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.

Breast cancer recurrence reduced by prolonged nightly fasting

JAMA Oncology breast cancer and prolonged nightly fastingBreast cancer risk and prognosis is affected by glucose and insulin regulation. The authors of a study recently published in JAMA Oncology demonstrate that fasting intermittently by extending the overnight fast between dinner the night before and eating the next day reduces the risk of cancer recurrence. They state:

“To our knowledge, no studies in humans have examined nightly fasting duration and cancer outcomes.”

So they set out to…

“…investigate whether duration of nightly fasting predicted recurrence and mortality among women with early-stage breast cancer and, if so, whether it was associated with risk factors for poor outcomes, including glucoregulation (hemoglobin A1c), chronic inflammation (C-reactive protein), obesity, and sleep.”

Breast cancer and HgbA1c reduced by prolonged nightly fasting; sleep improved

They analyzed data collected over 12 years for 2413 women with breast cancer but without diabetes aged 27 to 70 years at diagnosis who were participants in the Women’s Healthy Eating and Living study. Their main outcomes were recurrence, new primary tumors, mortality, assess concentrations of hemoglobin A1c and C-reactive protein. Happily their data show significant improvements in recurrence, HgbA1c and sleep duration:

“The cohort of 2413 women reported a mean (SD) fasting duration of 12.5 (1.7) hours per night. In repeated-measures Cox proportional hazards regression models, fasting less than 13 hours per night (lower 2 tertiles of nightly fasting distribution) was associated with an increase in the risk of breast cancer recurrence compared with fasting 13 or more hours per night (hazard ratio, 1.36). Nightly fasting less than 13 hours was not associated with a statistically significant higher risk of breast cancer mortality or a statistically significant higher risk of all-cause mortality. In multivariable linear regression models, each 2-hour increase in the nightly fasting duration was associated with significantly lower hemoglobin A1c levels and a longer duration of nighttime sleep.”

Intermittent fasting

The two most main methods of intermittent fasting are 5:2 and 16:8. 5:2 is 5 days of normal eating alternating with two very low calorie days (500 cal for females and 600 cal for males). 16:8, which I prefer, delays eating and drinking anything other than water, coffee or tea (black) until 16 hours after dinner the night before. This has numerous metabolic and immune benefits, and should be a mainstay in the ‘oncology toolbox.’ The authors conclude:

Prolonging the length of the nightly fasting interval may be a simple, nonpharmacologic strategy for reducing the risk of breast cancer recurrence. Improvements in glucoregulation and sleep may be mechanisms linking nightly fasting with breast cancer prognosis.”

Depression, inflammation and light therapy

JAMA PsychiatryDepression has much more going on under the surface than neurotransmitter deficiencies. A constellation of papers published recently illustrate the fascinating links between depression, inflammation and exposure to light (not just during the winter). The implies an exciting potential for relief from depression by combining management of chronic inflammation with bright light and chronotherapy to correct circadian dysregulation.

Depression and inflammation

Brain inflammation is recognized as a core contributing cause in numerous neuropsychiatric disorders (search ‘neuroinflammation‘ in this blog). A study just published in JAMA Psychiatry illustrates the association between depression and a variety of symptoms arising from systemic inflammation. The authors used C-reactive protein (CRP) as an inflammatory biomarker:

Elevated levels of inflammatory markers, such as C-reactive protein, are well-documented in people with depression. Raison and Miller suggested that this association may, in fact, be symptom-specific. Higher levels of inflammation are particularly likely to underlie depression symptoms that characterize sickness behavior, including fatigue, reduced appetite, withdrawal, and inhibited motivation…Here, we tested the hypothesis that the association between C-reactive protein and depression is symptom-specific.”

They examined the relationship between CRP and depression for specific symptoms using data on about 15,000 men and women in three US National Health and Nutrition Surveys. Inflammation was associated with cognitive and emotional symptoms including anhedonia, depressed mood, feelings of low self-worth, poor concentration, and thoughts of suicide though they were not independent of the other depression symptoms. Three symptoms particularly stood out:

Inflammation was associated with a range of depression symptoms, particularly with tiredness, lack of energy, sleep problems, and changes in appetite.”

Medscape Medical News quotes comments by Golam Khandaker, MBBS, MPhil, MRCPsych, PhD, clinical lecturer, Department of Psychiatry, University of Cambridge, United Kingdom (not an author of the study):

“While the association between inflammatory markers such as CRP and depression is well known, studies such as this looking at particular symptoms provide important clues for mechanism of illness pathogenesis…This work points to a potentially important role for inflammation in the pathogenesis of the so-called somatic symptoms of depression, such as sleep problems, anergia, and loss of appetite, which are, of course, an integral part of the syndrome of depression.”

The author of this coverage in also notes:

“As previously reported by Medscape Medical News, a recent meta-analysis of 14 relevant randomized, placebo-controlled studies found that nonsteroidal anti-inflammatory drugs (NSAIDs) may help ease depressive symptoms…Results showed that the adjunctive use of NSAIDs was associated with improved antidepressant treatment response without an increased risk for adverse effects.”

Of course safer antiinflammatory agents are readily available.

Circadian misalignment increases inflammation

Brain, Behavior, and ImmunityChronic inflammation can be caused by a disrupted circadian rhythm. In a study published in Brain, Behavior, and Immunity the authors investigated the effects of chronic circadian misalignment on cortisol levels and TNF-α, CRP and IL-10.

“How chronic circadian misalignment influences cortisol and inflammatory proteins, however, is largely unknown and this was the focus of the current study. Specifically, we examined the influence of weeks of chronic circadian misalignment on cortisol, stress ratings, and pro- and anti-inflammatory proteins in humans.”

After 3 weeks of maintaining regular sleep–wake schedules at home and six laboratory baseline days and nights, then a 40 hour constant routine (CR, total sleep deprivation) their subjects endured a 25-day laboratory entrainment protocol with eight of them selected for circadian disruption. Their data showed a shift in inflammatory biomarkers in the subjects induced for circadian misalignment:

Circadian misalignment significantly increased plasma tumor necrosis factor-alpha (TNF-α), interleukin 10 (IL-10) and C-reactive protein (CRP). Little change was observed for the TNF-α/IL-10 ratio during circadian misalignment, whereas the TNF-α/IL-10 ratio and CRP levels decreased in the synchronized control group across weeks of circadian entrainment.”

In other words, as the normally circadian synchronized subjects adapted to the lab conditions their TNF-α/IL-10 (pro/anti-inflammatory) ratio decreased, which was not the case in those subject to circadian misalignment. Interestingly, they also found a difference in cortisol levels between acute sleep deprivation which is used as a therapeutic intervention and chronic circadian misalignment:

“Acute total sleep deprivation significantly increased cortisol levels, whereas chronic circadian misalignment significantly reduced cortisol levels.”

Bottom line here is that circadian misalignment promotes a proinflammatory state.

Bright Light Therapy—Not Just For Seasonal Affective Disorder

Harvard Review of PsychiatryCommenting on the scope of bright light therapy in a paper published recently in the Harvard Review of Psychiatry entitled The Psychiatry of Light, the authors state:

“Bright light therapy and the broader realm of chronotherapy remain underappreciated and underutilized, despite their empirical support. Efficacy extends beyond seasonal affective disorder and includes nonseasonal depression and sleep disorders, with emerging evidence for a role in treating attention-deficit/hyperactivity disorder, delirium, and dementia. A practical overview is offered, including key aspects of underlying biology, indications for treatment, parameters of treatment, adverse effects, and transformation of our relationship to light and darkness in contemporary life.”

