Abstract
Background
Parkinson’s disease (PD) patients experience non-motor symptoms (NMS), which may appear before motor manifestations. The most common NMS is depression, affecting about 30–40% of PD patients. Both PD and depression are associated with an increased inflammatory burden, with studies showing elevation of diverse inflammatory markers in patients with both conditions.
Methods
A systematic review was conducted in PubMed and PsycINFO databases to investigate what inflammatory markers are associated with PD depression (PDD). Only studies in English that measured inflammatory markers and analyzed against depression scores in PD patients were included.
Results
A total of 1132 articles were retrieved, and 14 entries were found to be eligible. Twelve were cross-sectional studies, one was a cohort, and one was a non-randomized controlled trial. IL-17A was the only marker strongly associated with PDD, while studies assessing sIL-2R and serum amyloid A found a moderate correlation. C-reactive protein, IL-10, tumor necrosis factor-α, monocyte chemoattractant protein-1, and IL-6 yielded conflicting results. Their possible roles in PDD are discussed. PDD was also related to longer disease duration and other NMS, such as anxiety, fatigue, dementia, REM sleep behavior disorder, and autonomic dysfunction.
Conclusion
We suggest that these markers may be used for distinguishing isolated depression from that related to neurodegeneration, especially in individuals that concurrently present with other known prodromal symptoms of PD and other α-synucleinopathies. However, future prospective studies are warranted to confirm this hypothesis.
Similar content being viewed by others
References
De Lau LML, Breteler MMB (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535. https://doi.org/10.1016/S1474-4422(06)70471-9
Assogna F, Cravello L, Caltagirone C et al (2011) Anhedonia in Parkinson’s disease: a systematic review of the literature. Mov Disord 26(10):1825–1834. https://doi.org/10.1002/MDS.23815
Assogna F, Cravello L, Orfei MD et al (2016) Alexithymia in Parkinson’s disease: a systematic review of the literature. Parkinsonism Relat Disord 28:1–11. https://doi.org/10.1016/J.PARKRELDIS.2016.03.021
Leentjens AF, den Akker MV, Metsemakers JFM, ak, (2003) Higher incidence of depression preceding the onset of Parkinson’s disease: a register study. Mov Disord 18:414–418. https://doi.org/10.1002/MDS.10387
Caig G, Tolosa E (2009) When does Parkinson’s disease begin? Mov Disord 24(Suppl 2): S656–S664. https://doi.org/10.1002/MDS.22672
Hely MA, Morris JGL, Reid WGJ, Trafficante R (2005) Sydney Multicenter Study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 20:190–199. https://doi.org/10.1002/mds.20324
Reijnders JSAM, Ehrt U, Weber WEJ et al (2008) A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 23:183–189
Marsh L (2013) Depression and parkinson’s disease: current knowledge topical collection on movement disorders. Curr Neurol Neurosci Rep 13(409). https://doi.org/10.1007/s11910-013-0409-5
Pålhagen SE, Carlsson M, Curman E et al (2008) Depressive illness in Parkinson’s disease - indication of a more advanced and widespread neurodegenerative process? Acta Neurol Scand 117:295–304. https://doi.org/10.1111/j.1600-0404.2007.00986.x
Goodarzi Z, Mrklas KJ, Roberts DJ et al (2016) Detecting depression in Parkinson disease: a systematic review and meta-analysis. Neurol 87:426–437
Marsh L, McDonald WM, Cummings J et al (2006) Provisional diagnostic criteria for depression in Parkinson’s disease: report of an NINDS/NIMH Work Group. Mov Disord 21:148–158
Starkstein SE, Brockman S (2017) Management of depression in Parkinson’s disease: a systematic review. Mov Disord Clin Pract 4:470–477
Ravina B, Camicioli R, Como PG et al (2007) The impact of depressive symptoms in early Parkinson disease. Neurol 69:342–347. https://doi.org/10.1212/01.WNL.0000268695.63392.10
De La Riva P, Smith K, Xie SX, Weintraub D (2014) Course of psychiatric symptoms and global cognition in early Parkinson disease. Neurol 83:1096–1103. https://doi.org/10.1212/WNL.0000000000000801
Shulman LM, Taback RL, Rabinstein AA, Weiner WJ (2002) Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Park Relat Disord 8:193–197. https://doi.org/10.1016/S1353-8020(01)00015-3
