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A sensitive aβ oligomer assay discriminates Alzheimer's and aged control cerebrospinal fluid
A hallmark of Alzheimer's disease (AD) brain is the amyloid β (Aβ) plaque, which is comprised of Aβ peptides. Multiple lines of evidence suggest that Aβ oligomers are more toxic than other peptide forms. We sought to develop a robust assay to quantify oligomers from CSF. Antibody 19.3 was compa...
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Published in: | The Journal of neuroscience 2014-02, Vol.34 (8), p.2884-2897 |
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creator | Savage, Mary J Kalinina, Juliya Wolfe, Abigail Tugusheva, Katherine Korn, Rachel Cash-Mason, Tanesha Maxwell, Jill W Hatcher, Nathan G Haugabook, Sharie J Wu, Guoxin Howell, Bonnie J Renger, John J Shughrue, Paul J McCampbell, Alexander |
description | A hallmark of Alzheimer's disease (AD) brain is the amyloid β (Aβ) plaque, which is comprised of Aβ peptides. Multiple lines of evidence suggest that Aβ oligomers are more toxic than other peptide forms. We sought to develop a robust assay to quantify oligomers from CSF. Antibody 19.3 was compared in one-site and competitive ELISAs for oligomer binding specificity. A two-site ELISA for oligomers was developed using 19.3 coupled to a sensitive, bead-based fluorescent platform able to detect single photons of emitted light. The two-site ELISA was >2500× selective for Aβ oligomers over Aβ monomers with a limit of detection ∼ 0.09 pg/ml in human CSF. The lower limit of reliable quantification of the assay was 0.18 pg/ml and the antibody pairs recognized Aβ multimers comprised of either synthetic standards, or endogenous oligomers isolated from confirmed human AD and healthy control brain. Using the assay, a significant 3- to 5-fold increase in Aβ oligomers in human AD CSF compared with comparably aged controls was demonstrated. The increase was seen in three separate human cohorts, totaling 63 AD and 54 controls. CSF oligomers ranged between 0.1 and 10 pg/ml. Aβ oligomer levels did not strongly associate with age or gender, but had an inverse correlation with MMSE score. The C statistic for the Aβ oligomer ROC curve was 0.86, with 80% sensitivity and 88% specificity to detect AD, suggesting reasonable discriminatory power for the AD state and the potential for utility as a diagnostic marker. |
doi_str_mv | 10.1523/JNEUROSCI.1675-13.2014 |
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Multiple lines of evidence suggest that Aβ oligomers are more toxic than other peptide forms. We sought to develop a robust assay to quantify oligomers from CSF. Antibody 19.3 was compared in one-site and competitive ELISAs for oligomer binding specificity. A two-site ELISA for oligomers was developed using 19.3 coupled to a sensitive, bead-based fluorescent platform able to detect single photons of emitted light. The two-site ELISA was >2500× selective for Aβ oligomers over Aβ monomers with a limit of detection ∼ 0.09 pg/ml in human CSF. The lower limit of reliable quantification of the assay was 0.18 pg/ml and the antibody pairs recognized Aβ multimers comprised of either synthetic standards, or endogenous oligomers isolated from confirmed human AD and healthy control brain. Using the assay, a significant 3- to 5-fold increase in Aβ oligomers in human AD CSF compared with comparably aged controls was demonstrated. The increase was seen in three separate human cohorts, totaling 63 AD and 54 controls. CSF oligomers ranged between 0.1 and 10 pg/ml. Aβ oligomer levels did not strongly associate with age or gender, but had an inverse correlation with MMSE score. The C statistic for the Aβ oligomer ROC curve was 0.86, with 80% sensitivity and 88% specificity to detect AD, suggesting reasonable discriminatory power for the AD state and the potential for utility as a diagnostic marker.