Top

BMC Psychiatry

Published in:

Open Access 01-12-2021 | Obsessive-Compulsive Disorder | Research

Elevated levels of neutrophil gelatinase-associated lipocalin among OCD patients: an exploratory study

Authors: Catarina Raposo-Lima, Inês Miguel Pereira, Fernanda Marques, Pedro Morgado

Published in: BMC Psychiatry | Issue 1/2021

Abstract

Background

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disease that is characterized by its clinical heterogeneity and complex pathophysiology. This complexity comes from the diversity of pathophysiological factors that have been proposed to be involved in the natural history of the disorder. Many theories on OCD pathology support inflammation as a pathophysiological factor, although studies are not consistent on the presence of a pro-inflammatory state among OCD patients. However, some pre-clinical animal studies suggest lipocalin-2 (LCN2), an analogous form of the acute-phase pro-inflammatory protein neutrophil gelatinase-associated lipocalin (NGAL), may be involved in in the regulation of the stress response, which is thought to be disrupted in OCD.

Methods

Twenty-one OCD patients and 19 healthy subjects participated in this exploratory study. Levels of NGAL were assessed in the peripherous blood of all participants. Severity of disease was assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS).

Results

OCD patients exhibited significantly higher levels of NGAL when compared to healthy control subjects. No correlation was found between elevated levels of NGAL and severity of symptoms.

Conclusions

This is the first study to report elevated levels of NGAL among OCD patients, adding evidence for a possible role of immune dysregulation in the pathophysiology of OCD.

American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th edition (DSM-5). Arlington, VA: American Psychiatric Association; 2013. https://doi.org/10.1176/appi.books.9780890425596.CrossRef

Raposo-Lima C, Morgado P. The role of environmental factors in the pathogenesis of obsessive-compulsive and related disorders. In: Fontenelle LF, Yücel M, editors. A Transdiagnostic approach to obsessions, compulsions and related phenomena. Cambridge: Cambridge University Press; 2019. p. 39–50. https://doi.org/10.1017/9781108164313.006.CrossRef

Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998;155(2):264–71. https://doi.org/10.1176/ajp.155.2.264.CrossRefPubMed

Cutforth T, DeMille MM, Agalliu I, Agalliu D. CNS autoimmune disease after streptococcus pyogenes infections: animal models, cellular mechanisms and genetic factors. Future Neurol. 2016;11(1):63–76. https://doi.org/10.2217/fnl.16.4.CrossRefPubMedPubMedCentral

Pearlman DM, Vora HS, Marquis BG, Najjar S, Dudley LA. Anti-basal ganglia antibodies in primary obsessive–compulsive disorder: systematic review and meta-analysis. Br J Psychiatry. 2014;205(1):8–16. https://doi.org/10.1192/bjp.bp.113.137018.CrossRefPubMed

Snider LA, Swedo SE. Post-streptococcal autoimmune disorders of the central nervous system. Curr Opin Neurol. 2003;16(3):359–65. https://doi.org/10.1097/01.wco.0000073938.19076.31.CrossRefPubMed

Gerentes M, Pelissolo A, Rajagopal K, Tamouza R, Hamdani N. Obsessive-compulsive disorder: autoimmunity and Neuroinflammation. Curr Psychiatry Rep. 2019;21(8):78. https://doi.org/10.1007/s11920-019-1062-8.CrossRefPubMed

Mora S, Martín-González E, Flores P, Moreno M. Neuropsychiatric consequences of childhood group a streptococcal infection: a systematic review of preclinical models. Brain Behav Immun. 2020;86:53–62. https://doi.org/10.1016/j.bbi.2019.02.027.CrossRefPubMed

Martino D, Johnson I, Leckman JF. What does immunology have to do with Normal brain development and the pathophysiology underlying Tourette syndrome and related neuropsychiatric disorders? Front Neurol. 2020;11:1101.CrossRef

10.

Mitchell RH, Goldstein BI. Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review. J Am Acad Child Adolesc Psychiatry. 2014;53(3):274–96. https://doi.org/10.1016/j.jaac.2013.11.013.CrossRefPubMed

11.

Rao NP, Venkatasubramanian G, Ravi V, Kalmady S, Cherian A, YC JR. Plasma cytokine abnormalities in drug-naïve, comorbidity-free obsessive–compulsive disorder. Psychiatry Res. 2015;229(3):949–52. https://doi.org/10.1016/j.psychres.2015.07.009.CrossRefPubMed

12.

Rodríguez N, Morer A, González-Navarro EA, Serra-Pages C, Boloc D, Torres T, et al. Inflammatory dysregulation of monocytes in pediatric patients with obsessive-compulsive disorder. J Neuroinflammation. 2017;14(1):261. https://doi.org/10.1186/s12974-017-1042-z.CrossRefPubMedPubMedCentral

13.

