A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid

James N Baraniuk, Begona Casado, Hilda Maibach, Daniel J Clauw, Lewis K Pannell, Sonja Hess S, James N Baraniuk, Begona Casado, Hilda Maibach, Daniel J Clauw, Lewis K Pannell, Sonja Hess S

Abstract

Background: Chronic Fatigue Syndrome (CFS), Persian Gulf War Illness (PGI), and fibromyalgia are overlapping symptom complexes without objective markers or known pathophysiology. Neurological dysfunction is common. We assessed cerebrospinal fluid to find proteins that were differentially expressed in this CFS-spectrum of illnesses compared to control subjects.

Methods: Cerebrospinal fluid specimens from 10 CFS, 10 PGI, and 10 control subjects (50 mul/subject) were pooled into one sample per group (cohort 1). Cohort 2 of 12 control and 9 CFS subjects had their fluids (200 mul/subject) assessed individually. After trypsin digestion, peptides were analyzed by capillary chromatography, quadrupole-time-of-flight mass spectrometry, peptide sequencing, bioinformatic protein identification, and statistical analysis.

Results: Pooled CFS and PGI samples shared 20 proteins that were not detectable in the pooled control sample (cohort 1 CFS-related proteome). Multilogistic regression analysis (GLM) of cohort 2 detected 10 proteins that were shared by CFS individuals and the cohort 1 CFS-related proteome, but were not detected in control samples. Detection of >or=1 of a select set of 5 CFS-related proteins predicted CFS status with 80% concordance (logistic model). The proteins were alpha-1-macroglobulin, amyloid precursor-like protein 1, keratin 16, orosomucoid 2 and pigment epithelium-derived factor. Overall, 62 of 115 proteins were newly described.

Conclusion: This pilot study detected an identical set of central nervous system, innate immune and amyloidogenic proteins in cerebrospinal fluids from two independent cohorts of subjects with overlapping CFS, PGI and fibromyalgia. Although syndrome names and definitions were different, the proteome and presumed pathological mechanism(s) may be shared.

Figures

Figure 1
Figure 1
Venn diagram of co-morbid, overlapping syndromes. The numbers of subjects satisfying the case designation criteria for CFS, PGI and FM in the Cohort 1 pooled CFS and pooled PGI groups, and Cohort 2 CFS group are shown. Each group had a highly unique combination of these syndromes.
Figure 2
Figure 2
SF-36 scores for each group (mean ± 95% C.I.). Physical Function (PF), Social Function (SF), Role Physical (RP), Role Emotional (RE), Mental Health (MH), Vitality (Vit), Pain, General Health Perception (GH-P) and General Health Change (GHΔ) were identical for the set of pooled (Cohort 1; yellow bars) and individual (Cohort 2; beige bars) HC subjects. These domains were also identical for the set of pooled CFS (light blue bars), pooled PGI (light purple bars) and CFS individuals (teal bars). Significant differences between these datasets were found for all indicators except RE, MH and GPΔ (p

Figure 3

Multidimensional fatigue inventory scores (mean…

Figure 3

Multidimensional fatigue inventory scores (mean ± 95% C.I.). The healthy control (HC) pooled…

Figure 3
Multidimensional fatigue inventory scores (mean ± 95% C.I.). The healthy control (HC) pooled group (yellow bars) and individuals (beige bars) had lower scores for all categories than the pooled CFS (light blue bars), pooled PGI (light purple bars), and CFS individuals (teal bars) (p

Figure 4

Ceruloplasmin (ferroxidase II) peptide mass…

Figure 4

Ceruloplasmin (ferroxidase II) peptide mass spectrogram. This sequencing data was shown for the…

Figure 4
Ceruloplasmin (ferroxidase II) peptide mass spectrogram. This sequencing data was shown for the time-of-flight mass spectrometer (ToF, 2nd MS). The relative signal intensities for each fragment of the ceruloplasmin peptide (y-axis) were plotted against mass/charge (m/z; x-axis). The peptide, GVYSSDVFDIFPGTYQTLEMFPR, was sequenced from the y-series (right to left; N-terminal to C-terminal). It had m/z = 890.41 and z = 3+, for a mass of 2671.23.

