Suicide and biomarkers of gastrointestinal inflammation

Suicide and gastrointestinal inflammation

Suicide mostly occurs in association with neuropsychiatric disorders characterized by neuroinflammation (brain inflammation). Neuroinflammation often results from perturbations of the brain-gut axis, with pro-inflammatory immune signaling from the gut to the brain. An important study just published in Psychiatry Research offers data showing the connection between biomarkers of gastrointestinal inflammation and recent suicide attempt. The authors were motivated by the intent to validate biomarkers to help assess, treat and prevent suicide attempts.

Most attempting suicide have an illness associated with neuroinflammation

“Psychological autopsy and epidemiological studies indicate that more than 90% of people who die by suicide have a diagnosable psychiatric illness, particularly major depression, bipolar disorder, or schizophrenia…The identification of blood-based markers would provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts.”

It is an urgent clinical need to identify causes that promote dysregulated activation of the immune system against the neuronal antigens.

The GI tract is often the source of immune activation against the brain

Biomarkers of gastrointestinal inflammation are frequently increased in neuropsychiatric disorders.

“Many individuals with schizophrenia and mood disorders have evidence of immune activation suggesting that immune dysregulation may be part of the etiopathology of these disorders. Studies by our group and others indicate that the gastrointestinal tract is often the primary source of this immune activation as evidenced by increased levels of markers of gastrointestinal inflammation in individuals with serious mental illness.”

IBD (inflammatory bowel disease) and celiac disease appear to increase risk for suicide.

“Furthermore, increased rates of suicide and suicide attempts have been found in some populations of individuals with celiac disease or inflammatory bowel diseases.”

But previous studies have focused on a lifetime history rather than attempts, so the authors set out to:

“…examine the association between levels of markers of gastrointestinal inflammation and a recent suicide attempt in individuals with schizophrenia, bipolar disorder or major depressive disorder in comparison with non-psychiatric controls.”

Elevated IL-6

Interleukin-6 (IL-6), a key pro-inflammatory cytokine which can arise from the GI tract, is associated.

“Results from other investigators indicate that inflammation may be associated not only with a proclivity for a psychiatric disorder, but specifically with suicidal behavior. Studies have found an association between a suicide attempt history and the level of cytokines such as IL-6 which are cell signaling molecules involved in the immune response and which can arise from inflammation from many sources, including the gastrointestinal tract”

Gluten and brain inflammation

Neuroinflammation triggered by non-celiac gluten sensitivity is also implicated:

“Gliadin is a component of gluten, found in wheat and related cereals. Antibody response to dietary gliadin is associated with celiac disease, an immune-mediated enteropathy, and with non-celiac wheat sensitivity and is thought to indicate intestinal inflammation and/or intestinal barrier dysfunction. We have found increased levels of antibodies to gliadin in individuals with schizophrenia and with bipolar disorder and in individuals with acute mania during a hospital stay…”

Additionally, loss of tolerance to a commensal yeast may promote neuroinflammation.

“We also have studied the antibody response to yeast mannans represented by antibodies to Saccharomyces cerevisiae (ASCA), a commensal organism present in some foods and in the intestinal tract of many individuals. Elevated ASCA levels are associated with increased intestinal inflammation. We have previously found increased levels of ASCA in individuals with mood disorders.”

Pathogens and loss of immune tolerance

Various pathogens present at low levels can elicit a persistent cross-reaction to self-antigens, including brain antigens, in individuals disposed to loss of immune tolerance.

“An association between elevated antibodies to Toxoplasma gondii, an apicomplexan parasite, and suicide attempts have also been reported. In a recent study, we found that individuals with serious mental illness who had a lifetime history of a suicide attempt had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV); we also found an association between the levels of these antibodies and the number of suicide attempts.”

Significant link found

Association between suicide and markers of GI inflammation

The authors examined data for 282 participants: 90 with schizophrenia, 72 with bipolar disorder, 48 with major depressive disorder, and 72 non-psychiatric controls; who were enrolled in ongoing studies of the role the immune response to infections in individuals with serious psychiatric disorders. Biomarkers measured included IgA antibody to yeast mannan from Saccharomyces cerevisiae (ASCA), IgG antibody to gliadin, IgA antibody to bacterial lipopolysaccharide (LPS) from E. coli O111:B4, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and levels of C-Reactive protein.

“We found a statistically significant difference between the recent attempters and the control group in levels of IgA ASCA; the level in the recent attempt group was significantly higher…We also found that the level of IgG antibodies to gliadin was significantly higher in the recent attempters vs. the control group…We also found that the level of IgA antibodies to bacterial lipopolysaccharide (LPS) was significantly higher in the recent attempters vs. the control group…In terms of CRP, we found that there was a significantly higher level in the past attempter group.”

Predicting risk and protecting patients

These findings offer a valuable opportunity for clinicians to gauge and ameliorate risk of suicide in patients with serious neuropsychiatric disorders.

“The markers of gastrointestinal inflammation are of interest because they can be readily measured in blood samples. In addition, some of the markers studied here may be an attractive target for therapeutic intervention since intestinal inflammation can be modulated by dietary interventions as well as the administration of available prebiotic, probiotic, and antibiotic medications.”

The authors conclude:

“Suicide, for which a previous suicide attempt is the greatest risk factor, is a major cause of death worldwide and is highly prevalent in patients with serious mental illness. Unfortunately, the ability to predict suicide remains limited and no reliable biological markers are available. The identification of blood-based markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.”

For additional categories of importance in evaluating neuropsychiatric risk see The Parents’ Guide to Brain Health.

Bipolar disorder and neuroinflammation

Journal of NeuroinflammationBipolar disorder, like a host of other psychiatric illnesses, should be assessed for neuroinflammation and its underlying causes as evidenced by a wealth of recently published studies. The authors of a paper recently published in the Journal of Neuroinflammation state:

“Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders).”

Or great practical clinical significance…

“As biological abnormalities are increasingly identified among patients with psychiatric disorders, the distinction between neurological and psychiatric illness fades. In addition to systemic autoimmune diseases associated with psychiatric manifestations (for example, lupus), more recently, patients with acute isolated psychosis were identified with synaptic autoimmune encephalitides. These patients are often erroneously diagnosed with refractory primary psychotic disorders, delaying initiation of effective immune therapy. Additionally, growing evidence supports the pathogenic role of anti-neuronal antibodies in neuropsychiatric disorders.”

The authors undertake a review of the extensive literature documenting the role of common autoimmune disorders, autoimmune encephalitides associated with serum anti-synaptic and glutamic acid decarboxylase autoantibodies, anti-basal ganglia/thalamic autoantibodies, and innate inflammation with glial pathology, elevated cytokines levels, cyclooxygenase activation, glutamate dysregulation, increased S100B levels, increased oxidative stress, and blood brain barrier (BBB) dysfunction in bipolar disorder and other neuropsychiatric illnesses.

