Decreased CSF Transferrin in sCJD: A Potential Pre-Mortem Diagnostic Test for Prion Disorders
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{"title"=>"Decreased csf transferrin in scjd: A potential pre-mortem diagnostic test for prion disorders", "type"=>"journal", "authors"=>[{"first_name"=>"Ajay", "last_name"=>"Singh", "scopus_author_id"=>"55547111104"}, {"first_name"=>"Alim J.", "last_name"=>"Beveridge", "scopus_author_id"=>"42360923400"}, {"first_name"=>"Neena", "last_name"=>"Singh", "scopus_author_id"=>"7404364674"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"79952400329", "doi"=>"10.1371/journal.pone.0016804", "issn"=>"19326203", "pui"=>"361405595", "pmid"=>"21408069", "scopus"=>"2-s2.0-79952400329"}, "id"=>"515a2eb4-c850-3740-9c55-8ce79ef44e00", "abstract"=>"Sporadic Creutzfeldt-Jakob-disease (sCJD) is a fatal neurodegenerative condition that escapes detection until autopsy. Recently, brain iron dyshomeostasis accompanied by increased transferrin (Tf) was reported in sCJD cases. The consequence of this abnormality on cerebrospinal-fluid (CSF) levels of Tf is uncertain. We evaluated the accuracy of CSF Tf, a 'new' biomarker, as a pre-mortem diagnostic test for sCJD when used alone or in combination with the 'current' biomarker total-tau (T-tau). Levels of total-Tf (T-Tf), isoforms of Tf (Tf-1 and Tf-β2), and iron saturation of Tf were quantified in CSF collected 0.3-36 months before death (duration) from 99 autopsy confirmed sCJD (CJD+) and 75 confirmed cases of dementia of non-CJD origin (CJD-). Diagnostic accuracy was estimated by non-parametric tests, logistic regression, and receiver operating characteristic (ROC) analysis. Area under the ROC curve (AUC), sensitivity, specificity, positive and negative predictive values (PV), and likelihood ratios (LR) of each biomarker and biomarker combination were calculated. We report that relative to CJD-, CJD+ cases had lower median CSF T-Tf (125,7093 vs. 217,7893) and higher T-tau (11530 vs. 1266) values. AUC was 0.90 (95% confidence interval (CI), 0.85-0.94) for T-Tf, and 0.93 (95% CI, 0.89-0.97) for T-Tf combined with T-tau. With cut-offs defined to achieve a sensitivity of ∼85%, T-Tf identified CJD+ cases with a specificity of 71.6% (95% CI, 59.1-81.7), positive LR of 3.0 (95% CI, 2.1-4.5), negative LR of 0.2 (95% CI, 0.1-0.3), and accuracy of 80.1%. The effect of patient age and duration was insignificant. T-Tf combined with T-tau identified CJD+ with improved specificity of 87.5% (95%CI, 76.3-94.1), positive LR of 6.8 (95% CI, 3.5-13.1), negative LR of 0.2 (95% CI, 0.1-0.3), positive-PV of 91.0%, negative-PV of 80.0%, and accuracy of 86.2%. Thus, CSF T-Tf, a new biomarker, when combined with the current biomarker T-tau, is a reliable pre-mortem diagnostic test for sCJD.", "link"=>"http://www.mendeley.com/research/decreased-csf-transferrin-scjd-potential-premortem-diagnostic-test-prion-disorders", "reader_count"=>20, "reader_count_by_academic_status"=>{"Researcher"=>3, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>4, "Professor"=>3}, "reader_count_by_user_role"=>{"Researcher"=>3, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>4, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>5, "Medicine and Dentistry"=>7}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>5}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>3}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"United States"=>1, "Japan"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/791929"], "description"=>"<p>(<b>A</b>) Immunoblotting for Tf shows reduced levels of Tf-1 and Tf-β2 in the CSF of CJD+ relative to CJD- samples (lanes 1–13), and increased levels of both isoforms in the brain tissue of CJD+ relative to CJD- samples (lanes 14–17) (55). (<b>B</b>–<b>D</b>) Box and whisker plots of T-Tf (WB) indicating the median, 25–75<sup>th</sup> percentiles, and outliers. The top and bottom of the “box” represent 75<sup>th</sup> and 25<sup>th</sup> percentile respectively. The “whiskers” represent the highest and lowest values. Outliers are values over 1.5 times the interquartile range and are shown as circles away from the whiskers. Significance of biomarker differences between CJD- vs. CJD+ and AD vs. CJD+ was calculated by the M-W test.