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

Patrik Olausson, Bijar Ghafouri, Emmanuel Bäckryd, Björn Gerdle, Patrik Olausson, Bijar Ghafouri, Emmanuel Bäckryd, Björn Gerdle

Abstract

Introduction: Frequent 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 methods: This 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]).

Results: There 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.

Conclusion: The 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.

Keywords: biomarkers; inflammation; muscle pain.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Images of CSF before and after albumin/IgG removal. Notes: The figure shows the “raw” CSF (A) compared to the fractionated CSF (B). Abbreviations: CSF, cerebrospinal fluid; IgG, immunoglobulin G.
Figure 2
Figure 2
An OPLS-DA (the first principal component t[1] vs. the first orthogonal component to[1]) model showing the discriminant separation between the CWP patients (green filled circles) and the CON (blue filled circles). Notes: The longitudinal dimension (Y-axis) shows the interclass discrimination, and the latitudinal dimension (X-axis) shows the intraclass discrimination between CWP and CON. Abbreviations: OPLS-DA, orthogonal partial least square discriminant analysis; CWP, chronic widespread pain; CON, healthy controls.
Figure 3
Figure 3
The 2-DE CSF proteins. Notes: The image shows the proteins important for the group separation between CWP and CON. Protein numbers that are circled had a VIP>1.3 and were highly significant for the model. Abbreviations: 2-DE, two-dimensional gel electrophoresis; CSF, cerebrospinal fluid; CWP, chronic widespread pain; CON, healthy controls; VIP, variable of importance.

References

    1. Croft P, Burt J, Schollum J, Thomas E, Macfarlane G, Silman A. More pain, more tender points: is fibromyalgia just one end of a continuous spectrum? Ann Rheum Dis. 1996;55(7):482–485.
    1. Grimby-Ekman A, Gerdle B, Björk J, Larsson B. Comorbidities, intensity, frequency and duration of pain, daily functioning and health care seeking in local, regional, and widespread pain – a descriptive population-based survey (SwePain) BMC Musculoskelet Disord. 2015;16:165.
    1. Peolsson M, Borsbo B, Gerdle B. Generalized pain is associated with more negative consequences than local or regional pain: a study of chronic whiplash-associated disorders. J Rehabil Med. 2007;39(3):260–268.
    1. Mayer TG, Towns BL, Neblett R, Theodore BR, Gatchel RJ. Chronic widespread pain in patients with occupational spinal disorders: prevalence, psychiatric comorbidity, and association with outcomes. Spine (Phila Pa 1976) 2008;33(17):1889–1897.
    1. Schaefer C, Chandran A, Hufstader M, et al. The comparative burden of mild, moderate and severe fibromyalgia: results from a cross-sectional survey in the United States. Health Qual Life Outcomes. 2011;9:71.
    1. Kamaleri Y, Natvig B, Ihlebaek CM, Benth JS, Bruusgaard D. Number of pain sites is associated with demographic, lifestyle, and health-related factors in the general population. Eur J Pain. 2008;12(6):742–748.
    1. Gerdle B, Björk J, Cöster L, Henriksson K, Henriksson C, Bengtsson A. Prevalence of widespread pain and associations with work status: a population study. BMC Musculoskelet Disord. 2008;9:102.
    1. Mansfield KE, Sim J, Jordan JL, Jordan KP. A systematic review and meta-analysis of the prevalence of chronic widespread pain in the general population. Pain. 2016;157(1):55–64.
    1. Butler S, Landmark T, Glette M, Borchgrevink P, Woodhouse A. Chronic widespread pain-the need for a standard definition. Pain. 2016;157(3):541–543.
    1. Jensen KB, Loitoile R, Kosek E, et al. Patients with fibromyalgia display less functional connectivity in the brain’s pain inhibitory network. Mol Pain. 2012;8:32.
    1. Nijs J, Kosek E, Van Oosterwijck J, Meeus M. Dysfunctional endogenous analgesia during exercise in patients with chronic pain: to exercise or not to exercise? Pain Physician. 2012;15(3 suppl):ES205–ES213.
