</au><au>Kahn, Ilana</au><au>Krastins, Bryan</au><au>Outeiro, Tiago F.</au><au>Pepivani, Imelda</au><au>Ng, Juliana</au><au>Schulz-Schaeffer, Walter</au><au>Kretzschmar, Hans A.</au><au>McLean, Pamela J.</au><au>Trenkwalder, Claudia</au><au>Sarracino, David A.</au><au>VonSattel, Jean-Paul</au><au>Locascio, Joseph J.</au><au>El-Agnaf, Omar M.A.</au><au>Schlossmacher, Michael G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2008-10-01</date><risdate>2008</risdate><volume>213</volume><issue>2</issue><spage>315</spage><epage>325</epage><pages>315-325</pages><issn>0014-4886</issn><eissn>1090-2430</eissn><coden>EXNEAC</coden><abstract>Because accumulation of α-synuclein (αS) 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 αS-derived peptides by mass spectrometry. The concentration of αS 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 αS 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 αS concentrations ranged from 0.8 to 16.2 pg/μl. Mean CSF αS 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 αS levels (n=8; mean, 300 pg/μl; p<0.001). Our results unequivocally confirm the presence of αS in adult human CSF. In a first feasibility study employing a novel ELISA, we found relatively low CSF αS concentrations in subjects with parkinsonism linked to synucleinopathy, PD and DLB. In definite prion disease cases, we recorded a marked rise in total CSF αS resulting from rapid cell death. Our results will likely aid future biomarker explorations in neurodegenerative conditions and facilitate target validation studies.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>18625222</pmid><doi>10.1016/j.expneurol.2008.06.004</doi><tpages>11</tpages></addata></record> |
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| subjects | Adult Aged Aged, 80 and over alpha-Synuclein - cerebrospinal fluid alpha-Synuclein - genetics Amino Acid Sequence Animals Biological and medical sciences Biomarker Biomarkers - cerebrospinal fluid Cells, Cultured Cerebrospinal fluid Cross-Sectional Studies Dementia ELISA Enzyme-Linked Immunosorbent Assay - methods Enzyme-Linked Immunosorbent Assay - standards Female Humans Male Mass spectrometry Medical sciences Mice Middle Aged Molecular Sequence Data Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis Nerve Degeneration - cerebrospinal fluid Nerve Degeneration - genetics Nerve Degeneration - pathology Neurology Parkinsonism Rats α-synuclein |
| title | Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration |
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