Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the healthy and diseased brain. As a result, there is a large body of evidence that associates BDNF with neuronal ...maintenance, neuronal survival, plasticity, and neurotransmitter regulation. Patients with psychiatric and neurodegenerative disorders often have reduced BDNF concentrations in their blood and brain. A current hypothesis suggests that these abnormal BDNF levels might be due to the chronic inflammatory state of the brain in certain disorders, as neuroinflammation is known to affect several BDNF-related signaling pathways. Activation of glia cells can induce an increase in the levels of pro- and antiinflammatory cytokines and reactive oxygen species, which can lead to the modulation of neuronal function and neurotoxicity observed in several brain pathologies. Understanding how neuroinflammation is involved in disorders of the brain, especially in the disease onset and progression, can be crucial for the development of new strategies of treatment. Despite the increasing evidence for the involvement of BDNF and neuroinflammation in brain disorders, there is scarce evidence that addresses the interaction between the neurotrophin and neuroinflammation in psychiatric and neurodegenerative diseases. This review focuses on the effect of acute and chronic inflammation on BDNF levels in the most common psychiatric and neurodegenerative disorders and aims to shed some light on the possible biological mechanisms that may influence this effect. In addition, this review will address the effect of behavior and pharmacological interventions on BDNF levels in these disorders.
Review on the key role for activated microglia and monocytes in the pathogenesis of bipolar disorder and schizophrenia.
This review describes a key role for mononuclear phagocytes in the pathogenesis ...of major psychiatric disorders. There is accumulating evidence for activation of microglia (histopathology and PET scans) and circulating monocytes (enhanced gene expression of immune genes, an overproduction of monocyte/macrophage‐related cytokines) in patients with bipolar disorder, major depressive disorder, and schizophrenia. These data are strengthened by observations in animal models, such as the MIA models, the chronic stress models, and the NOD mouse model. In these animal models of depressive‐, anxiety‐, and schizophrenia‐like behavior, similar activations of microglia and circulating monocytes can be found. These animal models also make in‐depth pathogenic studies possible and show that microglia activation impacts neuronal development and function in brain areas congruent with the altered depressive and schizophrenia‐like behaviors.
Numerous studies have now implicated a role for inflammation in schizophrenia. However, many aspects surrounding this aspect of the disease are still controversial. This controversy has been driven ...by conflicting evidence on the role of both pro-and anti-inflammatory factors and by often contentious findings concerning cytokine and immune cell profiles in the central nervous system and periphery. Current evidence supports the point that interleukin-6 is elevated in CSF, but does not support activation of microglia, resident macrophage-like cells in the brain. Furthermore, the mechanisms involving transit of the peripheral immune system factors across the blood brain barrier to central parenchyma have still not been completely elucidated. This process appears to involve perivascular macrophages and accompanying dendritic cells retained in the parenchyma by the chemokine and cytokine composition of the surrounding milieu. In addition, a number of studies have shown that this can be modulated by infection with viruses such as herpes simplex virus type I which may disrupt antigen presentation in the perivascular space, with long-lasting consequences. In this review article, we discuss the role of inflammation and viral infection as potential disease modifiers in schizophrenia. The primary viral hit may occur in the fetus
in utero
, transforming the immune response regulatory T-cells or the virus may secondarily remain latent in immune cells or neurons and modify further immune responses in the developing individual. It is hoped that unraveling this pathway further and solidifying our understanding of the pathophysiological mechanisms involved will pave the way for future studies aimed at identification and implementation of new biomarkers and drug targets. This may facilitate the development of more effective personalized therapies for individuals suffering with schizophrenia.
