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.

CKD (chronic kidney disease) expected for 50% over age 30

American Journal of Kidney DiseasesChronic kidney disease (CKD) is rising steeply and projected to affect more than half of those aged 30 to 64 years in the coming twenty years according to a study just published in the American Journal of Kidney Diseases. The authors state:

“Awareness of chronic kidney disease (CKD), defined by kidney damage or reduced glomerular filtration rate, remains low in the United States, and few estimates of its future burden exist…We used the CKD Health Policy Model to simulate the residual lifetime incidence of CKD and project the prevalence of CKD in 2020 and 2030. The simulation sample was based on nationally representative data from the 1999 to 2010 National Health and Nutrition Examination Surveys.”

More than half of people aged 30 to 64 years likely to be affected

The authors’ data showed that…

For US adults aged 30 to 49, 50 to 64, and 65 years or older with no CKD at baseline, the residual lifetime incidences of CKD are 54%, 52%, and 42%, respectively. The prevalence of CKD in adults 30 years or older is projected to increase from 13.2% currently to 14.4% in 2020 and 16.7% in 2030.”

Currently one in seven adults is affected by chronic kidney disease. The public health consequences are enormous. The authors conclude:

“For an individual, lifetime risk of CKD is high, with more than half the US adults aged 30 to 64 years likely to develop CKD. Knowing the lifetime incidence of CKD may raise individuals’ awareness and encourage them to take steps to prevent CKD.”

Prevention: Metabolic syndrome and chronic kidney disease

Current Opinion in Nephrology and HypertensionComponents of metabolic syndrome (MetS) including insulin resistance, hypertension, dyslipidemia and inflammation are particularly rough on the kidneys. A review published in Current Opinion in Nephrology and Hypertension highlights the connection:

“The association of the metabolic syndrome (MetS) with cardiovascular risk, mortality, type 2 diabetes mellitus, stroke, nonfatty liver disease and gout is well known. However, the association of the MetS with chronic kidney disease (CKD) is now emerging…Studies show that patients with MetS have a 2.5-fold higher risk of developing CKD. The risk of microalbuminuria is also increased two-fold in the MetS. Renal dysfunction becomes apparent long before the appearance of hypertension or diabetes in MetS. Compared with healthy controls, patients with MetS have increased microvascular disease-tubular atrophy, interstitial fibrosis, arterial sclerosis and global and segmental sclerosis.”

Clinicians should especially note that metabolic syndrome is contributing to chronic kidney disease well before it evolves into diabetes and the development of hypertension. Regarding potential mechanisms:

“Studies suggest that the renal fibrosis seen in MetS might be caused by a constellation of insulin resistance, hypertension, dyslipidemias and inflammation, and result in a heightened expression of adipocytokines, angiotensin and inflammatory cytokines such as interleukin-6 and tumour necrosis factor-alpha.”

World Journal of NephrologyThe author of a paper published in the World Journal of Nephrology states:

“Despite the ambiguous definition of MetS, it has been clearly associated with chronic kidney disease markers including reduced glomerular filtration rate, proteinuria and/or microalbuminuria, and histopathological markers such as tubular atrophy and interstitial fibrosis. However, the etiological role of MetS in chronic kidney disease (CKD) is less clear. The relationship between MetS and CKD is complex and bidirectional, and so is best understood when CKD is viewed as a common progressive illness along the course of which MetS, another common disease, may intervene and contribute. Possible mechanisms of renal injury include insulin resistance and oxidative stress, increased proinflammatory cytokine production, increased connective tissue growth and profibrotic factor production, increased microvascular injury, and renal ischemia.

PLOS ONEThe authors of a study published in PLOS One on the relation between metabolic syndrome and chronic kidney disease in an adult Korean population came to the conclusion:

“The strength of association between MS [metabolic syndrome] and the development of CKD increase as the number of components increased from 1 to 5. In sub-analysis by men and women, MS and its each components were a significant determinant for CKDMS and its individual components can predict the risk of prevalent CKD for men and women.”

Moreover, they excluded patients with diabetes to more clearly isolate contribution of metabolic syndrome to CKD.

Cardiology Research and PracticeCommenting on the link between metabolic syndrome and chronic kidney disease in the development of cardiovascular disease in a paper published in Cardiology Research and Practice the authors note:

Microalbuminuria has been described as the earliest manifestation of MetS-associated kidney damage and diabetic nephropathy, and it is associated with insulin resistance independent of diabetes. MetS is often accompanied by increased plasma renin activity, angiotensinogen, angiotensin-converting enzyme activity, and angiotensin II (renin-angiotensin-aldosterone system) and with renal sympathetic activity. Hyperinsulinemia, insulin resistance, and increased plasma angiotensin II levels are potent activators of expression of transforming growth factor-β1, a fibrogenic cytokine that contributes to glomerular injury.”

Insulin resistance, of course, spurs chronic inflammation:

“The hallmark of MetS is insulin resistance. Inflammatory mediators, including tumor necrosis factor (TNF)-α, have been shown to mediate insulin resistance. Adipokines, including TNF-α, IL-6, and resistin, are cytokines secreted by adipose tissue, and their plasma concentrations are elevated in patients with MetS, whereas their plasma adiponectin levels are reduced. These findings may contribute to insulin resistance, and insulin resistance promotes chronic inflammation.”

Sugar versus salt in hypertension and chronic kidney disease

Open HeartA striking paper just published in the journal Open Heart (British Cardiovascular Society) identifying sugar as a worse culprit than salt for hypertension and cardiometabolic disease further links metabolic syndrome and chronic kidney disease. The authors note:

“Cardiovascular disease is the leading cause of premature mortality in the developed world, and hypertension is its most important risk factor. Controlling hypertension is a major focus of public health initiatives, and dietary approaches have historically focused on sodium. While the potential benefits of sodium-reduction strategies are debatable, one fact about which there is little debate is that the predominant sources of sodium in the diet are industrially processed foods.”

