Previous studies evidenced a link between metabolic dysregulation, inflammation, and neurodegeneration in multiple sclerosis (MS).
Objectives:
To explore whether increased adipocyte mass expressed as body mass index (BMI) and increased serum lipids influence cerebrospinal fluid (CSF) inflammation and disease severity.
Methods:
In this cross-sectional study, 140 consecutive relapsing-remitting (RR)-MS patients underwent clinical assessment, BMI evaluation, magnetic resonance imaging scan, and blood and CSF collection before any specific drug treatment. The CSF levels of the following cytokines, adipocytokines, and inflammatory factors were measured: interleukin (IL)-6, IL-13, granulocyte macrophage colony-stimulating factor, leptin, ghrelin, osteoprotegerin, osteopontin, plasminogen activator inhibitor-1, resistin, and Annexin A1. Serum levels of triglycerides, total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C) were assessed.
Results:
A positive correlation emerged between BMI and Expanded Disability Status Scale score. Obese RR-MS patients showed higher clinical disability, increased CSF levels of the proinflammatory molecules IL-6 and leptin, and reduced concentrations of the anti-inflammatory cytokine IL-13. Moreover, both the serum levels of triglycerides and TC/HDL-C ratio showed a positive correlation with IL-6 CSF concentrations.
Conclusion:
Obesity and altered lipid profile are associated with exacerbated central inflammation and higher clinical disability in RR-MS at the time of diagnosis. Increased adipocytokines and lipids can mediate the negative impact of high adiposity on RR-MS course.
de CandiaPMatareseG. Leptin and ghrelin: Sewing metabolism onto neurodegeneration. Neuropharmacology2017; 15(Pt B): 307–316.
2.
De RosaVLa CavaAMatareseG. Metabolic pressure and the breach of immunological self-tolerance. Nat Immunol2017; 18(11): 1190–1196.
3.
ConsidineRVSinhaMKHeimanML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med1996; 334(5): 292–295.
4.
RoytblatLRachinskyMFisherA, et al. Raised interleukin-6 levels in obese patients. Obes Res2000; 8(9): 673–675.
5.
SannaVDi GiacomoALa CavaA, et al. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J Clin Invest2003; 111(2): 241–250.
6.
MatareseGCarrieriPBLa CavaA, et al. Leptin increase in multiple sclerosis associates with reduced number of CD4+CD25+ regulatory T cells. Proc Natl Acad Sci USA2005; 102(14): 5150–5155.
7.
MungerKLChitnisTAscherioA.Body size and risk of MS in two cohorts of US women. Neurology2009; 73(19): 1543–1550.
8.
MungerKLBentzenJLaursenB, et al. Childhood body mass index and multiple sclerosis risk: A long-term cohort study. Mult Scler2013; 19(10): 1323–1329.
9.
TetteyPSimpsonSTaylorB, et al. An adverse lipid profile is associated with disability and progression in disability, in people with MS. Mult Scler2014; 20(13): 1737–1744.
10.
KvistadSSMyhrKMHolmøyT, et al. Body mass index influence interferon-beta treatment response in multiple sclerosis. J Neuroimmunol2015; 288(11): 92–97.
11.
OliveiraSRSimãoANKallaurAP, et al. Disability in patients with multiple sclerosis: Influence of insulin resistance, adiposity, and oxidative stress. Nutrition2014; 30(3): 268–273.
12.
TetteyPSimpsonSTaylorB, et al. An adverse lipid profile and increased levels of adiposity significantly predict clinical course after a first demyelinating event. J Neurol Neurosur Ps2017; 88(5): 395–401.
13.
CentonzeDMuzioLRossiS, et al. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci2009; 29(11): 3442–3452.
14.
Stampanoni BassiMIezziELandiD, et al. Delayed treatment of MS is associated with high CSF levels of IL-6 and IL-8 and worse future disease course. J Neurol2018; 265(11): 2540–2547.
15.
RossiSStuderVMottaC, et al. Cerebrospinal fluid detection of interleukin-1β in phase of remission predicts disease progression in multiple sclerosis. J Neuroinflamm2014; 11: 32.
16.
