Abstract
Depression affects 7% of the elderly population, and it often remains misdiagnosed or untreated. Peripheral biomarkers might aid clinicians by allowing more accurate and well-timed recognition of the disease. We sought to determine if plasma protein levels predict the severity of depressive symptomatology or distinguish patients from healthy individuals. The severity of depressive symptoms and global cognitive functioning were assessed by the Geriatric Depression Scale (GDS) and Mini-Mental State Examination (MMSE) in 152 elderly subjects, 76 of which with major depressive disorder (MDD). Plasma levels of 24 proteins were measured by multiplexing and analyzed as continuous predictors or dichotomized using the median value. The association between individual plasma proteins and MDD risk or depressive symptoms severity was investigated using multiple logistic and linear regressions including relevant covariates. Sensitivity analyses were performed excluding cognitively impaired individuals or non-acute patients with MDD. After adjusting for possible confounders and false discovery rate (FDR) correction, we found lower Fetuin-A levels in MDD patients vs. controls (pFDR = 1.95 × 10–6). This result was confirmed by the sensitivity and dichotomized analyses. Lower prolactin (PRL) levels predicted more severe depressive symptoms in acute MDD patients (pFDR = 0.024). Fetuin-A is a promising biomarker of MDD in the elderly as this protein was negatively associated with the disorder in our sample, regardless of the global cognitive functioning. Lower PRL levels may be a peripheral signature of impaired neuroprotective processes and serotoninergic neurotransmission in more severely depressed patients.
Similar content being viewed by others
References
UN, World Population Prospects (2017) The 2017 Revision, Key Findings and Advance Tables, in Working Paper No. ESA/P/WP/248. United Nations, Department of Economic and Social Affairs, Population Division
Lyness JM et al (2006) The relationship of medical comorbidity and depression in older, primary care patients. Psychosomatics 47(5):435–439
Laursen TM et al (2016) Mortality and life expectancy in persons with severe unipolar depression. J Affect Disord 193:203–207
Briggs R et al (2018) What is the prevalence of untreated depression and death ideation in older people? Data from the Irish Longitudinal Study on Aging. Int Psychogeriatr 30(9):1393–1401
WHO (2017) Mental health of older adults. https://www.who.int/news-room/fact-sheets/detail/mental-health-of-older-adults
Gottfries CG (2001) Late life depression. Eur Arch Psychiatry Clin Neurosci 251(Suppl 2):II57–II61
Taylor WD, Aizenstein HJ, Alexopoulos GS (2013) The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psychiatry 18(9):963–974
Sunday L et al (2007) Age alters cerebrovascular inflammation and effects of estrogen. Am J Physiol Heart Circ Physiol 292(5):H2333–H2340
Kealy J, Greene C, Campbell M (2018) Blood-brain barrier regulation in psychiatric disorders. Neurosci Lett. https://doi.org/10.1016/j.neulet.2018.06.033
Rothermundt M et al (2001) Different immune patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci 251(2):90–97
Lamers F et al (2016) Serum proteomic profiles of depressive subtypes. Transl Psychiatry 6(7):e851
Bot M et al (2015) Serum proteomic profiling of major depressive disorder. Transl Psychiatry 5:e599
Arnold SE et al (2012) Plasma biomarkers of depressive symptoms in older adults. Transl Psychiatry 2:e65
Schmidt HD, Shelton RC, Duman RS (2011) Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 36(12):2375–2394
Harris VK et al (2013) Cerebrospinal fluid fetuin-A is a biomarker of active multiple sclerosis. Mult Scler 19(11):1462–1472
Chatterjee P et al (2013) Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages. J Biol Chem 288(39):28324–28330
Druzhkova T et al (2019) Acute stress response to a cognitive task in patients with major depressive disorder: potential metabolic and proinflammatory biomarkers. Metab Brain Dis 34(2):621–629
Jia C et al (2019) Ciliary neurotrophic factor is a key sex-specific regulator of depressive-like behavior in mice. Psychoneuroendocrinology 100:96–105