Figure 5

The correlation between the frequencies…

Figure 5

The correlation between the frequencies of protein detection in the CFS (black triangles)…

Figure 5
The correlation between the frequencies of protein detection in the CFS (black triangles) and HC (open circles) groups were shown. Nineteen proteins were detected significantly more frequently in the CFS than HC group (p ≤ 0.05 by ANOVA). These CFS – associated proteins were shifted away from the line of identity. This line demonstrated the high correlation of detection frequencies between the CFS and HC samples for the remaining 98 proteins (R2 = 0.70).

Figure 6

Distributions of proteins in healthy…

Figure 6

Distributions of proteins in healthy control (HC) and CFS samples. The frequency of…

Figure 6
Distributions of proteins in healthy control (HC) and CFS samples. The frequency of detection for each protein was determined for the HC (left axis) and CFS (right axis) groups. These axes were divided into "bins" of 0% (absent), 1 to 15%, 16 to 30%, 31 to 45%, 46 to 60%, 61 to 75%, and 76 to 100%. The vertical axis was the percentage of all proteins detected within each intersection of the CFS vs. HC matrix. Most of the proteins were detected in less than 30% of each group. Proteins detected in both groups with roughly equal frequencies of detection were near the line of identity (white bars). The grid region corresponding to the CFS – associated proteome was highlighted by black bars.

Figure 7

Isoelectric point (pI) vs. logarithm…

Figure 7

Isoelectric point (pI) vs. logarithm of molecular weight. The frequencies of detection for…

Figure 7
Isoelectric point (pI) vs. logarithm of molecular weight. The frequencies of detection for proteins in the healthy control (HC) group were graded as 1 to 25% (small circles), 26 to 50% and 51 to 100% (large circles). Proteins detected in the CFS group (open squares) were similarly graded. The CFS – associated proteins detected in 26 to 50% and 51 to 100% of samples were depicted as smaller and larger grey squares, respectively.
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References
    1. Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER, International Chronic Fatigue Syndrome Study Group Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res. 2003;3:25. doi: 10.1186/1472-6963-3-25. - DOI - PMC - PubMed
    1. Fukuda K, Straus SE, Hickei I, Sharpe MC, Dobbins JC, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med. 1994;121:953–959. - PubMed
    1. Clauw DJ, Engel CC, Jr, Aronowitz R, Jones E, Kipen HM, Kroenke K, Ratzan S, Sharpe M, Wessely S. Unexplained symptoms after terrorism and war: an expert consensus statement. J Occup Environ Med. 2003;45:1040–1048. - PubMed
    1. Fukuda K, Nisenbaum R, Stewart G, Thompson WT, Robin L, Washko RM, Noah DL, Barrett DH, Randall B, Herwaldt BL, Mawle AC, Reeves WC. Chronic multisymptom illness affecting air force veterans of the gulf war. JAMA. 1999;280:981–988. doi: 10.1001/jama.280.11.981. - DOI - PubMed
    1. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160–72. - PubMed
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Figure 3
Figure 3
Multidimensional fatigue inventory scores (mean ± 95% C.I.). The healthy control (HC) pooled group (yellow bars) and individuals (beige bars) had lower scores for all categories than the pooled CFS (light blue bars), pooled PGI (light purple bars), and CFS individuals (teal bars) (p

Figure 4

Ceruloplasmin (ferroxidase II) peptide mass…

Figure 4

Ceruloplasmin (ferroxidase II) peptide mass spectrogram. This sequencing data was shown for the…

Figure 4
Ceruloplasmin (ferroxidase II) peptide mass spectrogram. This sequencing data was shown for the time-of-flight mass spectrometer (ToF, 2nd MS). The relative signal intensities for each fragment of the ceruloplasmin peptide (y-axis) were plotted against mass/charge (m/z; x-axis). The peptide, GVYSSDVFDIFPGTYQTLEMFPR, was sequenced from the y-series (right to left; N-terminal to C-terminal). It had m/z = 890.41 and z = 3+, for a mass of 2671.23.