    1. Petersel DL, Dror V, Cheung R. Central amplification and fibromyalgia: disorder of pain processing. J Neurosci Res. 2011;89(1):29–34.
    1. Heinrichera MM, Tavaresc I, Leith JL, Lumbe BM. Descending control of nociception: specificity, recruitment and plasticity. Brain Res Rev. 2009;60(1):214–225.
    1. Adler GK, Geenen R. Hypothalamic-pituitary-adrenal and autonomic nervous system functioning in fibromyalgia. Rheum Dis Clin North Am. 2005;31(1):187–202. xi.
    1. Dessein PH, Shipton EA, Stanwix AE, Joffe BI. Neuroendocrine deficiency-mediated development and persistence of pain in fibromyalgia: a promising paradigm? Pain. 2000;86(3):213–215.
    1. Bradley LA. Pathophysiology of fibromyalgia. Am J Med. 2009;122(12 suppl):S22–S30.
    1. Smith H, Harris R, Clauw D. Fibromyalgia: an afferent processing disorder leading to a complex pain generalized syndrome. Pain Physician. 2011;14(2):E217–E245.
    1. Gerdle B, Lemming D, Kristiansen J, Larsson B, Peolsson M, Rosendal L. Biochemical alterations in the trapezius muscle of patients with chronic whiplash associated disorders (WAD) – a microdialysis study. Eur J Pain. 2008;12(1):82–93.
    1. Üçeyler N, Zeller D, Kahn AK, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013;136(pt 6):1857–1867.
    1. Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013;154(11):2310–2316.
    1. Serra J, Collado A, Solà R, et al. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol. 2014;75(2):196–208.
    1. Bennett RM. Emerging concepts in the neurobiology of chronic pain: evidence of abnormal sensory processing in fibromyalgia. Mayo Clin Proc. 1999;74(4):385–398.
    1. Staud R. The role of peripheral input for chronic pain syndromes like fibromyalgia syndrome. J Musculoskelet Pain. 2008;16(1–2):67–74.
    1. Schneider GM, Smith AD, Hooper A, et al. Minimizing the source of nociception and its concurrent effect on sensory hypersensitivity: an exploratory study in chronic whiplash patients. BMC Musculoskelet Disord. 2010;11:29.
    1. Staud R, Nagel S, Robinson ME, Price DD. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double-blind, placebo-controlled study. Pain. 2009;145(1–2):96–104.
    1. Herren-Gerber R, Weiss S, Arendt-Nielsen L, et al. Modulation of central hypersensitivity by nociceptive input in chronic pain after whiplash injury. Pain Med. 2004;5(4):366–376.
    1. Staud R, Robinson ME, Weyl EE, Price DD. Pain variability in fibromyalgia is related to activity and rest: role of peripheral tissue impulse input. J Pain. 2010;11(12):1376–1383.
    1. Kosek E, Ekholm J, Hansson P. Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls. Pain. 1996;64(3):415–423.
    1. Mannes AJ, Martin BM, Yang HY, et al. Cystatin C as a cerebrospinal fluid biomarker for pain in humans. Pain. 2003;102(3):251–256.
    1. Romeo MJ, Espina V, Lowenthal M, Espina BH, Petricoin EF, 3rd, Liotta LA. CSF proteome: a protein repository for potential biomarker identification. Expert Rev Proteomics. 2005;2(1):57–70.
    1. Ortega E, García JJ, Bote ME, et al. Exercise in fibromyalgia and related inflammatory disorders: known effects and unknown chances. Exerc Immunol Rev. 2009;15:42–65.
    1. Shevchenko G, Konzer A, Musunuri S, Bergquist J. Neuroproteomics tools in clinical practice. Biochim Biophys Acta. 2015;1854(7):705–717.
    1. Johanson CE, Duncan JA, 3rd, Klinge PM, Brinker T, Stopa EG, Silver-berg GD. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res. 2008;5:10.
    1. Russell IJ, Orr MD, Littman B, et al. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum. 1994;37(11):1593–1601.
    1. Vaerøy H, Helle R, Førre O, Kåss E, Terenius L. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain. 1988;32(1):21–26.