Brambilla P et al (2014) Increased M1/decreased M2 signature and signs of Th1/Th2 shift in chronic patients with bipolar disorder, but not in those with schizophrenia. Transl Psychiatry 4:e406
Benedetti F et al (2017) Higher baseline proinflammatory cytokines mark poor antidepressant response in bipolar disorder. J Clin Psychiatry 78(8):e986–e993
Ramsey JM et al (2016) Sex differences in serum markers of major depressive disorder in the netherlands study of depression and anxiety (NESDA). PLoS ONE 11(5):e0156624
Torner L (2016) Actions of prolactin in the brain: from physiological adaptations to stress and neurogenesis to psychopathology. Front Endocrinol (Lausanne) 7:25
Nicholas L, Dawkins K, Golden RN (1998) Psychoneuroendocrinology of depression: prolactin. Psychiatr Clin N Am 21(2):341–358
Gu S et al (2018) Stress induced hormone and neuromodulator changes in menopausal depressive rats. Front Psychiatry 9:253
Ramachandran Pillai R et al (2017) Luteinizing hormone-follicle stimulating hormone ratio as biological predictor of post-partum depression. Compr Psychiatry 72:25–33
Huerta R et al (1995) Symptoms at perimenopausal period: its association with attitudes toward sexuality, life-style, family function, and FSH levels. Psychoneuroendocrinology 20(2):135–148
Harlow BL et al (2003) Depression and its influence on reproductive endocrine and menstrual cycle markers associated with perimenopause: the Harvard Study of Moods and Cycles. Arch Gen Psychiatry 60(1):29–36
Carvalho AF et al (2014) Adipokines as emerging depression biomarkers: a systematic review and meta-analysis. J Psychiatr Res 59:28–37
Lu XY (2007) The leptin hypothesis of depression: a potential link between mood disorders and obesity? Curr Opin Pharmacol 7(6):648–652
Dean J, Keshavan M (2017) The neurobiology of depression: an integrated view. Asian J Psychiatr 27:101–111
Pasquali MA et al (2018) A longitudinal study of neurotrophic, oxidative, and inflammatory markers in first-onset depression in midlife women. Eur Arch Psychiatry Clin Neurosci 268(8):771–781
Tsai SJ (2017) Role of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in psychological stress and depression. Oncotarget 8(68):113258–113268
Tsai SJ et al (2008) Plasminogen activator inhibitor-1 gene is associated with major depression and antidepressant treatment response. Pharmacogenet Genom 18(10):869–875
Han C et al (2009) Study design and methods of the Ansan Geriatric Study (AGE study). BMC Neurol 9:10
Park MH et al (2006) No difference in stroke knowledge between Korean adherents to traditional and western medicine—the AGE study: an epidemiological study. BMC Public Health 6:153
Yoo S-W et al (2006) Validity of Korean version of the mini-international neuropsychiatric interview. Anxiety Mood 2:50–55
McGivney SA, Mulvihill M, Taylor B (1994) Validating the GDS depression screen in the nursing home. J Am Geriatr Soc 42(5):490–492
Smarr KL, Keefer AL (2011) Measures of depression and depressive symptoms: Beck Depression Inventory-II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D), Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire-9 (PHQ-9). Arthritis Care Res (Hoboken) 63(Suppl 11):S454–S466
Mungas D et al (1996) Age and education correction of Mini-Mental State Examination for English and Spanish-speaking elderly. Neurology 46(3):700–706
Lee JH et al (2002) Development of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K): clinical and neuropsychological assessment batteries. J Gerontol B Psychol Sci Soc Sci 57(1):P47–53
Creavin ST et al (2016) Mini-Mental State Examination (MMSE) for the detection of dementia in clinically unevaluated people aged 65 and over in community and primary care populations. Cochrane Database Syst Rev (1):CD011145
Dols A et al (2015) BDNF serum levels are not related to cognitive functioning in older depressed patients and controls. Int Psychogeriatr 27(4):649–656
Shin C et al (2019) Increased plasma complement factor H is associated with geriatric depression. Int Psychogeriatr 31(1):101–108
