Cerebrospinal Fluid Inflammatory Markers in Alzheimer’s Disease: Influence of Comorbidities

Author(s): Ying Wang, Ceren Emre, Helena Gyllenhammar-Schill, Karin Fjellman, Helga Eyjolfsdottir, Maria Eriksdotter, Marianne Schultzberg, Erik Hjorth*

Journal Name: Current Alzheimer Research

Volume 18 , Issue 2 , 2021

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Background: Alzheimer's disease (AD) develops into dementia after several years, and subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are used as intermediary diagnoses of increasing severity. Inflammation is an important part of AD pathology and provides potential novel biomarkers and treatment targets.

Objective: To identify novel potential biomarkers of AD in cerebrospinal fluid (CSF) and create a molecular pattern of inflammatory factors providing differentiation between AD and SCI.

Methods: We analyzed 43 inflammatory-related mediators in CSF samples from a cohort of SCI and AD cases vetted for confounding factors (Training cohort). Using multivariate analysis (MVA), a model for discrimination between SCI and AD was produced, which we then applied to a larger nonvetted cohort (named Test cohort). The data were analyzed for factors showing differences between diagnostic groups and factors that differed between the vetted and non-vetted cohorts. The relationship of the factors to the agreement between model and clinical diagnosis was investigated.

Results: A good MVA model able to discriminate AD from SCI without including tangle and plaque biomarkers was produced from the Training cohort. The model showed 50% agreement with clinical diagnosis in the Test cohort. Comparison of the cohorts indicated different patterns of factors distinguishing SCI from AD. As an example, soluble interleukin (IL)-6Rα showed lower levels in AD cases in the Training cohort, whereas placental growth factor (PlGF) and serum amyloid A (SAA) levels were higher in AD cases of the Test cohort. The levels of p-tau were also higher in the Training cohort.

Conclusion: This study provides new knowledge regarding the involvement of inflammation in AD by indicating different patterns of factors in CSF depending on whether potential confounding comorbidities are present or not, and presents sIL-6Rα as a potential new biomarker for improved diagnosis of AD.

Keywords: Alzheimer's disease, biomarker, cerebrospinal fluid, diagnosis, inflammation, multivariate analysis.

Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14(4): 535-62.
[http://dx.doi.org/10.1016/j.jalz.2018.02.018 ] [PMID: 29653606]
Reisberg B, Prichep L, Mosconi L, et al. The pre-mild cognitive impairment, subjective cognitive impairment stage of Alzheimer’s disease. Alzheimers Dement 2008; 4(1): S98-S108.
[http://dx.doi.org/10.1016/j.jalz.2007.11.017 ] [PMID: 18632010]
Goedert M, Masuda-Suzukake M, Falcon B. Like prions: The propagation of aggregated tau and α-synuclein in neurodegeneration. Brain 2017; 140(2): 266-78.
[http://dx.doi.org/10.1093/brain/aww230 ] [PMID: 27658420]
Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: A systematic review and meta-analysis. Lancet Neurol 2016; 15(7): 673-84.
[http://dx.doi.org/10.1016/S1474-4422(16)00070-3 ] [PMID: 27068280]
Lue LF, Brachova L, Civin WH, Rogers J. Inflammation, A β deposition, and neurofibrillary tangle formation as correlates of Alzheimer’s disease neurodegeneration. J Neuropathol Exp Neurol 1996; 55(10): 1083-8.
[http://dx.doi.org/10.1097/00005072-199655100-00008 ] [PMID: 8858005]
Knopman DS, Haeberlein SB, Carrillo MC, et al. The national institute on aging and the Alzheimer’s association research framework for Alzheimer’s disease: Perspectives from the research roundtable. Alzheimers Dement 2018; 14(4): 563-75.
[http://dx.doi.org/10.1016/j.jalz.2018.03.002 ] [PMID: 29653607]
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015; 14(4): 388-405.
[http://dx.doi.org/10.1016/S1474-4422(15)70016-5 ] [PMID: 25792098]
Kobro-Flatmoen A, Lagartos-Donate MJ, Aman Y, Edison P, Witter MP, Fang EF. Re-emphasizing early Alzheimer’s disease pathology starting in select entorhinal neurons, with a special focus on mitophagy. Ageing Res Rev 2021; 67101307
[http://dx.doi.org/10.1016/j.arr.2021.101307 ] [PMID: 33621703]
Fang EF, Hou Y, Palikaras K, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci 2019; 22(3): 401-12.
[http://dx.doi.org/10.1038/s41593-018-0332-9 ] [PMID: 30742114]
Kuehn BM. In Alzheimer research, glucose metabolism moves to center stage. JAMA 2020; 323(4): 297-9.
[http://dx.doi.org/10.1001/jama.2019.20939 ] [PMID: 31913419]
Janota C, Lemere CA, Brito MA. Dissecting the contribution of vascular alterations and aging to Alzheimer’s disease. Mol Neurobiol 2016; 53(6): 3793-811.
[http://dx.doi.org/10.1007/s12035-015-9319-7 ] [PMID: 26143259]
Hamelin L, Lagarde J, Dorothée G, et al. Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer’s disease. Brain 2018; 141(6): 1855-70.
[http://dx.doi.org/10.1093/brain/awy079 ] [PMID: 29608645]
Chen X, Hu Y, Cao Z, Liu Q, Cheng Y. Cerebrospinal fluid inflammatory cytokine aberrations in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis: A systematic review and meta-analysis. Front Immunol 2018; 9: 2122.
[http://dx.doi.org/10.3389/fimmu.2018.02122 ] [PMID: 30283455]
Cacabelos R, Barquero M, García P, Alvarez XA, Varela de Seijas E. Cerebrospinal fluid interleukin-1 β (IL-1 β) in Alzheimer’s disease and neurological disorders. Methods Find Exp Clin Pharmacol 1991; 13(7): 455-8.
[PMID: 1784142]
Griffin WS, Stanley LC, Ling C, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 1989; 86(19): 7611-5.
[http://dx.doi.org/10.1073/pnas.86.19.7611 ] [PMID: 2529544]
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3): 189-98.
[http://dx.doi.org/10.1016/0022-3956(75)90026-6 ] [PMID: 1202204]