Regarding the use of antiinflammatory agents in the treatment of psychiatric disorders they state:

“Several human and animal studies suggest that certain antiinflammatory drugs may play an important adjunctive role in the treatment of psychiatric disorders…Although current immune therapies (for example, IVIG, plasmapheresis, corticosteroids and immunosuppressive agents) are often effective for treating autoimmune encephalitides wherein inflammation is acute, intense and predominately of adaptive origin, their efficacy in classical psychiatric disorders wherein inflammation is chronic, much milder, and predominately of innate origin, is limited. Development of novel therapeutics should aim at reversing glial loss, down-regulating harmful MAP [microglial activation and proliferation], while optimizing endogenous neuroprotective T regs and beneficial MAP, rather than indiscriminately suppressing inflammation as occurs with current immunosuppressive agents. Additionally, development of potent co-adjuvant antioxidants that would reverse oxidative injury in psychiatric disorders is needed.”

 

Current Psychiatry ReportsIn reference to bipolar disorder specifically the authors of a paper published in Current Psychiatry Reports state:

Bipolar disorder is now known to be associated not only with highly prevalent co-occurring psychiatric and substance use disorders but also with medical comorbidities, such as cardiovascular diseases, diabetes mellitus, obesity and thyroid dysfunction. Inflammatory disturbances repeatedly observed in bipolar disorder, can explain some of the comorbidity between bipolar disorder and medical disorder. This revised perspective of bipolar disorders should promote the development of therapeutic tools.”

In particular…

Immuno-inflammatory dysfunction may well represent a significant component of the underlying pathophysiology of the disorder. We therefore propose to review the immuno-inflammatory hypothesis in bipolar disorder considering the co-occurence with autoimmune diseases, immunological and inflammatory markers, as well as immuno-genetic markers which could lead to personalized treatments.”

 

Australian & New Zealand Journal of PsychiatryA recent paper in the Australian & New Zealand Journal of Psychiatry strikes a similar chord and highlights the role of autoimmunity:

“Increasing evidence suggests that inflammation and immune dysregulation play an important role in the pathogenesis of bipolar disorder. Because the brain can be affected by various autoimmune processes, it is possible that some psychiatric disorders may have an autoimmune basis.”

In review of the literature on peripheral and central immune dysregulation and autoimmunity in bipolar disorder they note, in addition to the mechanisms described above, association with common autoimmune conditions such as SLE and autoimmune thyroiditis:

Neuroinflammation and peripheral immune dysregulation may play a role in the pathophysiology of bipolar disorder. This involves a complex interaction between immune cells of the central nervous system and periphery resulting in cellular damage through mechanisms involving excitotoxicity, oxidative stress, and mitochondrial dysfunction. Neuropsychiatric systemic lupus erythematosus, anti-NMDA encephalitis, and Hashimoto’s encephalopathy are important differentials for a psychiatrist to consider when suspecting autoimmune encephalopathy.”

The authors conclude:

The link between immune dysregulation, autoimmunity, and bipolar disorder may be closer than previously thought. Psychiatrists should be vigilant for autoimmunity in presentations of bipolar disorder due to its high morbidity and therapeutic implications. Advances in neuroimaging and biomarker identification related to immune dysregulation and neuroinflammation will contribute to our knowledge of the pathophysiology of bipolar disorder.”

 

Journal of Affective DisordersIn a paper published in the Journal of Affective Disorders, the authors examine the incidence of comorbid medical disorders and present evidence that…

“…bipolar disorder can be effectively conceptualized as a multi-systemic inflammatory disease.”

They dispense with the notion that comorbid medical disorders are entirely due to the deleterious effects of psychotropic medications:

“Until recently, a lot of emphasis has been put on the fact that psychotropic medication contributes to cardiovascular risk factors. Lithium can cause weight gain and adversely influence glucose metabolism, valproic acid is associated to weight gain and insulin resistance, second generation anti-psychotics are associated to hyperlipidemia, increased risk with diabetes, and weight gain though the extent of weight gain depends on which antipsychotic is used. It should however be stressed that the increased mortality rate in bipolar predate modern pharmacologic treatments. In addition, the fact that the association between cardiovascular risk factors and bipolar disorder remains significant after controlling for these co-factors strongly suggests that mechanisms specific to bipolar disorder itself have yet to be identified.”

And in fact inflammation is common to both:

“Inflammation has been shown to be crucial throughout atherosclerosis from endothelial dysfunction to plaque rupture and thrombosis; a number of studies also suggest that inflammation may be implicated in the pathophysiology of bipolar disorder (for review see, Goldstein et al., 2009). The data supporting the hypothesis that inflammation could be a common factor underlying both cardio-vascular and bipolar disorder is important to be reviewed.”

Bipolar disorder and abnormal immuno-inflammationMoreover…

“Over the last two decades, it has been shown that inflammatory processes and neural immune interactions are involved in the pathophysiology of major depression, these data also shed light on how to explain the plausible link between increased levels of cytokines and mood states in bipolar disorder. A pro-inflammatory state is known to activate the tryptophan and serotonin-degrading-enzyme, indoleamine 2–3 dioxygenase (IDO), which has been found elevated in the plasma of bipolar patients. Activation of this enzyme leads to increased consumption of tryptophan, thus reducing the availability of serotonergic neurotransmission, as well as inducing the production of detrimental tryptophan catabolites with neurotoxic effects. It has also been shown that the activity of dopaminergic system is reduced in response to inflammation while cytokines enhance the re-uptake of monoamine neuro-transmitters thereby reducing their intra-synaptic concentrations in the brain.”

BDNF (brain derived neurotrophic factor) regulation is also disrupted:

“The pro-inflammatory cytokines also induce decrease in neurotrophins, and in particular diminished levels of Brain-Derived-Neurotrophic-Factor (BDNF) leading to decrease neuronal repair, decrease in neurogenesis and an increased activation in glutamatergic pathway which also contributes to neuronal apoptosis. It is noteworthy that serum BDNF has been associated both with changes in mood states in bipolar disorder as well as in coronary heart diseases.”

The autoimmune component is of premiere importance:

“A relationship between auto-immune disorders and bipolar disorder has been reported as early as 1888. Patients with bipolar disorder tend to develop organ-specific autoimmunity as shown, for example, by thyro-peroxidase antibodies (TPO-Abs) associated with thyroid failure, by antibodies to H/KAT-Pase associated with atrophic gastritis and by GAD65A, isoform of glutamic acid decarboxylase which is a marker of type-I diabetes. Recently, manic episodes with psychotic symptoms were observed during acute encephalitis with antibodies directed in particular against extracellular domains of the glutamatergic NMDA receptor. In addition, it has recently been reported that gastrointestinal processing of food antigens such as bovine caseins and wheat glutens is altered in bipolar disorder. Bipolar patients have been reported to have increased antibodies to gliadin, a glycoprotein derived from the ingestion of gluten from wheat or to casein activation, particularly during mania…Presence of these auto-antibodies might even precede the onset of bipolar disorder, as an increased prevalence of Multiple Sclerosis, thyrotoxicosis, ulcerative colitis, psoriasis and rheumatoid arthritis has been reported in unaffected relatives of patients with BD.”