Pan A et al (2008) The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. PLoS ONE 3(1):e1392
Bremmer MA et al (2008) Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord 106(3):249–255
Montorio I, Izal M (1996) The Geriatric Depression Scale: a review of its development and utility. Int Psychogeriatr 8(1):103–112
Eyre HA, Stuart MJ, Baune BT (2014) A phase-specific neuroimmune model of clinical depression. Prog Neuropsychopharmacol Biol Psychiatry 54:265–274
Benjamini Y, Krieger AM, Yekutieli DJB (2006) Adaptive linear step-up procedures that control the false discovery rate. Biometrika 93(3):491–507
Lebreton JP et al (1979) Serum concentration of human alpha 2 HS glycoprotein during the inflammatory process: evidence that alpha 2 HS glycoprotein is a negative acute-phase reactant. J Clin Invest 64(4):1118–1129
Mori K, Emoto M, Inaba M (2011) Fetuin-A: a multifunctional protein. Recent Pat Endocr Metab Immune Drug Discov 5(2):124–146
Heinen MC et al (2018) Fetuin-A protein distribution in mature inflamed and ischemic brain tissue. PLoS ONE 13(11):e0206597
Dabrowska AM et al (2015) Fetuin-A (AHSG) and its usefulness in clinical practice. Review of the literature. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 159(3):352–359
Laughlin GA et al (2014) Fetuin-A, a new vascular biomarker of cognitive decline in older adults. Clin Endocrinol (Oxf) 81(1):134–140
Smith ER et al (2011) Plasma fetuin-A is associated with the severity of cognitive impairment in mild-to-moderate Alzheimer's disease. J Alzheimers Dis 24(2):327–333
Herrmann LL, Goodwin GM, Ebmeier KP (2007) The cognitive neuropsychology of depression in the elderly. Psychol Med 37(12):1693–1702
Melchor JP, Strickland S (2005) Tissue plasminogen activator in central nervous system physiology and pathology. Thromb Haemost 93(4):655–660
Chevilley A et al (2015) Impacts of tissue-type plasminogen activator (tPA) on neuronal survival. Front Cell Neurosci 9:415
Gorska-Ciebiada M et al (2016) Plasma levels of thrombomodulin, plasminogen activator inhibitor-1 and fibrinogen in elderly, diabetic patients with depressive symptoms. Aging Clin Exp Res 28(5):843–851
von Känel R et al (2001) Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease? Psychosom Med 63(4):531–544
Fanelli G et al (2019) Reduced CXCL1/GRO chemokine plasma levels are a possible biomarker of elderly depression. J Affect Disord 249:410–417
Swiatkowska M, Szemraj J, Cierniewski CS (2005) Induction of PAI-1 expression by tumor necrosis factor alpha in endothelial cells is mediated by its responsive element located in the 4G/5G site. FEBS J 272(22):5821–5831
Jeon H et al (2012) Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity. J Neuroinflamm 9:149
Ajjan R et al (2007) Ethnic differences in cardiovascular risk factors in healthy Caucasian and South Asian individuals with the metabolic syndrome. J Thromb Haemost 5(4):754–760
McCartney CR, Marshall JC (2019) Neuroendocrinology of reproduction. In: Barbieri RL, Strauss III JF (eds) Yen & Jaffe’s reproductive endocrinology: physiology, pathophysiology, and clinical management. Elsevier
Saletu B et al (1995) Double-blind, placebo-controlled, hormonal, syndromal and EEG mapping studies with transdermal oestradiol therapy in menopausal depression. Psychopharmacology 122(4):321–329
Schmidt PJ et al (2002) Basal plasma hormone levels in depressed perimenopausal women. Psychoneuroendocrinology 27(8):907–920
Young EA et al (2000) Alteration in the hypothalamic-pituitary-ovarian axis in depressed women. Arch Gen Psychiatry 57(12):1157–1162
Freeman EW et al (2006) Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry 63(4):375–382
Ryan J et al (2009) A prospective study of the association between endogenous hormones and depressive symptoms in postmenopausal women. Menopause 16(3):509–517
Rubin RT, Poland RE, Lesser IM (1989) Neuroendocrine aspects of primary endogenous depression VIII. Pituitary-gonadal axis activity in male patients and matched control subjects. Psychoneuroendocrinology 14(3):217–229
Andre C et al (2018) mTORC1 pathway disruption abrogates the effects of the ciliary neurotrophic factor on energy balance and hypothalamic neuroinflammation. Brain Behav Immun 70:325–334