JAMA PsychiatryMore evidence supporting the use of this “underappreciated and underutilized” therapy was just added in a study published in JAMA Psychiatry in which bright light therapy outperformed fluoxetine (Prozac®) in the treatment of nonseasonal major depressive disorder (MDD). The authors set out to:

…determine the efficacy of light treatment, in monotherapy and in combination with fluoxetine hydrochloride, compared with a sham-placebo condition in adults with nonseasonal MDD.

In an eight week randomized, double-blind, placebo- and sham-controlled trial in adults with MDD of at least moderate severity were assigned to one of four interventions: (1) light monotherapy (active 10 000-lux fluorescent white light box for 30 minutes per day in the early morning plus placebo pill); (2) antidepressant monotherapy (inactive negative ion generator for 30 minutes per day plus fluoxetine 20 mg/day); (3) combination light and antidepressant; or (4) total placebo (inactive negative ion generator plus a placebo pill). The efficacy of bright light therapy shone clearly in this trial:

A total of 122 patients were randomized (light monotherapy, 32; fluoxetine monotherapy, 31; combination therapy, 29; placebo, 30). The mean (SD) changes in MADRS score for the light, fluoxetine, combination, and placebo groups were 13.4 (7.5), 8.8 (9.9), 16.9 (9.2), and 6.5 (9.6), respectively. The combination and light monotherapy were significantly superior to placebo in the MADRS change score, but fluoxetine monotherapy was not superior to placebo. For the respective placebo, fluoxetine, light, and combination groups at the end point, response was achieved by 10 (33.3%), 9 (29.0%), 16 (50.0%), and 22 (75.9%) and remission was achieved by 9 (30.0%), 6 (19.4%), 14 (43.8%), and 17 (58.6%).”

In other words, bright light therapy by itself was very effective. It was slightly more effective when combined with fluoxetine, but the fluoxetine (Prozac®) by itself did no better than placebo. The authors state in their conclusion:

Bright light treatment, both as monotherapy and in combination with fluoxetine, was efficacious and well tolerated in the treatment of adults with nonseasonal MDD.”

Medscape Medical News quotes comments on the study by Michael Terman, PhD, professor of psychiatry, Columbia University, and director of the Comprehensive Chronotherapy Group, New York City:

“The major surprise was the failure of a standard therapeutic dose of fluoxetine to beat the placebo rate, while light therapy showed a large effect size within 4 weeks…If light had proved ineffective or only weakly effective in comparison with fluoxetine, it would have consigned light therapy to the dustbin, but the dramatic, opposite result turns the tables on the choice of somatic treatment for major depression ― 10,000 lux light therapy upon awakening or, by implication, a walk outdoors if the sun is up ― now can be recommended to patients with recurrent depression, many of whom will respond without recourse to drugs.”

Medscape Medical News also quotes the original study in regard to circadian phase-shifting:

“Nonseasonal major depressive disorder may also be associated with disturbances in circadian rhythms,” they write. “And bright light has predictable circadian phase-shifting effectiveness in humans.”

Circadian rhythms and inflammation in rheumatoid arthritis

Nature Reviews RheumatologyClosing the biological circle connecting depression, inflammation, bright light therapy and circadian rhythm it’s edifying to consider a paper published in Nature Reviews Rheumatology in which the authors discuss inflammation, depression and chronobiology in the context of rheumatoid arthritis:

“Circadian rhythms are of crucial importance for cellular and physiological functions of the brain and body. Chronobiology has a prominent role in rheumatoid arthritis (RA), with major symptoms such as joint pain and stiffness being most pronounced in the morning, possibly mediated by circadian rhythms of cytokine and hormone levels. Chronobiological principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients (chronotherapy) could optimize results. Trials of NSAID or methotrexate chronotherapy for patients with RA suggest such an approach can improve outcomes and reduce adverse effects. The most compelling evidence for RA chronotherapy, however, is that coordinating the timing of glucocorticoid therapy to coincide with the nocturnal increase in blood IL-6 levels results in reduced morning stiffness and pain compared with the same glucocorticoid dose taken in the morning.”

Effect of RA Chronotherapy on associated depressionThis suggests significant potential for the treatment of depression:

Aside from optimizing relief of the core symptoms of RA, chronotherapy might also relieve important comorbid conditions such as depression and sleep disturbances. Surprisingly, chronobiology is not mentioned in official guidelines for conducting RA drug registration trials. Given the imperative to achieve the best value with approved drugs and health budgets, the time is ripe to translate the ‘circadian concept’ in rheumatology from bench to bedside.”

Chronotherapy with bright light beats exercise for depression

Acta Psychiatrica ScandinavicaExercise has been well-established as a remedy for depression, yet in a fascinating study recently published in Acta Psychiatrica Scandinavica chronotherapeutics with bright light therapy was significantly more effective. To investigate the long-term antidepressant effect of a chronotherapy they randomized 75 patients with major depression to fixed duloxetine and either a chronotherapeutic intervention (wake group) with three initial wake therapies, daily bright light therapy, and sleep time stabilization for 29 weeks. Chronotherapy was the clear winner for remission of major depression:

Patients in the wake group had a statistically significant higher remission rate of 61.9% vs. 37.9% in the exercise group at week 29. This indicated continued improvement compared with the 9 weeks of treatment response (44.8% vs. 23.4%) with maintenance of the large difference between groups. HAM-D17 endpoint scores were statistically lower in the wake group.”

Clinical note: All of the above argues in favor of a trial of chronotherapy with bright light plus exercise (free of fluoxetine or duloxetine) in case management of depression.

The authors of the this study conclude:

In this clinical study patients continued to improve in the follow-up phase and obtained very high remission rates. This is the first study to show adjunct short-term wake therapy and long-term bright light therapy as an effective and feasible method to attain and maintain remission.”

Bottom Line

  • Bright light therapy can be effective for major depression even when nonseasonal.
  • Brain inflammation is a core contributing biological cause of neuropsychiatric disorders including depression.
  • Correcting a misaligned circadian rhythm using early waking with bright light to phase shift is also anti-inflammatory.
  • These effective interventions combined can be enhanced by further optimizing brain metabolism and circulation based on appropriate tests.

Stroke risk reduced by magnesium

StrokeStroke risk is reduced by higher plasma magnesium levels according to data from 32,826 women in the Nurses’ Health Study presented in a paper just published in the journal Stroke. The authors note:

Lower plasma magnesium levels may be associated with higher blood pressure and endothelial dysfunction, but sparse prospective data are available for stroke.”

So they compared plasma magnesium in stroke cases with controls matched for age, race/ethnicity, smoking status, date of blood draw, fasting status, menopausal status, and hormone use. Women with magnesium levels* that I see in lab reports had a signficantly increased risk for stroke:

“Conditional on matching factors, women in the lowest magnesium quintile had a relative risk of 1.34 for total ischemic stroke compared with women in the highest quintile. Additional adjustment for risk factors and confounders did not substantially alter the risk estimates for total ischemic stroke. Women with magnesium levels <0.82 mmol/L* had significantly greater risk of total ischemic stroke (multivariable relative risk, 1.57) and thrombotic stroke (multivariable relative risk, 1.66) compared with women with magnesium levels ≥0.82 mmol/L. No significant effect modification was observed by age, body mass index, hypertension, or diabetes mellitus.”

Magnesium is an anti-inflammatory agent

Clinical key  point: Cardiovascular and cerebrovascular disease have a well-known inflammatory component. Besides lowering blood pressure and promoting healthy endothelial function, magnesium is ‘nature’s anti-inflammatory mineral’ that supports parasympathetic nervous system function with a calming, anti-spasmodic effect.