</description><identifier>ISSN: 0270-6474</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.1675-13.2014</identifier><identifier>PMID: 24553930</identifier><language>eng</language><publisher>United States: Society for Neuroscience</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Aging - cerebrospinal fluid ; Alzheimer Disease - cerebrospinal fluid ; Alzheimer Disease - diagnosis ; Alzheimer Disease - psychology ; Amyloid beta-Peptides - cerebrospinal fluid ; Amyloid beta-Peptides - immunology ; Antibodies - immunology ; Antibody Specificity ; Biomarkers - cerebrospinal fluid ; Enzyme-Linked Immunosorbent Assay ; False Positive Reactions ; Female ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Peptide Fragments - cerebrospinal fluid ; Reproducibility of Results ; ROC Curve ; Scattering, Radiation</subject><ispartof>The Journal of neuroscience, 2014-02, Vol.34 (8), p.2884-2897</ispartof><rights>Copyright © 2014 the authors 0270-6474/14/342884-14$15.00/0 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-479f2d014194e2c849e3028c5926e62c59a262da6e0cec898607dc1205f815443</citedby><cites>FETCH-LOGICAL-c447t-479f2d014194e2c849e3028c5926e62c59a262da6e0cec898607dc1205f815443</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608513/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608513/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24553930$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Savage, Mary J</creatorcontrib><creatorcontrib>Kalinina, Juliya</creatorcontrib><creatorcontrib>Wolfe, Abigail</creatorcontrib><creatorcontrib>Tugusheva, Katherine</creatorcontrib><creatorcontrib>Korn, Rachel</creatorcontrib><creatorcontrib>Cash-Mason, Tanesha</creatorcontrib><creatorcontrib>Maxwell, Jill W</creatorcontrib><creatorcontrib>Hatcher, Nathan G</creatorcontrib><creatorcontrib>Haugabook, Sharie J</creatorcontrib><creatorcontrib>Wu, Guoxin</creatorcontrib><creatorcontrib>Howell, Bonnie J</creatorcontrib><creatorcontrib>Renger, John J</creatorcontrib><creatorcontrib>Shughrue, Paul J</creatorcontrib><creatorcontrib>McCampbell, Alexander</creatorcontrib><title>A sensitive aβ oligomer assay discriminates Alzheimer's and aged control cerebrospinal fluid</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>A hallmark of Alzheimer's disease (AD) brain is the amyloid β (Aβ) plaque, which is comprised of Aβ peptides. Multiple lines of evidence suggest that Aβ oligomers are more toxic than other peptide forms. We sought to develop a robust assay to quantify oligomers from CSF. Antibody 19.3 was compared in one-site and competitive ELISAs for oligomer binding specificity. A two-site ELISA for oligomers was developed using 19.3 coupled to a sensitive, bead-based fluorescent platform able to detect single photons of emitted light. The two-site ELISA was >2500× selective for Aβ oligomers over Aβ monomers with a limit of detection ∼ 0.09 pg/ml in human CSF. The lower limit of reliable quantification of the assay was 0.18 pg/ml and the antibody pairs recognized Aβ multimers comprised of either synthetic standards, or endogenous oligomers isolated from confirmed human AD and healthy control brain. Using the assay, a significant 3- to 5-fold increase in Aβ oligomers in human AD CSF compared with comparably aged controls was demonstrated. The increase was seen in three separate human cohorts, totaling 63 AD and 54 controls. CSF oligomers ranged between 0.1 and 10 pg/ml. Aβ oligomer levels did not strongly associate with age or gender, but had an inverse correlation with MMSE score. The C statistic for the Aβ oligomer ROC curve was 0.86, with 80% sensitivity and 88% specificity to detect AD, suggesting reasonable discriminatory power for the AD state and the potential for utility as a diagnostic marker.