Naik M, Nygaard HA. Diagnosing dementia -- ICD-10 not so bad after all: A comparison between dementia criteria according to DSM-IV and ICD-10. Int J Geriatr Psychiatry 2008; 23(3): 279-82.
[http://dx.doi.org/10.1002/gps.1874 ] [PMID: 17702050]
Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment--beyond controversies, towards a consensus: Report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004; 256(3): 240-6.
[http://dx.doi.org/10.1111/j.1365-2796.2004.01380.x ] [PMID: 15324367]
Reisberg B, Gauthier S. Current evidence for subjective cognitive impairment (SCI) as the pre-mild cognitive impairment (MCI) stage of subsequently manifest Alzheimer’s disease. Int Psychogeriatr 2008; 20(1): 1-16.
[http://dx.doi.org/10.1017/S1041610207006412 ] [PMID: 18072981]
Lee JW, Devanarayan V, Barrett YC, et al. Fit-for-purpose method development and validation for successful biomarker measurement. Pharm Res 2006; 23(2): 312-28.
[http://dx.doi.org/10.1007/s11095-005-9045-3 ] [PMID: 16397743]
McGeer PL, McGeer EG. The inflammatory response system of brain: Implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995; 21(2): 195-218.
[http://dx.doi.org/10.1016/0165-0173(95)00011-9 ] [PMID: 8866675]
El Khoury JB, Moore KJ, Means TK, et al. CD36 mediates the innate host response to β-amyloid. J Exp Med 2003; 197(12): 1657-66.
[http://dx.doi.org/10.1084/jem.20021546 ] [PMID: 12796468]
Ban E, Milon G, Prudhomme N, Fillion G, Haour F. Receptors for interleukin-1 (α and β) in mouse brain: Mapping and neuronal localization in hippocampus. Neuroscience 1991; 43(1): 21-30.
[http://dx.doi.org/10.1016/0306-4522(91)90412-H ] [PMID: 1833666]
Maphis N, Xu G, Kokiko-Cochran ON, et al. Loss of tau rescues inflammation-mediated neurodegeneration. Front Neurosci 2015; 9: 196.
[http://dx.doi.org/10.3389/fnins.2015.00196 ] [PMID: 26089772]
Li Y, Liu L, Barger SW, Griffin WS. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 2003; 23(5): 1605-11.
[http://dx.doi.org/10.1523/JNEUROSCI.23-05-01605.2003 ] [PMID: 12629164]
Lee YJ, Kim JE, Kwak MH, et al. Selenium treatment significantly inhibits tumor necrosis factor-α-induced cell death and tau hyperphosphorylation in neuroblastoma cells. Mol Med Rep 2014; 10(4): 1869-74.
[http://dx.doi.org/10.3892/mmr.2014.2442 ] [PMID: 25109896]
Brown GC, Neher JJ. Microglial phagocytosis of live neurons. Nat Rev Neurosci 2014; 15(4): 209-16.
[http://dx.doi.org/10.1038/nrn3710 ] [PMID: 24646669]
Rajendran L, Paolicelli RC. Microglia-mediated synapse loss in Alzheimer’s disease. J Neurosci 2018; 38(12): 2911-9.
[http://dx.doi.org/10.1523/JNEUROSCI.1136-17.2017 ] [PMID: 29563239]
Cumiskey D, Pickering M, O’Connor JJ. Interleukin-18 mediated inhibition of LTP in the rat dentate gyrus is attenuated in the presence of mGluR antagonists. Neurosci Lett 2007; 412(3): 206-10.
[http://dx.doi.org/10.1016/j.neulet.2006.11.007 ] [PMID: 17123727]
Lynch MA. Neuroinflammatory changes negatively impact on LTP: A focus on IL-1β. Brain Res 2015; 1621: 197-204.
Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 2011; 25(2): 181-213.
[http://dx.doi.org/10.1016/j.bbi.2010.10.015 ] [PMID: 20970492]
Llano DA, Devanarayan V, Simon AJ. Evaluation of plasma proteomic data for Alzheimer disease state classification and for the prediction of progression from mild cognitive impairment to Alzheimer disease. Alzheimer Dis Assoc Disord 2013; 27(3): 233-43.
[http://dx.doi.org/10.1097/WAD.0b013e31826d597a ] [PMID: 23023094]