* Plasma magnesium <0.82 mmol/L = 2.0 mg/dL.

The authors conclude:

Lower plasma magnesium levels may contribute to higher risk of ischemic stroke among women.”

Magnesium, inflammation and endothelial function

American Journal of Clinical NutritionRegarding additional mechanisms by which magnesium status is linked to stroke and cardiovascular disease, a study published in the American Journal of Clinical Nutrition provides evidence that magnesium is important for endothelial (blood vessel lining) health:

“We conducted a cross-sectional study of 657 women from the Nurses’ Health Study cohort who were aged 43-69 y and free of cardiovascular disease, cancer, and diabetes mellitus when blood was drawn in 1989 and 1990. Plasma concentrations of C-reactive protein (CRP), interleukin 6 (IL-6), soluble tumor necrosis factor alpha receptor 2 (sTNF-R2), E-selectin, soluble intercellular adhesion molecule 1 (sICAM-1), and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured. Estimates from 2 semiquantitative food-frequency questionnaires, administered in 1986 and 1990, were averaged to assess dietary intakes.”

E-selectin recruits white blood cells to engage in the endothelial inflammatory process. The authors demonstrated a  role for magnesium significant for stroke:

“…magnesium intake was inversely associated with plasma concentrations of CRP, E-selectin, and sICAM-1. After further adjustment for physical activity, smoking status, alcohol use, postmenopausal hormone use, and body mass index, dietary magnesium intake remained inversely associated with CRP and E-selectin. Multivariate-adjusted geometric means for women in the highest quintile of dietary magnesium intake were 24% lower for CRP and 14% lower for E-selectin than those for women in the lowest quintile.”

Magnesium reduces CRP

Archives of Medical ResearchA recent study published in Archives of Medical Research also shows anti-inflammatory effect of magnesium in lowering CRP:

“It has been suggested that magnesium deficiency is associated with the triggering of acute phase response, which may contribute to type 2 diabetes and cardiovascular disease risk. We undertook this study to determine whether oral magnesium supplementation modifies serum levels of high-sensitivity C-reactive protein (hsCRP) in apparently healthy subjects with prediabetes and hypomagnesemia.”

The authors examined the effect of magnesium supplementation on 62 men and non-pregnant women aged 18–65 years who were newly diagnosed with prediabetes and hypomagnesemia (serum magnesium levels <0.74 mmol/L/1.8 mg/dL) for the effects of daily supplementation with magnesium in a double-blind placebo-controlled trial, leading to their conclusion…

Oral magnesium supplementation decreases hsCRP levels in apparently healthy subjects with prediabetes and hypomagnesemia.”

Fatigue commonly caused by iron deficiency without anemia

BMJ 2003; 326Fatigue, often accompanied by depression and anxiety, frequently has iron deficiency shown by suboptimal levels of serum ferritin but occurring without anemia. This often goes unrecognized in clinical practice. An earlier study published in BMJ (British Medical Journal) reports on the effect of iron on unexplained fatigue:

“Fatigue is common in the general population. Prevalence rates of 14% to 27% have been reported in primary care, and in 1-2% of patients fatigue is the main reason for consultation. Women were three times more likely than men to mention fatigue in a study conducted in general practice. Although the symptom of fatigue is related to iron deficiency anaemia, evidence is lacking for any association between iron deficiency and tiredness in the absence of anaemia. Iron deficiency associated with increased fatigue was, however, shown in a recent longitudinal study on women’s health. In a European study, about 20% of women of childbearing age had a serum ferritin concentration less than 15 μg/l, and only 4% of these women had iron deficiency anaemia. We examined the effect of iron therapy in women with unexplained fatigue in the absence of anaemia.”

The authors conducted a double blind randomized placebo controlled trial with 144 women aged 18 to 55 who were assigned to either 80 mg/day of oral ferrous sulphate or placebo for four weeks. Their results were of great significance to any practitioner who deals with fatigue:

“136 (94%) women completed the study. Most had a low serum ferritin concentration; <or= 20 microg/l in 69 (51%) women. Mean age, haemoglobin concentration, serum ferritin concentration, level of fatigue, depression, and anxiety were similar in both groups at baseline. Both groups were also similar for compliance and dropout rates. The level of fatigue after one month decreased by -1.82/6.37 points (29%) in the iron group compared with -0.85/6.46 points (13%) in the placebo group (difference 0.95 points). Subgroups analysis showed that only women with ferritin concentrations <or= 50 μg/l improved with oral supplementation.”

Ferritin reference range is often too low

50 μg/l = 50 ng/L, the level that I and numerous others have found more accurate for serum ferritin than what is often the standard reference range. Regarding this the authors state:

“We found a significant response only in the patients with a baseline serum ferritin concentration ≤ 50 μg/l. This suggests that iron deficiency could be present even with a “normal” concentration of serum ferritin. Indeed, the lower limit for serum ferritin concentration is controversial: iron stores in the bone marrow may serve as a better indicator of iron deficiency. One study compared serum ferritin concentrations with iron stores in the bone marrow and found that a serum ferritin concentration of 50 μg/l was associated with a 50% chance of iron deficiency occurring in the bone marrow. The lower reference limits for serum ferritin and haemoglobin concentrations have been considered too low for women. The authors of that study advocate the adoption of the same reference values for both men and women that “would be expected to have fundamental and positive implications for women’s health and welfare.” Our study indirectly supports their conclusion by showing that women can benefit from iron supplementation even if their red blood cell counts are considered normal.”

Iron, ferritin and neurotransmitters

Iron deficiency without anemia impairs production of the neurotransmitters dopamine and serotonin.

Iron deficiency even in the absence of anaemia is associated with decreased activity of iron dependent enzymes and therefore affects the metabolism of neurotransmitters. In people with iron deficiency anaemia the related symptoms will disappear more quickly than the accompanying increase in haematological indices.”

How many people, especially women, have been fed SSRIs or NSRIs when what they needed was some iron? All of this has widespread significance:

A frequently unrecognized problem

“Women with fatigue often associate their symptoms with psychosocial stressors and not a possible emotional or biomedical cause. Conversely, medical investigators tend to associate fatigue with emotional causes and more rarely with biomedical causes. We found that iron deficiency may be an under-recognised cause of fatigue in women of childbearing age. Thus, identifying iron deficiency without anaemia as a potential cause of fatigue is important. It may avoid the inappropriate attribution of symptoms to putative emotional causes or life stressors and thereby reduce unnecessary use of healthcare resources. Instituting iron therapy early may also improve quality of life.”

The authors conclude:

Non-anaemic women with unexplained fatigue may benefit from iron supplementation. The effect may be restricted to women with low or borderline serum ferritin concentrations.”

Pay attention to serum ferritin below 50 mg/mL

Medical Clinics of North AmericaA paper published in Medical Clinics of North America also recognizes serum ferritin below 50 mg/mL as a marker for fatigue. The authors include these key points:

  •   Further defining a patient’s complaint of “fatigue” as either sleepiness, dyspnea on exertion, weakness, generalized lack of energy, or feeling down or depressed can aid in evaluation and management.
  •   Even in the absence of anemia, in women of child-bearing age with a ferritin less than 50 ng/mL, iron replacement is associated with improvement of subjective fatigue.

 Low ferritin in non-anemic menstruating women

CMAJ Vol 184 (11)Research reported in CMAJ (Canadian Medical Association Journal) offered similar data from a double-blind, placebo-controlled trial:

“The true benefit of iron supplementation for nonanemic menstruating women with fatigue is unknown. We studied the effect of oral iron therapy on fatigue and quality of life, as well as on hemoglobin, ferritin and soluble transferrin receptor levels, in nonanemic iron-deficient women with unexplained fatigue.”