Attwells S, Setiawan E, Wilson AA, Rusjan PM, Mizrahi R, Miler L, et al. Inflammation in the neurocircuitry of obsessive-compulsive disorder. JAMA Psychiatry. 2017;74(8):833–40. https://doi.org/10.1001/jamapsychiatry.2017.1567.CrossRefPubMedPubMedCentral

14.

Cosco TD, Pillinger T, Emam H, Solmi M, Budhdeo S, Prina AM, et al. Immune aberrations in obsessive-compulsive disorder: a systematic review and meta-analysis. Mol Neurobiol. 2019;56(7):4751–9. https://doi.org/10.1007/s12035-018-1409-x.CrossRefPubMed

15.

Renna ME, O'Toole MS, Spaeth PE, Lekander M, Mennin DS. The association between anxiety, traumatic stress, and obsessive–compulsive disorders and chronic inflammation: a systematic review and meta-analysis. Depress Anxiety. 2018;35(11):1081–94. https://doi.org/10.1002/da.22790.CrossRefPubMed

16.

Dietrich D, Zhang Y, Bode L, Münte T, Hauser U, Schmorl P, et al. Brain potential amplitude varies as a function of Borna disease virus-specific immune complexes in obsessive–compulsive disorder. Mol Psychiatry. 2005;10(6):519–20. https://doi.org/10.1038/sj.mp.4001645.CrossRef

17.

Liu Q, Nilsen-Hamilton M. Identification of a new acute phase protein. J Biol Chem. 1995;270(38):22565–70. https://doi.org/10.1074/jbc.270.38.22565.CrossRefPubMed

18.

Bao G, Clifton M, Hoette TM, Mori K, Deng S-X, Qiu A, et al. Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex. Nat Chem Biol. 2010;6(8):602–9. https://doi.org/10.1038/nchembio.402.CrossRefPubMedPubMedCentral

19.

Ferreira AC, Da Mesquita S, Sousa JC, Correia-Neves M, Sousa N, Palha JA, et al. From the periphery to the brain: Lipocalin-2, a friend or foe? Prog Neurobiol. 2015;131:120–36. https://doi.org/10.1016/j.pneurobio.2015.06.005.CrossRefPubMed

20.

Marques F, Mesquita SD, Sousa JC, Coppola G, Gao F, Geschwind DH, et al. Lipocalin 2 is present in the EAE brain and is modulated by natalizumab. Front Cell Neurosci. 2012;6:33.CrossRefPubMedPubMedCentral

21.

Mommersteeg PM, Naudé PJ, Bagijn W, Widdershoven J, Westerhuis BW, Schoemaker RG. Gender differences in associations of depressive symptoms and anxiety with inflammatory markers in patients with non-obstructive coronary artery disease. J Psychosom Res. 2019;125:109779. https://doi.org/10.1016/j.jpsychores.2019.109779.CrossRefPubMed

22.

Naudé P, Eisel U, Comijs H, Groenewold N, De Deyn P, Bosker F, et al. Neutrophil gelatinase-associated lipocalin: a novel inflammatory marker associated with late-life depression. J Psychosom Res. 2013;75(5):444–50. https://doi.org/10.1016/j.jpsychores.2013.08.023.CrossRefPubMed

23.

Naudé PJ, Mommersteeg PM, Zijlstra WP, Gouweleeuw L, Kupper N, Eisel UL, et al. Neutrophil gelatinase-associated lipocalin and depression in patients with chronic heart failure. Brain Behav Immun. 2014;38:59–65. https://doi.org/10.1016/j.bbi.2013.12.023.CrossRefPubMed

24.

Veltman E, Lamers F, Comijs H, Stek M, Van der Mast R, Rhebergen D. Inflammatory markers and cortisol parameters across depressive subtypes in an older cohort. J Affect Disord. 2018;234:54–8. https://doi.org/10.1016/j.jad.2018.02.080.CrossRefPubMed

25.

Marques F, Rodrigues A-J, Sousa JC, Coppola G, Geschwind DH, Sousa N, et al. Lipocalin 2 is a choroid plexus acute-phase protein. J Cereb Blood Flow Metab. 2008;28(3):450–5. https://doi.org/10.1038/sj.jcbfm.9600557.CrossRefPubMed

26.

MacManus JP, Graber T, Luebbert C, Preston E, Rasquinha I, Smith B, et al. Translation-state analysis of gene expression in mouse brain after focal ischemia. J Cereb Blood Flow Metab. 2004;24(6):657–67. https://doi.org/10.1097/01.WCB.0000123141.67811.91.CrossRefPubMed

27.