Major depressive disorder (MDD) is a prevalent and disabling psychiatric disease with rates of non-responsiveness to antidepressants ranging from 30–50%. Historically, the monoamine depletion ...hypothesis has dominated the view on the pathophysiology of depression. However, the lack of responsiveness to antidepressants and treatment resistance suggests that additional mechanisms might play a role. Evidence has shown that a subgroup of depressive patients may have an underlying immune deregulation that could explain the lack of therapeutic benefit from antidepressants. Stimuli like inflammation and infection can trigger the activation of microglia to release pro-inflammatory cytokines, acting on two main pathways: (1) activation of the hypothalamic–pituitary adrenal axis, generating an imbalance in the serotonergic and noradrenergic circuits; (2) increased activity of the enzyme indoleamine-2,3-dioxygenase, resulting in depletion of serotonin levels and the production of quinolinic acid. If this hypothesis is proven true, the subgroup of MDD patients with increased levels of pro-inflammatory cytokines, mainly IL-6, TNF-α and IL-1β, might benefit from an anti-inflammatory intervention. Here, we discuss the pre-clinical and clinical studies that have provided support for treatment with non-steroidal anti-inflammatory drugs in depressed patients with inflammatory comorbidities or an elevated immune profile, as well as evidences for anti-inflammatory properties of standard antidepressants.
Schizophrenia (SZ) is a devastating disease with a life time incidence of 1%. The distinguishing symptoms for diagnosis of the disorder are thought disorders like formal incoherence of thoughts, but ...also bizarre contents of thoughts, like thoughts been taken over by foreign powers and among the symptoms are also hallucinations. Treatment with antipsychotics suppresses these psychotic symptoms (called positive, because normally not present in health persons), but patients remain handicapped in cognition, initiative and executive functions (called negative symptoms, because normally present in healthy individuals). The cause of psychosis and diagnostically “ensuing” SZ is an enigma, albeit genetic, imaging and post-mortem research indicate an inflammatory origin of the disease. In a recent opinion paper on the inflammatory origins of SZ, Corsi Zuelli, elegantly summarized the literature regarding the inflammation hypothesis, showing that presence of activated immune cells in the brain (microglia) might actually be immune repressive, and TGF-beta might be the major inhibitory immune factor explaining disturbances in the development of connections in the maturing human brain in adult life as observed in SZ. The brain is an immune privileged site, potent pro-inflammatory proteins like LPS (lipopolysaccharides) that result in oedema, microvascular proliferation and influx of macrophages shedding toxic cytokines in the periphery, do not mount a particularly strong response in the brain, preventing oedema, intracranial hypertension and death (when intracranial pressure exceeds the systolic blood pressure blood supply halts). Very potent anti-inflammatory mechanisms are in place. Therefore, a notable increase of the anti-inflammatory protein TGF-beta in the SZ brain, might indicate a strong trigger for inflammation, which needs to be suppressed and inflict exhaustion to prevent a too forceful pro-inflammatory response to prevent brain damage. No inflammatory damage has been found in SZ brain, like in bacterial or viral encephalitis, where glial scarring is a late sign of inflammatory damage. However, latent infections with known viruses, are present in the brain in many healthy individuals and as a rule do not cause full-blown encephalitis but still need a chronic inflammatory response to be kept latent. Of particular interest in this respect is HSV-1, which colonizes limbic regions of the brain, a region intrinsically associated with SZ (and psychotic mood disorders). Inflammatory changes in the hippocampal region occur both in herpes infections and psychotic disorders. In clinical herpes infections of the brain (severe encephalitis) major hippocampal volume reduction ensues after protracted inflammation (as imaged with PET). In SZ, hippocampal volume already becomes reduced, before the first psychosis sets in. Alzheimers’ disease (AD) is characterized by psychosis but cognitive decline (“negative symptoms”) predominate. Defining MRI feature of AD is a major reduction in hippocampal volume in addition to the cognitive, executive, and emotional changes of far more severity as in SZ. However, also in AD HSV-1 might be involved in the AD typical accumulation of toxic proteins like Abeta, with ensuing inflammation. Post mortem research in SZ shows that an inflammatory response is taking place, with HLA-DR presenting cells accumulating in various brain regions. Also T-cell infiltrates are present, which might indicate the encounter with (viral) proteins or DNA. It still remains unknown, whether the phenotype of these antigen presenting HLA-DR+ cells and T-cells are pro-inflammatory or are in contrast anti-inflammatory/exhausted. This presentation will address the proteins of the replication machinery that have a direct role in the inflammatory response early (in the first infection/psychotic episode) and might be found as tracers of the first encounter of the virus in post-mortem brains of SZ and AD patients alike.