Wang T, Wang BR, Zhao HZ, et al. Lipopolysaccharide up-regulates IL-6R α expression in cultured leptomeningeal cells via activation of ERK1/2 pathway. Neurochem Res 2008; 33(9): 1901-10.
[http://dx.doi.org/10.1007/s11064-008-9667-z ] [PMID: 18357518]
Birner P, Heider S, Petzelbauer P, et al. Interleukin-6 receptor α blockade improves skin lesions in a murine model of systemic lupus erythematosus. Exp Dermatol 2016; 25(4): 305-10.
[http://dx.doi.org/10.1111/exd.12934 ] [PMID: 26739431]
Ito Y, Yamamoto M, Li M, et al. Differential temporal expression of mRNAs for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTFR α, LIFR β, IL-6R α and gp130) in injured peripheral nerves. Brain Res 1998; 793(1-2): 321-7.
[http://dx.doi.org/10.1016/S0006-8993(98)00242-X ] [PMID: 9630704]
Baran P, Hansen S, Waetzig GH, et al. The balance of interleukin (IL)-6, IL-6•soluble IL-6 receptor (sIL-6R), and IL-6•sIL-6R•sgp130 complexes allows simultaneous classic and trans-signaling. J Biol Chem 2018; 293(18): 6762-75.
[http://dx.doi.org/10.1074/jbc.RA117.001163 ] [PMID: 29559558]
Rose-John S. The soluble interleukin 6 receptor: Advanced therapeutic options in inflammation. Clin Pharmacol Ther 2017; 102(4): 591-8.
[http://dx.doi.org/10.1002/cpt.782 ] [PMID: 28675418]
Carpenter LL, Gawuga CE, Tyrka AR, Lee JK, Anderson GM, Price LH. Association between plasma IL-6 response to acute stress and early-life adversity in healthy adults. Neuropsychopharmacology 2010; 35(13): 2617-23.
[http://dx.doi.org/10.1038/npp.2010.159 ] [PMID: 20881945]
Ting EY, Yang AC, Tsai SJ. Role of interleukin-6 in depressive disorder. Int J Mol Sci 2020; 21(6): 2194.
[http://dx.doi.org/10.3390/ijms21062194 ] [PMID: 32235786]
Newton TL, Fernandez-Botran R, Miller JJ, Burns VE. Interleukin-6 and soluble interleukin-6 receptor levels in posttraumatic stress disorder: Associations with lifetime diagnostic status and psychological context. Biol Psychol 2014; 99: 150-9.
[http://dx.doi.org/10.1016/j.biopsycho.2014.03.009 ] [PMID: 24695006]
Maes M, Lin AH, Delmeire L, et al. Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biol Psychiatry 1999; 45(7): 833-9.
[http://dx.doi.org/10.1016/S0006-3223(98)00131-0 ] [PMID: 10202570]
Clausen BH, Lambertsen KL, Dagnæs-Hansen F, et al. Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke. Acta Neuropathol 2016; 131(5): 775-91.
[http://dx.doi.org/10.1007/s00401-016-1541-5 ] [PMID: 26860727]
Oprica M, Hjorth E, Spulber S, et al. Studies on brain volume, Alzheimer-related proteins and cytokines in mice with chronic overexpression of IL-1 receptor antagonist. J Cell Mol Med 2007; 11(4): 810-25.
[http://dx.doi.org/10.1111/j.1582-4934.2007.00074.x ] [PMID: 17760842]
Spulber S, Mateos L, Oprica M, et al. Impaired long term memory consolidation in transgenic mice overexpressing the human soluble form of IL-1ra in the brain. J Neuroimmunol 2009; 208(1-2): 46-53.
[http://dx.doi.org/10.1016/j.jneuroim.2009.01.010 ] [PMID: 19211154]
Tarkowski E, Liljeroth AM, Nilsson A, Minthon L, Blennow K. Decreased levels of intrathecal interleukin 1 receptor antagonist in Alzheimer’s disease. Dement Geriatr Cogn Disord 2001; 12(5): 314-7.
[http://dx.doi.org/10.1159/000051276 ] [PMID: 11455132]
Taipa R. Proinflammatory and anti-inflammatory cytokines in the CSF of patients with Alzheimer’s disease and their correlation with cognitive decline. Neurobiol Aging 2019; 76: 125-32.