De Biase A, Knoblach SM, Di Giovanni S, Fan C, Molon A, Hoffman EP, et al. Gene expression profiling of experimental traumatic spinal cord injury as a function of distance from impact site and injury severity. Physiol Genomics. 2005;22(3):368–81. https://doi.org/10.1152/physiolgenomics.00081.2005.CrossRefPubMed

28.

Poh K-W, Yeo J-F, Stohler CS, Ong W-Y. Comprehensive gene expression profiling in the prefrontal cortex links immune activation and neutrophil infiltration to antinociception. J Neurosci. 2012;32(1):35–45. https://doi.org/10.1523/JNEUROSCI.2389-11.2012.CrossRefPubMedPubMedCentral

29.

Mesquita S, Ferreira A, Falcao A, Sousa J, Oliveira TG, Correia-Neves M, et al. Lipocalin 2 modulates the cellular response to amyloid beta. Cell Death Differ. 2014;21(10):1588–99. https://doi.org/10.1038/cdd.2014.68.CrossRefPubMedPubMedCentral

30.

Naudé PJ, Nyakas C, Eiden LE, Ait-Ali D, Van Der Heide R, Engelborghs S, et al. Lipocalin 2: novel component of proinflammatory signaling in Alzheimer's disease. FASEB J. 2012;26(7):2811–23. https://doi.org/10.1096/fj.11-202457.CrossRefPubMedPubMedCentral

31.

Kim B-W, Jeong KH, Kim J-H, Jin M, Kim J-H, Lee M-G, et al. Pathogenic upregulation of glial lipocalin-2 in the parkinsonian dopaminergic system. J Neurosci. 2016;36(20):5608–22. https://doi.org/10.1523/JNEUROSCI.4261-15.2016.CrossRefPubMedPubMedCentral

32.

Ferreira AC, Pinto V, Mesquita SD, Novais A, Sousa JC, Correia-Neves M, et al. Lipocalin-2 is involved in emotional behaviors and cognitive function. Front Cell Neurosci. 2013;7:122.CrossRefPubMedPubMedCentral

33.

Mucha M, Skrzypiec AE, Schiavon E, Attwood BK, Kucerova E, Pawlak R. Lipocalin-2 controls neuronal excitability and anxiety by regulating dendritic spine formation and maturation. Proc Natl Acad Sci U S A. 2011;108(45):18436–41. https://doi.org/10.1073/pnas.1107936108.CrossRefPubMedPubMedCentral

34.

Skrzypiec AE, Shah RS, Schiavon E, Baker E, Skene N, Pawlak R, et al. Stress-induced lipocalin-2 controls dendritic spine formation and neuronal activity in the amygdala. PLoS One. 2013;8(4):e61046.

35.

Ferreira A, Santos T, Sampaio-Marques B, Novais A, Mesquita S, Ludovico P, et al. Lipocalin-2 regulates adult neurogenesis and contextual discriminative behaviours. Mol Psychiatry. 2018;23(4):1031–9. https://doi.org/10.1038/mp.2017.95.CrossRefPubMed

36.

Rodrigues A-J, Leão P, Carvalho M, Almeida OF, Sousa N. Potential programming of dopaminergic circuits by early life stress. Psychopharmacology. 2011;214(1):107–20. https://doi.org/10.1007/s00213-010-2085-3.CrossRefPubMed

37.

Castro-Rodrigues P, Camacho M, Almeida S, Marinho M, Soares C, Barahona-Corrêa JB, et al. Criterion validity of the Yale-Brown obsessive-compulsive scale second edition for diagnosis of obsessive-compulsive disorder in adults. Front Psychiatry. 2018;9:431. https://doi.org/10.3389/fpsyt.2018.00431.CrossRefPubMedPubMedCentral

38.

Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale-Brown obsessive compulsive scale: I. development, use, and reliability. Arch Gen Psychiatry. 1989;46(11):1006–11. https://doi.org/10.1001/archpsyc.1989.01810110048007.CrossRefPubMed

39.

Corp I. SPSS statistics for Macintosh, version 27.0. IBM Corp: Armonk, NY; 2020.

40.

Naudé PJ, Mommersteeg PM, Gouweleeuw L, Eisel UL, Denollet J, Westerhuis LW, et al. NGAL and other markers of inflammation as competitive or complementary markers for depressive symptom dimensions in heart failure. World J Biol Psychiatry. 2015;16(7):536–41. https://doi.org/10.3109/15622975.2015.1062550.CrossRefPubMed

41.

Gouweleeuw L, Naudé P, Rots M, DeJongste M, Eisel U, Schoemaker R. The role of neutrophil gelatinase associated lipocalin (NGAL) as biological constituent linking depression and cardiovascular disease. Brain Behav Immun. 2015;46:23–32. https://doi.org/10.1016/j.bbi.2014.12.026.CrossRefPubMed

42.

