The relationship between HIV-1 neuroinflammation, neurocognitive impairment and encephalitis pathology: A systematic review of studies investigating post-mortem brain tissue.

The activities of HIV-1 in the central nervous system (CNS) are responsible for a dysregulated neuroinflammatory response and the subsequent development of HIV-associated neurocognitive disorders (HAND). The use of post-mortem human brain tissue is pivotal for studying the neuroimmune mechanisms of CNS HIV infection. To date, numerous studies have investigated HIV-1-induced neuroinflammation in post-mortem brain tissue. However, from the commonly investigated studies in this line of research, it is not clear which neuroinflammatory markers are consistently associated with HIV neurocognitive impairment (NCI) and neuropathology (i.e., HIV-encephalitis, HIVE). Therefore, we conducted a systematic review of the association between neuroinflammation and NCI/HIVE from studies investigating post-mortem brain tissue. Our aim was to synthesise the published data to date to provide commentary on the most noteworthy markers that are associated with NCI/HIVE. PubMed, Scopus, and Web of Science databases were searched using a search protocol designed specifically for this study. Sixty-one studies were included that investigated the levels of inflammatory markers based on their gene and protein expression in association with NCI/HIVE. The findings revealed that the (1) transcript expressions of IL-1ß and TNF-α were consistently associated with NCI/HIVE, whereas CCL2 and IL-6 were commonly not associated with NCI/HIVE, (2) protein expressions of CD14, CD16, CD68, Iba-1, IL-1ß and TNF-α were consistently associated with NCI/HIVE, while CD45, GFAP, HLA-DR, IL-1 and IL-6 were commonly not associated with NCI/HIVE, and (3) gene and protein expressions of CNS IL-1ß and TNF-α were consistently associated with NCI/HIVE, while IL-6 was consistently not associated with NCI/HIVE. These markers highlight the commonly investigated markers in this line of research and elucidates the neuroinflammatory mechanisms in the HIV-1 brain that are involved in the pathophysiology of NCI/HIVE. These markers and related pathways should be investigated for the development of improved diagnostics, prognostics, and therapeutics of HAND.

A TNF receptor 2 agonist ameliorates neuropathology and improves cognition in an Alzheimer's disease mouse model.

Tumor necrosis factor-α (TNF-α) is a pleiotropic, proinflammatory cytokine related to different neurodegenerative diseases, including Alzheimer's disease (AD). Although the linkage between increased TNF-α levels and AD is widely recognized, TNF-α-neutralizing therapies have failed to treat AD. Previous research has associated this with the antithetic functions of the two TNF receptors, TNF receptor 1, associated with inflammation and apoptosis, and TNF receptor 2 (TNFR2), associated with neuroprotection. In our study, we investigated the effects of specifically stimulating TNFR2 with a TNFR2 agonist (NewStar2) in a transgenic Aß-overexpressing mouse model of AD by administering NewStar2 in two different ways: centrally, via implantation of osmotic pumps, or systemically by intraperitoneal injections. We found that both centrally and systemically administered NewStar2 resulted in a drastic reduction in amyloid ß deposition and ß-secretase 1 expression levels. Moreover, activation of TNFR2 increased microglial and astrocytic activation and promoted the uptake and degradation of Aß. Finally, cognitive functions were also improved after NewStar2 treatment. Our results demonstrate that activation of TNFR2 mitigates Aß-induced cognitive deficits and neuropathology in an AD mouse model and indicates that TNFR2 stimulation might be a potential treatment for AD.

Joint effects of prenatal exposure to indoor air pollution and psychosocial factors on early life inflammation.