 

Current Opinion in PsychiatryThe authors of a paper just published in Current Opinion in Psychiatry note:

“Recent studies have shown that bipolar disorder involves microglial activation and alterations in peripheral cytokines and have pointed to the efficacy of adjunctive anti-inflammatory therapies in bipolar depression.”

They summarize their findings by stating:

“The presence of active microglia and increased proinflammatory cytokines in bipolar disorder suggests an important role of inflammatory components in the pathophysiology of the disease, as well as a possible link between neuroinflammation and peripheral toxicity.”

 

Biological PsychiatryInflammatory microglial activation due to a dysregulated immune system is identified as a key factor in psychosis of all types in a paper just published in Biological Psychiatry:

“Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions.”

Microglia are the immune cells of the brain, functioning as macrophages do in peripheral tissues…

“Indeed, there is some evidence of activation of the microglia as detected in positron emission tomography scans and in histopathology, and it is assumed that this activation disturbs the development and function of neuronal circuits in the brain. Further, animal models of psychotic conditions (maternal stress and inflammation paradigms) suggest that such monocyte/microglia activation could be seen as the result of a combination of genetic predisposition and an immune-mediated two-hit model.”

The ‘two-hit’ model features strongly in a multitude of immune and other disorders:

“Infection but also environmental stressors during gestation/early life activate microglia, perturbing neuronal development, thereby setting the stage for vulnerability for later psychotic disorders. A second hit, such as endocrine changes, stress, or infection, could further activate microglia, leading to functional abnormalities of the neuronal circuitry in the brain and psychosis.”

 

Journal of Affective DisordersA study also published recently in the Journal of Affective Disorders highlights C-reactive protein (CRP) as an inflammatory marker in bipolar disorder. The authors note:

“Some individuals with bipolar disorder have cognitive deficits even when euthymic. In previous studies, we found an association between elevated levels of C-reactive protein (CRP), a marker of inflammation, and reduced cognitive functioning in schizophrenia. This issue has not been examined in bipolar disorder.”

They measured CRP in 107 subjects with bipolar disorder correlated with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as a metric for cognitive function and found a significant association:

“There was a significantly increased odds of low RBANS total score for individuals who had a CRP level higher than the 90th percentile and the 75th percentile of the control group. There was an inverse relationship between CRP levels and performance on RBANS total ; RBANS immediate memory; RBANS attention; RBANS language…”

The authors conclude:

Inflammation may play a major role in the cognitive deficits associated with bipolar disorder.”

 

NeuropsychobiologyCRP also sorts out as a marker of brain inflammation in a study recently published in the journal Neuropsychobiology:

C-reactive protein (CRP), a marker of underlying low-grade inflammation, has been associated with the pathophysiology of bipolar disorder. Additionally, bipolar disorder may be accompanied by functional or structural cerebral alterations. We attempted to discover whether serum high-sensitivity CRP (hs-CRP) levels are linked to the structural volume change of a specific brain region along with cognitive performance.”

Examining the correlation between orbitofrontal cortex volume, CRP and cognitive function in bipolar disorder the authors conclude:

Elevation of serum hs-CRP levels, an indicator of inflammation, may be associated with reduced volume of the orbitofrontal cortex. Persistent inflammation in the euthymic phase of bipolar disorder may involve the pathogenesis or pathophysiology of alteration of the frontal pathway.”

 

Journal of Psychiatric ResearchCytokines, ‘immune messenger molecules of inflammation’, are naturally also observed in bipolar disorder as documented in a meta-analysis recently published in the Journal of Psychiatric Research:

“Bipolar disorder may be associated with peripheral immune system dysfunction…Our aim was to systematically review evidence of peripheral cytokine alterations in bipolar disorder integrating findings from various affective states.”

The authors conducted a meta-analysis of eighteen studies with a total of 761 bipolar disorder patients and 919 healthy controls comparing cytokine concentrations and found…

“Overall, concentrations of soluble Interleukin (IL)-2 receptor (sIL-2R), tumor necrosis factor-α (TNF-α), soluble tumor necrosis factor receptor type 1 (sTNFR1) and IL-4 were significantly higher in bipolar patients compared with healthy controls.”

 

Trends in ImmunologyOf course, pro-inflammatory cytokines have been recognized in the pathophysiology of depression for years as described in a much earlier paper published in the journal Trends in Immunology:

“Increasing amounts of data suggest that inflammatory responses have an important role in the pathophysiology of depression. Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules. In addition, therapeutic administration of the cytokine interferon-α leads to depression in up to 50% of patients. Moreover, proinflammatory cytokines have been found to interact with many of the pathophysiological domains that characterize depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and behavior.”

Regarding the role of stress and the autonomic nervous system in inflammation:

Stress, which can precipitate depression, can also promote inflammatory responses through effects on sympathetic and parasympathetic nervous system pathways.”

The two-hit model comes into play in the sense that earlier adaptations may set the stage for a subsequent trigger:

“…depression might be a behavioral byproduct of early adaptive advantages conferred by genes that promote inflammation.”

The authors conclude:

“These findings suggest that targeting proinflammatory cytokines and their signaling pathways might represent a novel strategy to treat depression.”

 

Medical HypothesesThe authors of a paper published in Medical Hypotheses describe pro-inflammatory cytokines as a mechanism shared by both bipolar disorder and migraine:

“A bi-directional association between mood disorders and migraine has been consistently reported… we review evidence for the role of inflammatory cytokines in the neurobiology of bipolar disorder and migraine. In addition, inflammation is hypothesized to be a shared pathophysiological mechanism subserving the bipolar disorder and migraine concomitance.”

And it stands to reason that…

“A derivative of this hypothesis is that pharmacological treatments primarily targeting the inflammatory system may have symptom suppressing effects in bipolar disorder.”

 

Journal of Affective DisordersAnother study published in the Journal of Affective Disorders examines the specific inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in regard to bipolar disorder and response to lithium:

“The role of inflammation in bipolar disorder has recently emerged as a potential pathophysiological mechanism. Tumor necrosis factor-alpha (TNF-α) modulation may represent a pathogenic molecular target and a biomarker for staging bipolar disorder. In this context, the possible association between lithium response and TNF-α level was examined.”

The authors assessed the TNF-α level in 60 bipolar patients receiving lithium therapy in correlation with the ALDA lithium response scale (LRS) to evaluate longitudinal lithium response and found a clear association:

“There was a significant increase in TNF-α level in patients with poor lithium response compared to those with good response, also after controlling for a range of potential confounders.”

Their conclusion is significant both for the role of inflammation marked by TNF-α in bipolar disorder and case management utilizing lithium:

“This study strengthens the hypothesis that TNF-α level may mark or mediate lithium response, and that continuous immune imbalance in poor lithium responders may occasion treatment resistance. Further investigation of immune alterations in treatment-resistant bipolar patients may be productive.”

 

BMC MedicineThe key clinical questions are (1) what are the underlying causes of inflammation? and (2) what sound therapies can be applied to those causes? A paper published recently in BMC Medicine discusses several common contributing causes:

“We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is ‘what is the source of this chronic low-grade inflammation?’