Pollmächer T, Haack M, Schuld A, Reichenberg A, Yirmiya R. Low levels of circulating inflammatory cytokines—do they affect human brain functions? Brain Behav Immun. 2002;16(5):525–32. https://doi.org/10.1016/S0889-1591(02)00004-1.CrossRefPubMed

43.

Wei L, Du Y, Wu W, Fu X, Xia Q. Elevation of plasma neutrophil gelatinase-associated lipocalin (NGAL) levels in schizophrenia patients. J Affect Disord. 2018;226:307–12. https://doi.org/10.1016/j.jad.2017.10.002.CrossRefPubMed

44.

Kang SS, Ren Y, Liu C-C, Kurti A, Baker KE, Bu G, et al. Lipocalin-2 protects the brain during inflammatory conditions. Mol Psychiatry. 2018;23(2):344–50. https://doi.org/10.1038/mp.2016.243.CrossRefPubMed

45.

Mike EV, Makinde HM, Gulinello M, Vanarsa K, Herlitz L, Gadhvi G, et al. Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus. J Autoimmun. 2019;96:59–73. https://doi.org/10.1016/j.jaut.2018.08.005.CrossRefPubMed

46.

Vichaya EG, Gross PS, Estrada DJ, Cole SW, Grossberg AJ, Evans SE, et al. Lipocalin-2 is dispensable in inflammation-induced sickness and depression-like behavior. Psychopharmacology. 2019;236(10):2975–82. https://doi.org/10.1007/s00213-019-05190-7.CrossRefPubMedPubMedCentral

47.

Bhusal A, Rahman MH, Lee W-H, Bae YC, Lee I-K, Suk K. Paradoxical role of lipocalin-2 in metabolic disorders and neurological complications. Biochem Pharmacol. 2019;113626.

48.

Pinyopornpanish K, Chattipakorn N, Chattipakorn SC. Lipocalin-2: its perspectives in brain pathology and possible roles in cognition. J Neuroendocrinol. 2019;31(10):e12779. https://doi.org/10.1111/jne.12779.CrossRefPubMed

49.

Bhattacharyya S, Khanna S, Chakrabarty K, Mahadevan A, Christopher R, Shankar S. Anti-brain autoantibodies and altered excitatory neurotransmitters in obsessive–compulsive disorder. Neuropsychopharmacology. 2009;34(12):2489–96. https://doi.org/10.1038/npp.2009.77.CrossRefPubMed

50.

Dekens DW, Naudé PJ, Engelborghs S, Vermeiren Y, Van Dam D, Oude Voshaar RC, et al. Neutrophil gelatinase-associated lipocalin and its receptors in Alzheimer’s disease (AD) brain regions: differential findings in AD with and without depression. J Alzheimers Dis. 2017;55(2):763–76. https://doi.org/10.3233/JAD-160330.CrossRefPubMed

51.

Rotge J, Aouizerate B, Tignol J, Bioulac B, Burbaud P, Guehl D. The glutamate-based genetic immune hypothesis in obsessive-compulsive disorder. An integrative approach from genes to symptoms. Neuroscience. 2010;165(2):408–17. https://doi.org/10.1016/j.neuroscience.2009.10.043.CrossRefPubMed

52.

Wu K, Hanna GL, Rosenberg DR, Arnold PD. The role of glutamate signaling in the pathogenesis and treatment of obsessive–compulsive disorder. Pharmacol Biochem Behav. 2012;100(4):726–35. https://doi.org/10.1016/j.pbb.2011.10.007.CrossRefPubMed

Title: Elevated levels of neutrophil gelatinase-associated lipocalin among OCD patients: an exploratory study
Authors: Catarina Raposo-Lima
Inês Miguel Pereira
Fernanda Marques
Pedro Morgado
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Obsessive-Compulsive Disorder
Published in: BMC Psychiatry / Issue 1/2021
Electronic ISSN: 1471-244X
DOI: https://doi.org/10.1186/s12888-021-03289-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Elevated levels of neutrophil gelatinase-associated lipocalin among OCD patients: an exploratory study

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Prevalence and associated factors of psychosocial distress among seafarers during COVID-19 pandemic

Heterogeneity in major depression and its melancholic and atypical specifiers: a secondary analysis of STAR*D

Correction to: Adherence among HIV-positive injection drug users undergoing methadone treatment in Taiwan

Low intensity technology-delivered cognitive behavioral therapy for obsessive-compulsive disorder: a meta-analysis

The relations between different components of intolerance of uncertainty and symptoms of generalized anxiety disorder: a network analysis

A survey of personnel and services offered in 32 outpatient US clozapine clinics