Background: In Huntington’s disease (HD) the innate immune system is activated, as reflected by increased plasma levels of different cytokines.
Objective: To explore whether increased cytokine levels are associated with neuropsychiatric symptoms and cognitive dysfunction in HD mutation carriers.
Method: Plasma cytokine levels of TNF-alpha, interleukin (IL)-1ra, IL-1β, IL-5, IL-6, IL-8 and Il-10 were assessed in 124 HD mutation carriers at two time points 2 years apart (totalling 214 observations). Using multilevel regression analysis, cytokines were analysed in relation to neuropsychiatric symptoms and cognitive dysfunction. Depressed mood was assessed with the depression subscale of the Problem Behaviours Assessment (PBA), apathy with the Apathy Scale, and irritability with the Irritability Scale. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) and a battery of executive cognitive functioning tests, aggregated into an executive cognitive functioning (ExCog) score.
Results: Inverse associations were found in adjusted models between IL-6 and ExCog score (β= –0.114; p = 0.01) and between IL-1ra and ExCog score (β= –0.110; p = 0.02). No associations between cytokine levels and any of the other neuropsychiatric symptom scores remained statistically significant in adjusted models.
Conclusion: Higher plasma levels of IL-6 and IL-1ra are weakly associated with cognitive dysfunction in HD, but not with other neuropsychiatric symptoms.
van DuijnE, KingmaEM, van der MastRC. Psychopathology in verified Huntington’s disease gene carriers. J Neuropsychiatry Clin Neurosci. 2007;19(4):441–8.
3.
ReedekerN, BouwensJA, GiltayEJ, Le MairSE, RoosRA, van der MastRC, et al. Irritability in Huntington’s disease. Psychiatry Res. 2012;200(2-3):813–8.
4.
ThompsonJC, HarrisJ, SollomAC, StopfordCL, HowardE, SnowdenJS, et al. Longitudinal evaluation of neuropsychiatric symptoms in Huntington’s disease. J Neuropsychiatry Clin Neurosci. 2012;24(1):53–60.
5.
TabriziSJ, ScahillRI, DurrA, RoosRAC, LeavittBR, JonesR, et al. Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: The 12-month longitudinal analysis. Lancet Neurol. 2011;10(1):31–42.
6.
EllrichmannG, ReickC, SaftC, LinkerRA. The role of the immune system in Huntington’s disease. Clin Dev Immunol. 2013;2013:541259.
SappE, KegelKB, AroninN, HashikawaT, UchiyamaY, TohyamaK, et al. Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol. 2001;60(2):161–72.
9.
TaiYF, PaveseN, GerhardA, TabriziSJ, BarkerRA, BrooksDJ, et al. Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain. 2007;130(Pt 7):1759–66.
10.
BjorkqvistM, WildEJ, ThieleJ, SilvestroniA, AndreR, LahiriN, et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med. 2008;205(8):1869–77.
11.
ChangKH, WuYR, ChenYC, ChenCM. Plasma inflammatory biomarkers for Huntington’s disease patients and mouse model. Brain Behav Immun. 2014;44:121–127.
12.
DalrympleA, WildEJ, JoubertR, SathasivamK, BjorkqvistM, PetersenA, et al. Proteomic profiling of plasma in Huntington’s disease reveals neuroinflammatory activation and biomarker candidates. J Proteome Res. 2007;6(7):2833–40.
13.
Sanchez-LopezF, TassetI, AgueraE, FeijooM, Fernandez-BolanosR, SanchezFM, et al. Oxidative stress and inflammation biomarkers in the blood of patients with Huntington’s disease. Neurol Res. 2012;34(7):721–4.
14.
BouwensJA, HubersAA, van DuijnE, CobbaertCM, RoosRA, van der MastRC, et al. Acute-phase proteins in relation to neuropsychiatric symptoms and use of psychotropic medication in Huntington’s disease. Eur Neuropsychopharmacol. 2014;24(8):1248–56.
15.
CapuronL, RavaudA, MillerAH, DantzerR. Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy. Brain Behav Immun. 2004;18(3):205–13.
16.
Kiecolt-GlaserJK, LovingTJ, StowellJR, MalarkeyWB, LemeshowS, DickinsonSL, et al. Hostile marital interactions, proinflammatory cytokine production, and wound healing. Arch Gen Psychiatry. 2005;62(12):1377–84.
17.
KrausMR, SchaferA, FallerH, CsefH, ScheurlenM. Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J Clin Psychiatry. 2003;64(6):708–14.
18.
LotrichFE, SearsB, McNamaraRK. Anger induced by interferon-alpha is moderated by ratio of arachidonic acid to omega-3 fatty acids. J Psychosom Res. 2013;75(5):475–83.
19.
McHutchisonJG, GordonSC, SchiffER, ShiffmanML, LeeWM, RustgiVK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339(21):1485–92.
20.
MichaudM, BalardyL, MoulisG, GaudinC, PeyrotC, VellasB, et al. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc. 2013;14(12):877–82.