The authors  randomly assigned 198 women aged 18–53 years who complained of fatigue and who had a ferritin level of less than 50 ug/L and hemoglobin greater than 12.0 g/dL to receive either oral ferrous sulfate (80 mg of elemental iron daily) or placebo for 12 weeks and measured fatigue as measured on the Current and Past Psychological Scale along with the biological markers at 6 and 12 weeks:

“The mean score on the Current and Past Psychological Scale for fatigue decreased by 47.7% in the iron group and by 28.8% in the placebo group (difference –18.9%)… Compared with placebo, iron supplementation increased hemoglobin (0.32 g/dL) and ferritin (11.4 μg/L) and decreased soluble transferrin receptor (−0.54 mg/L) at 12 weeks.”

Commenting on these results, the authors state:

“We found that iron supplementation for 12 weeks decreased fatigue by almost 50% from baseline, a significant difference of 19% compared with placebo, in menstruating iron-deficient nonanemic women with unexplained fatigue and ferritin levels below 50 μg/L. Iron supplementation did not have a significant effect on measured indicators of quality of life apart from those directly related to fatigue. However, our results suggest that iron supplementation improves hemoglobin, ferritin, hematocrit, mean corpuscular volume and soluble transferrin as early as six weeks after starting treatment.”

Ferritin, iron and the brain

The effects of iron deficiency on fatigue can be explained by decreased activity of iron-dependent enzymes; for example, those affecting the metabolism of neurotransmitters that enhance neurophysiologic changes. However, we presume that such physiologic changes could be confused with depression or anxiety; thus, the effect of iron supplementation on mood disorders remains unknown…Furthermore, blood markers do not necessarily reflect iron stores in other compartments. A recent study suggests that following blood donation, iron supplementation can improve erythropoiesis without affecting fatigue or muscular function. Therefore, fatigue might only occur once iron deficiency becomes present in brain tissue.”

Ferritin, iron and hemoglobin

“Our results suggest that an increase in erythropoiesis could be limited to women with a hemoglobin concentration below 13.0 g/dL. The appropriateness of the official definition of the lower limit for normal hemoglobin concentrations in women has been debated. The biological definition of iron-deficiency anemia is based on the reduction of erythropoiesis due to a lack of available iron. Hemoglobin cutoff values serve as a surrogate and do not truly reflect all individuals’ erythropoietic function correctly. Our results confirm that some women with 12.0 g/dL or higher hemoglobin concentrations have increased erythropoiesis following iron supplementation, suggesting that they were iron deficient.”

Clinicians should diligently attend to the authors’ concluding recommendations:

“For women with unexplained prolonged fatigue, iron deficiency should be considered when ferritin values are below 50 μg/L, even when hemoglobin values are above 12.0 g/dL. Biological markers can be tested at six weeks to confirm iron deficiency.”

A variety of possible symptoms

Vox SanguinisA program to supplement female blood donors without anemia with iron reported in a paper published in the journal Vox Sanguinis highlights some of the symptoms that can attend low ferritin:

“The determination of serum ferritin levels revealed iron deficiency in many non-anaemic premenopausal female blood donors at our Institution…Substitution lasted 16 weeks and the donation interval was extended… Significant results were serum ferritin increase (from a mean value of 7·12 to 25·2 ng/ml), resolution of prostration, fatigue, sleep disturbances, tension in the neck, hair loss and nail breakage. No case of anaemia occurred….”

 Frequently undiagnosed

PraxisThe problem of iron deficiency without anemia remaining undiagnosed persists since it was recognized in a paper published in the Swiss medical journal Praxis as long as twenty years ago:

Iron deficiency (ID) without anaemia frequently remains undiagnosed when symptoms are attributed to ID with anaemia. Serum ferritin is the primary diagnostic parameter, whereas <10 microg/l represent depleted iron stores, 10-30 microg/l can confirm ID without anaemia and 30-50 microg/l might indicate functional ID.”

Ferritin indicates inflammation when elevated

It’s very important for clinicians to remember that ferritin is an acute phase reactant (like CRP) that indicates inflammation when elevated (in the absence of hemochromatosis):

In case of increased CRP or ALT, normal/elevated ferritin should be interpreted with caution.”

Iron dosage

“Intravenous iron is indicated if oral iron is not effective or tolerated. At ferritin <10 microg/l, a cumulative dose of 1000 mg iron and at ferritin 10-30 microg/l, a cumulative dose of 500 mg is advised. At ferritin 30-50 microg/l a first dose of 200 mg might be considered. Ferritin shall be reassessed not sooner than 2 weeks after the last oral or 8-12 weeks after the last iv iron administration.”

Health care professionals also have undiagnosed iron deficiency

International Journal of Biomedical ScienceA study published in the International Journal of Biomedical Science showed that substantial percentage of educated hospital employees in Switzerland were suffering unknowingly of iron deficiency without anemia:

Iron deficiency (ID) has been associated with depression, chronic fatigue, impaired endurance performance and restless leg syndrome, all of which lead to sleep disturbances…We sought to examine the iron status of reportedly healthy individuals by a framed study design in 58 highly educated Swiss hospital employees and to compare the use of non invasive tests for assessing iron deficiency (ID)… All subjects felt well and were working at their maximum capacity. The male subjects were neither anaemic nor had decreased iron parameters however 50% (23/46) of the women had a serum ferritin of below 22 μg/L, still 33% (15/46) of the women had a ferritin value below the more stringent cut off value of 15 μg/L. In 15% (7/46) of the women we diagnosed iron deficient anaemia. Red meat consumption correlated with ferritin values as did the menstrual blood loss which was estimated by asking the amount of tampons used. Of the additionally analysed iron parameters only the percentage of hypochromic erythrocytes, soluble transferrin receptor and transferrin values were significantly correlated with ferritin and reached an AUCROC of ≥0.7 indicating good predictive tests. Nevertheless neither soluble transferrin receptor nor transferrin showed diagnostic advantages for the diagnosis of ID compared to ferritin alone or together with erythrocyte parameters. Working in a hospital environment and having access to health education does not seem to correlate with prevention of ID or ID anaemia in female hospital employees.”

Clinicians should note that other commonly used tests did not cut the mustard:

“As alternative tests we evaluated serum iron, transferrin and transferrin saturation, since these tests are commonly used to assess ID. We found these alternatives to be of little use. For example serum iron exhibits diurnal variations and may reach reference values after ingestion of red meat by iron depleted subjects. In our study serum iron had a poor diagnostic impact (AUCROC of 0.56), which is even lower than the reported (AUCROC of 0.7) (32). Transferrin saturation had a similarly poor AUCROC of 0.67. Transferrin had some diagnostic value as the AUCROC was found to be 0.8, a finding consistent with earlier studies in patients with ID anaemia. Nevertheless none of the above assays offers any advantage over determination of ferritin alone and should no longer be used for diagnosis.”

Anger, tension and fatigue in iron deficiency without anemia

Biological Trace Element ResearchHow often might biological symptoms be mistaken for neurotic conditions? A study recently published in Biological Trace Element Research demonstrates a correlation between anger and tension along with fatigue in iron deficiency without anemia:

Iron deficiency without anemia (IDNA), the most prevalent nutritional deficiency worldwide, affects young women of reproductive age. This study aimed to elucidate the relationship between IDNA and mental and somatic symptoms including anger and fatigue using the Japanese version of the Cornell Medical Index Health Questionnaire (CMI-J)…The subjects were classified as having IDNA (hemoglobin (Hb)≥12 g/dL and serum ferritin<20 ng/mL; n=29), having iron deficiency anemia (IDA) (Hb<12 g/dL and serum ferritin<20 ng/mL; n=10), or having a normal iron status (Hb≥12 g/dL and serum ferritin≥20 ng/mL; n=36).”