Lin HW et al (2009) Ciliary neurotrophic factor (CNTF) plus soluble CNTF receptor alpha increases cyclooxygenase-2 expression, PGE2 release and interferon-gamma-induced CD40 in murine microglia. J Neuroinflamm 6:7
Lee TI et al (2009) Role of ciliary neurotrophic factor in microglial phagocytosis. Neurochem Res 34(1):109–117
Carrillo-de Sauvage MA et al (2015) The neuroprotective agent CNTF decreases neuronal metabolites in the rat striatum: an in vivo multimodal magnetic resonance imaging study. J Cereb Blood Flow Metab 35(6):917–921
Peruga I et al (2012) Endogenous ciliary neurotrophic factor modulates anxiety and depressive-like behavior. Behav Brain Res 229(2):325–332
Beumer W et al (2012) The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol 92(5):959–975
Wang H et al (2010) Peripheral administration of fetuin-A attenuates early cerebral ischemic injury in rats. J Cereb Blood Flow Metab 30(3):493–504
Kahn MA et al (1995) CNTF regulation of astrogliosis and the activation of microglia in the developing rat central nervous system. Brain Res 685(1–2):55–67
Setiawan E et al (2015) Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry 72(3):268–275
Mechawar N, Savitz J (2016) Neuropathology of mood disorders: do we see the stigmata of inflammation? Transl Psychiatry 6(11):e946
Cavaillon JM (2001) Pro- versus anti-inflammatory cytokines: myth or reality. Cell Mol Biol (Noisy-le-grand) 47(4):695–702
Wohleb ES (2016) Neuron–microglia interactions in mental health disorders: “for better, and for worse”. Front Immunol 7:544
Busse M et al (2015) Decreased quinolinic acid in the hippocampus of depressive patients: evidence for local anti-inflammatory and neuroprotective responses? Eur Arch Psychiatry Clin Neurosci 265(4):321–329
Diniz BS et al (2010) Serum brain-derived neurotrophic factor level is reduced in antidepressant-free patients with late-life depression. World J Biol Psychiatry 11(3):550–555
Shi Y et al (2010) Plasma BDNF and tPA are associated with late-onset geriatric depression. Psychiatry Clin Neurosci 64(3):249–254
Ziegenhorn AA et al (2007) Serum neurotrophins—a study on the time course and influencing factors in a large old age sample. Neurobiol Aging 28(9):1436–1445
Bocchio-Chiavetto L et al (2010) Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. World J Biol Psychiatry 11(6):763–773
Rosenfeld RD et al (1995) Purification and identification of brain-derived neurotrophic factor from human serum. Protein Expr Purif 6(4):465–471
Tsuchimine S et al (2014) Preanalysis storage conditions influence the measurement of brain-derived neurotrophic factor levels in peripheral blood. Neuropsychobiology 69(2):83–88
Corona G et al (2014) Low prolactin is associated with sexual dysfunction and psychological or metabolic disturbances in middle-aged and elderly men: the European Male Aging Study (EMAS). J Sex Med 11(1):240–253
Prabhakar VK, Davis JR (2008) Hyperprolactinaemia. Best Pract Res Clin Obstet Gynaecol 22(2):341–353
Urban RJ, Veldhuis JD (1991) A selective serotonin reuptake inhibitor, fluoxetine hydrochloride, modulates the pulsatile release of prolactin in postmenopausal women. Am J Obstet Gynecol 164(1 Pt 1):147–152
Peeters F et al (2006) Diurnal mood variation in major depressive disorder. Emotion 6(3):383–391
Leyhe T et al (2017) A common challenge in older adults: Classification, overlap, and therapy of depression and dementia. Alzheimers Dement 13(1):59–71
Acknowledgements
This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (Grant Number: HC15C1405).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Prof. Alessandro Serretti is/has been consultant/speaker for Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier. The other authors declare no potential conflict of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Fanelli, G., Benedetti, F., Wang, SM. et al. Reduced plasma Fetuin-A is a promising biomarker of depression in the elderly. Eur Arch Psychiatry Clin Neurosci 270, 901–910 (2020). https://doi.org/10.1007/s00406-019-01090-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00406-019-01090-1