Janelidze S, Mattsson N, Stomrud E, et al. CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease. Neurology 2018; 91(9): e867-77.
[http://dx.doi.org/10.1212/WNL.0000000000006082 ] [PMID: 30054439]
Li M, Li Z, Yao Y, et al. Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity. Proc Natl Acad Sci USA 2017; 114(3): E396-405.
[http://dx.doi.org/10.1073/pnas.1612930114 ] [PMID: 27994144]
Wang X, Zhu M, Hjorth E, et al. Resolution of inflammation is altered in Alzheimer's disease 2015.
Zhou Z, Peng X, Insolera R, Fink DJ, Mata M. IL-10 promotes neuronal survival following spinal cord injury. Exp Neurol 2009; 220(1): 183-90.
[http://dx.doi.org/10.1016/j.expneurol.2009.08.018 ] [PMID: 19716366]
Gao Y, Tu D, Yang R, Chu CH, Hong JS, Gao HM. Through reducing ROS production, IL-10 suppresses caspase-1-dependent IL-1β maturation, thereby preventing chronic neuroinflammation and neurodegeneration. Int J Mol Sci 2020; 21(2): 465.
[http://dx.doi.org/10.3390/ijms21020465 ] [PMID: 31940754]
Fouda AY, Pillai B, Dhandapani KM, Ergul A, Fagan SC. Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury. Eur J Pharmacol 2017; 799: 128-34.
[http://dx.doi.org/10.1016/j.ejphar.2017.02.016 ] [PMID: 28192099]
Ryu JK, Cho T, Choi HB, Jantaratnotai N, McLarnon JG. Pharmacological antagonism of interleukin-8 receptor CXCR2 inhibits inflammatory reactivity and is neuroprotective in an animal model of Alzheimer’s disease. J Neuroinflammation 2015; 12: 144.
[http://dx.doi.org/10.1186/s12974-015-0339-z ] [PMID: 26255110]
Chakrabarty P, Ceballos-Diaz C, Beccard A, et al. IFN-γ promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice. J Immunol 2010; 184(9): 5333-43.
[http://dx.doi.org/10.4049/jimmunol.0903382 ] [PMID: 20368278]
Monsonego A, Imitola J, Petrovic S, et al. Abeta-induced meningoencephalitis is IFN-γ-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2006; 103(13): 5048-53.
[http://dx.doi.org/10.1073/pnas.0506209103 ] [PMID: 16549802]
Monteiro S, Ferreira FM, Pinto V, et al. Absence of IFNγ promotes hippocampal plasticity and enhances cognitive performance. Transl Psychiatry 2016; 6e707
Zhang J, He H, Qiao Y, et al. Priming of microglia with IFN-γ impairs adult hippocampal neurogenesis and leads to depression-like behaviors and cognitive defects. Glia 2020; 68(12): 2674-92.
[http://dx.doi.org/10.1002/glia.23878 ] [PMID: 32652855]
Liu J, Gao L, Zang D. Elevated levels of IFN-γ in CSF and serum of patients with amyotrophic lateral sclerosis. PLoS One 2015; 10(9)e0136937
[http://dx.doi.org/10.1371/journal.pone.0136937 ] [PMID: 26332465]
Cao X, Chen P. Changes in serum amyloid A (SAA) and 8-OHdG in patients with senile early cognitive impairment. Med Sci Monit 2020; 26e919586
Sack GH Jr. Serum amyloid A - a review. Mol Med 2018; 24(1): 46.
[http://dx.doi.org/10.1186/s10020-018-0047-0 ] [PMID: 30165816]
O’Hara R, Murphy EP, Whitehead AS, FitzGerald O, Bresnihan B. Acute-phase serum amyloid A production by rheumatoid arthritis synovial tissue. Arthritis Res 2000; 2(2): 142-4.
[http://dx.doi.org/10.1186/ar78 ] [PMID: 11062604]
Chen ES, Song Z, Willett MH, et al. Serum amyloid A regulates granulomatous inflammation in sarcoidosis through toll-like receptor-2. Am J Respir Crit Care Med 2010; 181(4): 360-73.
[http://dx.doi.org/10.1164/rccm.200905-0696OC ] [PMID: 19910611]
Brosseron F, Traschütz A, Widmann CN, et al. Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer’s disease. Alzheimers Res Ther 2018; 10(1): 25.
