Leonie Gouweleeuw

Neutrophil Gelatinase-Associated Lipocalin and depression in patients with chronic heart failure.

Depression adversely affects prognosis in heart failure (HF) patients. Inflammation is indicated as potential biological pathway in this co-morbidity. Since increased levels of the cytokine Neutrophil Gelatinase-Associated Lipocalin (NGAL) are predictive for HF prognosis, and recently indicated in patients with major depression, this study examined the association of serum NGAL levels with symptoms of depression in patients with HF. Serum NGAL levels were measured in 104 patients with HF (left ventricular ejection fraction, LVEF⩽40). Depression, evaluated using the Beck Depression Inventory (BDI; total score, somatic and cognitive component), and the Hamilton Depression Rating scale (HAMD), at baseline and 12months follow-up, was associated with NGAL levels using mixed model analysis. Analyses were adjusted for demographics measures, disease severity indicators, inflammation, comorbidity and medication. Increased serum NGAL levels were significantly associated with depression measured by HAMD (baseline: r=0.25, p<.05) and BDI (baseline: r=0.22, p<.05; 12months: r=0.37, p<.01). This association remained significant after adjustment for covariates; age, sex, time, LVEF, and creatinine (HAMD, t=2.01, p=.047; BDI, t=2.28, p=.024). NGAL was significantly associated with somatic- (p=0.004), but not cognitive depressive symptoms (p=0.32). NGAL levels were associated with the experienced HF-related functional limitations (6min walk test), rather than the severity of cardiac dysfunction (LVEF). This study indicates that depression in patients with chronic HF is associated with elevated NGAL levels, independent of clinical severity of the underlying disease.

The role of neutrophil gelatinase associated lipocalin (NGAL) as biological constituent linking depression and cardiovascular disease

Depression is more common in patients with cardiovascular disease than in the general population. Conversely, depression is a risk factor for developing cardiovascular disease. Comorbidity of these two pathologies worsens prognosis. Several mechanisms have been indicated in the link between cardiovascular disease and depression, including inflammation. Systemic inflammation can have long-lasting effects on the central nervous system, which could be associated with depression. NGAL is an inflammatory marker and elevated plasma levels are associated with both cardiovascular disease and depression. While patients with depression show elevated NGAL levels, in patients with comorbid heart failure, NGAL levels are significantly higher and associated with depression scores. Systemic inflammation evokes NGAL expression in the brain. This is considered a proinflammatory effect as it is involved in microglia activation and reactive astrocytosis. Animal studies support a direct link between NGAL and depression/anxiety associated behavior. In this review we focus on the role of NGAL in linking depression and cardiovascular disease.

Differences in the association between behavior and neutrophil gelatinase-associated lipocalin in male and female rats after coronary artery ligation

Heart failure is associated with an increased risk of developing depression and cognitive dysfunction, which negatively affects prognosis. Plasma levels of neutrophil gelatinase associated lipocalin (NGAL) are increased in heart failure and depression. Moreover, NGAL levels are associated with depression in heart failure patients. Since women are at a higher risk of developing comorbid depression with heart failure, the aim of this study was to examine sex differences in the link between NGAL and behavior in a rat model of heart failure. In young adult male and female Wistar rats, myocardial infarction (MI) was induced by means of coronary artery ligation, while control rats received sham surgery. We analyzed aspects of cognition and depression/anxiety using various behavioral tests starting three weeks after surgery. Hemodynamic measurements were performed and hearts and lungs were weighed. NGAL levels in plasma, cerebrospinal fluid (CSF) and brain tissue were analyzed. MI induced impairment in cardiac contractility and relaxation, and an increase in lung weight. NGAL correlated with signs of heart failure in male, but not female rats. Male MI rats displayed cognitive problems, but not depressive-like or anxiety-like behavior. No behavioral effects of MI were observed in female rats. Plasma NGAL levels were higher in male than female rats with higher concentrations in MI compared to sham. CSF NGAL was higher in MI rats compared to sham and higher in males compared to females. The number of NGAL positive cells in the paraventricular nucleus of the hypothalamus (PVN) was only increased in male MI rats. In male, but not in female rats, NGAL levels correlated with depressive-like behavior and cognitive dysfunction. Data indicate that while MI increased NGAL levels in plasma, CSF and PVN, correlations of NGAL with behavior are sex-specific, but independent of whether sham or MI surgery was performed. This suggests that inflammatory processes related to thorax surgery and their potential effects on depressive-like behavior and cognition may be sex-specific.

NGAL and other markers of inflammation as competitive or complementary markers for depressive symptom dimensions in heart failure

Objectives. Neutrophil gelatinase-associated lipocalin (NGAL) is an inflammatory marker associated with the pathophysiology of heart failure (HF), the psychopathology of depression and the co-existing symptoms of depression in HF patients. The aim of this study is to determine whether the association of serum NGAL levels with depressive symptoms dimensions in HF is independent of well-known inflammatory markers. Methods. Serum NGAL, high sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α), its two soluble receptors; sTNFR1, sTNFR2, Interleukin-6 (IL-6) and leukocytes were measured in 104 patients with HF at baseline and 12 months. Depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at both timepoints. Correlations between NGAL and inflammatory markers and depressive symptoms dimensions were determined. The effect of hsCRP, IL-6, TNF-α, sTNFR1, sTNFR2 and leukocytes on the association of NGAL with depressive symptoms was determined and adjusted for time, demographics, cardiac disease severity, and kidney function. Results. NGAL levels were significantly correlated with hsCRP, TNF-α, sTNFR1, sTNFR2 and leukocytes. NGAL was significantly associated with somatic depressive symptoms, independent of abovementioned markers. Conclusions. Serum NGAL is an independent inflammatory marker for somatic depressive symptoms in HF and may function as an immunopathogen linking somatic symptoms of depression to HF.

Neutrophil gelatinase-associated lipocalin and microglial activity are associated with distinct postoperative behavioral changes in rats

Neutrophil gelatinase-associated lipocalin (NGAL) has recently gained interest as a marker for neuroinflammation and associated behavioral dysfunction. We aimed to explore the link between NGAL and behavior in a rat model of postoperative cognitive dysfunction (POCD). Material collected in two previous studies on POCD was analyzed and associated with outcomes for exploratory behavior and spatial learning. Plasma and hippocampal NGAL and microglial activity were analyzed. Pearsons correlations and backward linear regression were performed to study the associations between behavioral parameters, NGAL concentrations, and microglial activity. Plasma and hippocampal NGAL were increased following surgery. Plasma NGAL was associated with impaired spatial learning only, microglial activity was associated with exploratory behavior only, while hippocampal NGAL was associated with both behavioral aspects. Spatial learning was best predicted by a model containing plasma NGAL concentrations and hippocampal microglial activity. NGAL may serve as a sensitive marker in connecting the peripheral inflammatory state to POCD, while postoperative changes in exploratory behavior are better reflected by hippocampal neuroinflammation. These findings warrant further exploration in the role of NGAL in development of postoperative behavioral deficits.