Inflammatory biomarkers predict depressive, but not anxiety symptoms during aging: The prospective Sydney Memory and Aging Study
Introduction
Aging processes have been associated with a pro-inflammatory state in the body (Bruunsgaard et al., 2001) and the brain, mediated by increased immune responses in the periphery, disruption of the periphery-CNS immune communication, and increased and discordant CNS response (Alexopoulos and Morimoto, 2011). The complex process of age-associated inflammation is underpinned by an age-dependent up-regulation of genes regulating inflammatory processes (Lee et al., 2000, Lu et al., 2004, Lucin and Wyss-Coray, 2009) which is thought to contribute to the onset of various age-associated diseases (Bruunsgaard et al., 2001) and to pre-mature mortality (Baune et al., 2011).
While some forms of adult depression have been suggested to be caused by inflammation in the brain (Rothermundt et al., 2001, Dantzer et al., 2008a, Dantzer et al., 2008b, Dowlati et al., 2010), the potential role of inflammation in geriatric depression appears to be complicated by age-associated factors (e.g. cardiovascular diseases, metabolic changes, morphological brain changes). These factors may contribute to both inflammation and depressive symptoms leaving the question unanswered if inflammation may be a cause or consequence or both of geriatric depression (Alexopoulos et al., 1997).
Studies in the elderly on potential effects of an age-associated pro-inflammatory state on brain function and behavior have focused on peripheral inflammatory markers, such as cytokines, based on the assumption that pro-inflammatory cytokines can contribute to the development of depressive symptoms (Dantzer et al., 2008a, Dantzer et al., 2008b) as well as induce neurotransmitter changes in the brain as seen in depression (Anisman et al., 2008).
Several community-based epidemiological studies during aging have been carried out to address the question whether peripheral cytokines are related to depressive symptoms in older adults, primarily using cross-sectional designs (Dentino et al., 1999, Penninx et al., 2003, Tiemeier et al., 2003, Bremmer et al., 2008) with only a few prospective studies (van den Biggelaar et al., 2007, Milaneschi et al., 2009, Stewart et al., 2009). The most consistent finding has been a cross-sectional association of elevated IL-6 with depressive symptoms or depression after controlling for likely confounding variables (Dentino et al., 1999, Penninx et al., 2003, Tiemeier et al., 2003, Bremmer et al., 2008). Only recently, a prospective association of IL-1β and interleukin 1 receptor antagonist (IL1ra) with depressive symptoms in the elderly was suggested (van den Biggelaar et al., 2007, Milaneschi et al., 2009).
Since there is a paucity of studies addressing the association of depressive symptoms and inflammation in a prospective design in aging cohorts, it is unclear whether the cytokine elevations are secondary to the illness (i.e., being directly or indirectly brought on by the depression), or contributes to the provocation of the disorder. In addition, previous studies have suggested that systemic inflammation might also be associated with anxiety disorders/anxiety symptoms (Capuron and Miller, 2011, Liukkonen et al., 2011, Oxenkrug, 2011); however, an analysis of both depressive and anxiety mood states at the same time considering a range of inflammatory markers during aging processes has not been carried out yet and might add to the emerging evidence in the clinical area of anxiety.
While the above cited research indicates that selected inflammatory markers may reflect current depressive/anxiety symptoms, some first research has reported that low-grade systemic inflammation as measured by C-reactive protein and serum amyloid A was associated with remitted depression (Kling et al., 2007). Interestingly, no studies have been published to investigate whether inflammatory markers are predictive of first onset of depressive symptoms in previously non-depressed individuals during aging. Furthermore, research as to whether inflammatory markers may act as markers of current mood symptoms, remitted depression/anxiety or first onset of depressive/anxiety symptoms would be helpful to clarify the potential biological role in these mood states.
In this study, it was firstly hypothesized that peripheral inflammatory markers are associated with acute symptoms of depression, with positive and negative mood and anxiety symptoms during healthy aging (i.e., inflammation is a state marker) at baseline. Secondly, it was hypothesized that inflammatory markers are prospectively associated with symptoms of depression, anxiety and positive/negative mood over two years. Thirdly, it was hypothesized that inflammatory markers at baseline are associated with remitted depression at baseline. Finally, it was hypothesized that inflammatory markers at baseline are associated with first onset of depressive symptoms over 2-years follow-up in previously non-depressed individuals.