The authors discuss several well-known factors including psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency. And neuroinflammation is shared characteristic of bipolar disorder, depression, schizophrenia, PTSD, and other psychiatric illnesses:

“There is also evidence that many other major psychiatric disorders are accompanied by activation of inflammatory and cell-mediated immune pathways, for example, mania, schizophrenia, post-traumatic stress disorder (PTSD)…A recent meta-analysis confirmed that mania and bipolar disorder are accompanied by activation of inflammatory, cell-mediated and negative immunoregulatory cytokines. Based on the first results obtained in schizophrenia, Smith and Maes in 1995 launched the monocyte-T lymphocyte theory of schizophrenia, which considered that activation of immuno-inflammatory processes may explain the neurodevelopmental pathology related to gestational infections. Results of recent meta-analyses showed that schizophrenia is accompanied by activation of inflammatory and cell mediated pathways. PTSD patients also show higher levels of pro-inflammatory cytokines, including IL-1, IL-6 and TNFα…It is evident that the sources of inflammation and immune activation, which play a role in depression, may contribute to the inflammatory burden in patients with mania. Schizophrenia is also associated with some but not all sources of inflammation and immune activation that play a role in depression. For example, a recent review showed that stress and trauma (first and second hits), nutritional factors and vitamin D may play a role in schizophrenia. The strong associations among schizophrenia and smoking, obesity, some atopic disorders, sleep disorders and poor periodontal and oral health may further contribute to the inflammatory burden in schizophrenia patients.”

Regarding the treatment and prevention of bipolar disorder, depression and other psychiatric illnesses the authors conclude:

“The pivotal element is that most of these are plastic, and amenable to intervention, both therapeutic and preventative…Psychiatry largely lacks an integrated model for conceptualizing modifiable risk factors for depression. It has, therefore, lacked conceptually and pragmatically coherent primary prevention strategies, prioritizing the treatment of established disorders. Yet the rationale, targets and imperative to focus on prevention of depression at a population level is clear.”

 

American Journal of PsychiatryFurther evidence for maternal infection as a trigger for autoimmune brain inflammation in bipolar disorder is presented in a study hot off the digital presses from the American Journal of Psychiatry:

“The authors examined whether serologically confirmed maternal exposure to influenza was associated with an increased risk of bipolar disorder in the offspring and with subtypes of bipolar disorder, with and without psychotic features.”

Their data disclosed a specific connection with bipolar disorder with psychotic features:

“…maternal serological influenza exposure was related to a significant fivefold greater risk of bipolar disorder with psychotic features…The results suggest that maternal influenza exposure may increase the risk for offspring to develop bipolar disorder with psychotic features. Taken together with earlier associations between prenatal influenza exposure and schizophrenia, these results may suggest that prenatal influenza is a risk factor for psychosis rather than for a specific psychotic disorder diagnosis.”

NEJM Journal WatchInterestingly, in a comment on this study published online in NEJM (New England Journal of Medicine) Journal Watch, psychiatrist Joel Yager, MD states:

“Together with research linking maternal influenza to schizophrenia risk, the current finding that influenza during pregnancy greatly increases the risk for bipolar disorder with psychotic features points to potentially similar prenatal mechanisms in the pathogenesis of diverse psychotic disorders. Other research suggests that prenatal priming of such vulnerabilities is in part due to prenatal immune activation of dopaminergic hyperactivity. Overall, such observations hint at common features and mechanisms in psychosis and may lead to better diagnostic conceptualizations.”

 

Progress in Neuro-Psychopharmacology and Biological PsychiatryIt stands to reason then that anti-inflammatory strategies must figure prominently in case management of bipolar disorder and other psychiatric conditions. The authors of a paper just published in Progress in Neuro-Psychopharmacology and Biological Psychiatry highlight the use of anti-inflammatory agents:

“Mood disorders have been recognized by the World Health Organization (WHO) as the leading cause of disability worldwide. Notwithstanding the established efficacy of conventional mood agents, many treated individuals continue to remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Therefore, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy…During the past decade, inflammation has been revisited as an important etiologic factor of mood disorders.”

Furthermore, the depredations of brain inflammation encompass a wide range:

“Accumulating evidence implicates inflammation as a critical mediator in the pathophysiology of mood disorders. Indeed, elevated levels of pro-inflammatory cytokines have been repeatedly demonstrated in both major depressive disorder (MDD) and bipolar disorder (BD) patients. Further, the induction of a pro-inflammatory state in healthy or medically ill subjects induces ‘sickness behavior’ resembling depressive symptomatology…Potential mechanisms involved include, but are not limited to, direct effects of pro-inflammatory cytokines on monoamine levels, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes.”

They identify several anti-inflammatory agents under investigation:

“Anti-inflammatory agents, such as acetyl-salicylic acid (ASA), celecoxib, anti-TNF-α agents, minocycline, curcumin and omega-3 fatty acids, are being investigated for use in mood disorders. Current evidence shows improved outcomes in mood disorder patients when anti-inflammatory agents are used as an adjunct to conventional therapy…”

 

Bipolar DisordersFoods, especially gluten and casein, must never be overlooked as potential triggers of neuroinflammation in bipolar disorder. A study recently published in the journal Bipolar Disorders focuses on this clinically important topic. The authors are also attentive to the issue of gastrointestinal inflammation and compromised barrier function as a sensitizing factor:

Immune sensitivity to wheat glutens and bovine milk caseins may affect a subset of individuals with bipolar disorder. Digested byproducts of these foods are exorphins that have the potential to impact brain physiology through action at opioid receptors. Inflammation in the gastrointestinal (GI) tract might accelerate exposure of food antigens to systemic circulation and help explain elevated gluten and casein antibody levels in individuals with bipolar disorder.”

They examined GI inflammation using ASCA in 207 non‐psychiatric controls, 226 in patients with bipolar disorder without a recent onset of psychosis, and 38 patients with bipolar disorder with a recent onset of psychosis, comparing it to antibodies against gluten, casein, Epstein–Barr virus (EBV), herpes simplex virus 1 (HSV‐1), influenza A, influenza B, measles, and Toxoplasma gondii and found a marked association with gluten and casein:

Elevated ASCA conferred a 3.5–4.4‐fold increased odds ratio of disease association that was independent of type of medication received. ASCA correlated with food antibodies in both bipolar disorder groups, and with measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group.”

The authors conclude:

Elevated seropositivity of a GI‐related marker and its association with antibodies to food‐derived proteins and self‐reported GI symptoms suggest a GI comorbidity in at least a subgroup of individuals with bipolar disorder. Marker seroreactivity may also represent part of an overall heightened activated immune state inherent to this mood disorder.”

 

Case management of neuroinflammation and the numerous and complex elements of autoimmunity could hardly be covered in a massive textbook much less a post here. A few among many potential therapeutic agents can be considered here by way of example.

Neurochemisty InternationalThe authors of a paper just published in the journal Neurochemistry International offering interesting evidence that alpha-lipoic acid can protect against neuroinflammation in neuropsychiatric disorders:

“Double-stranded RNAs (dsRNA) serve as viral ligands that trigger innate immunity in astrocytes and microglial…Beneficial transient TLR3 and PKR anti-viral signaling can become deleterious when events devolve into inflammation and cytotoxicity.”