    1. Bjurstrom MF, Giron SE, Griffis CA. Cerebrospinal fluid cytokines and neurotrophic factors in human chronic pain populations: a comprehensive review. Pain Pract. 2016;16(2):183–203.
    1. Kalso E. Biomarkers for pain. Pain. 2004;107(3):199–201.
    1. Wheelock AM, Wheelock CE. Trials and tribulations of ’omics data analysis: assessing quality of SIMCA-based multivariate models using examples from pulmonary medicine. Mol Biosyst. 2013;9(11):2589–2596.
    1. Görg A, Drews O, Lück C, Weiland F, Weiss W. 2-DE with IPGs. Electrophoresis. 2009;30(suppl 1):S122–S132.
    1. Liu XD, Zeng BF, Xu JG, Zhu HB, Xia QC. Proteomic analysis of the cerebrospinal fluid of patients with lumbar disk herniation. Proteomics. 2006;6(3):1019–1028.
    1. Conti A, Ricchiuto P, Iannaccone S, et al. Pigment epithelium-derived factor is differentially expressed in peripheral neuropathies. Proteomics. 2005;5(17):4558–4567.
    1. Lu J, Katano T, Nishimura W, et al. Proteomic analysis of cerebrospinal fluid before and after intrathecal injection of steroid into patients with postherpetic pain. Proteomics. 2012;12(19–20):3105–3112.
    1. Pattini L, Mazzara S, Conti A, Iannaccone S, Cerutti S, Alessio M. An integrated strategy in two-dimensional electrophoresis analysis able to identify discriminants between different clinical conditions. Exp Biol Med (Maywood) 2008;233(4):483–491.
    1. Cannistraci CV, Ravasi T, Montevecchi FM, Ideker T, Alessio M. Nonlinear dimension reduction and clustering by Minimum Curvilinearity unfold neuropathic pain and tissue embryological classes. Bioinformatics. 2010;26(18):i531–i539.
    1. Bäckryd E, Ghafouri B, Carlsson AK, Olausson P, Gerdle B. Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls – a hypothesis-generating pilot study. J Pain Res. 2015;8:321–333.
    1. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33(2):160–172.
    1. Sjörs A, Larsson B, Persson AL, Gerdle B. An increased response to experimental muscle pain is related to psychological status in women with chronic non-traumatic neck-shoulder pain. BMC Musculoskelet Disord. 2011;12:230.
    1. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res. 2002;52(2):69–77.
    1. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361–370.
    1. Sullivan MJL, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychol Assess. 1995;7:524–532.
    1. Osman A, Barrios FX, Gutierrez PM, Kopper BA, Merrifield T, Grittmann L. The Pain Catastrophizing Scale: further psychometric evaluation with adult samples. J Behav Med. 2000;23(4):351–365.
    1. Scott W, Wideman TH, Sullivan MJ. Clinically meaningful scores on pain catastrophizing before and after multidisciplinary rehabilitation: a prospective study of individuals with subacute pain after whiplash injury. Clin J Pain. 2014;30(3):183–190.
    1. Burckhardt CS, Archenholtz B, Bjelle A. Measuring the quality of life of women with rheumatoid arthritis or systemic lupus erythematosus: a Swedish version of the Quality of Life Scale (QOLS) Scand J Rheumatol. 1992;21(4):190–195.
    1. Osman I, Gaillard O, Meillet D, et al. A sensitive time-resolved immunofluorometric assay for the measurement of apolipoprotein B in cerebrospinal fluid. Application to multiple sclerosis and other neurological diseases. Eur J Clin Chem Clin Biochem. 1995;33(1):53–58.
    1. Olausson P, Gerdle B, Ghafouri N, Sjöström D, Blixt E, Ghafouri B. Protein alterations in women with chronic widespread pain – an explorative proteomic study of the trapezius muscle. Sci Rep. 2015;5:11894.
    1. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–254.
    1. Rosendal L, Larsson B, Kristiansen J, et al. Increase in muscle nociceptive substances and anaerobic metabolism in patients with trapezius myalgia: microdialysis in rest and during exercise. Pain. 2004;112(3):324–334.
    1. Eriksson L, Byrne T, Johansson E, Trygg J, Vikström C. Multi- and Megavariate Data Analysis: Basic Principles and Applications. 3rd revised ed. Malmö: MKS Umetrics AB; 2013.