</p>", "links"=>[], "tags"=>["csf"], "article_id"=>462304, "categories"=>["Cell Biology", "Infectious Diseases", "Neuroscience"], "users"=>["Ajay Singh", "′Alim J. Beveridge", "Neena Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016804.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tf_is_decreased_in_the_CSF_and_increased_in_the_brain_of_CJD_cases_/462304", "title"=>"Tf is decreased in the CSF and increased in the brain of CJD+ cases.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-09 00:38:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/792117"], "description"=>"<p>(<b>A & B</b>) Box and whisker plots of T-tau comparing CJD- vs. CJD+ and AD vs. CJD+ cases. Plot shows median, 25 to 75<sup>th</sup> percentiles, and outliers as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016804#pone-0016804-g001\" target=\"_blank\">Figures 1</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016804#pone-0016804-g002\" target=\"_blank\">2</a>.</p>", "links"=>[], "tags"=>["csf", "t-tau", "dementias"], "article_id"=>462485, "categories"=>["Cell Biology", "Infectious Diseases", "Neuroscience"], "users"=>["Ajay Singh", "′Alim J. Beveridge", "Neena Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016804.g003", "stats"=>{"downloads"=>2, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantitative_comparison_of_CSF_T_tau_between_CJD_and_other_dementias_by_the_M_W_U_test_/462485", "title"=>"Quantitative comparison of CSF T-tau between CJD+ and other dementias by the M–W <i>U</i> test.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-09 00:41:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/792244"], "description"=>"<p>Note: The n ranges from 87 to 99 for biomarkers in the CJD+ group and from 64 to 67 for the CJD- group due to insufficient CSF volume. To ensure that varying n does not introduce bias, an additional analysis was performed using cases with only non-missing values for all biomarkers (87 for CJD+ and 64 for CJD-). The results did not differ noticeably from those reported above.</p>", "links"=>[], "tags"=>["biomarker", "mann-whitney"], "article_id"=>462620, "categories"=>["Cell Biology", "Infectious Diseases", "Neuroscience"], "users"=>["Ajay Singh", "′Alim J. Beveridge", "Neena Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016804.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Individual_biomarker_performance_by_the_Mann_Whitney_U_test_/462620", "title"=>"Individual biomarker performance by the Mann-Whitney <i>U</i> test.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-03-09 00:43:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/792185"], "description"=>"<p>(<b>A & B</b>) ROC curve of T-Tf (WB) and T-Tf (WB) in combination with T-tau. (<b>C</b>) Scatter graph shows separation of CJD+ from cases of AD and other dementias. Reference line shows the cut-off equation derived to achieve a sensitivity of ∼85%.</p>", "links"=>[], "tags"=>["csf", "t-tf", "t-tau", "diagnostic"], "article_id"=>462553, "categories"=>["Cell Biology", "Infectious Diseases", "Neuroscience"], "users"=>["Ajay Singh", "′Alim J. Beveridge", "Neena Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016804.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Potential_of_CSF_T_Tf_alone_or_in_combination_with_T_tau_as_a_diagnostic_test_for_CJD_/462553", "title"=>"Potential of CSF T-Tf alone or in combination with T-tau as a diagnostic test for CJD+.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-09 00:42:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/792271"], "description"=>"<p>Note: Accuracy was defined as true positives + true negatives/total number tested.</p><p>Cut-off was chosen to achieve a sensitivity of ∼85% <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016804#pone.0016804-Consensus1\" target=\"_blank\">[38]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016804#pone.0016804-Mattsson1\" target=\"_blank\">[39]</a>.</p><p>Positive/negative LR results are robust to variations in prevalence rates between the study and overall population, and are provided in addition to PPV/NPV that are highly dependent on the population tested.