Lachner C, Armstrong MJ, Gruber-Baldini AL et al (2017) Discordance between physician assessment and patient-reported depressive symptoms in Parkinson disease. J Geriatr Psychiatry Neurol 30:191–195. https://doi.org/10.1177/0891988717710335
Bomasang-Layno E, Fadlon I, Murray AN, Himelhoch S (2015) Antidepressive treatments for Parkinson’s disease: a systematic review and meta-analysis. Park Relat Disord 21:833–842
Qin XY, Zhang SP, Cao C et al (2016) Aberrations in peripheral inflammatory cytokine levels in Parkinson disease: a systematic review and meta-analysis. JAMA Neurol 73:1316–1324. https://doi.org/10.1001/jamaneurol.2016.2742
Chen X, Hu Y, Cao Z et al (2018) Cerebrospinal fluid inflammatory cytokine aberrations in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis: a systematic review and meta-analysis. Front Immunol 9:2122. https://doi.org/10.3389/fimmu.2018.02122
Howren MB, Lamkin DM, Suls J (2009) Associations of depression with c-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 71:171–186. https://doi.org/10.1097/PSY.0b013e3181907c1b
Dowlati Y, Herrmann N, Swardfager W et al (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67:446–457. https://doi.org/10.1016/j.biopsych.2009.09.033
Valkanova V, Ebmeier KP, Allan CL (2013) CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord 150:736–744
Köhler CA, Freitas TH, Maes M et al (2017) Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand 135:373–387. https://doi.org/10.1111/acps.12698
Ng A, Tam WW, Zhang MW et al (2018) IL-1β, IL-6, TNF- α and CRP in elderly patients with depression or Alzheimer’s disease: systematic review and meta-analysis. Sci Rep 8:12050. https://doi.org/10.1038/s41598-018-30487-6
Enache D, Pariante CM, Mondelli V (2019) Markers of central inflammation in major depressive disorder: a systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue. Brain Behav Immun 81:24–40
Modesti PA, Reboldi G, Cappuccio FP et al (2016) Panethnic differences in blood pressure in Europe: a systematic review and meta-analysis. PLoS One 11(1):e0147601. https://doi.org/10.1371/journal.pone.0147601
Lindqvist D, Kaufman E, Brundin L et al (2012) Non-motor symptoms in patients with Parkinson’s disease – correlations with inflammatory cytokines in serum. PLoS One 7(10):e47387. https://doi.org/10.1371/journal.pone.0047387
Lindqvist D, Hall S, Surova Y et al (2013) Cerebrospinal fluid inflammatory markers in Parkinson’s disease—associations with depression, fatigue, and cognitive impairment. Brain Behav Immun 33:183–189
Hall S, Janelidze S, Surova Y et al (2018) Cerebrospinal fluid concentrations of inflammatory markers in Parkinson’s disease and atypical parkinsonian disorders. Sci Rep 8:1–9. https://doi.org/10.1038/s41598-018-31517-z
Pålhagen S, Qi H, Mårtensson B et al (2010) Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson’s disease and major depression. J Neurol 257:524–532. https://doi.org/10.1007/s00415-009-5353-6
Santos-García D, de Deus FT, Suárez Castro E et al (2019) High ultrasensitive serum C-reactive protein may be related to freezing of gait in Parkinson’s disease patients. J Neural Transm 126:1599–1608. https://doi.org/10.1007/s00702-019-02096-8
Green HF, Khosousi S, Svenningsson P (2019) Plasma IL-6 and IL-17A Correlate with severity of motor and non-motor symptoms in Parkinson’s disease. J Parkinsons Dis 9:705–709. https://doi.org/10.3233/JPD-191699
Veselý B, Dufek M, Thon V et al (2018) Interleukin 6 and complement serum level study in Parkinson’s disease. J Neural Transm 125:875–881
Lian T, Guo P, Zhang Y et al (2020) Parkinson’s disease with depression: the correlations between neuroinflammatory factors and neurotransmitters in cerebrospinal fluid. Front Aging Neurosci 12:574776
Selikhova MV, Kushlinskii NE, Lyubimova NV, Gusev EI (2002) Impaired production of plasma interleukin-6 in patients with Parkinson’s disease. Bull Exp Biol Med 133:81–83. https://doi.org/10.1023/a:1015120930920
Menza M, DeFronzo DR, Marin H et al (2010) The role of inflammatory cytokines in cognition and other non-motor symptoms of Parkinson’s disease. Psychosom J Consult Liaison Psychiatry 51:474–479
Hassin-Baer S, Cohen OS, Vakil E et al (2011) Is C-reactive protein level a marker of advanced motor and neuropsychiatric complications in Parkinson’s disease? J Neural Transm 118:539–543