Psychological complaints were clearly higher in iron deficiency without anemia:

“Sections M-R (mental complaints) were significantly higher in the IDNA subjects than in the normal subjects. No significant difference in CMI scores was found between the normal and IDA subjects. Sections I (fatigability), Q (anger), and R (tension) were significantly higher in the IDNA subjects than in the normal subjects, regardless of no significant differences between the normal and IDA subjects in those sections. Young women with IDNA demonstrated a significantly higher proportion of neurotic tendencies (grades II-IV)….The findings suggest that IDNA may be a risk factor for anger, fatigue, and tension in women of childbearing age.”

Mental quality of life and cognitive function

PLOS ONEA study recently published in PLOS One (Public Library of Science) demonstrated improvements in general mental well-being in addition to fatigue from a single dose of IV iron in the form of ferric carboxymaltose:

Unexplained fatigue is often left untreated or treated with antidepressants. This randomized, placebo-controlled, single-blinded study evaluated the efficacy and tolerability of single-dose intravenous ferric carboxymaltose (FCM) in iron-deficient, premenopausal women with symptomatic, unexplained fatigue.”

The authors also note:

“Since iron is not only a component of hemoglobin (Hb) but also a key element of various essential enzymes in all metabolic pathways (e.g. oxidative phosphorylation), ID can have an Hb-independent effect on physical performance and fatigue…A slow onset of ID-associated symptoms may lead patients to adapt to fatigue and consequently, they may not request medical help. Therefore, ID may be broadly unrecognized despite being one of the most prevalent nutrient deficiencies affecting human health.”

In their study that included 290 women, 144 of whom were given the IV FCM and the rest placebo…

Fatigue was reduced in 65.3% (FCM) and 52.7% (placebo) of patients (OR 1.68). A 50% reduction of PFS score was achieved in 33.3% FCM- vs. 16.4% placebo-treated patients At Day 56, all FCM-treated patients had hemoglobin levels ≥120 g/L (vs. 87% at baseline); with placebo, the proportion decreased from 86% to 81%. Mental quality-of-life (SF-12) and the cognitive function scores improved better with FCM.”

The authors concluded:

“A single infusion of FCM improved fatigue, mental quality-of-life, cognitive function and erythropoiesis in iron-deficient women with normal or borderline hemoglobin. Although more side effects were reported compared to placebo, FCM can be an effective alternative in patients who cannot tolerate or use oral iron, the common treatment of iron deficiency. Overall, the results support the hypothesis that iron deficiency can affect women’s health, and a normal iron status should be maintained independent of hemoglobin levels.”

Fatigue, lack of concentration, headache and sleep disorders

Geburtshilfe und FrauenheilkundeEffectiveness of a single IV dose of FCM was also demonstrated in a study published this year in Geburtshilfe und Frauenheilkunde (Obstetrics and Gynecology):

“In total, data from 273 patients was evaluated. 193 of these patients displayed iron deficiency anaemia (IDA), and 68 had iron deficiency without anaemia (ID). The reasons for the ID/IDA were hypermenorrhoea (HyM) (n = 170), post-partum condition (PP) (n = 53) or another indication (n = 53)…The primary, serious accompanying symptoms of anaemia were fatigue (72 %), lack of concentration (42 %), pale mucous membranes (42 %), headache (26 %) and sleep disorders (21 %)…FCM was most frequently administered via infusion (92 %; average infusion duration 21 minutes)…In all subgroups, 92 % of women displayed a marked improvement in all of their symptoms.”

Low ferritin can be obscured by inflammation

New England Journal of MedicineFerritin is, of course, a acute-phase reactant that can increased by inflammation. A recent paper published in The New England Journal of Medicine on microcytic anemia describes how ferritin levels that would otherwise appear low are elevated due to inflammation:

“Although the transcription of ferritin mRNA is up-regulated by inflammation, the synthesis of ferritin is regulated by cellular iron content, with ferritin mRNA being translated to protein only when the cell is iron-replete. Thus, a patient with adequate iron may have a very high ferritin level with inflammation, whereas it is rare for a patient with iron deficiency to have a ferritin level of more than 100 ng per milliliter. The lower limit of the normal range depends on the clinical situation. A ferritin level of 15 ng per milliliter is very specific for iron deficiency, but in older patients or those with inflammatory states, one cannot rule out iron deficiency until the ferritin level is more than 100 ng per milliliter. Guyatt et al. found that the likelihood ratio for iron deficiency is positive up to a ferritin level of 40 ng per milliliter in the absence of inflammation and up to 70 ng per milliliter in the presence of inflammation. Although not perfect, the serum ferritin assay is the test most likely to provide information about a patient’s iron status, but the patient’s age and clinical condition need to be considered in the interpretation of results.”

Clinical Bottom Line

In cases of fatigue unexplained by other causes, depression, sleep disorders, poor concentration, hair loss, and restless legs syndrome (since iron is necessary for the production of dopamine), iron should be considered when serum ferritin is below 50 ng/L even in the absence of anemia and below 70 ng/L in the presence of inflammation.

Nuts reduce inflammation and all-cause mortality

Asia Pacific Journal of Clinical NutritionNuts have been shown to confer multiple health benefits, so it’s disconcerting to see  some apparently popular paleo diet plans that forbid them. In the absence of a nut allergy it’s a shame to forgo the benefit of such a healthful and convenient food. The intent of the paleo diet is to reduce inflammation, so it’s worth considering a paper published in the Asia Pacific Journal of Clinical Nutrition offering evidence that nuts reduce inflammation. The authors note:

“Several large epidemiological studies have associated the frequency of nut consumption with reduced risk of coronary heart disease (CHD), CVD, myocardial infarction, sudden death, and all causes of mortality, Type 2 diabetes (T2D) and other chronic disease.

Nuts are anti-inflammatory

Key inflammatory markers including CRP and IL-6 are reduced by nut consumption:

“Epidemiological and clinical studies suggest that some dietary factors, such as n–3 polyunsaturated fatty acids, antioxidant vitamins, dietary fiber, L-arginine and magnesium may play an important role in modulating inflammation. The relationship observed between frequent nut consumption and the reduced risk of cardiovascular mortality and type 2 diabetes in some prospective studies could be explained by the fact that nuts are rich in all of these modulator nutrients. In fact, frequent nut consumption has been associated with lower concentrations of some peripheral inflammation markers in cross-sectional studies. Nut consumption has also been shown to decrease the plasma concentration of CRP, IL-6 and some endothelial markers in recent clinical trials.”

Nuts also benefit cholesterol and lipids

“In the last two decades, a considerable number of clinical trials have consistently demonstrated beneficial effects on blood lipids and lipoproteins, primarily a decrease in Low-density lipoprotein (LDL) cholesterol, a classical CHD risk factor. This effect has been demonstrated consistently in different population groups, using different types of nuts (walnuts, hazelnuts, almonds, pecan, pistachio and macadamia nuts) and study designs. The favourable effects of tree nuts or tree nut oils on plasma lipid and lipoprotein profiles is a mechanism that appears to account for some of the cardio protective effects observed in the epidemiological studies.”