It is hypothesized that air pollution and stress impact the central nervous system through neuroinflammatory pathways Despite this, the association between prenatal exposure to indoor air pollution and psychosocial factors on inflammatory markers in infancy has been underexplored in epidemiology studies. This study investigates the individual and joint effects of prenatal exposure to indoor air pollution and psychosocial factors on early life inflammation (interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)). We analyzed data from the South African Drakenstein Child Health Study (N = 225). Indoor air pollution and psychosocial factor measurements were taken in the 2nd trimester of pregnancy. Circulating inflammatory markers (IL-1ß, Il-6, and TNF-α) were measured in serum in the infants at 6 weeks postnatal. Linear regression models were used to investigate associations between individual exposures and inflammatory markers. To investigate joint effects of environmental and psychosocial factors, Self-Organizing Maps (SOM) were used to create exposure profile clusters. These clusters were added to linear regression models to investigate the associations between exposure profiles and inflammatory markers. All models were adjusted for maternal age, maternal HIV status, and ancestry to control for confounding. Most indoor air pollutants were positively associated with inflammatory markers, particularly benzene and TNF-α in single pollutant models. No consistent patterns were found for psychosocial factors in single-exposure linear regression models. In joint effects analyses, the SOM profile with high indoor air pollution, low SES, and high maternal depressive symptoms were associated with higher inflammation. Indoor air pollutants were consistently associated with increased inflammation in both individual and joint effects models, particularly in combination with low SES and maternal depressive symptoms. The trend for individual psychosocial factors was not as clear, with mainly null associations. As we have observed pro- and anti-inflammatory effects, future research should investigate joint effects of these exposures on inflammation and their health effects.

Viral protein R (Vpr)-induced neuroinflammation and its potential contribution to neuronal dysfunction: a scoping review.

HIV-associated neurocognitive disorders (HAND) are the result of the activity of HIV-1 within the central nervous system (CNS). While the introduction of antiretroviral therapy (ART) has significantly reduced the occurrence of severe cases of HAND, milder cases still persist. The persistence of HAND in the modern ART era has been linked to a chronic dysregulated inflammatory profile. There is increasing evidence suggesting a potential role of Viral protein R (Vpr) in dysregulating the neuroinflammatory processes in people living with HIV (PLHIV), which may contribute to the development of HAND. Since the role of Vpr in neuroinflammatory mechanisms has not been clearly defined, we conducted a scoping review of fundamental research studies on this topic. The review aimed to assess the size and scope of available research literature on this topic and provide commentary on whether Vpr contributes to neuroinflammation, as highlighted in fundamental studies. Based on the specified selection criteria, 10 studies (6 of which were cell culture-based and 4 that included both animal and cell culture experiments) were eligible for inclusion. The main findings were that (1) Vpr can increase neuroinflammatory markers, with studies consistently reporting higher levels of TNF-α and IL-8, (2) Vpr induces (neuro)inflammation via specific pathways, including the PI3K/AKT, p38-MAPk, JNK-SAPK and Sur1-Trpm4 channels in astrocytes and the p38 and JNK-SAPK in myeloid cells, and (3) Vpr-specific protein amino acid signatures (73R, 77R and 80A) may play an important role in exacerbating neuroinflammation and the neuropathophysiology of HAND. Therefore, Vpr should be investigated for its potential contribution to neuroinflammation in the development of HAND.

Antenatal maternal depression, early life inflammation and neurodevelopment in a South African birth cohort.

BACKGROUND: Antenatal exposure to maternal psychological adversity, including depression, increases the risk of impaired neurodevelopment in children. The underlying biological mechanisms remain unclear, especially in early life during critical windows of development and maturation. This study investigated the association of antenatal maternal depression, maternal and early life inflammatory markers and neurodevelopmental outcomes in children at 2 years of age. METHODS: A subgroup of mothers and their children (n = 255) that were enrolled in a South African birth cohort study, the Drakenstein Child Health Study, were followed from the antenatal period through to 2 years of child age. Maternal depressive symptoms were measured by the Beck Depression Inventory (BDI-II) at 26 weeks gestation. Serum inflammatory markers [granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), interleukin IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, tumour necrosis factor-α (TNF-α), neutrophil gelatinase-associated lipocalin (NGAL) and metalloproteinase-9 (MMP-9)] were measured in mothers at enrolment and in their children at 6-10 weeks and at 2 years. Neurodevelopment was assessed at 2 years using the Bayley Scales of Infant and Toddler Development III. RESULTS: Antenatal depressive symptoms (present in 25% of the mothers) were significantly associated with higher levels of IL-7 (p = 0.008), IL-8 (p = 0.019) and TNF-α (p = 0.031) in the mothers after correcting for sociodemographic and lifestyle factors. Serum IL-1ß and NGAL levels were significantly elevated over time in children born to mothers with depressive symptoms compared to those without depression, after controlling for maternal and child health and sociodemographic factors. Elevated infant IL-1ß at 6-10 weeks of age partially mediated the association of maternal depressive symptoms with poorer language scores at 2 years. CONCLUSION: Alterations in early life immunity, as reflected by elevated IL-1ß, is a potential pathway through which antenatal maternal depressive symptoms may impact language development in young children.