Highlight • There is increased 11 C-( R )-PK11195 binding in the right hippocampus in bipolar I disorder, consistent with the monocyte-T-cell theory of mood disorders.
Schizophrenia is a chronic and disabling brain disease characterized by psychotic episodes with unknown etiology. It is suggested that neuroinflammation plays a role in the pathophysiology of ...schizophrenia. Neuroinflammation is characterized by the activation of microglia cells, which show an increase in the expression of the peripheral benzodiazepine receptor. The isoquinoline (R)-N-(11)C-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide ((11)C-(R)-PK11195) is a peripheral benzodiazepine receptor ligand that can be used for the imaging of activated microglia cells, and thus neuroinflammation, with PET. We hypothesized that neuroinflammation would be more profound in schizophrenic patients during psychosis, and it was therefore investigated whether neuroinflammation was present in patients within the schizophrenia spectrum who were in a psychotic phase.
Seven patients within the schizophrenia spectrum who were recovering from psychosis were included. Recovering psychosis was defined by a score of 5 or more on 1 item of the positive scale of the positive and negative symptoms scale (PANSS) or a score of 4 on 2 items. The patients were compared with 8 age-matched healthy volunteers. Dynamic 60-min PET scans were acquired after the injection of (11)C-(R)-PK11195. All subjects underwent T1- and T2-weighted MRI, and the scans were visually examined for abnormalities and used for anatomic coregistration in data analysis. The PET data were analyzed with a 2-tissue-compartment model to calculate the binding potential, using the metabolite-corrected plasma curve as input.
A significantly higher binding potential of (11)C-(R)-PK11195, indicative of neuroinflammation, was found in the hippocampus of schizophrenic patients than in healthy volunteers (2.07 +/- 0.42 vs. 1.37 +/- 0.30; P = 0.004). A nonsignificant 30% higher (11)C-(R)-PK11195 binding potential was found in the whole-brain gray matter of schizophrenic patients. The MR images did not reveal any visual abnormalities.
The present study suggests that focal neuroinflammation may play an important role in schizophrenia during psychosis.
Community assembly processes do not only influence community structure, but can also affect ecosystem processes. To understand the effect of initial community development on ecosystem processes, we ...studied natural fungal community dynamics during initial wood decay. We hypothesize that fungal community assembly dynamics are driven by strong priority effects of early‐arriving species, which lead to predictable successional patterns and wood decay rates. Alternatively, equivalent colonization success of randomly arriving spores has the potential to drive stochastic community composition and wood decay rates over time. To test these competing hypotheses, we explored the changes in fungal community composition in logs of two tree species (one coniferous and one broadleaf) during the early stages of wood decomposition in a common garden approach. Initial communities were characterized by endophytic fungi, which were highly diverse and variable among logs. Over the first year of decomposition, there was little evidence for priority effects, as early colonizers displaced the endophytic species, and diversity fell as logs were dominated by a few fungal species. During this period, the composition of colonizing fungi was related to the decomposition rates of sapwood. During the second year of decomposition, fungal community composition shifted drastically and the successional dynamics varied considerably between tree species. Variation in fungal community composition among coniferous (Larix kaempferi) logs increased, and there remained no evidence for any priority effects as community composition became stochastic. In contrast, early colonizers still dominated many of the deciduous (Quercus rubra) logs, with a temporally consistent impact on community composition. For both tree species, wood decay rates levelled off and the relationship with fungal community composition disappeared. Our results indicate that priority effects are relatively minimal in naturally occurring fungal community assembly processes. Instead, fungal successional dynamics are governed predominantly by combative abilities of colonizing fungi, and factors that shape fungal communities over time can differ considerably between tree species. Our results indicate that an increased focus of competitive strength among species, rather than priority effects, may be key to predict community assembly and the ecosystem process they provide.
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