title: Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls - a hypothesis-generating pilot study.
abstract: Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin-angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin-angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.
authors.affiliation: Division of Community Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden ; Pain and Rehabilitation Centre, Anaesthetics, Operations and Specialty Surgery Centre, Region Östergötland, Linköping, Sweden.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bäckryd
authors.affiliation: Division of Community Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden ; Pain and Rehabilitation Centre, Anaesthetics, Operations and Specialty Surgery Centre, Region Östergötland, Linköping, Sweden.
authors.forename: Bijar
authors.initials: B
authors.lastname: Ghafouri
authors.affiliation: Division of Community Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden ; Pain and Rehabilitation Centre, Anaesthetics, Operations and Specialty Surgery Centre, Region Östergötland, Linköping, Sweden.
authors.forename: Anders K
authors.initials: AK
authors.lastname: Carlsson
authors.affiliation: Division of Community Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden ; Pain and Rehabilitation Centre, Anaesthetics, Operations and Specialty Surgery Centre, Region Östergötland, Linköping, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Olausson
authors.affiliation: Division of Community Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden ; Pain and Rehabilitation Centre, Anaesthetics, Operations and Specialty Surgery Centre, Region Östergötland, Linköping, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Gerdle
keywords: cerebrospinal fluid; multivariate data analysis; neuropathic pain; proteomics