But processed foods are high in sugar as well as salt, and it may be unwise to aggressively change sodium consumption…

‘Strategies to lower dietary sodium intake focus (implicitly if not explicitly) on reducing consumption of processed foods: the predominant sources of sodium in the diet…Nonetheless, the mean intake of sodium in Western populations is approximately 3.5–4 g/day. Five decades worth of data indicates that sodium intake has not changed from this level across diverse populations and eating habits, despite population-wide sodium-reduction efforts and changes in the food supply.Such stability in intake suggests tight physiologic control, which if indeed the case, could mean that lowering sodium levels in the food supply could have unintended consequences. Because processed foods are the principal source of dietary sodium, if these foods became less salty, there could be a compensatory increase in their consumption to obtain the sodium that physiology demands.

Highly refined carbohydrates, the fuel for metabolic syndrome, worse than salt

This includes fructose:

“Coincidentally, processed foods happen to be major sources of not just sodium but of highly refined carbohydrates: that is, various sugars, and the simple starches that give rise to them through digestion. Compelling evidence from basic science, population studies, and clinical trials implicates sugars, and particularly the monosaccharide fructose, as playing a major role in the development of hypertension. Moreover, evidence suggests that sugars in general, and fructose in particular, may contribute to overall cardiovascular risk through a variety of mechanisms. Lowering sodium levels in processed foods could lead to an increased consumption of starches and sugars and thereby increase in hypertension and overall cardiometabolic disease.”

Hypertensive mechanisms of fructose. NO, nitric oxide; RAS, renin-angiotensin system; RNS, reactive nitrogen species; ROS, reactive oxygen species.

Hypertensive mechanisms of fructose. NO, nitric oxide; RAS, renin-angiotensin system; RNS, reactive nitrogen species; ROS, reactive oxygen species.

 “Although high intakes of either fructose alone or sucrose may lead to insulin resistance, it is fructose that has been implicated as the sugar responsible for reducing sensitivity of adipose tissue to insulin.Insulin stimulates the SNS and hyperinsulinaemia may lead to hypertension, with the degree of insulin resistance in peripheral tissues directly correlated with hypertension severity. Reducing insulin resistance may lead to a reduction in blood pressure, and hyperinsulinaemia seems more related to fructose than glucose.”

The authors make a distinction between fructose added to foods and that found naturally in whole fruit as stated in their conclusion:

“While naturally occurring sugars in the form of whole foods like fruit are of no concern, epidemiological and experimental evidence suggest that added sugars (particularly those engineered to be high in fructose) are a problem and should be targeted more explicitly in dietary guidelines to support cardiometabolic and general health…Evidence from epidemiological studies and experimental trials in animals and humans suggests that added sugars, particularly fructose, may increase blood pressure and blood pressure variability, increase heart rate and myocardial oxygen demand, and contribute to inflammation, insulin resistance and broader metabolic dysfunction. Thus, while there is no argument that recommendations to reduce consumption of processed foods are highly appropriate and advisable, the arguments in this review are that the benefits of such recommendations might have less to do with sodium—minimally related to blood pressure and perhaps even inversely related to cardiovascular risk—and more to do with highly-refined carbohydrates. It is time for guideline committees to shift focus away from salt and focus greater attention to the likely more-consequential food additive: sugar.”

Quoted in Medscape Medical News, Richard Krasuski, MD, from the Cleveland Clinic in Ohio commented on the study:

“”It is a little bit frightening that we have been focusing on salt for so long.”…The conclusion that sugar represents a greater danger to the heart than salt, Dr Krasuski said, was an “eye opener.” He acknowledged, though, that he should have anticipated it. He and other cardiologists have noticed that the recommendations to increasingly lower salt intake have not resulted in the expected positive cardiovascular outcomes.”

Bottom line for chronic kidney disease

CKD incidence is rising steeply and projected to affect half the population aged 30 to 64. Key causal factors are metabolic syndrome with insulin resistance and hypertension. These are made worse by added sugars than by salt. Appropriate diet, objective determination of individual genetic and circumstantial needs for supplementation, regular exercise, not smoking, stress management and addressing sleep disordered breathing are common sense preventive and remedial measures.

Hair loss frequently associated with autoimmunity

Italian Journal of Dermatology and VenereologyHair loss (alopecia) has a number of possible contributing causes including low iron (measured by serum ferritin) and hypothyroid, but it frequently occurs due to autoimmune inflammation. This may be hard to recognize when instead of a full-blown autoimmune disease there are diffuse autoimmune inflammatory phenomena that are a milder forerunner known as Undifferentiated connective tissue disease (UCTD). A paper just published in the Italian Journal of Dermatology and Venereology discusses the importance of considering autoimmunity when investigating the causes of hair loss.

Hair loss can occur in various patterns

“Hair disorders are frequently observed in various systemic diseases, including autoimmune connective tissue diseases (CTDs), with predilection of lupus erythematosus (LE), followed by dermatomyositis (DM) and scleroderma. Hair disorders in CTDs may manifest as various clinical patterns, such as telogen hair loss, diffuse thinning or fragility of hair, and scarring alopecia. Less common hair disorders include anagen effluvium, alopecia areata, and trichomegaly. Some drugs used to treat CTDs may cause hair loss in a drug-related manner or hyperthrichosis.”