Moreover…

Viral products in the brain cause glial cell dysfunction, and are a putative etiologic factor in neuropsychiatric disorders, notably schizophrenia, bipolar disorder, Parkinson’s, and autism spectrum.”

Of great clinical interest as a benign physiologic intervention…

Alpha-lipoic acid (LA) has been proposed as a possible therapeutic neuroprotectant. The objective of this study was to test our hypothesis that LA can control untoward antiviral mechanisms associated with neural dysfunction.”

They treated glial cultures viral mimetic dsRNA LA reduction of the effects of glial signaling, in other words a dampening of inflammation signaling:

LA blunted the dsRNA-stimulated expression of IFNα/β-inducible genes Mx1, PKR, and TLR3. And in polyI:C treated cells, LA promoted gene expression of rate-limiting steps that benefit healthy neural redox status in glutamateric systems. To this end, LA decreased dsRNA-induced inflammatory signaling by downregulating IL-1β, IL-6, TNFα, iNOS, and CAT2 transcripts.”

Considering the crucial role of glutathione metabolism and glutamate expression in regulation of neuroimmunity, their findings in this regard are of particular interest:

“In the presence of polyI:C, LA prevented cultured glial cytotoxicity which was correlated with increased expression of factors known to cooperatively control glutamate/cystine/glutathione redox cycling, namely glutamate uptake transporter GLAST/EAAT1, γ-glutamyl cysteine ligase catalytic and regulatory subunits, and IL-10. Glutamate exporting transporter subunits 4F2hc and xCT were downregulated by LA in dsRNA-stimulated glia. l-Glutamate net uptake was inhibited by dsRNA, and this was relieved by LA. Glutathione synthetase mRNA levels were unchanged by dsRNA or LA.

Clinicians should consider the authors’ conclusion:

“This study demonstrates the protective effects of LA in astroglial/microglial cultures, and suggests the potential for LA efficacy in virus-induced CNS pathologies, with the caveat that antiviral benefits are concomitantly blunted. It is concluded that LA averts key aspects of TLR3- and PKR-provoked glial dysfunction, and provides rationale for exploring LA in whole animal and human clinical studies to blunt or avert neuropsychiatric disorders.”

 

Medical HypothesesCucurmin, of course, is always worthy of consideration in case management of inflammatory and autoimmune disorders. The authors of a paper published last spring in Medical Hypotheses comment on the use of curcumin for bipolar disorder:

“Curcumin is a polyphenolic nonflavonoid compound extracted from the rhizome of turmeric (Curcuma longa)…Curcumin putative targets, known based on studies of diverse central nervous system disorders other than bipolar disorders (BD) include several proteins currently implicated in the pathophysiology of BD. These targets include, but are not limited to, transcription factors activated by environmental stressors and pro-inflammatory cytokines, protein kinases (PKA, PKC), enzymes, growth factors, inflammatory mediators, and anti-apoptotic proteins (Bcl-XL). Herein, we review previous studies on the anti-inflammatory and anti-oxidant properties of curcumin and discuss its therapeutic potential in BD.”

 

BMC MedicineInterestingly, aspirin is a potential therapeutic agent for bipolar disorder and other mental illnesses. An excellent paper recently published in BMC Medicine extensively reviews the mechanisms for its beneficial effects. Regarding the position of aspirin and other anti-inflammatory agents in the evolution of therapy for neuropsychiatric disorders:

“Historically, treatment options for common neuropsychiatric disorders, including depression, schizophrenia, and bipolar disorder, have focused on medications that modify the activity of monoamine neurotransmitter systems. Monoamines may play a large role in the pathophysiology of these disorders, but the monoaminergic theory of illness has failed to deliver novel agents beyond the limited treatment options currently available. There is now a clear body of recent evidence to support an etiologic role for other factors in the pathophysiology of depression, schizophrenia, and bipolar disorder, including oxidative and nitrosative stress (O&NS), mitochondrial dysfunction, and activation of the immune-inflammatory system.”

Specifically for aspirin:

“There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer’s disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory ‘braking signals’, including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α and interleukin (IL)-6, but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.”

Regarding the autoimmune aspect:

“To further support a role for therapeutic agents targeting inflammation in psychiatry, there is a large body of evidence linking autoimmune disease to psychiatric disorders. For example, clinical depression is associated with diverse autoimmune disorders, including diabetes type 1 and 2, inflammatory bowel disease, psoriasis, rheumatoid arthritis, atherosclerosis, lupus erythematosus, and multiple sclerosis (MS). Patients with clinical depression have a high degree of auto-immunity directed against a number of different selfepitopes, including serotonin and phospholipids (for example, cardiolipin and antinuclear factor). Recently, a new type of autoimmune response has been described, which is an autoimmune response secondary to O&NS damage [oxidative and nitrosative damage]. Thus, it is possible that increased O&NS levels may damage endogenous molecules, such as fatty acids and proteins, thereby changing their structure. As a consequence, the O&NS-modified self determinants may be rendered immunogenic, and an autoimmune response is then directed against the modified epitopes (neo-epitopes). For example, clinical depression is accompanied by IgG-mediated immune responses directed against oxidized low-density lipoprotein. Moreover, there is an association between this kind of autoimmune response and progression (or staging) of depression. Consequently, some of these autoimmune responses are significantly higher in depressed individuals with chronic depression (duration of >2 years) compared with patients who are depressed but do not have chronic depression. These findings suggest that O&NS damage, the consequent formation of neo-epitopes, an enhancement of the natural autoimmune response, and even a transition to pathological damaging auto-immunity increase the risk of neuroprogression and of chronic depression.”

The authors also note the interplay between genetic potential and the expression of autoimmunity in bipolar disorder:

“Evidence from the literature on bipolar disorder also supports the role of a genetic component; patients with bipolar disorder and their relatives have been shown to be more prone to develop thyroid auto-immunity, and this association is not attributable to the use of lithium or to the severity of psychiatric symptoms. Moreover, in addition to a higher prevalence of thyroid autoantibodies, patients with bipolar disorder have a higher prevalence of organ-specific autoantibodies, including autoantibodies to hydrogen/potassium ATP and glutamic acid decarboxylase-65. The aforementioned Danish national study confirmed these findings by showing an association of bipolar disorder with a family history of pernicious anemia, and with presence of Guillain-Barré syndrome, inflammatory bowel disease, and autoimmune hepatitis in individual patients.”

As for indicating the use of aspirin:

“Collectively, these findings imply shared immune pathogenic factors for mood disorders, schizophrenia, and organ-specific autoimmune diseases. One of these shared factors is thought to be an intrinsically high activation set-point for the MPS [mononuclear phagocyte system, in this case monocytes present as microglia in the brain]. It is thought that the high activation set-point of these cells of the MPS can be down-regulated by aspirin.”

 

Bipolar DisordersWhile on the topic of aspirin, it’s worth noting a study published last summer in Bipolar Disorders offering evidence that aspirin improves lithium-related sexual in men with bipolar disorder:

“The aim of the present study was to assess the effect of aspirin on lithium‐related sexual dysfunction in men with stable bipolar affective disorder (BAD).”