Nuts and olive oil are a great combination for cardiovascular risk:

“…in a cross-sectional study we evaluated the association between components of the Mediterranean diet and circulating markers of inflammation in a large cohort of asymptomatic subjects with high risk of cardiovascular disease. Subjects with the highest consumption of nuts and virgin olive oil showed the lowest concentrations of VCAM-1, ICAM-1, IL-6 and CRP; although this difference was statistically significant for ICAM-1 only in the case of nuts and for VCAM-1 in the case of olive oil.”

After reviewing several other studies documenting improvements in inflammation and endothelial function the authors conclude:

“In conclusion, nuts are complex food matrices containing diverse nutrients and other chemical constituents that may favourably influence human physiology. These sub- stances may inhibit the activation of the innate immune system, probably by decreasing the production of proinflammatory cytokines such as CRP, IL-6, TNF-α or IL-18, and increase the production of antiinflammatory cytokines such as adiponectin. This may improve the proinflammatory milieu, which in turn ameliorates endothelial dysfunction at the vascular level, and ultimately decreases the risk of insulin resistance, type 2 diabetes and coronary heart disease. The capacity of nuts to modulate inflammation may explain at least in part why frequent nut consumption is associated with reduced risk of diabetes and cardiovascular disease in epidemiological studies.”

Nut consumption reduces total and cause-specific mortality

New England Journal of MedicineA paper published earlier this year in The New England Journal of Medicine add more extensive data presenting evidence that eating nuts reduces death from cancer, heart disease, respiratory disease and ‘all causes’.

“Observational and intervention studies of nut consumption have also shown reductions in various mediators of chronic diseases, including oxidative stress, inflammation, visceral adiposity, hyperglycemia, insulin resistance, and endothelial dysfunction. In prospective cohort studies, increased nut intake has been associated with reduced risks of type 2 diabetes mellitus, the metabolic syndrome, colon cancer, hypertension, gallstone disease, diverticulitis, and death from inflammatory diseases.”

To extend the data to encompass the effects of eating nuts and all causes of death the authors:

“…examined the association of nut consumption with total and cause-specific mortality in two large, independent cohort studies of nurses and other health professionals. These studies provide repeated measures of diet (including separate data on peanuts and tree nuts), extensive data on known or suspected confounding variables, 30 years of follow-up, and data on more than 27,000 deaths for analysis.”

Their data suggest that nuts are among the healthiest foods to eat:

“In two large prospective U.S. cohorts, we found a significant, dose-dependent inverse association between nut consumption and total mortality, after adjusting for potential confounders. As compared with participants who did not eat nuts, those who consumed nuts seven or more times per week had a 20% lower death rate. Inverse associations were observed for most major causes of death, including heart disease, cancer, and respiratory diseases. Results were similar for peanuts and tree nuts, and the inverse association persisted across all subgroups.”

Some nuts every day was the best:

“Our results are consistent with the findings in previous, smaller studies. The Adventist Health Study showed that, as compared with nut consumption less than once per week, consumption five or more times per week was associated with reduced total mortality among whites, blacks, and elderly persons, with hazard ratios ranging from 0.56 to 0.82. Similarly, a study of a U.K. cohort, the Iowa Women’s Health Study, the Netherlands Cohort Study, and an earlier analysis of the NHS all showed significant inverse associations between nut intake and total mortality. Finally, in a recent secondary analysis within the PREDIMED (Prevención con Dieta Mediterránea) trial, a hazard ratio for death of 0.61 (95% CI, 0.45 to 0.83) was found for consumption of more than three servings of nuts per week, as compared with no nut consumption.”

Bottom line: ‘paleo’ and ‘autoimmune’ paleo diets can be fine healing diets for many, but like everything else should not be applied dogmatically or in a ‘rubber stamp’, ‘one-size-fits-all’ manner. In the absence of allergy, the evidence supports the consumption of nuts as wholesome foods with anti-inflammatory and metabolic benefits, exactly what paleo diets intend to accomplish.

Lung cancer, inflammation, and tumor microenvironment

PLOS ONELung cancer is the leading cause of cancer deaths worldwide. As with all other cancers, untangling the role of systemic inflammation (cancer promoting) versus inflammation in the tumor microenvironment (cancer fighting) is of fundamental clinical importance. A welcome study just published in PLOS One (Public Library of Science) sheds light on this critical conundrum while including the aspect of nutritional status. The authors state:

“The interactions between systemic inflammation and tumoral immune microenvironment are increasingly investigated in cancer patients. Pro-inflammatory cytokines and associated growth factors are involved in carcinogenesis through their effects on tumor cell growth, survival, proliferation and migration. It has been shown that slight elevations of inflammatory markers are associated with an increased risk of non-small cell lung carcinoma (NSCLC) occurrence, and serum C-reactive protein (CRP) has been identified as a prognostic factor in both advanced and resectable NSCLC. The tumoral immune microenvironment has been also shown to be an important determinant of long-term outcome in primary and metastatic tumors: particularly in NSCLC, high levels of mature dendritic cells (mDC) and of CD8+ lymphocytes have been both identified as robust prognostic factors …Hypothesizing that nutritional status, systemic inflammation and tumoral immune microenvironment play a role as determinants of lung cancer evolution, the purpose of this study was to assess their respective impact on long-term survival in resected non-small cell lung cancers (NSCLC).”

They acquired data for 303 patients surgically treated for NSCLC that included C-reactive protein (CRP) for systemic inflammation, prealbumin levels for nutritional status, and tumoral infiltration by CD8+ lymphocytes and mature dendritic cells in correlation with relevant clinical-pathological parameters. The significance was striking:

“In multivariate analysis, prealbumin levels (Relative Risk (RR): 0.34, CD8+ cell count in tumor tissue (RR = 0.37), and disease stage (RR 1.73 – stage I vs II vs III-IV) were independent prognostic markers. When taken together, parameters related to systemic inflammation, nutrition and tumoral immune microenvironment allowed robust prognostic discrimination; indeed patients with undetectable CRP, high (>285 mg/L) prealbumin levels and high (>96/mm2) CD8+ cell count had a 5-year survival rate of 80% as compared to 18%] in patients with an opposite pattern of values. When stages I-II were considered alone, the prognostic significance of these factors was even more pronounced.”

 Role of systemic inflammation

Commenting on the crucial role of systemic inflammation the authors note:

CRP is secreted by hepatocytes following stimulation by circulating pro-inflammatory cytokines, in particular IL-1, TNF-α, and mainly IL-6. Experimental studies have suggested that NSCLC cells are able to release IL-6 and TNF-α. In spite of this, the exact role of systemic inflammation and tumor burden in determining progression and outcome is still controversial. This relationship is even more questionable in “pre-clinical disease”: a study on a large cohort showed that increased CRP levels in cancer-free subjects were associated with a higher risk of lung cancer occurrence. This finding has been recently confirmed by a nested case-control study: among 77 evaluated inflammatory biomarkers, 11 were found to be associated with an increased risk of developing lung cancer, even after adjustment for smoking. Among these 11 markers, CRP was the most robust predictor of lung cancer risk.”

Of particular importance for all cancers:

“Moreover, increased baseline CRP levels were associated with early death after diagnosis of any cancer in patients without metastatic disease at diagnosis. These findings strongly suggest a possible role of pre-existing systemic inflammation in determining the occurrence and prognosis of lung cancer…Similarly, systemic inflammation has been reported to be an independent negative prognostic marker in patients with advanced non-small cell lung cancer.”