The signs of common autoimmune connective tissue disorders often include hair loss:

In the assessment of common hair loss patterns, such as telogen effluvium, the possible association with CTDs must be borne in mind and should not be overlooked. Alopecia appears to be a significant sign in the course of LE and especially systemic LE. In DM, the involvement of the scalp is common, and is often characterized by a diffuse, violaceous, scaly, non-scarring and symptomatic hair loss…The most important variant of scarring alopecia in the context of CTDs is that associated with discoid lupus erythematosus (DLE). In the diagnostic work-up of DLE-related cicatrical alopecia, histopathological and immunopathological studies are useful, and a relevant role has been attributed to dermatoscopy (trichoscopy) over the last years. Hair loss has been reported in several other CTDs, including mixed and undifferentiated CTDs, and primary Sjögren’s syndrome, although it is likely to be underestimated in such diseases.”

Undifferentiated connective tissue disease

Clinical Reviews in Allergy & ImmunologyUndifferentiated connective tissue disease is an extremely important clinical topic because this precursor to more developed autoimmune diseases likely accounts for a high percentage of human aches, pains and numerous other symptoms including hair loss. A paper just published in Clinical Reviews in Allergy & Immunology defines the pattern of cytokine imbalance often seen in UCTDs:

Undifferentiated connective tissue disease (UCTD) is a unique clinical entity, a potential forerunner of well-established systemic autoimmune/rheumatic diseases. UCTD is characterized by the presence of various clinical symptoms, as well as a diverse repertoire of autoantibodies, resembling systemic autoimmune diseases. Since approximately one third of these patients consequently transform into a full-blown systemic autoimmune/rheumatic disease, it is of major importance to assess pathogenic factors leading to this progression. In view of the fact that the serological and clinical picture of UCTD and systemic autoimmune diseases are very similar, it is assumed that analogous pathogenic factors perpetuate both disease entities.”

Th17/Treg dominance

Typical of most autoimmune inflammatory disorders throughout the whole spectrum is an imbalance between proinflammatory Th17 and antiinflammatory Treg (regulatory) immune cells with their associated cytokines as described for UCTD:

“In systemic autoimmune conditions, a quantitative and qualitative impairment of regulatory T cells has been shown previously, and in parallel, a relative dominance of pro-inflammatory Th17 cells has been introduced. Moreover, the imbalance between regulatory and Th17 cells plays a pivotal role in the initiation and propagation of UCTD.”

Th17/Treg dominance with its associated cytokine imbalance is of significant for both diagnosis and treatment:

“Additionally, we depict a cytokine imbalance, which give raise to a biased T cell homeostasis from the UCTD phase throughout the fully developed systemic autoimmune disease stage. The levels of interleukin (IL)-6, IL-12, IL-17, IL-23, and interferon (IFN)-γ were pathologically increased with a parallel reduction of IL-10. We believe that the assessment of Th17/Treg cell ratio, as well as the simultaneous quantitation of cytokines may give a useful diagnostic tool at the early UCTD stage to identify patients with a higher chance of consecutive disease progression toward serious systemic autoimmune diseases. Moreover, the early targeted immunomodulating therapy in these patients may decelerate, or even stop this progression, before the development of serious autoimmune conditions with organ damage.”

An opportunity to prevent further harm

In this respect, identifying hair loss as associated with early immune system dysregulation not only permits proper treatment of the presenting complaint but becomes an opportunity to ward off progression to more debilitating autoimmune disease.

Clinical note: Screening for UCTD is aided by a multiple antibody autoimmune screen.

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.

Cognitive decline: major overlooked causes

Cognitive decline, the insidious thief of quality of life in its milder forms and appalling despoiler of human qualities in more advanced dementia and Alzheimer’s disease, is fueled by NEJM Journal Watchbiological causes that have not received adequate attention as noted in an editorial in NEJM Journal Watch under the title What Most Causes Cognitive Decline Is Not What We’ve Been Looking For. Stating…

“The most common factors are not the common degenerative diseases.”

Annals of Neurology…the editor is commenting on a study just published in Annals of Neurology in which the authors examined whether the commonly assumed causes were largely to blame:

“The pathologic indices of Alzheimer disease, cerebrovascular disease, and Lewy body disease accumulate in the brains of older persons with and without dementia, but the extent to which they account for late life cognitive decline remains unknown. We tested the hypothesis that these pathologic indices account for the majority of late life cognitive decline.”

They correlated measures of Alzheimer pathology (amyloid load and tangle density), cardiovascular disease (macroscopic and microscopic infarcts) and Lewy bodies with global cognitive decline in the brains of 856 deceased subjects. While important, these measures failed to accounted for the bulk of it:

“In separate analyses, global Alzheimer pathology, amyloid, tangles, macroscopic infarcts, and neocortical Lewy bodies were associated with faster rates of decline and explained 22%, 6%, 34%, 2%, and 8% of the variation in decline, respectively. When analyzed simultaneously, the pathologic indices accounted for a total of 41% of the variation in decline, and the majority remained unexplained. Furthermore, in random change point models examining the influence of the pathologic indices on the onset of terminal decline and the preterminal and terminal components of the cognitive trajectory, the common pathologic indices accounted for less than a third of the variation in the onset of terminal decline and rates of preterminal and terminal decline.”

In other words, there’s a lot more contributing to cognitive decline than the Alzheimer’s form of dementia and strokes. The authors conclude:

“The pathologic indices of the common causes of dementia are important determinants of cognitive decline in old age and account for a large proportion of the variation in late life cognitive decline. Surprisingly, however, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identified. Identification of the mechanisms that contribute to the large unexplained proportion of cognitive decline is urgently needed to prevent late life cognitive decline.”

 

Neurology Vol 81 Num 20Of particular importance because this risk factor is relatively easy to modify is another study,  just published this time in Neurology, showing that glucose levels when only mildly elevated contribute to cognitive decline. The authors determined to see if there is a correlation between HgbA1c (hemoglobin A1c), memory and brain atrophy (specifically in the hippocampus, the ‘center’ for short-term memory) at mildly elevated, non-diabetic levels of glucose:

“For this cross-sectional study, we aimed to elucidate whether higher glycosylated hemoglobin (HbA1c) and glucose levels exert a negative impact on memory performance and hippocampal volume and microstructure in a cohort of healthy, older, nondiabetic individuals without dementia.”