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Aging - cerebrospinal fluid</subject><subject>Alzheimer Disease - cerebrospinal fluid</subject><subject>Alzheimer Disease - diagnosis</subject><subject>Alzheimer Disease - psychology</subject><subject>Amyloid beta-Peptides - cerebrospinal fluid</subject><subject>Amyloid beta-Peptides - immunology</subject><subject>Antibodies - immunology</subject><subject>Antibody Specificity</subject><subject>Biomarkers - cerebrospinal fluid</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>False Positive Reactions</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neuropsychological Tests</subject><subject>Peptide Fragments - cerebrospinal fluid</subject><subject>Reproducibility of Results</subject><subject>ROC Curve</subject><subject>Scattering, Radiation</subject><issn>0270-6474</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNpVkU1OHDEQha2IKEwgV0DehU1Pyv_dG6TRCAgIgZTAMrKMu3ow8rQn7R4kOBYH4Ux4BBmRVS3eq1ev9BFywGDKFBc_zi-Pb35d_Z6fTZk2qmJiyoHJT2RS1KbiEtgOmQA3UGlp5C75mvM9ABhg5gvZ5VIp0QiYkD8zmrHPYQwPSN3LM00xLNISB-pydo-0DdkPYRl6N2Kms_h0h6Go3zN1fUvdAlvqUz8OKVKPA94OKa-KOdIurkO7Tz53Lmb89j73yM3J8fX8Z3VxdXo2n11UXkozVtI0HW9Lf9ZI5L6WDQrgtVcN16h5mY5r3jqN4NHXTa3BtJ5xUF3NlJRijxy95a7Wt0tsPZZGLtpVae6GR5tcsP8rfbizi_RgtYZaMVECDt8DhvR3jXm0y_I4xuh6TOtsWc1NwxTUUKz6zerLr3nAbnuGgd2wsVs2dsPGMmE3bMriwceS27V_MMQrI16Nig</recordid><startdate>20140219</startdate><enddate>20140219</enddate><creator>Savage, Mary J</creator><creator>Kalinina, Juliya</creator><creator>Wolfe, Abigail</creator><creator>Tugusheva, Katherine</creator><creator>Korn, Rachel</creator><creator>Cash-Mason, Tanesha</creator><creator>Maxwell, Jill W</creator><creator>Hatcher, Nathan G</creator><creator>Haugabook, Sharie J</creator><creator>Wu, Guoxin</creator><creator>Howell, Bonnie J</creator><creator>Renger, John J</creator><creator>Shughrue, Paul J</creator><creator>McCampbell, Alexander</creator><general>Society for Neuroscience</general><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>5PM</scope></search><sort><creationdate>20140219</creationdate><title>A sensitive aβ oligomer assay discriminates Alzheimer's and aged control cerebrospinal fluid</title><author>Savage, Mary J ; Kalinina, Juliya ; Wolfe, Abigail ; Tugusheva, Katherine ; Korn, Rachel ; Cash-Mason, Tanesha ; Maxwell, Jill W ; Hatcher, Nathan G ; Haugabook, Sharie J ; Wu, Guoxin ; Howell, Bonnie J ; Renger, John J ; Shughrue, Paul J ; McCampbell, Alexander</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-479f2d014194e2c849e3028c5926e62c59a262da6e0cec898607dc1205f815443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Aging - cerebrospinal fluid</topic><topic>Alzheimer Disease - cerebrospinal fluid</topic><topic>Alzheimer Disease - diagnosis</topic><topic>Alzheimer Disease - psychology</topic><topic>Amyloid beta-Peptides - cerebrospinal fluid</topic><topic>Amyloid beta-Peptides - immunology</topic><topic>Antibodies - immunology</topic><topic>Antibody Specificity</topic><topic>Biomarkers - cerebrospinal fluid</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>False Positive Reactions</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Neuropsychological Tests</topic><topic>Peptide Fragments - cerebrospinal fluid</topic><topic>Reproducibility of Results</topic><topic>ROC Curve</topic><topic>Scattering, Radiation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Savage, Mary