Nutritional status and adequate nutrition

Prealbumin, a plasma protein made by the liver, reflects nutritional status (over a 2 day period) and is valued as a marker for malnutrition. The authors state:

“…we found that CRP levels were strongly and independently correlated (in an inverse manner) with prealbumin levels. Prealbumin levels were in turn correlated with pT parameter, vascular embols, and, as for CRP levels, intra-tumoral density of mDC. Such correlations underline the complex interplay between systemic inflammation, malnutrition, and tumoral immune microenvironment; we may theorize that malnutrition is the first cause of immunodeficiency, and in lung cancer patients this could result in poor infiltration of anti-tumoral immune cells. Therefore, this would explain the strong negative impact of low prealbumin levels on long-term survival. Furthermore, inflammatory status (pre-existent or concomitant with lung cancer) with subsequent increased energy consumption might contribute to malnutrition.”

Inflammatory immune response in the tumor microenvironment

In the tumor microenvironment, more inflammation characterized by higher levels of mature dendritic and CD8+ ‘killer’ cells is favorable:

“…high intra-tumoral densities of mDC and CD8+ T lymphocytes were associated with improved outcome. Interestingly, mDC density in lung cancer reflects the immune response organization within tertiary lymphoid structures (TLS) adjacent to the tumor nests, where CD8+ T cells are supposed to be educated for an efficient antitumor immune response…

And a key point that helps resolve the conundrum of balancing treament of systemic inflammation with the important intra-tumoral inflammatory response:

“In our study, intratumoral mDC density was associated with relevant clinical and biological parameters including not only nutritional ones but also (in an inverse manner) those associated with systemic (CRP levels) and local (smoking, COPD) inflammation…Overall, our results suggest that preexisting systemic inflammation/poor nutritional status could impact the intra-tumoral immune contexture and the patient survival.”

In other words, lower systemic inflammation correlated with a better inflammatory response to the tumor. This certainly makes sense considering the pivotal role of systemic inflammation in promoting the development and spread of cancer stem cells, a major determinant of metastasis.

Biomarkers in clinical practice

“Our data show that nutrition, systemic inflammation and tumoral immune contexture are prognostic determinants that, taken together, may predict outcome…The best discrimination was achieved when taking into account simultaneously biomarkers related to inflammation with nutritional status and intra-tumoral immune infiltration. With this model, the differences in survival were remarkable when comparing, in the whole population as in stage I-II disease, patients with high CD8+ T cells density, low CRP levels and high prealbumin levels to those with low CD8+ T cells density, high CRP levels and low prealbumin levels. Interestingly, groups with intermediate biological characteristics had intermediate long-term outcomes.”

This speaks volumes for the importance of structuring treatment plans to ensure well-regulated immune function.

IL-10 regulates both systemic and intra-tumoral inflammation

Cancer Immunology ResearchHere we can appreciate a fascinating study published recently in Cancer Immunology Research that demonstrates how the cytokine interleukin-10 (IL-10) both calms systemic inflammation and stimulates anti-tumor immunity:

“Human cancer is characterized by deficits in antigen-specific immunity and intratumoral CD8+ T cells. On the other hand, inflammatory macrophages and mediators of chronic inflammation are highly prevalent in patients with late-stage cancer. Intratumoral T-cell deficiency and chronic inflammation have been linked independently to a poor prognosis in patients with cancer, and therapeutic approaches to overcome either pathology separately are in clinical testing. The anti-inflammatory cytokine interleukin (IL)-10 suppresses macrophage and proinflammatory Th17 T-cell responses by inhibiting the inflammatory cytokines IL-6 and IL-12/23. Corroborating the anti-inflammatory action of IL-10, deficiency in IL-10 leads to a stimulation of inflammatory responses and inflammatory bowel disease.”

However, many of us have had a serious concern that IL-10 might suppress the anti-tumor immune response. The authors present data which happily support the opposite conclusion:

“The anti-inflammatory role of IL-10 fostered the assumption that IL-10 undermines the immune response to cancer. However, mice and humans deficient in IL-10 signaling develop tumors spontaneously and at high rates. Overexpression of IL-10 in models of human cancer or treatment with a pegylated IL-10 (PEG-IL-10) led to tumor rejection and long-lasting tumor immunity. IL-10 stimulates cytotoxicity of CD8+ T cells and the expression of IFN-γ in CD8+ T cells. IL-10–induced tumor rejections are dependent on the expression of IFN-γ and granzymes in tumor-resident CD8+ T cells and the upregulation of MHC molecules. These findings reconcile earlier clinical data, which showed that recombinant IL-10 increased IFN-γ and granzymes in the blood of treated individuals. PEG-IL-10 is therefore a unique therapeutic agent, which simultaneously stimulates antitumor immunity and inhibits tumor-associated inflammation.”

This is particularly welcome information for clinicians who use low dose cytokine therapy including recombinant IL-10.

Depression and brain inflammation

JAMAEvidence for the role of brain inflammation in depression is proliferating as noted in a report published recently in JAMA (Journal of the American Medical Association):

Activation of the immune system is the body’s natural reaction to infection or tissue damage, but when this protective response is prolonged or excessive, it can play a role in many chronic illnesses, not only of the body, but also of the brain...Psychiatric and neurodevelopmental disorders are being thought of more and more as systemic illnesses in which inflammation is involved,” noted Eric Hollander, MD, of Montefiore Medical Center and Albert Einstein College of Medicine, New York City.

Certain biomarkers including the proinflammatory cytokines interleukin-6 (IL-6) and TNF, and CRP are standing out in depression:

“…early studies showing that patients with depression, regardless of their physical health status, exhibited cardinal features of inflammation, including increases in inflammatory cytokines in the blood and cerebrospinal fluid.”

 IL-6 and CRP In Neuropsychiatric Disorders

JAMA PsychiatryAlong these lines, a study just published in JAMA Psychiatry shows that higher levels of the proinflammatory cytokine IL-6 and the inflammatory biomarker CRP (C-reactive protein) are associated with depression in childhood and psychosis in young adulthood. Noting that…

Recent meta-analyses of cross-sectional studies have reported increased serum levels of these inflammatory markers in depression, first-episode psychosis, and acute psychotic relapse; however, the direction of the association has been unclear“…

The authors determined to…

“..test the hypothesis that higher serum levels of IL-6 and CRP in childhood would increase future risks for depression and psychosis.”

To do so they measured levels of IL-6 and CRP in 4500 individuals at age 9 years, then assessed them at age 18 years for depression using the Clinical Interview Schedule–Revised (CIS-R) and Mood and Feelings Questionnaire (MFQ); and psychotic experiences (PEs) and psychotic disorder by semistructured interviews. Their data were particularly striking for IL-6 in depression and psychosis:

“After adjusting for sex, age, body mass index, ethnicity, social class, past psychological and behavioral problems, and maternal postpartum depression, participants in the top third of IL-6 values compared with the bottom third at age 9 years were more likely to be depressed (CIS-R) at age 18 years (adjusted odds ratio [OR], 1.55). Results using the MFQ were similar. Risks of PEs and of psychotic disorder at age 18 years were also increased with higher IL-6 levels at baseline (adjusted OR, 1.81). Higher IL-6 levels in childhood were associated with subsequent risks of depression and PEs in a dose-dependent manner.”

IL-6 proved to be a more robust biomarker than CRP as there was no association of childhood CRP levels and psychiatric illness at age 18, while IL-6 was a good predictor. The authors conclude:

Higher levels of the systemic inflammatory marker IL-6 in childhood are associated with an increased risk of developing depression and psychosis in young adulthood. Inflammatory pathways may provide important new intervention and prevention targets for these disorders. Inflammation might explain the high comorbidity between heart disease, diabetes mellitus, depression, and schizophrenia.