Section snippets
Participants and procedure
Participants were recruited from the electoral roll of the Eastern suburbs of Sydney, Australia as part of the Memory and Aging Study (MAS), an ongoing longitudinal study examining the predictors of cognitive decline in an aged, non-demented community sample (Sachdev et al., 2010). Registration on the electoral roll is compulsory in Australia. Participants were excluded from the study if any of the following was evident: dementia (according to DSM-IV criteria), developmental disabilities,
Design
In this 2-year follow-up study, 1037 participants aged between 70 and 90 years were assessed at baseline using a detailed neuropsychological and medical assessment, brain MRI (n = 544) and blood tests (n = 943), including measurement of inflammatory biomarkers. Participants were assessed either at a study center or in their own homes. At follow-up, 889 participants (85.73% of the sample) for the 2-year follow up assessment and N = 722 blood samples were available. This indicates an attrition rate of
Clinical characteristics of the sample
In the entire sample, N = 160 (16.0%) participants reported a previous depressive episode. Although no significant age and gender difference between those with and without history depression were reported, females were more likely to have had a previous depressive episode (chi2 = 4.41, p = 0.036). Of these 160 participants, 139 subjects had no clinically significant symptoms of depression at baseline (remitted depression) and the remaining 21 subjects (12.9%) scored above the GDS cut-off for
Discussion
This study was performed to investigate whether inflammatory markers were prospectively associated with symptoms of depression and anxiety, and specifically to address the question whether inflammatory markers of current, remitted or novel onset of various mood symptoms during normal aging in a large community sample using a prospective design of community dwellings and accounting for a range of potential confounders.
Role of the funding source
All authors declare that the funding source had no impact on the study design, the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.
Conflict of interest
All authors declare no conflict of interest.
Acknowledgements
This study was supported by a Dementia Research Grant through the Australian National Health and Medical Research Council (Grant ID 510124). The Sydney MAS is supported by the Australian National Health and Medical Research Council Program Grant (Grant ID 350833). The authors wish to acknowledge the contributions of Brain and Aging Research Program Staff especially Kristan Kang and Melissa Slavin, all research assistants and administrative assistants as well as all MAS participants. We would
References (63)
- et al.
Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders
Prog. Neurobiol.
(2008) - et al.
Interleukin-1 beta production in dysthymia before and after pharmacotherapy
Biol. Psychiatry
(1999) - et al.
Association between IL-8 cytokine and cognitive performance in an elderly general population – the MEMO-study
Neurobiol. Aging
(2008) - et al.
Inflammatory markers in late-life depression: results from a population-based study
J. Affect. Disord.
(2008) - et al.
Immune system to brain signaling: neuropsychopharmacological implications
Pharmacol. Ther.
(2011) - et al.
Increased plasma levels of 8-iso-PGF2alpha and IL-6 in an elderly population with depression
Psychiatry Res.
(2008) - et al.
A meta-analysis of cytokines in major depression
Biol. Psychiatry
(2010) - et al.
“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975) - et al.
Immunohistochemical localization of plasminogen activator inhibitor-1 in rat and human brain tissues
Neurosci. Lett.
(2001) - et al.
Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A
Biol. Psychiatry
(2007)
Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease
Am. J. Cardiol.
The association between anxiety and C-reactive protein (CRP) levels: results from the Northern Finland 1966 Birth Cohort Study
Eur Psychiatry
Immune activation in brain aging and neurodegeneration: too much or too little?
Neuron
Lower serum zinc in major depression in relation to changes in serum acute phase proteins
J. Affect. Disord.
“Killing the Blues”: a role for cellular suicide (apoptosis) in depression and the antidepressant response?
Prog. Neurobiol.
Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis
Eur. Neuropsychopharmacol.
Interleukin-1 receptor antagonist and incident depressive symptoms over 6 years in older persons: the InCHIANTI study
Biol. Psychiatry
Interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions
Cytokine Growth Factor Rev.
Cytokines involved in CNS manifestations caused by mycoplasma pneumoniae
Pediatr. Neurol.
Cytokine profiles in bipolar affective disorder: focus on acutely ill patients
J. Affect. Disord.
Inflammatory markers and depressed mood in older persons: results from the health, aging and body composition study
Biol. Psychiatry
Inflammatory markers in major depression and melancholia
J. Affect. Disord.
A prospective evaluation of the directionality of the depression–inflammation relationship
Brain Behav. Immun.
Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age
Exp. Gerontol.
Gene expression profiling of amyloid beta peptide-stimulated human post-mortem brain microglia
Neurobiol. Aging
Development and validation of a geriatric depression screening scale: a preliminary report
J. Psychiatr. Res.
‘Vascular depression’ hypothesis
Arch. Gen. Psychiatry
The inflammation hypothesis in geriatric depression
Int. J. Geriatr. Psychiatry
Chemokines and leukozyte traffic
Nature
Systemic inflammation (Interleukin 6) predicts all-cause mortality in men: results from a 9-year follow-up of the MEMO study
Age (Dordr.)
Tissue-type plasminogen activator crosses the intact blood–brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis
Circulation
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