They tested memory, fasting HbA1c, glucose, and insulin and did MRI scans for hippocampal volume and microstructure in 141 subjects:

Lower HbA1c and glucose levels were significantly associated with better scores in delayed recall, learning ability, and memory consolidation. In multiple regression models, HbA1c remained strongly associated with memory performance. Moreover, mediation analyses indicated that beneficial effects of lower HbA1c on memory are in part mediated by hippocampal volume and microstructure.”

There is really no excuse for clinicians to not make glucose and insulin regulation a top priority in case management for healthy aging and prevention of cognitive decline. The authors conclude:

“Our results indicate that even in the absence of manifest type 2 diabetes mellitus or impaired glucose tolerance, chronically higher blood glucose levels exert a negative influence on cognition, possibly mediated by structural changes in learning-relevant brain areas. Therefore, strategies aimed at lowering glucose levels even in the normal range may beneficially influence cognition in the older population, a hypothesis to be examined in future interventional trials.”

 

Biological PharmacologyThe authors of a paper published in Biological Pharmacology associate insulin with the crucial issue of neuroinflammation.

“The disappointments of a series of large anti-amyloid trials have brought home the point that until the driving force behind Alzheimer’s disease, and the way it causes harm, are firmly established and accepted, researchers will remain ill-equipped to find a way to treat patients successfully. The origin of inflammation in neurodegenerative diseases is still an open question. We champion and expand the argument that a shift in intracellular location of α-synuclein, thereby moving a key methylation enzyme from the nucleus, provides global hypomethylation of patients’ cerebral DNA that, through being sensed by TLR9, initiates production of the cytokines that drive these cerebral inflammatory states. After providing a background on the relevant inflammatory cytokines, this commentary then discusses many of the known alternatives to the primary amyloid argument of the pathogenesis of Alzheimer’s disease, and the treatment approaches they provide.”

Altered cytokine-insulin axis in neurodegenerative diseaseThey underline a connection between inflammatory cytokines, insulin resistance in the brain and neurodegeneration:

“A key point to appreciate is the weight of evidence that inflammatory cytokines, largely through increasing insulin resistance and thereby reducing the strength of the ubiquitously important signaling mediated by insulin, bring together most of these treatments under development for neurodegenerative disease under the one roof. Moreover, the principles involved apply to a wide range of inflammatory diseases on both sides of the blood brain barrier.”

 

Neuroscience ResearchCommenting on the importance of neuroinflammation, the authors of a paper published in Neuroscience Research state:

Neuroinflammation is central to the common pathology of several acute and chronic brain diseases. This review examines the consequences of excessive and prolonged neuroinflammation, particularly its damaging effects on cellular and/or brain function, as well as its relevance to disease progression and possible interventions. The evidence gathered here indicates that neuroinflammation causes and accelerates long-term neurodegenerative disease, playing a central role in the very early development of chronic conditions including dementia. The wide scope and numerous complexities of neuroinflammation suggest that combinations of different preventative and therapeutic approaches may be efficacious.”

They articulate these critical highlights:

  • Neuroinflammation is central to the common pathology of diseases/disorders.
  • Neuroinflammation causes acute brain cell death.
  • Neuroinflammation causes and accelerates long-term neurodegenerative disease.
  • Preventative and therapeutic approaches are needed to dampen-down neuroinflammation.

 

Frontiers In Integrative NeuroscienceA paper recently published in Frontiers In Integrative Neuroscience expands of the role of neuroinflammation in Alzheimer’s disease:

“Although there are different genetic and environmental causes, all patients have a similar clinical behavior and develop identical brain lesions: NFTs (neurofibrillary tangles) consisting of Tau (τ) protein and NPs (neuritic plaques) consisting of amyloid-β (Aβ) peptides. These alterations are the final result of post-translational modifications and involve different genes and render AD as a complex multigenic neurodegenerative disorder.”

The identify the activation of inflammation by amyloid-β as a pivotal step:

“In addition to this multi-genic complexity in AD, now we know that Aβ promotes an inflammatory response mediated by microglia and astrocytes, thus activating signaling pathways that could lead to neurodegeneration…Although it was previously thought that the central nervous system (CNS) was an immune-privileged site, now is well known that certain features of inflammatory processes occur normally in response to an injury, infection or disease. The resident CNS cells generate inflammatory mediators, such as pro-inflammatory cytokines, prostaglandins (PGs), free radicals, complement factors, and simultaneously induce the production of adhesion molecules and chemokines, which could recruit peripheral immune cells. This review describes the cellular and molecular mediators involved in the inflammatory process associated with AD and several possible therapeutic approaches describe recently.”

Inflammation in Alzheimer's diseaseThey summarize their extensive review of this topic:

“…inflammation induced by Aβ has an important role in the neurodegenerative process. The inflammatory process itself is driven by microglial and astrocytic activation through the induction of pro-inflammatory molecules and related signaling pathways, thus leading to synaptic damage, neuronal loss, and the activation of other inflammatory participants… Although, the role of amyloid as a potential initiator of inflammation is not obvious, its accumulation exerts an indirect effect by activating caspases and transcription factors, such as NF-κ B and AP-1, which produce numerous inflammation amplifiers (IL-1β, TNF-α, and IL-6). Pro-inflammatory cytokines, such as TNF-α and IL-1β and IL-6, could act directly on the neuron and induce apoptosis. Similarly, TNF-α and IL-1β can activate astrocytes, which could release factors that have the capacity to activate microglia… Furthermore, APP, BACE1, and PSEN expression is governed by factors such as NF-κ B. The genes encoding these proteins have sites in their promoter regions, which are recognized by NF-κ B; in turn, the expression of these factors is upregulated by the presence of pro-inflammatory cytokines.”