Rocha NP, Scalzo PL, Barbosa IG et al (2014) Cognitive status correlates with CXCL10/IP-10 levels in Parkinson’s disease. Parkinsons Dis 2014:903796. https://doi.org/10.1155/2014/903796
Wang X-M, Zhang Y-G, Li A-L et al (2016) Relationship between levels of inflammatory cytokines in the peripheral blood and the severity of depression and anxiety in patients with Parkinson’s disease. Eur Rev Med Pharmacol Sci 20:3853–3856
Karpenko MN, Vasilishina AA, Gromova EA et al (2018) Interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-10, and tumor necrosis factor-α levels in CSF and serum in relation to the clinical diversity of Parkinson’s disease. Cell Immunol 327:77–82. https://doi.org/10.1016/j.cellimm.2018.02.011
Hunter CA, Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16:448–457
Campbell IL, Erta M, Lim SL et al (2014) Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain. J Neurosci 34:2503–2513. https://doi.org/10.1523/JNEUROSCI.2830-13.2014
Nehring SM, Goyal A, Bansal P, Patel BC (2021) C reactive protein StatPearls 65:237–244
Qiu X, Xiao Y, Wu J et al (2019) C-reactive protein and risk of Parkinson’s disease: a systematic review and meta-analysis. Front Neurol 10:384. https://doi.org/10.3389/fneur.2019.00384
Osimo EF, Baxter LJ, Lewis G et al (2019) Prevalence of low-grade inflammation in depression: a systematic review and meta-Analysis of CRP levels. Psychol Med 49:1958–1970
Haider S, Knöfler M (2009) Human tumour necrosis factor: physiological and pathological roles in placenta and endometrium. Placenta 30:111–123. https://doi.org/10.1016/j.placenta.2008.10.012
Peter I, Dubinsky M, Bressman S et al (2018) Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol 75:939–946. https://doi.org/10.1001/jamaneurol.2018.0605
Liu Y, Ho RC-M, Mak A (2012) Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord 139:230–239. https://doi.org/10.1016/J.JAD.2011.08.003
Goldsmith DR, Rapaport MH, Miller BJ (2016) A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 21(12):1696–1709.
Chen J, Liu X, Zhong Y (2020) Interleukin-17A: the key cytokine in neurodegenerative diseases. Front Aging Neurosci 12:566922. https://doi.org/10.3389/FNAGI.2020.566922
Storelli E, Cassina N, Rasini E et al (2019) Do Th17 lymphocytes and IL-17 contribute to Parkinson’s disease? A systematic review of available evidence. Front Neurol 10:13. https://doi.org/10.3389/FNEUR.2019.00013
Liu Z, Qiu AW, Huang Y et al (2019) IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson’s disease. Brain Behav Immun 81:630–645. https://doi.org/10.1016/j.bbi.2019.07.026
Beurel E, Lowell JA (2018) Th17 cells in depression. Brain Behav Immun 69:28–34
Nothdurfter C, Milenkovic VM, Sarubin N et al (2021) The cytokine IL-17A as a marker of treatment resistance in major depressive disorder? Eur J Neurosci 53:172–182. https://doi.org/10.1111/EJN.14636
Bryleva EY, Keaton SA, Grit J et al (2017) The acute-phase mediator serum amyloid A is associated with symptoms of depression and fatigue. Acta Psychiatr Scand 135:409–418. https://doi.org/10.1111/ACPS.12730
van Dooren FEP, Schram MT, Schalkwijk CG et al (2016) Associations of low grade inflammation and endothelial dysfunction with depression - the Maastricht Study. Brain Behav Immun 56:390–396. https://doi.org/10.1016/J.BBI.2016.03.004
Kurvits L, Reimann E, Kadastik-Eerme L et al (2019) Serum amyloid alpha is downregulated in peripheral tissues of Parkinson’s disease patients. Front Neurosci 13:13. https://doi.org/10.3389/FNINS.2019.00013
Hiles SA, Baker AL, de Malmanche T et al (2012) A meta-analysis of differences in IL-6 and IL-10 between people with and without depression: exploring the causes of heterogeneity. Brain Behav Immun 26:1180–1188. https://doi.org/10.1016/J.BBI.2012.06.001
Porro C, Cianciulli A, Panaro MA (2020) The regulatory role of IL-10 in neurodegenerative diseases. Biomolecules 10:1–15
Santaella A, Kuiperij HB, van Rumund A et al (2020) Inflammation biomarker discovery in Parkinson’s disease and atypical parkinsonisms. BMC Neurol 20(1):26. https://doi.org/10.1186/S12883-020-1608-8
Santaella A, Kuiperij HB, van Rumund A et al (2020) Cerebrospinal fluid monocyte chemoattractant protein 1 correlates with progression of Parkinson’s disease. npj Parkinsons Dis 6:21. https://doi.org/10.1038/s41531-020-00124-z
Wang Y, Zhou M, Wang Y et al (2019) Association of polymorphisms in the MCP-1 and CCR2 genes with the risk of Parkinson’s disease. J Neural Transm 126:1465–1470. https://doi.org/10.1007/S00702-019-02072-2
