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Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome.

Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, Camp DG, Holland BK, Bergquist J, Coyle PK, Smith RD, Fallon BA, Natelson BH - PLoS ONE (2011)

Bottom Line: We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p<0.01).Each condition has a number of CSF proteins that can be useful in providing candidates for future validation studies and insights on the respective mechanisms of pathogenesis.Distinguishing nPTLS and CFS permits more focused study of each condition, and can lead to novel diagnostics and therapeutic interventions.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, United States of America. schutzer@umdnj.edu

ABSTRACT

Background: Neurologic Post Treatment Lyme disease (nPTLS) and Chronic Fatigue (CFS) are syndromes of unknown etiology. They share features of fatigue and cognitive dysfunction, making it difficult to differentiate them. Unresolved is whether nPTLS is a subset of CFS.

Methods and principal findings: Pooled cerebrospinal fluid (CSF) samples from nPTLS patients, CFS patients, and healthy volunteers were comprehensively analyzed using high-resolution mass spectrometry (MS), coupled with immunoaffinity depletion methods to reduce protein-masking by abundant proteins. Individual patient and healthy control CSF samples were analyzed directly employing a MS-based label-free quantitative proteomics approach. We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p<0.01). CFS (n = 43) had 2,783 non-redundant proteins, nPTLS (n = 25) contained 2,768 proteins, and healthy normals had 2,630 proteins. Preliminary pathway analysis demonstrated that the data could be useful for hypothesis generation on the pathogenetic mechanisms underlying these two related syndromes.

Conclusions: nPTLS and CFS have distinguishing CSF protein complements. Each condition has a number of CSF proteins that can be useful in providing candidates for future validation studies and insights on the respective mechanisms of pathogenesis. Distinguishing nPTLS and CFS permits more focused study of each condition, and can lead to novel diagnostics and therapeutic interventions.

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Related in: MedlinePlus

Characterization of the proteome from pooled and individual CSF samples.A) Venn diagram of the qualitative distribution of proteins identified in the pooled, immunodepleted, and fractionated cerebrospinal fluid (CSF) from normal healthy control subjects, Chronic Fatigue Syndrome (CFS), and Neurologic Post Treatment Lyme Syndrome (nPTLS). The numbers of proteins for each of these three categories separately is shown outside the circles below the category (2,630 for true normal controls, 2,783 for CFS, and 2,768 for nPTLS). The subsets of intersections between these categories are shown within the circles. There were 1) 738 proteins that were identified in CFS, but not in either healthy normal controls or nPTLS; 2) 1,582 proteins that were not identified in CFS, but were in either nPTLS disease or healthy normal controls; 3) 692 proteins that were identified in the nPTLS patients, but not in healthy normal controls or CFS; and 4) 1,597 proteins that were not identified in nPTLS, but were identified in either healthy normal controls or CFS. This figure also shows that the nPTLS and CFS groups shared significantly more proteins (n = 305) than each disease group shared with controls (n's = 135 and 166). The specific lists of these subsets are presented in additional Table S1.
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pone-0017287-g001: Characterization of the proteome from pooled and individual CSF samples.A) Venn diagram of the qualitative distribution of proteins identified in the pooled, immunodepleted, and fractionated cerebrospinal fluid (CSF) from normal healthy control subjects, Chronic Fatigue Syndrome (CFS), and Neurologic Post Treatment Lyme Syndrome (nPTLS). The numbers of proteins for each of these three categories separately is shown outside the circles below the category (2,630 for true normal controls, 2,783 for CFS, and 2,768 for nPTLS). The subsets of intersections between these categories are shown within the circles. There were 1) 738 proteins that were identified in CFS, but not in either healthy normal controls or nPTLS; 2) 1,582 proteins that were not identified in CFS, but were in either nPTLS disease or healthy normal controls; 3) 692 proteins that were identified in the nPTLS patients, but not in healthy normal controls or CFS; and 4) 1,597 proteins that were not identified in nPTLS, but were identified in either healthy normal controls or CFS. This figure also shows that the nPTLS and CFS groups shared significantly more proteins (n = 305) than each disease group shared with controls (n's = 135 and 166). The specific lists of these subsets are presented in additional Table S1.

Mentions: In the pooled analysis, we examined individual sets of CSF samples from CFS patients (n = 43) and nPTLS patients (n = 25), respectively. We used the proteomic strategy described in Methods to assure that the maximum number of proteins would be analyzed and the more abundant proteins did not obscure the less abundant ones having biomarker potential. The bound fraction of abundant proteins from the immunoaffinity depleted flow through fraction was analyzed separately and included in the subsequent analysis. Combining immunoaffinity-based partitioning, SCX fractionation and LC-MS/MS, we identified approximately 30,000 peptides for each pooled sample corresponding to 2,783 nonredundant proteins in CFS patient samples and 2,768 proteins in nPTLS patient samples, compared to the 2,630 proteins present in the CSF of healthy normal control subjects. These can be graphically seen in Figure 1 which shows the number of proteins identified solely in each group, and shared or not shared between the groups (see Table S1). Figure 1 also shows that the nPTLS and CFS groups shared significantly more proteins (n = 305) than each disease group shared with healthy controls (n's = 135 and 166, respectively). (Note that, as with any assay, when we indicate that a protein was “not found” or “not identified” that is defined as within the limits of detection).


Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome.

Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, Camp DG, Holland BK, Bergquist J, Coyle PK, Smith RD, Fallon BA, Natelson BH - PLoS ONE (2011)

Characterization of the proteome from pooled and individual CSF samples.A) Venn diagram of the qualitative distribution of proteins identified in the pooled, immunodepleted, and fractionated cerebrospinal fluid (CSF) from normal healthy control subjects, Chronic Fatigue Syndrome (CFS), and Neurologic Post Treatment Lyme Syndrome (nPTLS). The numbers of proteins for each of these three categories separately is shown outside the circles below the category (2,630 for true normal controls, 2,783 for CFS, and 2,768 for nPTLS). The subsets of intersections between these categories are shown within the circles. There were 1) 738 proteins that were identified in CFS, but not in either healthy normal controls or nPTLS; 2) 1,582 proteins that were not identified in CFS, but were in either nPTLS disease or healthy normal controls; 3) 692 proteins that were identified in the nPTLS patients, but not in healthy normal controls or CFS; and 4) 1,597 proteins that were not identified in nPTLS, but were identified in either healthy normal controls or CFS. This figure also shows that the nPTLS and CFS groups shared significantly more proteins (n = 305) than each disease group shared with controls (n's = 135 and 166). The specific lists of these subsets are presented in additional Table S1.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3044169&req=5

pone-0017287-g001: Characterization of the proteome from pooled and individual CSF samples.A) Venn diagram of the qualitative distribution of proteins identified in the pooled, immunodepleted, and fractionated cerebrospinal fluid (CSF) from normal healthy control subjects, Chronic Fatigue Syndrome (CFS), and Neurologic Post Treatment Lyme Syndrome (nPTLS). The numbers of proteins for each of these three categories separately is shown outside the circles below the category (2,630 for true normal controls, 2,783 for CFS, and 2,768 for nPTLS). The subsets of intersections between these categories are shown within the circles. There were 1) 738 proteins that were identified in CFS, but not in either healthy normal controls or nPTLS; 2) 1,582 proteins that were not identified in CFS, but were in either nPTLS disease or healthy normal controls; 3) 692 proteins that were identified in the nPTLS patients, but not in healthy normal controls or CFS; and 4) 1,597 proteins that were not identified in nPTLS, but were identified in either healthy normal controls or CFS. This figure also shows that the nPTLS and CFS groups shared significantly more proteins (n = 305) than each disease group shared with controls (n's = 135 and 166). The specific lists of these subsets are presented in additional Table S1.
Mentions: In the pooled analysis, we examined individual sets of CSF samples from CFS patients (n = 43) and nPTLS patients (n = 25), respectively. We used the proteomic strategy described in Methods to assure that the maximum number of proteins would be analyzed and the more abundant proteins did not obscure the less abundant ones having biomarker potential. The bound fraction of abundant proteins from the immunoaffinity depleted flow through fraction was analyzed separately and included in the subsequent analysis. Combining immunoaffinity-based partitioning, SCX fractionation and LC-MS/MS, we identified approximately 30,000 peptides for each pooled sample corresponding to 2,783 nonredundant proteins in CFS patient samples and 2,768 proteins in nPTLS patient samples, compared to the 2,630 proteins present in the CSF of healthy normal control subjects. These can be graphically seen in Figure 1 which shows the number of proteins identified solely in each group, and shared or not shared between the groups (see Table S1). Figure 1 also shows that the nPTLS and CFS groups shared significantly more proteins (n = 305) than each disease group shared with healthy controls (n's = 135 and 166, respectively). (Note that, as with any assay, when we indicate that a protein was “not found” or “not identified” that is defined as within the limits of detection).

Bottom Line: We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p<0.01).Each condition has a number of CSF proteins that can be useful in providing candidates for future validation studies and insights on the respective mechanisms of pathogenesis.Distinguishing nPTLS and CFS permits more focused study of each condition, and can lead to novel diagnostics and therapeutic interventions.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, United States of America. schutzer@umdnj.edu

ABSTRACT

Background: Neurologic Post Treatment Lyme disease (nPTLS) and Chronic Fatigue (CFS) are syndromes of unknown etiology. They share features of fatigue and cognitive dysfunction, making it difficult to differentiate them. Unresolved is whether nPTLS is a subset of CFS.

Methods and principal findings: Pooled cerebrospinal fluid (CSF) samples from nPTLS patients, CFS patients, and healthy volunteers were comprehensively analyzed using high-resolution mass spectrometry (MS), coupled with immunoaffinity depletion methods to reduce protein-masking by abundant proteins. Individual patient and healthy control CSF samples were analyzed directly employing a MS-based label-free quantitative proteomics approach. We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p<0.01). CFS (n = 43) had 2,783 non-redundant proteins, nPTLS (n = 25) contained 2,768 proteins, and healthy normals had 2,630 proteins. Preliminary pathway analysis demonstrated that the data could be useful for hypothesis generation on the pathogenetic mechanisms underlying these two related syndromes.

Conclusions: nPTLS and CFS have distinguishing CSF protein complements. Each condition has a number of CSF proteins that can be useful in providing candidates for future validation studies and insights on the respective mechanisms of pathogenesis. Distinguishing nPTLS and CFS permits more focused study of each condition, and can lead to novel diagnostics and therapeutic interventions.

Show MeSH
Related in: MedlinePlus