Neuronal damage and Aβ deposition trigger inflammationMoreover…

Inflammatory mediators acting on neurons contribute to an increase in amyloid production and activate microglia-mediated inflammation. The microglia-neuron communication amplifies the production of factors that contribute to AD-type pathology.”

IL-1β plays a key role:

“This cascade is primarily mediated by the pro-inflammatory cytokine IL-1β, which is expressed by microglia cells. IL-1β may cause neuronal death via various pathways, which activate microglia and consequently increase the release of IL-1β, thus generating a self-sustaining mechanism that is amplified by itself. This slow but steady inflammation state, generated for long periods in the brain eventually can destroy neurons and contribute to the clinical symptoms observed in the disease.”

 

Journal of Alzheimer's DiseaseAutoimmunity in cognitive decline and dementia is a major topic on its own and will be featured in forthcoming posts. For now, an interesting study just published in the Journal of Alzheimer’s Disease describes how early changes in cognitive function due to autoimmune inflammation precede amyloid-β or tau pathologies. The authors set out to discriminate whether autoimmunity is causal or consquential:

“Immune system activation is frequently reported in patients with Alzheimer’s disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration… The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology.”

They assessed behavioral performance and autoimmune/inflammatory markers in a group of study animals genetically predisposed to Alzheimer’s disease and a control group, and found an association between cognitive impairment that predated the onset of AD and autoimmune inflammation:

“Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory disease, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired “cognitive” flexibility in the first six months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology.”

In other words, they found that Alzheimer’s disease is a smoldering process that coincides with systemic inflammation and takes years to evolve:

The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior.”

 

Journal of NeuroinflammationA fascinating paper recently published in the Journal of Neuroinflammation demonstrates how Down syndrome (DS) and Alzheimer’s disease share similar cytokine-driven neuroinflammatory gial activity:

“In the brain, neuritic amyloid-β (Aβ) plaques – a characteristic neuropathological feature of Alzheimer’s disease (AD) – are a virtually certain finding in adults with DS and have been noted in some children with DS. For instance, among 12 children with DS, two (ages 8 and 9 years) had Aβ plaques, and among those between the ages of 35 and 45 years, all had neuritic Aβ plaques and other AD pathologies, such as neurofibrillary tangles and glial activation… the prediction of AD neuropathological changes at middle age is reported to be a virtual certainty in those with DS.”

The process starts right away in Down syndrome:

“Three such early events have been reported in DS fetuses and each is related to the others as they induce, and are induced by each other and by cytokines subsequent to neuroinflammatory changes. In particular, these include overexpression of two chromosome 21 gene products – APP and S100B – and the resultant overexpression of the pluripotent neuroinflammatory cytokine IL-1, which is encoded by chromosome 2 genes IL-1A and IL-1B. Complex interactions between APP, glial activation, S100B, and IL-1 include upregulation of the expression of IL-1α and β by both APP and S100B, and induction of both APP and S100B by IL-1β. Such interactions have been shown to be elicited by multiple neural insults, each of which is characterized by gliosis-related neuroinflammation and risk for development of the characteristic neuropathological changes of AD… Such glial activation and cytokine overexpression occurs years before the virtually certain appearance at middle age of the Aβ plaques in DS.”

They note that this process is not confined to DS and AD, but associated with cognitive decline in other conditions:

“By analogy, without regard to the diversity of the source of neuronal stress, for example, traumatic brain injury, epilepsy, aging, or AIDS, the downstream consequence is increased risk for development of the neuropathological changes of AD marked by increased expression of neuronal APP, activation of glia, and neuroinflammatory cytokine expression.”

Inflammation-associated genes in the promotion of Alzheimer neuropathogenesis in trisomy 21And a particularly evil aspect of this process is that it is self-propagating, that is it feeds on itself:

“The danger of chronic induction of neuroinflammation with its manifestation of glial activation and cytokine overexpression is related to the capacity of proinflammatory cytokines such as IL-1β to self-propagate as they, themselves, activate microglia and astrocytes and further excess expression of IL-1β. In addition to IL-1β induction of the precursors of the principal neuropathological changes in AD, viz., APP for Aβ plaques, S100B for non-sensical growth of dystrophic neurites in plaques, synthesis and activation of MAPK-p38 for hyperphosphorylation of tau, favors formation of neurofibrillary tangles. In addition to favoring formation of these anomalies, IL-1β induces the synthesis and the activity of acetylcholinesterase, thus favoring the breakdown of acetylcholine, an important neurotransmitter in learning and memory, which is known to be decreased in AD. Similarly devastating, excess IL-1β, as observed in DS and AD, is associated in vitro and in vivo with decreases in the expression of synaptophysin, which is a hallmark of the synaptic loss in AD. Such neuropathophysiological changes would be expected to further stress neurons, promote more neuroinflammation, and in this way create a self-propagating cycle of ever increasing neuronal stress, dysfunction, and loss.”

This is one important reason why once ‘the train leaves the station and gets up to full speed’ it’s so hard to treat.

 

Food and Chemical ToxicologyA paper recently published in Food and Chemical Toxicology directs attention to the contribution of oxidative stress and glycation along with inflammation. In measuring markers of oxidative stress and endothelial dysfunction in the blood of 21 AD patients under standard treatment for AD compared with 10 controls, they saw significant differences in the ability to manage oxidative damage with glutathione and in levels of glycation end-products due to poor blood glucose regulation:

“Results indicate that IL-6, TNF-α, ADMA and homocysteine levels were significantly elevated in AD patients. Protein carbonyls levels were higher in AD group, while glutathione reductase and total antioxidant capacity were lower, depicting decreased defense ability against reactive oxygen species. Besides, a higher level of advanced glycation end-products was observed in AD patients. Depending on the treatment received, a distinct inflammatory and oxidative stress profile was observed: in Rivastigmine-treated group, IL6 levels were 47% lower than the average value of the remaining AD patients; homocysteine and glutathione reductase were statistically unchanged in the Rivastigmine and Donepezil–Memantine, respectively Donepezil group.”