Proteomics and metabolomics of HIV-associated neurocognitive disorders: A systematic review.

HIV-associated neurocognitive disorders (HAND) are common features of the effect of human immunodeficiency virus (HIV)-1 within the central nervous system (CNS). The underlying neuropathophysiology of HAND is incompletely known. Furthermore, there are no markers to effectively predict or stratify the risk of HAND. Recent advancements in the fields of proteomics and metabolomics have shown promise in addressing these concerns, however, it is not clear if these approaches may provide new insight into pathways and markers related to HAND. We therefore conducted a systematic review of studies using proteomic and/or metabolomic approaches in the aim of identifying pathways or markers associated with neurocognitive impairment in people living with HIV (PLWH). Thirteen studies were eligible, including 11 proteomic and 2 metabolomic investigations of HIV-positive clinical samples (cerebrospinal fluid (CSF), brain tissue, and serum). Across varying profiling techniques and sample types, the majority of studies found an association of markers with neurocognitive function in PLWH. These included metabolic marker myo-inositol and proteomic markers superoxide dismutase, gelsolin, afamin, sphingomyelin, and ceramide. Certain markers were found to be dysregulated across various sample types. Afamin and gelsolin overlapped in studies of blood and CSF and sphingomyelin and ceramide overlapped in studies of CSF and brain tissue. The association of these markers with neurocognitive functioning may indicate the activity of certain pathways, potentially those related to the underlying neuropathophysiology of HAND.

Association of maternal and infant inflammation with neurodevelopment in HIV-exposed uninfected children in a South African birth cohort.

HIV-exposed uninfected (HEU) children may have altered immune regulation and poorer neurodevelopment outcomes compared to their HIV-unexposed (HU) counterparts. However, studies investigating the association of maternal and infant inflammation with neurodevelopment in HEU children are limited and longitudinal data are lacking. This study investigated serum inflammatory markers in women living with HIV vs. HIV-uninfected women during pregnancy and in their children, as well as associations with neurodevelopmental outcomes at two years of age in an African birth cohort study. A sub-group of mother-child dyads from the Drakenstein Child Health Study had serum inflammatory markers measured at ≈26 week's gestation (n = 77 HIV-infected mothers; n = 190 HIV-uninfected mothers), at 6-10 weeks (n = 63 HEU infants and n = 159 HU infants) and at 24-28 months (n = 77 HEU children and n = 190 HU children). Serum inflammatory markers [granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), interleukin IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor-α (TNF-α), neutrophil gelatinase-associated lipocalin (NGAL) and metalloproteinase-9 (MMP-9)] were analyzed with a multiplex bead array and ELISA assays. The Bayley Scales of Infant and Toddler Development, third edition, was used to assess neurodevelopment at 24-28 months. After correcting for multiple comparisons, HIV infection during pregnancy was associated with lower serum levels of inflammatory markers in mothers at 26 weeks gestation (GM-CSF and MMP-9, p < 0.05) and HEU children at 6-10 weeks (IFN-γ and IL-1ß, p < 0.01), and at 24-28 months (IFN-γ, IL-1ß, IL-2 and IL-4, p < 0.05) compared to HIV-uninfected mothers and HU children. In HEU infants at 6-10 weeks, inflammatory markers (GM-CSF, IFN-γ, IL-10, IL-12p70, IL-1ß, IL-2, IL-4, IL-6 and NGAL, all p < 0.05) were associated with poorer motor function at two years of age. This is the first study to evaluate the associations of follow-up immune markers in HEU children with neurodevelopment. These findings suggest that maternal HIV infection is associated with immune dysregulation in mothers and their children through two years of age. An altered immune system in HEU infants is associated with poorer follow-up motor neurodevelopment. These data highlight the important role of the immune system in early neurodevelopment and provide a foundation for future research.

Signatures of HIV-1 subtype B and C Tat proteins and their effects in the neuropathogenesis of HIV-associated neurocognitive impairments.

