Clear differences in cerebrospinal fluid proteome between women with chronic widespread pain and healthy women – a multivariate explorative cross-sectional study

Abstract

IntroductionFrequent chronic local pain can develop into chronic widespread pain (CWP). The spread of pain is correlated with pain intensity, anxiety, and depression, conditions that ultimately lead to a poor quality of life. Knowledge is incomplete about CWP’s etiology, although it has been suggested that both central hyperexcitability and/or a combination with peripheral factors may be involved. Cerebrospinal fluid (CSF) could act as a mirror for the central nervous system as proteins are signal substances that activate the formation of algesics and control nociceptive processes. To this end, this study investigates the CSF protein expression in women with CWP and in female healthy controls.Materials and methodsThis study included 12 female patients with CWP diagnosed according to the American College of Rheumatology criteria with 13 healthy age- and sex-matched pain-free subjects. All subjects went through a clinical examination and answered a health questionnaire that registered sociodemographic and anthropometric data, pain characteristics, psychological status, and quality of life rating. CSF was collected by lumbar puncture from each subject. Two-dimensional gel electrophoresis in combination with mass spectrometry was used to analyze the CSF proteome. This study identifies proteins that significantly discriminate between the two groups using multivariate data analysis (MVDA) (i.e., orthogonal partial least squares discriminant analysis [OPLS-DA]).ResultsThere were no clinically significant levels of psychological distress and catastrophization presented in subjects with CWP. MVDA revealed a highly significant OPLS-DA model where 48 proteins from CSF explained 91% (R2) of the variation and with a prediction of 90% (Q2). The highest discriminating proteins were metabolic, transport, stress, and inflammatory.ConclusionThe highest discriminating proteins (11 proteins), according to the literature, are involved in apoptotic regulations, anti-inflammatory and anti-oxidative processes, the immune system, and endogenous repair. The results of this explorative study may indicate the presence of neuro-inflammation in the central nervous system of CWP patients. Future studies should be larger and control for confounders and determine which alterations are unspecific/general and which are specific changes.

Protein Signature in Saliva of Temporomandibular Disorders Myalgia

“…PCA and OPLS-DA were applied to identify multivariate correlations between proteins and group membership, using SIMCA-p+ v.15.0 (UMETRICS, Umeå, Sweden), as described earlier [16], and in accordance with Wheelock and Wheelock [58]. First, PCA, that is an unsupervised method, was used to check multivariate outliers.…”

“…Proteomics, defined as the systematic analysis of proteins expressed by an organism at a given time, under certain conditions, has become a powerful tool in bioscience to identify new disease-specific proteins [8][9][10][11]. Several proteomic studies have been successfully performed for different painful condition, e.g., rheumatoid arthritis, neuropathic pain, fibromyalgia, burning mouth syndrome, and trapezius myalgia by analyzing proteins in saliva, plasma, synovial fluid, interstitial fluid, or biopsies [12][13][14][15][16][17][18][19][20][21].…”

Plasma Protein Pattern Correlates With Pain Intensity and Psychological Distress in Women With Chronic Widespread Pain

“…The peptides were mixed in a 1:1 ratio with matrix solution (dihydroxybenzoic acid in 70% acetonitrile/0.3% TFA) and 1 μl was spotted on a target plate (stainless steel). The peptide masses were analyzed and the mass range of 300–3500 Da was used, including external mass calibration using a peptide calibration standard (Bruker) ( Olausson et al, 2017 ).…”

“…This and other studies from our group focus on exploring such activated mechanisms with the long-term goal of identifying clinically applicable biomarkers that can facilitate mechanism-based diagnoses and choice of treatments. Many biomarker studies have analyzed protein patterns, cytokines/chemokines, lipids, and metabolites in plasma/serum, muscles, and saliva to understand activated nociceptive mechanisms in patients with CWP/FMS ( Bazzichi et al, 2009 ; Zanette et al, 2014 ; Hadrevi et al, 2015 ; Culic et al, 2016 ; Gerdle et al, 2017 ; Olausson et al, 2017 ; Wåhlén et al, 2017 ). Taken together, these studies clearly indicate that peripheral (muscle and/or blood) nociceptive and inflammatory mechanisms are active and differ between patients and healthy controls.…”

Signs of ongoing inflammation in female patients with chronic widespread pain

“…[66] All in all, a broad picture emerges that characterizes FMS/CWP according to inflammation processes in muscle tissue, systemic low-grade inflammation, and central neuroinflammation. Biomarker studies of this kind are arguably an important complement to psychophysical and imaging studies that endeavor to better understand the pathophysiology of FMS/CWP and contribute to substantiating the biological part of the biopsychosocial model of chronic pain.…”