The authors staged a randomized, double‐blind, placebo‐controlled study, in which 32 men with stable BAD who had been on lithium maintenance therapy randomly received aspirin (240 mg/day) or placebo for six weeks. They used the International Index for Erectile Function (IIEF) was used to assess sexual symptoms at the start, week 3, and week 6. The results were gratifying:

“Significant effects of time × treatment interaction were observed for total score [Greenhouse–Geisser: F(1.410,39.466) = 6.084, p = 0.010] and erectile function [Greenhouse–Geisser: F(1.629,45.602) = 7.250, p = 0.003]. By Week 6, patients in the aspirin group showed significantly greater improvement in the total (63.9% improvement from the baseline) and erectile function domain (85.4% improvement from the baseline) scores than the placebo group (14.4% and 19.7% improvement from the baseline). By Week 6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo group met the criteria of minimal clinically important change. Other IIEF domains also showed significant improvement at the end of the trial. The frequency of side effects was similar between the two groups.”

The authors conclude:

Aspirin effectively improves lithium‐related sexual dysfunction in men with stable BAD.”

Bottom line: There is a massive amount of evidence supporting the importance of assessing and treating neuroinflammation in bipolar disorder and other neuropsychiatric illnesses. This makes necessarily the comprehensive examination of autoimmunity and its numerous underlying contributory causes. Past and future posts focus on this crucial dimension of clinical practice.

Depression, aging and brain inflammation: indications for sustainable treatment

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Depression and aging, not only diminished cognitive function but the level of physiological competence throughout the body, have brain inflammation in common. This fact is of premiere importance when designing rational treatment plans for both depression and high functioning longevity. Consider an important paper just published in the journal Depression and Anxiety which the authors the association of major depression and suicidal ideation with inflammatory biomarkers:

Depression and Anxiety“Patients with major depressive disorder (MDD) who attempt or complete suicide have elevated inflammation compared to nonsuicidal patients with MDD. However, greater severity of depression and the medical lethality of suicide attempts could account for such elevated inflammation in suicide attempters and suicide completers…To clarify, we measured inflammatory markers in patients with MDD with and without high levels of suicidal ideation and in nondepressed controls (N = 124). Levels of suicidal ideation, depression severity, and recent suicide attempts were assessed by structured clinical interviews. A composite score including the inflammatory markers tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and C-reactive protein (CRP) was used as an inflammatory index.”

Their data showed a correlation supporting their striking conclusion:

“Patients with MDD and high suicidal ideation had significantly higher inflammatory index scores than both controls…Suicidal ideation may be uniquely associated with inflammation in depressed patients.”

 

Comprehensive PsychiatryWe should bear in mind that these inflammatory cytokines and CRP are not specific for depression. Moreover, there is a strong association between psychological stress and trauma and inflammatory biomarkers. A study just published in Comprehensive Psychiatry adds to the body of evidence supporting the relationship between depression, inflammation and stress:

“Taking into consideration the previous evidence of revealing the relationship of early life adversity, major depressive disorder (MDD), and stress-linked immunological changes, we recruited 22 MDD patients with childhood trauma exposures (CTE), 21 MDD patients without CTE, and 22 healthy controls without CTE, and then utilized a novel cytokine antibody array methodology to detect potential biomarkers underlying MDD in 120 peripheral cytokines and to evaluate the effect of CTE on cytokine changes in MDD patients.”

Their data showed a particular correlation between major depression with childhood trauma and inflammatory cytokines:

“Depressed individuals with CTE (TD patients) were more likely to have higher peripheral levels of those cytokines. Severity of depression was associated with plasma levels of certain increased cytokines; meanwhile, the increased cytokines led to a proper separation of TD patients from normal controls during clustering analyses. Our research outcomes add great strength to the relationship between depression and cytokine changes and suggest that childhood trauma may play a vital role in the co-appearance of cytokine changes and depression.”

 

Progress in Neuro-Psychopharmacology and Biological PsychiatryInflammatory cytokines come into play with bipolar disorder too as expressed in a paper published in Progress in Neuro-Psychopharmacology and Biological Psychiatry:

“An emerging body of evidence points to impairments in neuroplasticity, cell resilience and neuronal survival as the main neuropathological correlates of BD. It has been suggested that inflammatory cytokines, particularly TNF-α may play a critical role in this process.”

They examined evidence suggesting that TNF-α may regulate brain cell loss related to bipolar disorder:

“Current evidence suggests that an increase in serum levels of TNF-α takes place during manic and depressive episodes.”

And we’ll see that it is crucial for clinicians to be aware of the central role played by nuclear factor kappa-beta (NF-kB) in driving inflammatory cytokines in the brain in both depression and aging.

 

American Journal of PsychiatryMen with depression and history of early life stress are featured in a study published in The American Journal of Psychiatry. They evaluated innate immune system activation following psychosocial stress in patients with major depression and increased early life stress by measuring plasma interleukin (IL)-6, lymphocyte subsets, and DNA binding of nuclear factor (NF)-kB in peripheral blood mononuclear cells in medically healthy male subjects with current major depression and increased early life stress and comparing them to nondepressed male comparison subjects before and after completion of a stress test. They found that…

“Trier Social Stress Test-induced increases in IL-6 and NF-κB DNA-binding were greater in major depression patients with increased early life stress and independently correlated with depression severity…Male major depression patients with increased early life stress exhibit enhanced inflammatory responsiveness to psychosocial stress, providing preliminary indication of a link between major depression, early life stress and adverse health outcomes in diseases associated with inflammation.”

 

PNAS Vol 105 No 2Many reading this are aware that the proinflammatory cytokine IL-1β is a ‘mother cytokine’ in the inflammatory cascade involved in most autoimmune inflammation. The authors of a fascinating study published in PNAS (Proceedings of the National Academy of the Sciences of the USA) demonstrate that IL-1β impairs neurogenesis in the hippocampus of the adult brain. Bear in mind that the hippocampus is the primary locus for short-term memory and adrenal regulation, and is a therapeutic target in the treatment of depression. The authors state:

“The profound consequences of stress exposure, defined as disturbances of physiological homeostasis, include a detrimental impact on certain aspects of brain function. In particular, uncontrollable stress is a major contributing factor for neuropsychiatric disorders such as major depression and posttraumatic stress disorders. Alterations at the cellular level in the hippocampus have been linked to the pathophysiology of stress-related mood disorders. Many studies demonstrate that stressful experiences suppress hippocampal neurogenesis, which could contribute to the hippocampal atrophy observed in depressed patients. In contrast, antidepressant treatment increases hippocampal neurogenesis, blocks the antineurogenic effects of stress, and reduces or even reverses hippocampal atrophy. Recent studies demonstrate that new hippocampal neurons are required for the actions of antidepressants in behavioral models of depression and anxiety with some exceptions.”