HIV-associated neurocognitive impairments (HANI) are a spectrum of neurological disorders due to the effects of HIV-1 on the central nervous system (CNS). The HIV-1 subtypes; HIV-1 subtype B (HIV-1B) and HIV-1 subtype C (HIV-1C) are responsible for the highest prevalence of HANI and HIV infections respectively. The HIV transactivator of transcription (Tat) protein is a major contributor to the neuropathogenesis of HIV. The effects of the Tat protein on cells of the CNS is determined by the subtype-associated amino acid sequence variations. The extent to which the sequence variation between Tat-subtypes contribute to underlying mechanisms and neurological outcomes are not clear. In this review of the literature, we discuss how amino acid variations between HIV-1B Tat (TatB) and HIV-1C Tat (TatC) proteins contribute to the potential underlying neurobiological mechanisms of HANI. Tat-C is considered to be a more effective transactivator, whereas Tat-B may exert increased neurovirulence, including neuronal apoptosis, monocyte infiltration into the brain, (neuro)inflammation, oxidative stress and blood-brain barrier damage. These findings support the premise that Tat variants from different HIV-1 subtypes may direct neurovirulence and neurological outcomes in HANI.

The association of peripheral immune markers with brain cortical thickness and surface area in South African people living with HIV.

A spectrum of cognitive impairments known as HIV-associated neurocognitive disorders (HAND) are consequences of the effects of HIV-1 within the central nervous system. Regardless of treatment status, an aberrant chronic neuro-immune regulation is a crucial contributor to the development of HAND. However, the extent to which inflammation affects brain structures critical for cognitive status remains unclear. The present study aimed to determine associations of peripheral immune markers with cortical thickness and surface area. Participants included 65 treatment-naïve HIV-positive individuals and 26 HIV-negative controls. Thickness and surface area of all cortical regions were derived using automated parcellation of T1-weighted images acquired at 3 T. Peripheral immune markers included C-C motif ligand 2 (CCL2), matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), thymidine phosphorylase (TYMP), transforming growth factor (TGF)-ß1, and vascular endothelial growth factor (VEGF), which were measured using enzyme-linked immunosorbent assays. Associations of these markers with thickness and surface area of cortical regions were evaluated. A mediation analysis examined whether associations of inflammatory markers with cognitive functioning were mediated by brain cortical thickness and surface area. After controlling for multiple comparisons, higher NGAL was associated with reduced thickness of the bilateral orbitofrontal cortex in HIV-positive participants. The association of NGAL with worse motor function was mediated by cortical thickness of the bilateral orbitofrontal region. Taken together, this study suggests that NGAL plays a potential role in the neuropathophysiology of neurocognitive impairments of HIV.

Association of maternal prenatal psychological stressors and distress with maternal and early infant faecal bacterial profile.

OBJECTIVE: Findings from animal studies indicate that the early gut bacteriome is a potential mechanism linking maternal prenatal stress with health trajectories in offspring. However, clinical studies are scarce and the associations of maternal psychological profiles with the early infant faecal bacteriome are unknown. This study aimed to investigate the associations of prenatal stressors and distress with early infant faecal bacterial profiles in a South African birth cohort study. METHODS: Associations between prenatal symptoms of depression, distress, intimate partner violence (IPV) and posttraumatic stress disorder (PTSD) and faecal bacterial profiles were evaluated in meconium and subsequent stool specimens from 84 mothers and 101 infants at birth, and longitudinally from a subset of 69 and 36 infants at 4-12 and 20-28 weeks of age, respectively, in a South African birth cohort study. RESULTS: Infants born to mothers that were exposed to high levels of IPV had significantly higher proportions of Citrobacter and three unclassified genera, all of which belonging to the family Enterobacteriaceae detected at birth. Proportions of these Enterobacteriaceae remained significantly increased over time (birth to 20-28 weeks of life) in infants born to mothers with high levels of IPV exposure compared to infants from mothers with no/low IPV exposure. Infants born to mothers exposed to IPV also had higher proportions of the genus Weissella at 4-12 weeks compared to infants from mothers with no/low IPV exposure. Faecal specimens from mothers exposed to IPV had higher proportions of the family Lactobacillaceae and lower proportions of Peptostreptococcaceae at birth. Maternal psychological distress was associated with decreased proportions of the family Veillonellaceae in infants at 20-28 weeks and a slower decline in Gammaproteobacteria over time. No changes in beta diversity were apparent for maternal or infant faecal bacterial profiles in relation to any of the prenatal measures for psychological adversities. CONCLUSION: Maternal lifetime IPV and antenatal psychological distress are associated with altered bacterial profiles in infant and maternal faecal bacteria. These findings may provide insights in the involvement of the gut bacteria linking maternal psychological adversity and the maturing infant brain.