21.
PreauM, MarcellinF, SpireB, RavauxI, DellamonicaP, BlancD, et al. Impaired anger control as an underappreciated side effect of treatments for chronic HCV infection in HIV-HCV coinfected patients. J Clin Gastroenterol. 2008;42(1):92–6.
22.
SuarezEC, LewisJG, KrishnanRR, YoungKH. Enhanced expression of cytokines and chemokines by blood monocytes to in vitro lipopolysaccharide stimulation are associated with hostility and severity of depressive symptoms in healthy women. Psychoneuroendocrinology. 2004;29(9):1119–28.
23.
SuarezEC, LewisJG, KuhnC. The relation of aggression, hostility, and anger to lipopolysaccharide-stimulated tumor necrosis factor (TNF)-alpha by blood monocytes from normal men. Brain Behav Immun. 2002;16(6):675–84.
24.
KingmaEM, van DuijnE, TimmanR, van der MastRC, RoosRA. Behavioural problems in Huntington’s disease using the Problem Behaviours Assessment. Gen Hosp Psychiatry. 2008;30(2):155–61.
25.
SarwarN, ButterworthAS, FreitagDF, GregsonJ, WilleitP, GormanDN, et al. Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies. Lancet. 2012;379(9822):1205–13.
ChatterjeeA, AndersonKE, MoskowitzCB, HauserWA, MarderKS. A comparison of self-report and caregiver assessment of depression, apathy, and irritability in Huntington’s disease. J Neuropsychiatry Clin Neurosci. 2005;17(3):378–83.
28.
FolsteinMF, FolsteinSE, McHughPR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–98.
29.
HodgesJR. Initiation: Verbal fluency tests. Cognitive Assessment for Clinicians: Oxford University Press, Oxford, United Kingdom.; 2003. pp. 118–9.
30.
SmithA. The Symbol Digit Modalities Test: A neuropsychological test for economic screening of learning and other cerebral disorders. Learn Disord. 1968;3:83–91.
31.
StroopJR. Studies of interference in serial verbal reactions. J Exp Psychol. 1935;18:643–62.
32.
Unified Huntington’s disease rating scale: Reliability and consistency. Huntington Study Group. Mov Disord. 1996;11(2):136–42.
33.
HeinrichPC, CastellJV, AndusT. Interleukin-6 and the acute phase response. Biochem J. 1990;265(3):621.
34.
NishimotoN. Interleukin-6 as a therapeutic target in candidate inflammatory diseases. Clin Pharmacol Ther. 2010;87(4):483–7.
35.
GabayC, KushnerI. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340(6):448–54.
36.
MastorakosG, ChrousosGP, WeberJS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab. 1993;77(6):1690–4.
37.
TilgH, TrehuE, AtkinsMB, DinarelloCA, MierJW. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: Induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood. 1994;83(1):113–8.
38.
DinarelloCA, van der MeerJW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol. 2013;25(6):469–84.
39.
RosanoC, MarslandAL, GianarosPJ. Maintaining brain health by monitoring inflammatory processes: A mechanism to promote successful aging. Aging Dis. 2012;3(1):16–33.
40.
BanksWA. Blood-brain barrier transport of cytokines: A mechanism for neuropathology. Curr Pharm Des. 2005;11(8):973–84.
de VriesHE, Blom-RoosemalenMC, van OostenM, de BoerAG, van BerkelTJ, BreimerDD, et al. The influence of cytokines on the integrity of the blood-brain barrier in vitro. J Neuroimmunol. 1996;64(1):37–43.
43.
LicinioJ, WongML. Pathways and mechanisms for cytokine signaling of the central nervous system. J Clin Invest. 1997;100(12):2941–7.
44.
HanischUK. Microglia as a source and target of cytokines. Glia. 2002;40(2):140–55.
45.
SmithJA, DasA, RaySK, BanikNL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull. 2012;87(1):10–20.
46.
GodboutJP, JohnsonRW. Interleukin-6 in the aging brain. J Neuroimmunol. 2004;147(1-2):141–4.
47.
VallieresL, CampbellIL, GageFH, SawchenkoPE. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci. 2002;22(2):486–92.
48.
RossR. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340(2):115–26.
49.
HowrenMB, LamkinDM, SulsJ. Associations of depression with C-reactive protein, IL-1, and IL- A meta-analysis. Psychosom Med. 2009;71(2):171–86.
50.
SpallettaG, CravelloL, ImperialeF, SalaniF, BossuP, PicchettoL, et al. Neuropsychiatric symptoms and interleukin-6 serum levels in acute stroke. J Neuropsychiatry Clin Neurosci. 2013;25(4):255–63.
51.
DowlatiY, HerrmannN, SwardfagerW, LiuH, ShamL, ReimEK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446–57.
52.
de JagerW, BourcierK, RijkersGT, PrakkenBJ, Seyfert-MargolisV. Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays. BMC Immunol. 2009;10:52–.