By administering exogenous IL-1β they compiled in vivo and in vitro evidence that stress exerts its effects on the hippocampus through activation of IL-1β signaling:

“Here, we demonstrate an essential role for the proinflammatory cytokine IL-1β. Administration of IL-1β or acute stress suppressed hippocampal cell proliferation. Blockade of the IL-1β receptor, IL-1RI, by using either an inhibitor or IL-1RI null mice blocks the antineurogenic effect of stress and blocks the anhedonic behavior caused by chronic stress exposure. In vivo and in vitro studies demonstrate that hippocampal neural progenitor cells express IL-1RI and that activation of this receptor decreases cell proliferation via the nuclear factor-κB signaling pathway. These findings demonstrate that IL-1β is a critical mediator of the antineurogenic and depressive-like behavior caused by acute and chronic stress.”

 

PNAS Vol 107 No 6Now we move further into the clinically extremely important role of nuclear factor-κB (NF-κB) signaling in autoimmune and brain inflammation. In a study also published in PNAS the authors build on the earlier insights regarding IL-1β and note:

“Exposure to stress and depression can result in atrophy of limbic brain regions that control emotion and mood, including inhibition of neurogenesis in the adult hippocampus…A role for proinflammatory cytokines is supported by a recent report that IL-1β signaling is necessary and sufficient for the antineurogenic and behavioral effects of stress. One possible signaling cascade that could mediate the effects of IL-1β is NF-κB, which is activated by IL-1β and other cytokines both in peripheral immune cells and in the brain. Chronic stress enhances the activation of NF-κB in response to inflammatory stimuli, and social stress increases NF-κB signaling in healthy subjects and produces an exaggerated response in depressed patients…In the present study, we investigate the role of NF-κB in the cellular and behavioral responses to acute and chronic stress. The results demonstrate that the inhibition of neurogenesis by stress occurs via activation of NF-κB in NSCs and that stress-induced anhedonia, a core symptom of depression, is dependent on NF-κB.”

Stress, depression, IL-1β and NF-κBTheir conclusion points to NF-κB signaling as a particularly important therapeutic target, especially considering that there are natural agents that can help:

Stress inhibition of neurogenesis in the adult hippocampus, which has been implicated in the prodepressive effects of stress, is blocked by administration of an inhibitor of NF-κB. Further analysis reveals that stress activates NF-κB signaling and decreases proliferation of neural stem-like cells but not early neural progenitor cells in the adult hippocampus. We also find that depressive-like behaviors caused by exposure to chronic stress are mediated by NF-κB signaling. Together, these data identify NF-κB signaling as a critical mediator of the antineurogenic and behavioral actions of stress and suggest previously undescribed therapeutical targets for depression.

 

Journal of NeuroscienceThen how fascinating is it that researchers publishing in The Journal of Neuroscience demonstrate that darkness (light deprivation), known to induce depression, does so through the NF-κB signaling pathway:

Depression has been tightly linked to disturbances of circadian rhythms, and alterations in emotional states have been found to affect circadian rhythms. Seasonal affective disorders, a subtype of major depressive disorders related to seasonal variations in natural light levels, occur at higher prevalence in the more northern latitudes, in regions with extended periods of restricted sunlight…Disturbed day–night cycles and altered sleep patterns are also known to affect the rhythmic intradiem oscillations of elements of the immune system, such as IL-6. Interestingly, elevated inflammatory parameters, including IL-6, are also frequently observed in depressed patients…We therefore decided to use a particular case of circadian disruption, light deprivation in the DD paradigm, and to examine the potential involvement of inflammatory signaling in the associated depressive state.”

Their data showed not only IL-6 activity, but that NF-κB signaling again plays a pivotal role in depression induced by light deprivation:

“We find that after 4 weeks of DD, mice display depression-like behavior, which is paralleled by reduced hippocampal cell proliferation. This chronobiologically induced depressive state is associated with elevated levels of plasma IL-6 (interleukin-6) and IL-6 and Il1-R1 (interleukin 1 receptor, type I) protein levels in the hippocampus and also alters hippocampal protein levels of the clock genes per2 and npas2. Using pharmacological blockers of the NF-κB pathway, we provide evidence that the effects of DD on depression-like behavior, on hippocampal cell proliferation, on altered expressional levels of brain and plasma IL-6, and on the modulation of clock gene expression are mediated through NF-κB signaling. Moreover, NF-κB activity is enhanced in hippocampal tissue of DD mice. Mice with a deletion of IL-6, one of the target genes of NF-κB, are resistant to DD-induced depression-like behavior, which suggests a pivotal role for this cytokine in the constant darkness mouse model of depression.”

 

Brain, Behavior, and ImmunityAnd increased NF-κB pathway signaling is also reported in women suffering childhood abuse-related post-traumatic stress disorder in a study published in the journal Brain, Behavior, and Immunity:

“In addition to neuroendocrine changes PTSD pathophysiology may also involve dysfunction of the innate immune inflammatory system. PTSD patients have been found to exhibit increased concentrations of circulating inflammatory markers such as C-reactive protein and interleukin-6, suggesting dysfunction of the innate immune inflammatory system.”

So the authors examined NF-κB activity obtained from 12 women with childhood abuse-related PTSD and 24 healthy controls. They also measured glucocorticoid sensitivity of monocytes in a clever wsy by observing the amount of dexamethasone needed to suppress lipopolysaccharide-induced tumor necrosis factor-alpha production by 50%. Sure enough, NF-κB was pivotal here too:

Women with PTSD displayed increased NF-κB pathway activity compared to controls that was positively correlated with PTSD severity (determined by PTSD symptom severity scale). Increased NF-κB pathway activity was associated with increased whole blood monocyte DEX IC50 (i.e. decreased sensitivity of monocytes to glucocorticoids) across all participants.”

In other words, the PTSD symptoms were promoted by immune inflammatory acitivity hinging on NF-κB signaling. The authors conclude:

“These findings suggest that enhanced inflammatory system activity in participants with childhood abuse-related PTSD is observable at the level of NF-κB, and that in general decreased immune cell glucocorticoid sensitivity may contribute to increased NF-κB pathway activity. Enhanced inflammation may contribute to co-morbid somatic disease risk in persons with childhood abuse-related PTSD.”

 

Journal of NeuroinflammationMore evidence that NF-κB plays a key role in central nervous system inflammation is offered by a study published in the Journal of Neuroinflammation. The authors observe by way of background:

Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system (CNS). The development of autoimmune diseases such as MS requires the coordinated expression of a number of pro-inflammatory genes. These factors…encompass a variety of cytokines, chemokines, adhesion molecules as well as other inflammatory factors…Nuclear factor (NF-) kappaB (NF-κB) is essential for both innate and adaptive immunity…and is involved in many inflammatory processes…The transcriptional activation of the NF-κB pathway is controlled by the inhibitor of NF-κB, IκB…Besides the involvement of NF-κB in T-cell proliferation and activation, it is also a key element in coordinately controlling gene expression during monocyte/macrophage activation. In particular the macrophage-derived cytokines interleukin-1beta (IL-1 β) and tumor necrosis factor-alpha (TNF-α), are potent activators of NF-κB. In turn, their expression is controlled by NF-κB thus resulting in a positive feedback loop. Hence, NF-κB signalling pathways may play a pivotal role in activating myeloid cell function during autoimmune inflammation. In addition to its central mediatory function in cytokine expression, NF-κB in myeloid cells may be induced by physical as well as oxidative stress to cells, e.g. via the inducible nitric oxide synthase (iNOS) or cyclooxygenase-2 (COX-2).”