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration.

Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNFR2, an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNFR2 into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases.

Psychological distress and C-reactive protein in a South African national survey.

OBJECTIVE: To examine the association of psychological distress with serum C-reactive protein (CRP) in a South African cohort. METHODS: Data were analysed on individuals aged ≥15 years from the South African National Health and Nutrition Examination Survey (SANHANES) of 2012. Psychological distress was evaluated using the Kessler Psychological Distress Scale. Linear regression models assessed the association of psychological distress with serum CRP, adjusting for possible confounding factors. RESULTS: The analytic sample comprised n = 3944 individuals (mean age = 40 and sex = 36% males). Psychological distress was significantly associated with increased serum CRP levels (B = 0.31 and p = 0.001). This association was no longer significant after adjusting for demographic variables, lifestyle factors, cardiac disease, diabetes, hypertension, trauma and anti-inflammatory medication use (B = 0.15 and p = 0.062). CONCLUSION: Psychological distress was associated with elevated levels of CRP among South African adults. However, the association was confounded by a range of factors, with demographic variables (age, sex and population group) having the largest confounding effect. These findings indicate that CRP is not a useful biomarker of psychological distress, and that additional work is needed on the underlying psychobiology of psychological distress.

Lipocalin 2 contributes to brain iron dysregulation but does not affect cognition, plaque load, and glial activation in the J20 Alzheimer mouse model.

BACKGROUND: Lipocalin 2 (Lcn2) is an acute-phase protein implicated in multiple neurodegenerative conditions. Interestingly, both neuroprotective and neurodegenerative effects have been described for Lcn2. Increased Lcn2 levels were found in human post-mortem Alzheimer (AD) brain tissue, and in vitro studies indicated that Lcn2 aggravates amyloid-ß-induced toxicity. However, the role of Lcn2 has not been studied in an in vivo AD model. Therefore, in the current study, the effects of Lcn2 were studied in the J20 mouse model of AD. METHODS: J20 mice and Lcn2-deficient J20 (J20xLcn2 KO) mice were compared at the behavioral and neuropathological level. RESULTS: J20xLcn2 KO and J20 mice presented equally strong AD-like behavioral changes, cognitive impairment, plaque load, and glial activation. Interestingly, hippocampal iron accumulation was significantly decreased in J20xLcn2 KO mice as compared to J20 mice. CONCLUSIONS: Lcn2 contributes to AD-like brain iron dysregulation, and future research should further explore the importance of Lcn2 in AD.

Dynamics of neutrophil gelatinase-associated lipocalin plasma and cerebrospinal fluid concentrations in older males.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is an inflammatory protein with gaining increasing interest for its use as marker in blood and cerebrospinal fluid (CSF) for several chronic diseases. Its biochemical properties make it an attractive marker. However, changes in blood and CSF NGAL concentrations during the diurnal rhythm in the elderly are unknown. This information is important for its optimal use as marker in studies with older people. METHODS: Serial paired plasma and CSF samples were obtained from 8 healthy elderly males over a 30-hour period. NGAL and cortisol were quantified with ELISA. RESULTS: No significant changes in plasma and CSF NGAL concentrations over time were found, whereas cortisol (included as internal control) concentrations displayed significant changes over time. Significant circadian patterns were found for plasma NGAL and for cortisol in both plasma and CSF. However, CSF NGAL concentrations did not follow a diurnal pattern in elderly males. CONCLUSIONS: This study illustrates the temporal regulation of NGAL in plasma and CSF, which potentially is a useful reference for studies measuring NGAL as biomarker in older individuals.

Depression and markers of inflammation as predictors of all-cause mortality in heart failure.