Inflammation and Antidepressants

American Journal of PsychiatryThe authors of a study recently published in the American Journal of Psychiatry report that levels of CRP predicted the response to a SSRI (escitalopram/Lexapro®) versus nortryptipline (tricyclic antidepressant that is primarily a norepinephrine reuptake inhibitor):

Major depressive disorder has been linked with inflammatory processes, but it is unclear whether individual differences in levels of inflammatory biomarkers could help match patients to treatments that are most likely to be beneficial. The authors tested the hypothesis that C-reactive protein (CRP), a commonly available marker of systemic inflammation, predicts differential response to escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor).”

They measured CRP in 241 adult men and women with major depressive disorder who were randomly allocated to 12 weeks of treatment with Lexapro® or nortriptyline and rated their response weekly with the Montgomery-Åsberg Depression Rating Scale (MADRS). CRP levels were indeed able to predict the response:

CRP level at baseline differentially predicted treatment outcome with the two antidepressants (CRP-drug interaction: β=3.27, 95% CI=1.65, 4.89). For patients with low levels of CRP (<1 mg/L), improvement on the MADRS score was 3 points higher with escitalopram than with nortriptyline. For patients with higher CRP levels, improvement on the MADRS score was 3 points higher with nortriptyline than with escitalopram. CRP and its interaction with medication explained more than 10% of individual-level variance in treatment outcome.”

These data lead the authors to conclude:

“An easily accessible peripheral blood biomarker may contribute to improvement in outcomes of major depressive disorder by personalizing treatment choice.”

So inflammation impaired the response to the SSRI Lexapro®. Patients with higher levels of inflammation did better with nortryptiline, but why?

Norepinephrine reduces  brain oinflammation

PNASA fascinating study published in PNAS (Proceedings of the National Academy of Sciences) sheds light on this by demonstrating that norepinephrine (the levels of which are raised by nortryptiline, a norepinephrine reuptake inhibitor), acts as an antiinflammatory agent in the brain. The authors observed this in the course of investigating the role of norepinephrine in promoting brain inflammation that clears the amyloid beta (Aβ) associated with Alzheimer’s disease:

Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer’s disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed Aβ-induced cytokine and chemokine production and increased microglial migration and phagocytosis of Aβ… In vivo laser microscopy confirmed a Aβ deposition in response to noradrenergic depletionreduced recruitment of microglia to Aβ plaque sites and impaired microglial Aβ phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced Aβ clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion.”

In other words, inflammation went up as norepinephrine went down. This informs us that well-regulated inflammation is an important housekeeping function of the brain’s glial cells, but also reveals the link between the relief of depression due dysregulated inflammation when suppressed by norepinephrine.

Clinical note: no analysis and treatment plan for depression is complete without investigating for neuroinflammation and its causes, for which there are numerous sustainable interventions.

PTSD, inflammation and magnesium

JAMA PsychiatryPTSD (post-traumatic stress disorder) may be more likely to occur in the presence of pre-existing inflammation according to a study just published in JAMA Psychiatry. Noting that earlier studies have demonstrated an association of PTSD with peripheral inflammation, the authors set out to…

“…determine whether plasma concentration of the inflammatory marker C-reactive protein (CRP) helps predict PTSD symptoms.”

The authors examined pre and post-deployment data on combat-related trauma for 1861 subjects and PTSD symptoms for 1617 in the Marine Resiliency Study, using the Clinician-Administered PTSD Scale (CAPS) as a metric for PTSD symptoms. The data demonstrated a correlation between inflammation and risk of PTSD:

“We determined the effects of baseline plasma CRP concentration on postdeployment CAPS using zero-inflated negative binomial regression (ZINBR), a procedure designed for distributions, such as CAPS in this study, that have an excess of zeroes in addition to being positively skewed. Adjusting for the baseline CAPS score, trauma exposure, and other relevant covariates, we found baseline plasma CRP concentration to be a highly significant overall predictor of postdeployment CAPS scores: each 10-fold increment in CRP concentration was associated with an odds ratio of nonzero outcome (presence vs absence of any PTSD symptoms) of 1.51 and a fold increase in outcome with a nonzero value (extent of symptoms when present) of 1.06.”

Medpage Today: Psychiatry quotes Paul E. Schulz, MD, of the University of Texas Health Science Center in Houston:

“Schulz said the inflammation-PTSD relationship was definitely plausible on the basis of several lines of research. For example, he told MedPage Today in an email, previous traumatic brain injury is a known risk factor for PTSD, and the mechanism may involve chronic brain inflammation resulting from the injury. Other lines of research have implicated immunological factors in promoting susceptibility to PTSD, he said.”

It certainly stands to reason that chronic brain inflammation from autoimmune or traumatic causes would render the brain more susceptible to stress-related anxiety disorders. Medscape also quotes the authors:

“”If peripheral inflammation contributes to the development of PTSD, interventions to decrease inflammation, such as dietary or lifestyle modifications, might ameliorate the severity of this disorder,” they wrote.”

The authors of the study conclude:

“A marker of peripheral inflammation, plasma CRP may be prospectively associated with PTSD symptom emergence, suggesting that inflammation may predispose to PTSD.”

 

European Journal of Clinical NutritionPractitioners reading this post are likely aware of the anti-inflammatory and calming virtues of magnesium but may not have seen the study just published in the European Journal of Clinical Nutrition offering evidence that magnesium lowers CRP:

“The aim of this study was to quantitatively summarize the association of dietary magnesium (Mg) intake with serum C-reactive protein (CRP) levels in the general population.”

They examined data from observational and experimental studies in PubMed, EMBASE, Google and hand searches of related reference lists for the likelihood of having serum CRP greater than or equal to 3 mg/l and used meta-regression was to determine the linear association of dietary Mg intake and CRP levels. The data showed a significant association between higher magnesium and lower CRP:

“A data set derived from seven cross-sectional studies including 32,918 participants was quantitatively assessed. A weighted inverse association between Mg intake and serum CRP levels was observed from four cross-sectional studies. The pooled OR of having CRP greater than or equal to 3  mg/l was 1.49 on comparing the lowest to the highest group of Mg intake from three studies with the data available. Qualitative assessment among five intervention studies also showed a potential beneficial effect of Mg intake on serum CRP levels.”

These authors conclude:

“This meta-analysis and systematic review indicates that dietary Mg intake is significantly and inversely associated with serum CRP levels. The potential beneficial effect of Mg intake on chronic diseases may be, at least in part, explained by inhibiting inflammation.”

 

Clinical note: considering that PTSD is characterized by SNS (sympathetic nervous system) hyperarousal and inflammation, and that magnesium is ‘nature’s SNS calming mineral’ that supports PSNS (parasympathetic nervous system) function and has a natural anti-inflammatory effect, magnesium is certainly worthy of consideration in the case management of PTSD.

Magnesium measurement and dosage considerations: Serum magnesium and even RBC membrane magnesium are poor indicators of tissue magnesium status. When objective determination of tissue mineral status is required the Exa Test is definitive. Both clincians and patients should bear in mind that magnesium needs can fluctuate due to stress, inflammation and other causes, and the latter can learn to adjust their dosage as needed. Moreover, magnesium assimilation can be impaired by gut epithelial microinflammation and stomach acid blocking medications. Some earlier studies on magnesium and muscle cramps, a common clinical indicator of suboptimal magnesium status related to the role of magnesium in regulating neuromuscular excitability, are flawed by dosages that were too low.

Depression, aging and brain inflammation: indications for sustainable treatment

[fvplayer src=’http://www.lapislight.com/wp/wp-content/uploads/2013/05/Post-05161.flv’ width=384 height=216 autoplay=false splash=’http://www.lapislight.com/wp/wp-content/uploads/2013/05/JDM-for-FLV-logo1.png’ splashend=show]

 

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.