</p>", "links"=>[], "tags"=>["biomarkers", "logistic"], "article_id"=>462645, "categories"=>["Cell Biology", "Infectious Diseases", "Neuroscience"], "users"=>["Ajay Singh", "′Alim J. Beveridge", "Neena Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016804.t002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_8216_new_8217_and_8216_current_8217_biomarkers_by_logistic_regression_/462645", "title"=>"Comparison of ‘new’ and ‘current’ biomarkers by logistic regression.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-03-09 00:44:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/792034"], "description"=>"<p>(<b>A–F</b>) Box and whisker plots of different biomarkers indicating the median, 25–75<sup>th</sup> percentiles, and outliers as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016804#pone-0016804-g001\" target=\"_blank\">Figure 1</a> B–D. Significance of biomarker differences between CJD- vs. CJD+ and AD vs. CJD+ was calculated by the M–W test.</p>", "links"=>[], "tags"=>["csf", "tf", "dementias", "m-w"], "article_id"=>462405, "categories"=>["Cell Biology", "Infectious Diseases", "Neuroscience"], "users"=>["Ajay Singh", "′Alim J. Beveridge", "Neena Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016804.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantitative_comparison_of_CSF_Tf_between_CJD_and_other_dementias_by_the_M_W_U_test_/462405", "title"=>"Quantitative comparison of CSF Tf between CJD+ and other dementias by the M-W <i>U</i> test.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-09 00:40:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/396462", "https://ndownloader.figshare.com/files/396492"], "description"=>"<div><p>Sporadic Creutzfeldt-Jakob-disease (sCJD) is a fatal neurodegenerative condition that escapes detection until autopsy. Recently, brain iron dyshomeostasis accompanied by increased transferrin (Tf) was reported in sCJD cases. The consequence of this abnormality on cerebrospinal-fluid (CSF) levels of Tf is uncertain. We evaluated the accuracy of CSF Tf, a ‘new’ biomarker, as a pre-mortem diagnostic test for sCJD when used alone or in combination with the ‘current’ biomarker total-tau (T-tau). Levels of total-Tf (T-Tf), isoforms of Tf (Tf-1 and Tf-β2), and iron saturation of Tf were quantified in CSF collected 0.3–36 months before death (duration) from 99 autopsy confirmed sCJD (CJD+) and 75 confirmed cases of dementia of non-CJD origin (CJD-). Diagnostic accuracy was estimated by non-parametric tests, logistic regression, and receiver operating characteristic (ROC) analysis. Area under the ROC curve (AUC), sensitivity, specificity, positive and negative predictive values (PV), and likelihood ratios (LR) of each biomarker and biomarker combination were calculated. We report that relative to CJD-, CJD+ cases had lower median CSF T-Tf (125,7093 vs. 217,7893) and higher T-tau (11530 vs. 1266) values. AUC was 0.90 (95% confidence interval (CI), 0.85–0.94) for T-Tf, and 0.93 (95% CI, 0.89–0.97) for T-Tf combined with T-tau. With cut-offs defined to achieve a sensitivity of ∼85%, T-Tf identified CJD+ cases with a specificity of 71.6% (95% CI, 59.1–81.7), positive LR of 3.0 (95% CI, 2.1–4.5), negative LR of 0.2 (95% CI, 0.1–0.3), and accuracy of 80.1%. The effect of patient age and duration was insignificant. T-Tf combined with T-tau identified CJD+ with improved specificity of 87.5% (95%CI, 76.3–94.1), positive LR of 6.8 (95% CI, 3.5–13.1), negative LR of 0.2 (95% CI, 0.1–0.3), positive-PV of 91.0%, negative-PV of 80.0%, and accuracy of 86.2%. Thus, CSF T-Tf, a new biomarker, when combined with the current biomarker T-tau, is a reliable pre-mortem diagnostic test for sCJD.</p> </div>", "links"=>[], "tags"=>["decreased", "csf", "transferrin", "pre-mortem", "diagnostic", "prion", "disorders"], "article_id"=>138322, "categories"=>["Cancer", "Cell Biology", "Neuroscience"], "users"=>["Ajay Singh", "′Alim J. Beveridge", "Neena Singh"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0016804.s001", "https://dx.doi.org/10.1371/journal.pone.0016804.s002"], "stats"=>{"downloads"=>8, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Decreased_CSF_Transferrin_in_sCJD_A_Potential_Pre_Mortem_Diagnostic_Test_for_Prion_Disorders/138322", "title"=>"Decreased CSF Transferrin in sCJD: A Potential Pre-Mortem Diagnostic Test for Prion Disorders", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-03-09 02:18:42"}

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