Peptide Fingerprinting of Alzheimer's Disease in Cerebrospinal Fluid: Identification and Prospective Evaluation of New Synaptic Biomarkers
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{"title"=>"Peptide fingerprinting of Alzheimer's disease in cerebrospinal fluid: Identification and prospective evaluation of new synaptic biomarkers", "type"=>"journal", "authors"=>[{"first_name"=>"Holger", "last_name"=>"Jahn", "scopus_author_id"=>"7102175826"}, {"first_name"=>"Stefan", "last_name"=>"Wittke", "scopus_author_id"=>"9335173600"}, {"first_name"=>"Petra", "last_name"=>"Zürbig", "scopus_author_id"=>"12806664300"}, {"first_name"=>"Thomas J.", "last_name"=>"Raedler", "scopus_author_id"=>"6602356091"}, {"first_name"=>"Sönke", "last_name"=>"Arlt", "scopus_author_id"=>"7003742867"}, {"first_name"=>"Markus", "last_name"=>"Kellmann", "scopus_author_id"=>"9840503500"}, {"first_name"=>"William", "last_name"=>"Mullen", "scopus_author_id"=>"7003512289"}, {"first_name"=>"Martin", "last_name"=>"Eichenlaub", "scopus_author_id"=>"24477067500"}, {"first_name"=>"Harald", "last_name"=>"Mischak", "scopus_author_id"=>"7004897973"}, {"first_name"=>"Klaus", "last_name"=>"Wiedemann", "scopus_author_id"=>"7103009555"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-80055039372", "sgr"=>"80055039372", "pui"=>"362825560", "isbn"=>"1932-6203", "pmid"=>"22046305", "doi"=>"10.1371/journal.pone.0026540"}, "id"=>"d0c35303-9ae1-363c-a679-bb83a534c5f4", "abstract"=>"BACKGROUND: Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer's disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD.\\n\\nMETHODS AND FINDINGS: Cerebrospinal fluid (CSF) of 159 out-patients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer's disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho(181)-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A.\\n\\nCONCLUSIONS: The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis.", "link"=>"http://www.mendeley.com/research/peptide-fingerprinting-alzheimers-disease-cerebrospinal-fluid-identification-prospective-evaluation", "reader_count"=>95, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>15, "Student > Doctoral Student"=>2, "Student > Ph. D. 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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/364377", "https://ndownloader.figshare.com/files/364388", "https://ndownloader.figshare.com/files/364400", "https://ndownloader.figshare.com/files/364410", "https://ndownloader.figshare.com/files/364428", "https://ndownloader.figshare.com/files/364446", "https://ndownloader.figshare.com/files/364468", "https://ndownloader.figshare.com/files/364491"], "description"=>"<div><h3>Background</h3><p>Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer's disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD.</p> <h3>Methods and Findings</h3><p>Cerebrospinal fluid (CSF) of 159 out-patients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer's disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho<sub>181</sub>-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A.</p> <h3>Conclusions</h3><p>The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis.</p> </div>", "links"=>[], "tags"=>["peptide", "fingerprinting", "cerebrospinal", "prospective", "synaptic", "biomarkers"], "article_id"=>132017, "categories"=>["Cell Biology", "Neuroscience", "Biochemistry", "Biotechnology", "Chemistry"], "users"=>["Holger Jahn", "Stefan Wittke", "Petra Zürbig", "Thomas J. Raedler", "Sönke Arlt", "Markus Kellmann", "William Mullen", "Martin Eichenlaub", "Harald Mischak", "Klaus Wiedemann"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0026540.s001", "https://dx.doi.org/10.1371/journal.pone.0026540.s002", "https://dx.doi.org/10.1371/journal.pone.0026540.s003", "https://dx.doi.org/10.1371/journal.pone.0026540.s004", "https://dx.doi.org/10.1371/journal.pone.0026540.s005", "https://dx.doi.org/10.1371/journal.pone.0026540.s006", "https://dx.doi.org/10.1371/journal.pone.0026540.s007", "https://dx.doi.org/10.1371/journal.pone.0026540.s008"], "stats"=>{"downloads"=>9, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Peptide_Fingerprinting_of_Alzheimer_s_Disease_in_Cerebrospinal_Fluid_Identification_and_Prospective_Evaluation_of_New_Synaptic_Biomarkers/132017", "title"=>"Peptide Fingerprinting of Alzheimer's Disease in Cerebrospinal Fluid: Identification and Prospective Evaluation of New Synaptic Biomarkers", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-10-26 00:33:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/720187"], "description"=>"<p><b>A</b>) Compiled 3-D protein contour plot from CSF samples of 34 patients with Alzheimer's disease. The normalized CE-migration time (in min) is plotted on the x-axis and the relative molecular mass (in kDa) on the y-axis. As a third dimension, the signal intensity is colour coded (blue lowest and white highest signal intensity). Each dot represents one peptide. <b>B</b>) Compiled 3-D protein contour plot for healthy controls (n = 17). <b>C</b>) Discriminative biomarker pattern for subjects suffering from Alzheimer's disease (n = 34). Depicted is a 3-D plot of 12 peptides that serve as specific biomarkers for AD brain damage. The normalized CE-migration time (in min) is plotted on the x-axis and the relative molecular mass (in Da) on the y-axis. As a third dimension, the signal intensity is colour coded.</p>", "links"=>[], "tags"=>["chemistry", "biotechnology", "neuroscience", "pathology", "neurological disorders", "Biochemistry"], "article_id"=>390527, "categories"=>["Cell Biology", "Neuroscience", "Biochemistry", "Biotechnology", "Chemistry"], "users"=>["Holger Jahn", "Stefan Wittke", "Petra Zürbig", "Thomas J. Raedler", "Sönke Arlt", "Markus Kellmann", "William Mullen", "Martin Eichenlaub", "Harald Mischak", "Klaus Wiedemann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026540.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Contour_plots_of_the_training_set_/390527", "title"=>"Contour-plots of the training set.