They highlighted these conclusions:

  • IL-6, TNF-α, ADMA and homocysteine levels were significantly elevated in AD patients compared to controls.
  • Protein carbonyls levels were increased in AD patients.
  • GSH (glutathione) level and TAC (total antioxidant capacity) were lower in AD patients, suggesting an impaired self-defense ability against oxidative stress.
  • Depending on the treatment received, a distinct inflammatory and oxidative stress profile was observed.

 

Journal of Alzheimer's Disease & Other DementiasReaders of earlier posts on histamine intolerance will be particularly interested in a paper published this summer in the American Journal of Alzheimer’s Diseaes & Other Dementias in which the authors describe the role of histamine regulation in AD:

“Histamine is a biogenic monoamine that plays a role in several physiological functions, including induction of inflammatory reactions, wound healing, and regeneration. The Histamine mediates its functions via its 4 G-protein-coupled Histamine H1 receptor (H1R) to histamine H1 receptor (H4R). The histaminergic system has a role in the treatment of brain disorders by the development of histamine receptor agonists, antagonists. The H1R and H4R are responsible for allergic inflammation. But recent studies show that histamine antagonists against H3R and regulation of H2R can be more efficient in AD therapy. In this review, we focus on the role of histamine and its receptors in the treatment of AD, and we hope that histamine could be an effective therapeutic factor in the treatment of AD.”

 

Ageing Research ReviewsPrevention and treatment of cognitive decline is a huge topic that invites forthcoming posts. A nod in that direction considers the use of polyphenols such as resveratrol and curcumin that are shown to help quench neuroinflammation, as recognized in a paper just published in Ageing Research Reviews:

“Alzheimer’s disease (AD) is characterised by extracellular amyloid deposits, neurofibrillary tangles, synaptic loss, inflammation and extensive oxidative stress. Polyphenols, which include resveratrol, epigallocatechin gallate and curcumin, have gained considerable interest for their ability to reduce these hallmarks of disease and their potential to slow down cognitive decline. Although their antioxidant and free radical scavenging properties are well established, more recently polyphenols have been shown to produce other important effects including anti-amyloidogenic activity, cell signalling modulation, effects on telomere length and modulation of the sirtuin proteins.”

Moreover…

Brain accessible polyphenols with multiple effects on pathways involved in neurodegeneration and ageing may therefore prove efficacious in the treatment of age-related diseases such as AD, although the evidence for this so far is limited. This review aims to explore the known effects of polyphenols from various natural and synthetic sources on brain ageing and neurodegeneration, and to examine their multiple mechanisms of action, with an emphasis on the role that the sirtuin pathway may play and the implications this may have for the treatment of AD.”

They draw these highlights from their findings:

  • Polyphenols have been shown to act on many of the pathways involved in the pathogenesis of Alzheimer’s disease.
  • Polyphenols activate members of the sirtuin family of proteins which play an important role in cell survival and longevity.
  • Polyphenols positively influence oxidative stress, amyloid aggregation, inflammation, mitochondrial function and telomere maintenance.
  • Utilising synergistic combinations of polyphenols may prove beneficial in developing treatment strategies for Alzheimer’s disease.

 

The FASEB Journal Vol 27 Num 9Concerns for cognitive decline certainly come to the fore on the occasion of hospitalization for major surgery or illness. The authors of a study published in The FASEB Journal describe how a compound derived from aspirin can play a therapeutic role:

Hospitalization for major surgery or critical illness often associates with cognitive decline. Inflammation and dysregulation of the innate immune system can exert broad effects in the periphery and central nervous system (CNS)… Endogenous regulation of acute inflammation is providing novel approaches to treat several disease states including sepsis, pain, obesity and diabetes.”

The draw attention to the activity of resolvins:

Resolvins are potent endogenous lipid mediators biosynthesized during the resolution phase of acute inflammation that display immunoresolvent actions. Here, using a mouse model of surgery-induced cognitive decline we report that orthopedic surgery affects hippocampal neuronal-glial function, including synaptic transmission and plasticity. Systemic prophylaxis with aspirin-triggered resolvin D1 (AT-RvD1: 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, as little as 100 ng dose per mouse) improved memory decline following surgery and abolished signs of synaptic dysfunction. Moreover, delayed administration 24 h after surgery also attenuated signs of neuronal dysfunction postoperatively. AT-RvD1 also limited peripheral damage by modulating the release of systemic interleukin (IL)-6 and improved other clinical markers of tissue injury.”

The authors conclude:

“Collectively, these results demonstrate a novel role of AT-RvD1 in modulating the proinflammatory milieu after aseptic injury and protecting the brain from neuroinflammation, synaptic dysfunction and cognitive decline. These findings provide novel and safer approaches to treat postoperative cognitive decline and potentially other forms of memory dysfunctions.”

 

Note: Prevention and treatment of cognitive decline in its various manifestations is a complex and demanding clinical challenge emerging as one of the key responsibilities of any clinician. It requires a working familiarity with every facet of clinical systems biology. Forthcoming posts will highlight the emerging science in this critical area.

Quercetin may protect against LPS-induced inflammation

Thrombosis ResearchQuercetin, a flavonoid compound known for its anti-inflammatory and anti-histamine properties, may help to prevent inflammation induced by reactions to lipopolysaccharides (LPS). LPS are potent stimulators of immune reactions, so much so that they are used as adjuvants in vaccines. Do you manage patients with autoimmune disorders and impaired gut barrier function who have a bacterial or fungal gut infection? Then you’re familiar with the clinical plight of needing to clear the infection but avoid amplifying the autoimmune inflammatory response by exposure to LPS and the cell walls of pathogenic organisms break down.

This is certainly a complex matter of timing in case management, yet a paper recently published in the journal Thrombosis Research offers evidence that quercetin may help protect patients from autoimmune flare-ups while treating associated gut infections. The authors examined the effects of quercitin on LPS-induced disseminated intravascular coagulation (DIC), a condition that includes the activation of coagulation pathways by pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), ‘players’ in autoimmunity. The authors state:

“Quercetin is widely distributed in plants and has been reported to have effects of anti-inflammation and anti-thrombosis. In this study, we evaluated the protective effect of quercetin on LPS-induced experimental DIC in rabbits, and tried to clarify its mechanism against DIC.”

They induced DIC in their study animals by LPS and observed quercetin-treated groups of several dosages, the LPS control group, a heparin control group and a saline control group for APTT, PT, and plasma levels of FIB, ALT, BUN, along with the activity of Protein C and ATIII. Quercetin had a marked protective effect:

“A continuous injection of LPS induced a gradual impairment of hemostatic parameters, a rise in plasma level of TNF-α, and damage in renal and hepatic function. The intravenous administration of quercetin significantly attenuated the increase of APTT, PT, ALT, BUN, and TNF-α, and the decrease of plasma FIB level and activity of Protein C and ATIII.”

Clinical note: Caution should still be observed when treating chronic infections complicating autoimmune disorders and careful thought given to timing and the recovery of tolerance, but quercetin can be considered as part of the treatment plan when risking exposure to LPS as a consequence of antimicrobial therapy.

The authors conclude:

Quercetin may have a protective effect against LPS-induced DIC in rabbits through anti-inflammation and anticoagulation.”

Metabolic health status and aging determined by inflammation, not weight

JCEM Vol 98 Number 9Metabolic health is not reliably determined by weight or BMI (body mass index). Lean individuals can suffer from cardiovascular and other diseases involving metabolism, and  evidence has been mounting that supports the notion of a subtype of obesity that is metabolically healthy. A study recently published in JCEM (The Journal of Clinical Endocrinology & Metabolism) shows that inflammation can determine metabolic health in both obese and non-obese populations. The authors state:

Inflammation is a potential mechanism linking obesity and cardiometabolic risk… The aim of the study was to investigate the extent to which differences between metabolically healthy and unhealthy obese and nonobese adults, defined using a range of metabolic health definitions, are correlated with a range of inflammatory markers.”

To do so they measured serum acute-phase reactants, adipocytokines, proinflammatory cytokines, and white blood cell counts in 2047 men and women who they classified as obese (BMI more than 30 kg/m2) and nonobese (BMI less than kg/m2). They established metabolic health status with five definitions that included markers such as blood pressure, triglycerides, LDL, HDL, total cholesterol, fasting glucose, and insulin resistance (HOMA). Several of the inflammatory markers were more strongly associated with metabolic health:

“According to most definitions, metabolically healthy obese and nonobese individuals presented with lower concentrations of complement component 3, C-reactive protein, TNF-α, IL-6, and plasminogen activator inhibitor-1; higher adiponectin levels; and reduced white blood cell count compared to their metabolically unhealthy counterparts. Logistic regression analysis identified greater likelihood of metabolically healthy obesity among individuals with lower levels of complement component 3 (odds ratios [ORs], 2–3.5), IL-6 (ORs, 1.7–2.9), plasminogen activator inhibitor-1 (ORs, 1.7–2.9), and white blood cells (ORs, 2.1–2.5) and higher adiponectin concentrations (ORs, 2.6–4.0).”

In other words, lower C3, CRP, TNF-α, IL-6, PAI-1, and white blood cells, along with higher adiponectin were associated with metabolic health in both groups. Lower C3, IL-6, PAI-1 and higher adiponectin were most strongly indicative of metabolic health among the obese. The authors’ conclusion highlights what clinicians should bear in mind:

Favorable inflammatory status is positively associated with metabolic health in obese and nonobese individuals. These findings are of public health and clinical significance in terms of screening and stratification based on metabolic health phenotype to identify those at greatest cardiometabolic risk for whom appropriate therapeutic or intervention strategies should be developed. “

 

CMAJ Vol 185 Num 13Furthermore, inflammation is turning out to be a key determinant of the quality of aging. The authors of a paper recently published in CMAJ (Canadian Medical Association Journal) state:

Chronic inflammation has been implicated in the pathogenesis of age-related conditions, such as type 2 diabetes, cardiovascular disease, cognitive impairment and brain atrophy… For example, obesity increases inflammation, and chronic inflammation, in turn, contributes to the development of type 2 diabetes by inducing insulin resistance, and to coronary artery disease by promoting atherogenesis. Thus, raised levels of inflammation appear to be implicated in various pathological processes leading to diseases in older age… We assessed inflammatory markers twice over a 5-year exposure period to examine the association between chronic inflammation and future aging phenotypes in a large population of men and women.”

They examined interleukin-6 (IL-6) levels for 3044 middle-aged adults at baseline and 5 years earlier and correlated it with cause-specific mortality, chronic disease and functioning from hospital and register data and clinical examinations. The authors focused on IL-6 because:

“Of the various markers of systemic inflammation, interleukin-6 is particularly relevant to aging outcomes. There is increasing evidence that interleukin-6 is the pro-inflammatory cytokine that “drives” downstream inflammatory markers, such as C-reactive protein and fibrinogen. Interleukin-6, in contrast to C-reactive protein and fibrinogen, is also likely to play a causal role in aging owing to its direct effects on the brain and skeletal muscles. In addition, results of Mendelian randomization studies of interleukin-6 and studies of antagonists are consistent with a causal role for interleukin-6 in relation to coronary artery disease, again in contrast to C-reactive protein and fibrinogen.”

They created four aging phenotypes at the 10-year follow-up defined as:

  • Successful aging (free of major chronic disease and with optimal physical, mental and cognitive functioning)
  • Incident fatal or nonfatal cardiovascular disease
  • Death from noncardiovascular causes
  • Normal aging (all other participants)

Chronic inflammation as determined by higher IL-6 levels was clearly associated with the poorer aging phenotypes:

“Of the 3044 participants, 721 (23.7%) met the criteria for successful aging at the 10-year follow-up, 321 (10.6%) had cardiovascular disease events, 147 (4.8%) died from noncardiovascular causes, and the remaining 1855 (60.9%) were included in the normal aging phenotype. After adjustment for potential confounders, having a high interleukin-6 level (> 2.0 ng/L) twice over the 5-year exposure period nearly halved the odds of successful aging at the 10-year follow-up (odds ratio [OR] 0.53) and increased the risk of future cardiovascular events (OR 1.64) and noncardiovascular death (OR 2.43).”

IL-6 is not the only useful metric for chronic inflammation in aging, but the authors interpret their data as offering good evidence for its use:

Chronic inflammation, as ascertained by repeat measurements, was associated with a range of unhealthy aging phenotypes and a decreased likelihood of successful aging. Our results suggest that assessing long-term chronic inflammation by repeat measurement of interleukin-6 has the potential to guide clinical practice.

And, not surprisingly, two measurements of IL-6 were better than one:

“Our results on the associations between inflammation, cardiovascular events and death from noncardiovascular causes are concordant with those reported in the literature. However, our results also show that measuring chronic inflammation twice may be a better predictor of future cardiovascular disease and noncardiovascular death than measuring inflammation only once.”

In conclusion:

“We found that chronic inflammation characterized by a high interleukin-6 level (> 2.0 ng/L) measured twice over the 5-year exposure period nearly halved the odds of successful aging after 10 years of follow-up compared with maintaining a low level of interleukin-6 (< 1.0 ng/L twice over the exposure period). Our study showed that high interleukin-6 levels at baseline were inversely associated with most of the individual components that characterize successful aging…”

 

Experimental GerontologyIn this context it’s important to consider the role of autoimmunity in inflammation that produces poor aging outcomes. A paper just published in Experimental Gerontology shows how an increase in the Th17/Treg ratio, a pro-inflammatory shift that is a hallmark of autoimmune phenomena, is also associated with increased inflammation of aging called ‘inflammaging‘.

Aging is associated with multiple changes in the proliferative and functional abilities of the immune system which are not related to any pathology but consequences in immunosenescence and inflammagingT helper (TH) 17 cells have been implicated in the development of autoimmune and chronic inflammatory diseases in humans. Additionally, a reciprocal relationship between these pro-inflammatory TH17 and the anti-inflammatory regulatory T cells (Tregs) has been described.”

The authors investigated the proportion of pro-inflammatory TH17 cells (CD4 + IL23R +) and anti-inflammatory Tregs (regulatory T cells that modulate the immune response and depend on vitamin D) along with their respective cytokines IL-17 and IL-10 in human healthy donors:

“The data revealed a continual increase of basal CD4 + IL23R + cell amounts in the different age groups. By analyzing the balance of both T-cell subsets it was observed that, on a basal resting level, TH17 cells were significantly increased in older individuals whereas Tregs were reduced.”

Clinical note: This is of great practical significance since almost all the manifold disorders associated with aging, from diminished cognitive function to osteoporosis, have an inflammatory component. The authors conclude:

“…changes of the TH17/Treg ratios in combination with altered cytokine expression during aging may contribute to an imbalance between the pro-inflammatory and the anti-inflammatory immune response. This indicates a higher susceptibility to develop inflammatory diseases with increasing age.”

Biopsy of breast tumors may spread cancer cells through the acute inflammatory response

Breast Cancer Research and TreatmentBiopsy is the next logical step for tumors screened by mammography, but a study just published in the journal Breast Cancer Research and Treatment demonstrates that it is possible for tumor cells to be spread by the acute inflammatory response to the biopsy procedure. Happily, the authors also show that anti-inflammatory treatment prior to the biopsy can protect against metastasis. The authors state:

“Development of metastasis in peripheral tissues is a major problem in the fight to cure breast cancer. Although it is becoming evident that chronic inflammation can contribute to tumor progression and metastasis, the effect of acute inflammation in primary tumor is less known. Using mouse models for breast cancer here we show that biopsy of mammary tumors increases the frequency of lung metastases.”

The specific mechanism they examined involves the systemic increase in the pro-inflammatory cytokines including interleukin-6 (IL-6):

“This effect is associated with the recruitment of inflammatory cells to the lung and elevated levels of certain cytokines such as IL-6 in the lung airways.”

Fortunately, there is a silver lining:

Antiinflammatory treatment prior to and after the biopsy reduces the development of metastases triggered by the biopsy. In addition, while lack of IL-6 does not affect primary tumor development, it protects from increasing number of metastases upon biopsy.”

Of course there are a number of limitations to this study. But the role of inflammation in the development and spread of cancer is so important, and anti-inflammatory prophylaxis before and after biopsy so benign, this may offer a massive opportunity to be “safe rather than sorry”. The authors conclude:

“Thus, our studies show that in addition to chronic inflammation, acute immune response caused by invasive procedures in the primary tumor may cause an increased risk on peripheral metastases, but the risk could be decreased by anti-inflammatory treatments.”