J</creatorcontrib><creatorcontrib>Kalinina, Juliya</creatorcontrib><creatorcontrib>Wolfe, Abigail</creatorcontrib><creatorcontrib>Tugusheva, Katherine</creatorcontrib><creatorcontrib>Korn, Rachel</creatorcontrib><creatorcontrib>Cash-Mason, Tanesha</creatorcontrib><creatorcontrib>Maxwell, Jill W</creatorcontrib><creatorcontrib>Hatcher, Nathan G</creatorcontrib><creatorcontrib>Haugabook, Sharie J</creatorcontrib><creatorcontrib>Wu, Guoxin</creatorcontrib><creatorcontrib>Howell, Bonnie J</creatorcontrib><creatorcontrib>Renger, John J</creatorcontrib><creatorcontrib>Shughrue, Paul J</creatorcontrib><creatorcontrib>McCampbell, Alexander</creatorcontrib><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>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Savage, Mary J</au><au>Kalinina, Juliya</au><au>Wolfe, Abigail</au><au>Tugusheva, Katherine</au><au>Korn, Rachel</au><au>Cash-Mason, Tanesha</au><au>Maxwell, Jill W</au><au>Hatcher, Nathan G</au><au>Haugabook, Sharie J</au><au>Wu, Guoxin</au><au>Howell, Bonnie J</au><au>Renger, John J</au><au>Shughrue, Paul J</au><au>McCampbell, Alexander</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A sensitive aβ oligomer assay discriminates Alzheimer's and aged control cerebrospinal fluid</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2014-02-19</date><risdate>2014</risdate><volume>34</volume><issue>8</issue><spage>2884</spage><epage>2897</epage><pages>2884-2897</pages><issn>0270-6474</issn><eissn>1529-2401</eissn><abstract>A hallmark of Alzheimer's disease (AD) brain is the amyloid β (Aβ) plaque, which is comprised of Aβ peptides. Multiple lines of evidence suggest that Aβ oligomers are more toxic than other peptide forms. We sought to develop a robust assay to quantify oligomers from CSF. Antibody 19.3 was compared in one-site and competitive ELISAs for oligomer binding specificity. A two-site ELISA for oligomers was developed using 19.3 coupled to a sensitive, bead-based fluorescent platform able to detect single photons of emitted light. The two-site ELISA was >2500× selective for Aβ oligomers over Aβ monomers with a limit of detection ∼ 0.09 pg/ml in human CSF. The lower limit of reliable quantification of the assay was 0.18 pg/ml and the antibody pairs recognized Aβ multimers comprised of either synthetic standards, or endogenous oligomers isolated from confirmed human AD and healthy control brain. Using the assay, a significant 3- to 5-fold increase in Aβ oligomers in human AD CSF compared with comparably aged controls was demonstrated. The increase was seen in three separate human cohorts, totaling 63 AD and 54 controls. CSF oligomers ranged between 0.1 and 10 pg/ml. Aβ oligomer levels did not strongly associate with age or gender, but had an inverse correlation with MMSE score. The C statistic for the Aβ oligomer ROC curve was 0.86, with 80% sensitivity and 88% specificity to detect AD, suggesting reasonable discriminatory power for the AD state and the potential for utility as a diagnostic marker.</abstract><cop>United States</cop><pub>Society for Neuroscience</pub><pmid>24553930</pmid><doi>10.1523/JNEUROSCI.1675-13.2014</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adult Aged Aged, 80 and over Aging - cerebrospinal fluid Alzheimer Disease - cerebrospinal fluid Alzheimer Disease - diagnosis Alzheimer Disease - psychology Amyloid beta-Peptides - cerebrospinal fluid Amyloid beta-Peptides - immunology Antibodies - immunology Antibody Specificity Biomarkers - cerebrospinal fluid Enzyme-Linked Immunosorbent Assay False Positive Reactions Female Humans Male Middle Aged Neuropsychological Tests Peptide Fragments - cerebrospinal fluid Reproducibility of Results ROC Curve Scattering, Radiation |
title | A sensitive aβ oligomer assay discriminates Alzheimer's and aged control cerebrospinal fluid |
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