BACKGROUND: In patients with heart failure (HF) depressive symptoms have been associated with mortality, as well as biological risk factors, including inflammation, nitric oxide (NO) regulation, and oxidative stress. We investigated the joint predictive value of depressive symptoms, inflammation and NO regulation on all-cause mortality in patients with HF, adjusted for covariates. METHODS: Serum levels of inflammation (TNFα, sTNFr1, sTNFr2, IL-6, hsCRP, NGAL), NO regulation (l-arginine, ADMA, and SDMA), and oxidative stress (isoprostane 8-Epi Prostaglandin F2 Alpha) were measured in 104 patients with HF (mean age 65.7±SD 8.4years, 28% women). Depressive symptoms (Beck Depression Inventory, BDI) were measured as continuous total, cognitive, and somatic symptoms, as well as categorized presence of mild/moderate depression (cut-off BDI ⩾10). In Cox proportional hazard models we adjusted for age, sex, poor exercise tolerance and comorbidity. RESULTS: After on average 6.1years follow-up (SD=2.9, range 0.4-9.2), 49 patients died. Total and somatic depressive symptoms, mild/moderate depression, higher NGAL, sTNFr2, IL-6, hsCRP and SDMA serum levels were significantly associated with a higher all-cause mortality rate, adjusted for covariates. The findings were most consistent for CRP level and somatic depressive symptoms. When combined, both depressive symptoms and markers of inflammation and NO regulation remained significantly associated with all-cause mortality. These associations were not confounded by age, sex, poor exercise tolerance and comorbidity. CONCLUSION: Depressive symptoms and markers of inflammation and NO regulation are codominant risk factors for all-cause mortality in heart failure.

Waist circumference and neutrophil gelatinase-associated lipocalin in late-life depression.

Both visceral obesity and depression are associated with impaired health and excess mortality, possibly through overlapping pathophysiological mechanisms like adipose tissue derived inflammatory markers. These results, however, are primarily based on population-based surveys, often restricted to a young population and depression severity scales instead of patients with established diagnosis of depressive disorder. We examined the relation between waist circumference and late-life depression using the baseline data of The Netherlands Study of Depression in Older people (NESDO). Psychopathology has been assessed with Composite International Diagnostic Interview version 2.1. Adjusted for age, sex, education, lifestyle (smoking, alcohol, physical activity), drug use, cognition and chronic diseases as well as adjusted for body mass index (BMI), analysis of covariance showed that depressed older patients (n=376) had a significantly lower waist circumference (WC) compared to their non-depressed comparisons (n=130): estimated marginal mean (SE)=93.9 (0.5) versus 97.8 (0.8) cm (F=15.9; df=1467; p<.001). Multiple linear regression analyses within the depressed group showed that both, depression severity (Inventory of Depressive Symptoms) as well as duration-related depression characteristics (age of onset, duration of illness, life-time comorbid dysthymia), were associated with the WC. Only the severity of depressive symptoms remained significant after further adjusted for the BMI. Interestingly, a recently discovered adipokine, Neutrophil Gelatinase-Associated Lipocalin (NGAL), was associated with late-life depression, but only in the subgroup of patients with a pathologically increased WC. Population-based findings on the positive association between obesity and depressive symptoms can thus not be generalised to a clinical sample of depressed older patients. The impact of the WC on course and treatment outcome of late-life depression should be examined in clinical samples, taken into account the relative impact of the WC in proportion to the general level of obesity as indexed by the BMI and the role of adipokines.

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.

Use of Post-mortem Brain Tissue in Investigations of Obsessive- Compulsive Disorder: A Systematic Review.

BACKGROUND: Post-mortem examination of the brain is a key strategy to increase our understanding of the neurobiology of mental disorders. While extensive post-mortem research has been undertaken on some mental disorders, others appear to have been relatively neglected. OBJECTIVE: The objective of the study was to conduct a systematic review of post-mortem research on obsessive-compulsive disorder (OCD). METHODS: A systematic review was performed in accordance with PRISMA guidelines to provide an overview of quantitative, qualitative, or mixed methods primary research studies on OCD. Search platforms included NCBI Pubmed, SCOPUS, and Web of Science. RESULTS: A total of 52 publications were found, and after the removal of works not meeting the inclusion criteria, six (6) peer-reviewed publications remained. These post-mortem studies have provided data on DNA methylation, cellular and molecular alterations, and gene expression profiling in brain areas associated with OCD. DISCUSSION AND CONCLUSION: Included studies highlight the potential value of post-mortem brains from well-characterized individuals with OCD and suggest the need for additional work in this area.

Lipocalin 2: novel component of proinflammatory signaling in Alzheimer's disease.

Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-α. TNF-α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF-α-induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to ß-amyloid toxicity. Moreover, Lcn2 silences a TNFR2-mediated protective neuronal signaling cascade in neurons, pivotal for TNF-α-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.