    1. Scalia P, Heart E, Comai L, Vigneri R, Sung CK. Regulation of the Akt/Glycogen synthase kinase-3 axis by insulin-like growth factor-II via activation of the human insulin receptor isoform-A. J Cell Biochem. 2001;82(4):610–618.
    1. Hughes A, Mohanasundaram D, Kireta S, Jessup CF, Drogemuller CJ, Coates PT. Insulin-Like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation. Transplantation. 2013;95(5):671–678.
    1. Hughes A, Rojas-Canales D, Drogemuller C, Voelcker NH, Grey ST, Coates PT. IGF2: an endocrine hormone to improve islet transplant survival. J Endocrinol. 2014;221(2):R41–R48.
    1. Yeh CC, Sun HL, Huang CJ, et al. Long-term anti-allodynic effect of immediate pulsed radiofrequency modulation through down-regulation of insulin-like growth factor 2 in a neuropathic pain model. Int J Mol Sci. 2015;16(11):27156–27170.
    1. Chen X, Kong X, Zhang Z, et al. Alpha-2-macroglobulin as a radio-protective agent: a review. Chin J Cancer Res. 2014;26(5):611–621.
    1. Rehman AA, Ahsan H, Khan FH. alpha-2-Macroglobulin: a physiological guardian. J Cell Physiol. 2013;228(8):1665–1675.
    1. Bhamra MS, Ashton NJ. Finding a pathological diagnosis for Alzheimer’s disease: are inflammatory molecules the answer? Electrophoresis. 2012;33(24):3598–3607.
    1. Kanoh Y, Ohtani H. Levels of interleukin-6, CRP and alpha 2 macroglobulin in cerebrospinal fluid (CSF) and serum as indicator of blood-CSF barrier damage. Biochem Mol Biol Int. 1997;43(2):269–278.
    1. Hayes LN, Severance EG, Leek JT, et al. Inflammatory molecular signature associated with infectious agents in psychosis. Schizophr Bull. 2014;40(5):963–972.
    1. Ditzen C, Tang N, Jastorff AM, et al. Cerebrospinal fluid biomarkers for major depression confirm relevance of associated pathophysiology. Neuropsychopharmacology. 2012;37(4):1013–1025.
    1. Diaz-Ramos A, Roig-Borrellas A, García-Melero A, López-Alemany R. alpha-Enolase, a multifunctional protein: its role on pathophysiological situations. J Biomed Biotechnol. 2012;2012:156795.
    1. Royds JA, Davies-Jones GA, Lewtas NA, Timperley WR, Taylor CB. Enolase isoenzymes in the cerebrospinal fluid of patients with diseases of the nervous system. J Neurol Neurosurg Psychiatry. 1983;46(11):1031–1036.
    1. Ohashi K, Hara M, Kawai R, et al. Cervical discs are most susceptible to beta 2-microglobulin amyloid deposition in the vertebral column. Kidney Int. 1992;41(6):1646–1652.
    1. Svatoňová J, Bořecká K, Adam P, Lánská V. Beta2-microglobulin as a diagnostic marker in cerebrospinal fluid: a follow-up study. Dis Markers. 2014;2014:495402.
    1. Anckarsäter R, Vasic N, Jidéus L, et al. Cerebrospinal fluid protein reactions during non-neurological surgery. Acta Neurol Scand. 2007;115(4):254–259.
    1. Buchwald D, Wener MH, Pearlman T, Kith P. Markers of inflammation and immune activation in chronic fatigue and chronic fatigue syndrome. J Rheumatol. 1997;24(2):372–376.
    1. Kepplinger B, Baran H, Kainz A, Ferraz-Leite H, Newcombe J, Kalina P. Age-related increase of kynurenic acid in human cerebrospinal fluid – IgG and beta2-microglobulin changes. Neurosignals. 2005;14(3):126–135.
    1. Zellner M, Veitinger M, Umlauf E. The role of proteomics in dementia and Alzheimer’s disease. Acta Neuropathol. 2009;118(1):181–195.