Hu S, Huang S, Ma J et al (2021) Correlation of decreased serum pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide levels with non-motor symptoms in patients with Parkinson’s disease. Front Aging Neurosci 13:1–10. https://doi.org/10.3389/fnagi.2021.689939
Ryan M, Eatmon CV, Slevin JT (2019) Drug treatment strategies for depression in Parkinson disease. Expert Opin Pharmacother 20:1351–1363
Anders S, Sack B, Pohl A et al (2012) Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele. Brain 135:1128–1140. https://doi.org/10.1093/brain/aws040
Borgonovo J, Allende-Castro C, Laliena A et al (2017) Changes in neural circuitry associated with depression at pre-clinical, pre-motor and early motor phases of Parkinson’s disease. Parkinsonism Relat Disord 35:17–24. https://doi.org/10.1016/j.parkreldis.2016.11.009
Assogna F, Pellicano C, Savini C et al (2020) Drug choices and advancements for managing depression in Parkinson’s disease. Curr Neuropharmacol 18:277–287. https://doi.org/10.2174/1570159X17666191016094857
Zaminelli T, Gradowski RW, Bassani TB et al (2014) Antidepressant and antioxidative effect of ibuprofen in the rotenone model of Parkinson’s disease. Neurotox Res 26:351–362. https://doi.org/10.1007/s12640-014-9467-y
Santiago RM, Tonin FS, Barbiero J et al (2015) The nonsteroidal antiinflammatory drug piroxicam reverses the onset of depressive-like behavior in 6-OHDA animal model of Parkinson’s disease. Neurosci 300:246–253. https://doi.org/10.1016/J.NEUROSCIENCE.2015.05.030
Campolo M, Paterniti I, Siracusa R et al (2019) TLR4 absence reduces neuroinflammation and inflammasome activation in Parkinson’s diseases in vivo model. Brain Behav Immun 76:236–247. https://doi.org/10.1016/j.bbi.2018.12.003
Huang J, Hong W, Yang Z et al (2020) Efficacy of pramipexole combined with levodopa for Parkinson’s disease treatment and their effects on QOL and serum TNF-α levels. J Int Med Res 48:300060520922449. https://doi.org/10.1177/0300060520922449
Daneshvar Kakhaki R, Ostadmohammadi V, Kouchaki E et al (2020) Melatonin supplementation and the effects on clinical and metabolic status in Parkinson’s disease: a randomized, double-blind, placebo-controlled trial. Clin Neurol Neurosurg 195:105878. https://doi.org/10.1016/j.clineuro.2020.105878
Greenland JC, Cutting E, Kadyan S et al (2020) Azathioprine immunosuppression and disease modification in Parkinson’s disease (AZA-PD): a randomised double-blind placebo-controlled phase II trial protocol. BMJ Open 10:e040527. https://doi.org/10.1136/bmjopen-2020-040527
Santos-García D, Mir P, Cubo E et al (2016) COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015 a global –clinical evaluations, serum biomarkers, genetic studies and neuroimaging– prospective, multicenter, non-interventional, long-term study on Parkinson’s disease progressio. BMC Neurol 16:26.
Picca A, Guerra F, Calvani R et al (2019) Mitochondrial-derived vesicles as candidate biomarkers in Parkinson’s disease: rationale, design and methods of the EXosomes in PArkiNson Disease (EXPAND) Study. Int J Mol Sci 20(10):2373. https://doi.org/10.3390/ijms20102373
Author information
Authors and Affiliations
Contributions
Luís Guilherme Ramanzini: conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, visualization, writing – original draft preparation, writing – review and editing. Luís Fernando Camargo: conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, visualization, writing – original draft preparation, writing – review and editing. Juliana Oliveira Freitas Silveira: validation, writing – original draft preparation, writing – review and editing. Guilherme Vargas Bochi: conceptualization, data curation, investigation, methodology, project administration, supervision, visualization, writing – original draft preparation, writing – review and editing.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Ethical approval
Not required.
Informed consent statement
Not required.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Ramanzini, L., Camargo, L.M., Silveira, J.O.F. et al. Inflammatory markers and depression in Parkinson’s disease: a systematic review. Neurol Sci 43, 6707–6717 (2022). https://doi.org/10.1007/s10072-022-06363-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10072-022-06363-7