Figure 5

The correlation between the frequencies…

Figure 5

The correlation between the frequencies of protein detection in the CFS (black triangles)…

Figure 5
The correlation between the frequencies of protein detection in the CFS (black triangles) and HC (open circles) groups were shown. Nineteen proteins were detected significantly more frequently in the CFS than HC group (p ≤ 0.05 by ANOVA). These CFS – associated proteins were shifted away from the line of identity. This line demonstrated the high correlation of detection frequencies between the CFS and HC samples for the remaining 98 proteins (R2 = 0.70).

Figure 6

Distributions of proteins in healthy…

Figure 6

Distributions of proteins in healthy control (HC) and CFS samples. The frequency of…

Figure 6
Distributions of proteins in healthy control (HC) and CFS samples. The frequency of detection for each protein was determined for the HC (left axis) and CFS (right axis) groups. These axes were divided into "bins" of 0% (absent), 1 to 15%, 16 to 30%, 31 to 45%, 46 to 60%, 61 to 75%, and 76 to 100%. The vertical axis was the percentage of all proteins detected within each intersection of the CFS vs. HC matrix. Most of the proteins were detected in less than 30% of each group. Proteins detected in both groups with roughly equal frequencies of detection were near the line of identity (white bars). The grid region corresponding to the CFS – associated proteome was highlighted by black bars.

Figure 7

Isoelectric point (pI) vs. logarithm…

Figure 7

Isoelectric point (pI) vs. logarithm of molecular weight. The frequencies of detection for…

Figure 7
Isoelectric point (pI) vs. logarithm of molecular weight. The frequencies of detection for proteins in the healthy control (HC) group were graded as 1 to 25% (small circles), 26 to 50% and 51 to 100% (large circles). Proteins detected in the CFS group (open squares) were similarly graded. The CFS – associated proteins detected in 26 to 50% and 51 to 100% of samples were depicted as smaller and larger grey squares, respectively.
All figures (7)
Figure 4
Figure 4
Ceruloplasmin (ferroxidase II) peptide mass spectrogram. This sequencing data was shown for the time-of-flight mass spectrometer (ToF, 2nd MS). The relative signal intensities for each fragment of the ceruloplasmin peptide (y-axis) were plotted against mass/charge (m/z; x-axis). The peptide, GVYSSDVFDIFPGTYQTLEMFPR, was sequenced from the y-series (right to left; N-terminal to C-terminal). It had m/z = 890.41 and z = 3+, for a mass of 2671.23.
Figure 5
Figure 5
The correlation between the frequencies of protein detection in the CFS (black triangles) and HC (open circles) groups were shown. Nineteen proteins were detected significantly more frequently in the CFS than HC group (p ≤ 0.05 by ANOVA). These CFS – associated proteins were shifted away from the line of identity. This line demonstrated the high correlation of detection frequencies between the CFS and HC samples for the remaining 98 proteins (R2 = 0.70).
Figure 6
Figure 6
Distributions of proteins in healthy control (HC) and CFS samples. The frequency of detection for each protein was determined for the HC (left axis) and CFS (right axis) groups. These axes were divided into "bins" of 0% (absent), 1 to 15%, 16 to 30%, 31 to 45%, 46 to 60%, 61 to 75%, and 76 to 100%. The vertical axis was the percentage of all proteins detected within each intersection of the CFS vs. HC matrix. Most of the proteins were detected in less than 30% of each group. Proteins detected in both groups with roughly equal frequencies of detection were near the line of identity (white bars). The grid region corresponding to the CFS – associated proteome was highlighted by black bars.
Figure 7
Figure 7
Isoelectric point (pI) vs. logarithm of molecular weight. The frequencies of detection for proteins in the healthy control (HC) group were graded as 1 to 25% (small circles), 26 to 50% and 51 to 100% (large circles). Proteins detected in the CFS group (open squares) were similarly graded. The CFS – associated proteins detected in 26 to 50% and 51 to 100% of samples were depicted as smaller and larger grey squares, respectively.

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