RossiSMancinoRBergamiA, et al. Potential role of IL-13 in neuroprotection and cortical excitability regulation in multiple sclerosis. Mult Scler2011; 17(11): 1301–1312.
17.
Stampanoni BassiMIezziEMarfiaGA, et al. Platelet-derived growth factor predicts prolonged relapse-free period in multiple sclerosis. J Neuroinflamm2018; 15(1): 108.
18.
PolmanCHReingoldSCBanwellB, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol2011; 69(2): 292–302.
19.
KurtzkeJF.Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology1983; 33(11): 1444–1452.
20.
PassingHBablokW.A new biometrical procedure for testing the equality of measurements from two different analytical methods. Application of linear regression procedures for method comparison studies in Clinical Chemistry, Part I. J Clin Chem Clin Biochem1983; 21(11): 709–720.
21.
World Health Organization (WHO). Expert Committee on Physical Status. Physical status: The use and interpretation of anthropometry. Geneva: World Health Organization; 1995, p. 420.
22.
OuchiNParkerJLLugusJJ, et al. Adipokines in inflammation and metabolic disease. Nat Rev Immunol2011; 11(2): 85–97.
23.
O’BrienPDHinderMLCallaghanBC, et al. Neurological consequences of obesity. Lancet Neurol2017; 16(6): 465–477.
24.
Weinstock-GuttmanBZivadinovRMahfoozN, et al. Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis. J Neuroinflamm2011; 48: 127.
25.
Weinstock-GuttmanBZivadinovRHorakovaD, et al. Lipid profiles are associated with lesion formation over 24 months in interferon-β treated patients following the first demyelinating event. J Neurol Neurosur Ps2013; 84(11): 1186–1191.
26.
Langer-GouldABraraSMBeaberBE, et al. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology2013; 80(6): 548–552.
27.
BriggsFBSThompsonNRConwayDS.Prognostic factors of disability in relapsing remitting multiple sclerosis. Mult Scler Relat Dis2019; 30: 9–16.
28.
MatsushitaTTateishiTIsobeN, et al. Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis. PLoS ONE2013; 8(4): 61835.
29.
StelmasiakZKozioł-MontewkaMDoboszB, et al. Interleukin-6 concentration in serum and cerebrospinal fluid in multiple sclerosis patients. Med Sci Monitor2000; 6(6): 1104–1108.
30.
FiedlerSEGeorgeJDLoveHN, et al. Analysis of IL-6, IL-1β and TNF-α production in monocytes isolated from multiple sclerosis patients treated with disease modifying drugs. J Syst Integr Neurosci2017; 3(3).
MowryEMAzevedoCJMcCullochCE, et al. Body mass index, but not vitamin D status, is associated with brain volume change in MS. Neurology2018; 91(24): e2256–e2264.
33.
ManouchehriniaAHedströmAKAlfredssonL, et al. Association of pre-disease body mass index with multiple sclerosis prognosis. Front Neurol2018; 9(5): 232.
34.
FriedmanJMHalaasJL.Leptin and the regulation of body weight in mammals. Nature1998; 395(6704): 763–770.
35.
PattersonCMLeshanRLJonesJC, et al. Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells. Brain Res2011; 1378(3): 18–28.
36.
La CavaAMatareseG. The weight of leptin in immunity. Nat Rev Immunol2004; 4(5): 371–379.
37.
Moraes-VieiraPMLaroccaRABassiEJ, et al. Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells. Eur J Immunol2014; 44(3): 794–806.
38.
De RosaVProcacciniCLa CavaA, et al. Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis. J Clin Invest2006; 116(2): 447–455.
39.
MatareseGDi GiacomoASannaV, et al. Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol2001; 166(10): 5909–5916.
40.
BatocchiAPRotondiMCaggiulaM, et al. Leptin as a marker of multiple sclerosis activity in patients treated with interferon-beta. J. Neuroimmunol2003; 139(1–2): 150–154.
41.
LockCHermansGPedottiR, et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med2002; 8(5): 500–508.
42.
LanzilloRCarboneFQuarantelliM, et al. Immunometabolic profiling of patients with multiple sclerosis identifies new biomarkers to predict disease activity during treatment with interferon beta-1a. Clin Immunol2017; 183(10): 249–253.