The authors shed light on the role of NF-κB in CNS inflammation by examining experimental autoimmune encephalomyelitis (MOG-EAE, a well established experimental model for autoimmune demyelination of the CNS) in mice whose NF-κB inhibitor IκB was rendered genetically inactive. They found that…

“…loss of IκB in monocytes and macrophages leads to constitutive expression of NF-κB. In turn, this results in an increased expression of NF-κB regulated monocyte/macrophage cytokines and subsequently enhanced macrophage infiltration and iNOS expression in the spinal cord…Thus macrophage derived, NF-κB dependent cytokines may play a pivotal role in the pathogenesis of EAE and determine the outcome of autoimmune inflammation in the CNS without interfering with Th1 and Th17 T-cell responses. Our findings suggest that NF-κB in myeloid cells is a master regulator for regulation of inflammation and tissue damage in autoimmune inflammation of the CNS.”

Consider how surprisingly decisive the NF-κB activity is since it determined the outcome of the autoimmune inflammation without modifying the Th17 response. These authors conclude:

“In summary, myeloid cell derived NF-κB plays a crucial role in autoimmune inflammation of the CNS and drives a pathogenic role of monocytes and macrophages independently from T-cells.”

 

PNAS Vol 109 No 45T-helper (Th) 17 cells and the proinflammatory cytokine IL-17 are a ‘common pathway’ in autoimmunity. While the previous paper showed that NF-κB can drive autoimmune inflammation by other means as well, another study recently published in PNAS shows that NF-κB also promotes Th17 differentiation. The authors state:

IL-17–producing CD4 T cells play a key role in immune responses against extracellular bacteria and autoimmunity. Nuclear factor κB (NF-κB) is required for T-cell activation and selected effector functions, but its role in Th17 differentiation is controversial.”

They used genetic models to demonstrate that NF-κB signaling controls survival and proliferation of activated T cells, and has an additional role in promoting completion of Th17 differentiation. Specifically the CARD-containing MAGUK protein 1 (CARMA1)is an adapter TCR/NF-κB signaling, resulting in the production of the pro-inflammatory cytokines IL-17A, IL-17F, IL-21, IL-22, IL-23R, and CCR6…

“Consistent with these data, CARMA1-KO [knockout] mice were resistant to experimental autoimmune encephalomyelitis…Our results demonstrate that TCR/CARMA1/NF-κB controls completion of Th17 differentiation by enabling chromatin accessibility of Th17 effector molecule loci.”

Annals of The New York Academy of Sciences Vol 1179Moreover, NF-κB and pro-inflammatory cytokines contribute to major depression by altering glucocorticoid receptor function as presented in a paper published in the Annals of The New York Academy of Sciences:

“Data suggest that the activation of immune responses and the release of inflammatory cytokines may play a role in the pathophysiology of major depression. One mechanism by which cytokines may contribute to depression is through their effects on the glucocorticoid receptor (GR)…Relevant to the GR, cytokines have been shown to decrease GR expression, block translocation of the GR from cytoplasm to nucleus, and disrupt GR-DNA binding through nuclear protein-protein interactions. In addition, cytokines have been shown to increase the expression of the relatively inert GR beta isoform.

Clinicians take note: this is an important dimension to consider in assessing HPA and adrenocortical function and cortisol effectiveness. Cortisol levels might be looking OK but not working properly. Regarding NF-κB:

“Specific cytokine signaling molecules that have been shown to be involved in the disruption of GR activity include p38 mitogen-activated protein kinase…and signal transducer and activator of transcription (STAT)5, which binds to GR in the nucleus. Nuclear factor-κB (NF-κB) also has been shown to lead to GR suppression through mutually inhibitory GR-NF-κB nuclear interactions.”

Moreover…

“Interestingly, several antidepressants have been shown to enhance GR function, as has activation of protein kinase A (PKA). Antidepressants and PKA activation have also been found to inhibit inflammatory cytokines and their signaling pathways, suggesting that drugs that target both inflammatory responses and the GR may have special efficacy in the treatment of depression.”

 

Inflammation in the hypothalamus drives aging throughout the body

Nature Vol 496 No 7448To top it all off, there is emerging evidence that inflammation enacted by NF-κB in the brain, specifically the hypothalamus, drives many aspects of aging throughout the body. In what has been described as “a major breakthrough in ageing research”, by David Sinclair, a molecular biologist at Harvard Medical School, researchers publishing in the esteemed journal Nature reveal how…

“…the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IκB kinase-β (IKK-β), nuclear factor κB (NF-κB) and related microglia–neuron immune crosstalk.”

Using several models they were able to slow aging and extend lifespan by preventing aging-related hypothalamic or brain IKK-β and NF-κB activation. They also demonstrated that IKK-β and NF-κB inhibit gonadotropin-releasing hormone (GnRH), a ‘master switch’ hormone for the whole body, causing a decline in hypothalamic GnRH. Moreover, they showed that GnRH treatment ameliorated aging-impaired neurogenesis and slowed down aging. Commenting on this study, another author reporting in the same journal noted:

“The area of the brain that controls growth, reproduction and metabolism also kick-starts ageing…Dongsheng Cai, a physiologist at Albert Einstein College of Medicine in New York, and his colleagues tracked the activity of NF-κB…They found that the molecule becomes more active in the brain area called the hypothalamus as a mouse grows older…Further tests suggested that NF-κB activity helps to determine when mice display signs of ageing. Animals lived longer than normal when they were injected with a substance that inhibited the activity of NF-κB in immune cells called microglia in the hypothalamus. Mice that received a substance to stimulate the activity of NF-κB died earlier. “We have provided scientific evidence for the concept that systemic ageing is influenced by a particular tissue in the body,” says Cai.”

NF-kB activation in neurons in the hypothalamusDavid Cai, the lead author, also states:

Inflammation involves hundreds of molecules, and NF-κB sits right at the center of that regulatory map…The mice showed a decrease in muscle strength and size, in skin thickness, and in their ability to learn — all indicators of aging. Activating this pathway promoted systemic aging that shortened the lifespan.”

Also noted by David Sinclair:

“…a key finding is that blocking the effects of NF-κB produced anti-ageing effects even when it was done in middle age.”

The authors state in their conclusion:

“…the hypothalamus has a programmatic role in ageing development via immune–neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems.”

And in another comment in the same edition of Nature:

Inflammation-activated signalling pathways in the brain’s hypothalamus control the production of ageing-related hormones. This finding provides a link between inflammation, stress responses and systemic ageing.”

This installment presents a few drops from an ocean of science implicating brain inflammation as a key factor in cognitive and emotional disorders and global impairments in physiological competence, including loss of function associated with aging. Forthcoming posts will present studies demonstrating resources for sustainable treatment of NF-κB driven inflammation and autoimmunity.