    1. Matejčíková Z, Mareš J, Přikrylová Vranová H, et al. Cerebrospinal fluid inflammatory markers in patients with multiple sclerosis: a pilot study. J Neural Transm (Vienna) 2015;122(2):273–277.
    1. Carrieri PB, Indaco A, Maiorino A, et al. Cerebrospinal fluid beta-2-microglobulin in multiple sclerosis and AIDS dementia complex. Neurol Res. 1992;14(3):282–283.
    1. Sladkova V, Mareš J, Lubenova B, et al. Degenerative and inflammatory markers in the cerebrospinal fluid of multiple sclerosis patients with relapsing-remitting course of disease and after clinical isolated syndrome. Neurol Res. 2011;33(4):415–420.
    1. Herbert J, Wilcox JN, Pham KT, et al. Transthyretin: a choroid plexus-specific transport protein in human brain. The 1986 S. Weir Mitchell award. Neurology. 1986;36(7):900–911.
    1. Chanoine JP, Alex S, Fang SL, et al. Role of transthyretin in the transport of thyroxine from the blood to the choroid plexus, the cerebrospinal fluid, and the brain. Endocrinology. 1992;130(2):933–938.
    1. Chanoine JP, Braverman LE. The role of transthyretin in the transport of thyroid hormone to cerebrospinal fluid and brain. Acta Med Austriaca. 1992;19(suppl 1):25–28.
    1. Rialland P, Otis C, de Courval ML, et al. Assessing experimental visceral pain in dairy cattle: a pilot, prospective, blinded, randomized, and controlled study focusing on spinal pain proteomics. J Dairy Sci. 2014;97(4):2118–2134.
    1. Sullivan GM, Mann JJ, Oquendo MA, Lo ES, Cooper TB, Gorman JM. Low cerebrospinal fluid transthyretin levels in depression: correlations with suicidal ideation and low serotonin function. Biol Psychiatry. 2006;60(5):500–506.
    1. Huang JT, Leweke FM, Oxley D, et al. Disease biomarkers in cerebrospinal fluid of patients with first-onset psychosis. PLoS Med. 2006;3(11):e428.
    1. Maetzler W, Tian Y, Baur SM, et al. Serum and cerebrospinal fluid levels of transthyretin in Lewy body disorders with and without dementia. PLoS One. 2012;7(10):e48042.
    1. Strekalova H, Buhmann C, Kleene R, et al. Elevated levels of neural recognition molecule L1 in the cerebrospinal fluid of patients with Alzheimer disease and other dementia syndromes. Neurobiol Aging. 2006;27(1):1–9.
    1. Weledji EP, Assob JC. The ubiquitous neural cell adhesion molecule (N-CAM) Ann Med Surg (Lond) 2014;3(3):77–81.
    1. Sakai A, Asada M, Seno N, Suzuki H. Involvement of neural cell adhesion molecule signaling in glial cell line-derived neurotrophic factor-induced analgesia in a rat model of neuropathic pain. Pain. 2008;137(2):378–388.
    1. Gnanapavan S, Grant D, Illes-Toth E, Lakdawala N, Keir G, Giovannoni G. Neural cell adhesion molecule – description of a CSF ELISA method and evidence of reduced levels in selected neurological disorders. J Neuroimmunol. 2010;225(1–2):118–122.
    1. Jorgensen OS. Neural cell adhesion molecule (NCAM) and prealbumin in cerebrospinal fluid from depressed patients. Acta Psychiatr Scand Suppl. 1988;345:29–37.
    1. Daniloff JK, Levi G, Grumet M, Rieger F, Edelman GM. Altered expression of neuronal cell adhesion molecules induced by nerve injury and repair. J Cell Biol. 1986;103(3):929–945.
    1. Tzeng SF, Cheng H, Lee YS, Wu JP, Hoffer BJ, Kuo JS. Expression of neural cell adhesion molecule in spinal cords following a complete transection. Life Sci. 2001;68(9):1005–1012.
    1. Abraham JD, Calvayrac-Pawlowski S, Cobo S, et al. Combined measurement of PEDF, haptoglobin and tau in cerebrospinal fluid improves the diagnostic discrimination between Alzheimer’s disease and other dementias. Biomarkers. 2011;16(2):161–171.