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-26 00:08:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/720638"], "description"=>"<p>Baseline data of training sets for cognitively healthy controls and trainings sets for AD, FTD and schizophrenia. Given are numbers for gender, and the averages for age and the scores of the Mini Mental State Examination (MMSE).</p>", "links"=>[], "tags"=>["chemistry", "biotechnology", "neuroscience", "pathology", "neurological disorders", "Biochemistry"], "article_id"=>390984, "categories"=>["Cell Biology", "Neuroscience", "Biochemistry", "Biotechnology", "Chemistry"], "users"=>["Holger Jahn", "Stefan Wittke", "Petra Zürbig", "Thomas J. Raedler", "Sönke Arlt", "Markus Kellmann", "William Mullen", "Martin Eichenlaub", "Harald Mischak", "Klaus Wiedemann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026540.t001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Demographic_data_of_training_sets_/390984", "title"=>"Demographic data of training sets.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-26 00:16:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/720388"], "description"=>"<p>Shown are the ROC analyses of all biomarkers. In the table unique internal protein-ID, mass, CE-migration time, observed frequency of occurrence, the corresponding mean amplitudes, and AUC values (as a biomarker quality measure) in the different groups for the final peptide panels. Five peptides, which are marked in yellow, are already identified (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026540#pone-0026540-t004\" target=\"_blank\"><b>Table 4</b></a>).</p>", "links"=>[], "tags"=>["chemistry", "biotechnology", "neuroscience", "pathology", "neurological disorders", "Biochemistry"], "article_id"=>390729, "categories"=>["Cell Biology", "Neuroscience", "Biochemistry", "Biotechnology", "Chemistry"], "users"=>["Holger Jahn", "Stefan Wittke", "Petra Zürbig", "Thomas J. Raedler", "Sönke Arlt", "Markus Kellmann", "William Mullen", "Martin Eichenlaub", "Harald Mischak", "Klaus Wiedemann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026540.g002", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Peptide_pattern_identifying_AD_/390729", "title"=>"Peptide pattern identifying AD.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-26 00:12:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/720501"], "description"=>"<p>Identified sequences of 57 out of the initial set of 131 putative AD biomarkers are listed. Shown are unique internal protein ID (Pr ID), molecular mass (in Dalton), CE-migration time (in minutes), sequence, originating protein name, and calculated mass (in Dalton). Peptides that are utilized in the final AD pattern are highlighted in bold letters.</p>", "links"=>[], "tags"=>["chemistry", "biotechnology", "neuroscience", "pathology", "neurological disorders", "Biochemistry"], "article_id"=>390842, "categories"=>["Cell Biology", "Neuroscience", "Biochemistry", "Biotechnology", "Chemistry"], "users"=>["Holger Jahn", "Stefan Wittke", "Petra Zürbig", "Thomas J. Raedler", "Sönke Arlt", "Markus Kellmann", "William Mullen", "Martin Eichenlaub", "Harald Mischak", "Klaus Wiedemann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026540.t004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sequence_analysis_/390842", "title"=>"Sequence analysis.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-26 00:14:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/720594"], "description"=>"<p>Shown are unique internal protein-IDs, mass, CE-migration time, observed frequency of occurrence, the corresponding mean amplitudes, and AUC values (as a biomarker quality measure) for the final peptide panel. Five peptides, which are marked in bold, are already identified (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026540#pone-0026540-t004\" target=\"_blank\"><b>Table 4</b></a>).</p>", "links"=>[], "tags"=>["chemistry", "biotechnology", "neuroscience", "pathology", "neurological disorders", "Biochemistry"], "article_id"=>390939, "categories"=>["Cell Biology", "Neuroscience", "Biochemistry", "Biotechnology", "Chemistry"], "users"=>["Holger Jahn", "Stefan Wittke", "Petra Zürbig", "Thomas J. Raedler", "Sönke Arlt", "Markus Kellmann", "William Mullen", "Martin Eichenlaub", "Harald Mischak", "Klaus Wiedemann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026540.t002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Peptide_pattern_identifying_AD_/390939", "title"=>"Peptide pattern identifying AD.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-26 00:15:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/720547"], "description"=>"<p>Clinical outcome of MCI cases (n = 32) followed up for a mean of 57 months. MCI cases with a positive score for the AD-pattern (n = 21) or a negative score for the AD-pattern (n = 11) according to our peptide panel. From 21 MCI patients originally identified as having a positive score for the AD pattern in CSF, only 7 patients are still clinically diagnosed with MCI, while 14 progressed into clinical AD. The other MCI group with negative score for the AD pattern showed a different outcome. Here only 2 patients progressed into AD so far, while 5 patients are still diagnosed with a stable MCI, one patient progressed into a vascular dementia (other dementia, OD), and 3 patients developed a complete remission of cognitive symptoms.</p>", "links"=>[], "tags"=>["mci", "cases", "peptide"], "article_id"=>390895, "categories"=>["Cell Biology", "Neuroscience", "Biochemistry", "Biotechnology", "Chemistry"], "users"=>["Holger Jahn", "Stefan Wittke", "Petra Zürbig", "Thomas J. Raedler", "Sönke Arlt", "Markus Kellmann", "William Mullen", "Martin Eichenlaub", "Harald Mischak", "Klaus Wiedemann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026540.t003", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clinical_outcome_of_MCI_cases_by_peptide_pattern_/390895", "title"=>"Clinical outcome of MCI cases by peptide pattern.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-26 00:14:55"}

PMC Usage Stats | Further Information

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Relative Metric

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