[http://dx.doi.org/10.1186/s13195-018-0353-3 ] [PMID: 29482610]
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473(7347): 298-307.
[http://dx.doi.org/10.1038/nature10144 ] [PMID: 21593862]
Greenberg SM, Bacskai BJ, Hernandez-Guillamon M, Pruzin J, Sperling R, van Veluw SJ. Cerebral amyloid angiopathy and Alzheimer disease - one peptide, two pathways. Nat Rev Neurol 2020; 16(1): 30-42.
[http://dx.doi.org/10.1038/s41582-019-0281-2 ] [PMID: 31827267]
Biron KE, Dickstein DL, Gopaul R, Jefferies WA, Jefferies WA. Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer’s disease. PLoS One 2011; 6(8)e23789
[http://dx.doi.org/10.1371/journal.pone.0023789 ] [PMID: 21909359]
Du H, Li P, Pan Y, et al. Vascular endothelial growth factor signaling implicated in neuroprotective effects of placental growth factor in an in vitro ischemic model. Brain Res 2010; 1357: 1-8.
[http://dx.doi.org/10.1016/j.brainres.2010.07.015 ] [PMID: 20637183]
Liu H, Honmou O, Harada K, et al. Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. Brain 2006; 129(Pt 10): 2734-45.
[http://dx.doi.org/10.1093/brain/awl207 ] [PMID: 16901914]
Khurana R, Moons L, Shafi S, et al. Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation. Circulation 2005; 111(21): 2828-36.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.104.495887 ] [PMID: 15911697]
Sainz J, Sata M. Is PlGF a plaque growth factor? Cardiovasc Res 2010; 86(1): 4-5.
[http://dx.doi.org/10.1093/cvr/cvq037 ] [PMID: 20123695]
Yoo SA, Yoon HJ, Kim HS, et al. Role of placenta growth factor and its receptor flt-1 in rheumatoid inflammation: A link between angiogenesis and inflammation. Arthritis Rheum 2009; 60(2): 345-54.
[http://dx.doi.org/10.1002/art.24289 ] [PMID: 19180491]
Saccenti E, Timmerman ME. Approaches to sample size determination for multivariate data: Applications to PCA and PLS-DA of omics data. J Proteome Res 2016; 15(8): 2379-93.
[http://dx.doi.org/10.1021/acs.jproteome.5b01029 ] [PMID: 27322847]
Pang Z, Wang G, Wang C, Zhang W, Liu J, Wang F. Serum metabolomics analysis of asthma in different inflammatory phenotypes: A cross-sectional study in Northeast China. BioMed Res Int 2018; 20182860521
[http://dx.doi.org/10.1155/2018/2860521 ] [PMID: 30345296]
Sjöbom U, Christenson K, Hellström A, Nilsson AK. Inflammatory markers in suction blister fluid: A comparative study between interstitial fluid and plasma. Front Immunol 2020; 11597632
[http://dx.doi.org/10.3389/fimmu.2020.597632 ] [PMID: 33224151]
Probert F, Walsh A, Jagielowicz M, et al. Plasma nuclear magnetic resonance metabolomics discriminates between high and low endoscopic activity and predicts progression in a prospective cohort of patients with ulcerative colitis. J Crohn’s Colitis 2018; 12(11): 1326-37.
[http://dx.doi.org/10.1093/ecco-jcc/jjy101 ] [PMID: 30016408]
Peng Y, Ren H, Tao H, et al. Metabolomics study of the anti-inflammatory effects of endogenous ω-3 polyunsaturated fatty acids. RSC Advances 2019; 9(71): 41903-12.
Ma H, Hong M, Duan J, et al. Altered cytokine gene expression in peripheral blood monocytes across the menstrual cycle in primary dysmenorrhea: A case-control study. PLoS One 2013; 8(2)e55200
[http://dx.doi.org/10.1371/journal.pone.0055200 ] [PMID: 23390521]

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Year: 2021
Published on: 30 March, 2021
Page: [157 - 170]
Pages: 14
DOI: 10.2174/1567205018666210330162207

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