    1. Tombran-Tink J, Barnstable CJ. PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci. 2003;4(8):628–636.
    1. Craword SE, Fitchev P, Veliceasa D, Volpert OV. The many facets of PEDF in drug discovery and disease: a diamond in the rough or split personality disorder? Expert Opin Drug Discov. 2013;8(7):769–792.
    1. Baraniuk JN, Casado B, Maibach H, Clauw DJ, Pannell LK, Hess SS. A Chronic Fatigue Syndrome – related proteome in human cerebrospinal fluid. BMC Neurol. 2005;5:22.
    1. Amano S, Yamagishi S, Inagaki Y, et al. Pigment epithelium-derived factor inhibits oxidative stress-induced apoptosis and dysfunction of cultured retinal pericytes. Microvasc Res. 2005;69(1–2):45–55.
    1. Praissman JL, Live DH, Wang S, et al. B4GAT1 is the priming enzyme for the LARGE-dependent functional glycosylation of alpha-dystroglycan. Elife. 2014;3:e03943.
    1. Buysse K, Riemersma M, Powell G, et al. Missense mutations in beta-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome. Hum Mol Genet. 2013;22(9):1746–1754.
    1. Kingwell BA. Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease. FASEB J. 2000;14(12):1685–1696.
    1. Akyol O, Zoroglu SS, Armutcu F, Sahin S, Gurel A. Nitric oxide as a physiopathological factor in neuropsychiatric disorders. In Vivo. 2004;18(3):377–390.
    1. Larson AA, Giovengo SL, Russell IJ, Michalek JE. Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain. 2000;87(2):201–211.
    1. Russell IJ, Michalek JE, Flechas JD, Abraham GE. Treatment of fibromyalgia syndrome with Super Malic: a randomized, double blind, placebo controlled, crossover pilot study. J Rheumatol. 1995;22(5):953–958.
    1. Harada S, Matsuura W, Takano M, Tokuyama S. Proteomic profiling in the spinal cord and sciatic nerve in a global cerebral ischemia-induced mechanical allodynia mouse model. Biol Pharm Bull. 2016;39(2):230–238.
    1. Heywood WE, Galimberti D, Bliss E, et al. Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay. Mol Neurodegener. 2015;10:64.
    1. Ahn VE, Chu ML, Choi HJ, Tran D, Abo A, Weis WI. Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6. Dev Cell. 2011;21(5):862–873.
    1. Bruggink KA, Kuiperij HB, Gloerich J, et al. Dickkopf-related protein 3 is a potential Abeta-associated protein in Alzheimer’s Disease. J Neurochem. 2015;134(6):1152–1162.
    1. Kroksveen AC, Guldbrandsen A, Vedeler C, Myhr KM, Opsahl JA, Berven FS. Cerebrospinal fluid proteome comparison between multiple sclerosis patients and controls. Acta Neurol Scand. 2012;126:90–96.
    1. Walker AK, Kavelaars A, Heijnen CJ, Dantzer R. Neuroinflammation and comorbidity of pain and depression. Pharmacol Rev. 2014;66(1):80–101.
    1. Kosek E, Altawil R, Kadetoff D, et al. Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain – interleukin-8 in fibromyalgia and interleukin-1 beta in rheumatoid arthritis. J Neuroimmunol. 2015;280:49–55.
    1. Olausson P, Gerdle B, Ghafouri N, Larsson B, Ghafouri B. Identification of proteins from interstitium of trapezius muscle in women with chronic myalgia using microdialysis in combination with proteomics. PLoS One. 2012;7(12):e52560.
    1. Olausson P, Gerdle B, Ghafouri N, Sjöström D, Blixt E, Ghafouri B. Protein alterations in women with chronic widespread pain – an explorative proteomic study of the trapezius muscle. Sci Rep. 2015;5:11894.
    1. González-Marrero I, Castañeyra-Ruiz L, González-Toledo JM, et al. High blood pressure effects on the blood to cerebrospinal fluid barrier and cerebrospinal fluid protein composition: a two-dimensional electrophoresis study in spontaneously hypertensive rats. Int J Hypertens. 2013;2013:164653.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj