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.”
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 dietaryinterventions 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.”
Prediabetes, blood glucose is slightly higher than normal but not enough to qualify for diabetes, is associated with an increased systemic burden of inflammation and elevated risk for cardiovascular, cancer, dementia and other diseases. The first study described in this post, published in the European Journal of Nutrition, highlights the link between prediabetes, chronic inflammation and mortality from a range of diseases tied to HgbA1c (hemoglobin A1c, glycosylated hemoglobin), the key biomarker for glucose regulation. The authors state:
“Chronic inflammation is associated with increased risk of cancer, cardiovascular disease (CVD), and diabetes. The role of pro-inflammatory diet in the risk of cancer mortality and CVD mortality in prediabetics is unclear. We examined the relationship between diet-associated inflammation, as measured by dietary inflammatory index (DII) score, and mortality, with special focus on prediabetics.”
Pro-inflammatory diet plus prediabetes (increased HgbA1c)
Of great significance is the effect they reveal when a pro-inflammatory diet, measured by the dietary inflammatory index (DII) score, is consumed when there is elevated HgbA1c. They categorized 13,280 subjects between the ages 20 of and 90 years according to whether or not they were prediabetic, which they defined as a HgbA1c percentage of 5.7–6.4. Their data highlighted this connection between all-cause mortality, a pro-inflammatory diet and prediabetes:
“The prevalence of prediabetes was 20.19 %. After controlling for age, sex, race, HgbA1c, current smoking, physical activity, BMI, and systolic blood pressure, DII scores in tertile III (vs tertile I) was significantly associated with mortality from all causes (HR 1.39, 95 % CI 1.13, 1.72), CVD (HR 1.44, 95 % CI 1.02, 2.04), all cancers (HR 2.02, 95 % CI 1.27, 3.21), and digestive-tract cancer (HR 2.89, 95 % CI 1.08, 7.71). Findings for lung cancer (HR 2.01, 95 % CI 0.93, 4.34) suggested a likely effect.”
The authors conclude:
“A pro-inflammatory diet, as indicated by higher DII scores, is associated with an increased risk of all-cause, CVD, all-cancer, and digestive-tract cancer mortality among prediabetic subjects.”
Prediabetes and cardiovascular risk
Research published in The BMJ (British Medical Journal) focusses on the substantial impact of prediabetes on the risk of heart attack and ischemic stroke. The authors set out to…
“…evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality…”
…by analyzing 53 prospective cohort studies with 1,611,339 individuals that passed the screening tests for validity. In this study they applied several definitions of prediabetes:
“Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L = 101-124 mg/dL), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L = 110-124 mg/dL), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L = 141-198 mg/dL during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol [5.7-6.4%] according to ADA criteria or 42-47 mmol/mol [6.0-6.4%] according to the National Institute for Health and Care Excellence (NICE) guideline.”
Their data show that prediabetes with a ‘mildly’ elevated HgbA1c was clearly associated with increased cardiovascular risk:
“Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol [5.7-6.4%] or 42-47 mmol/mol [6.0-6.4%] were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.”
Interestingly, risk of stroke does not emerge from these data, suggesting other factors promoting vascular inflammation. The authors conclude:
“…we found that prediabetes defined as impaired fasting glucose or impaired glucose tolerance is associated with an increased risk of composite cardiovascular events, coronary heart disease, stroke, and all cause mortality. There was an increased risk in people with fasting plasma glucose as low as 5.6 mmol/L [100 mg/dL]. Additionally, the risk of composite cardiovascular events and coronary heart disease increased in people with raised HbA1c. These results support the lower cut-off point for impaired fasting glucose according to ADA criteria as well as the incorporation of HbA1c in defining prediabetes.”
HgbA1c and risk of all-cause and cause-specific mortality without diabetes
Similar results were obtained in a study published in Scientific Reports. Here the authors concluded:
“We found evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer in this meta-analysis. The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. This fact reveals a clear threshold effect for the association of HbA1clevels with mortality. In addition, from the perspective of mortality benefit and health care burden, it suggests that the most appropriate HbA1c level of initiating intervention is approximately 5.7%…higher HbA1c level is associated with increased mortality from all causes, CVD, and cancer among subjects without known diabetes. However, this association is influenced by those with undiagnosed diabetes or prediabetes .Because of limited studies, the results in relation to cancer mortality should be treated with caution, and more studies are therefore warranted to investigate whether higher HbA1c level is associated with increased cancer mortality.”
‘Leaky gut‘ is abnormalintestinal permeability that occurs when the epithelial tissues that comprise the gut barrier have been damaged. When intact the gut barrier prohibits antigenic contents of the intestines from access to the gut-associated lymphoid tissue (GALT) right on the other side of the intestinal wall. Gut barrier integrity (absence of leaky gut) is crucial to prevent loss of immune tolerance (autoimmunity) since the GALT comprises 60-80% of all immune tissue in the body.
Normalization of leaky gut improves chronic fatigue
LPS (lipopolysaccharide from bacterial cell walls) is so highly antigenic that it’s used as an adjuvant in vaccines. Translocation of LPS across a damaged gut barrier elicits systemic inflammation, accompanied by oxidative and nitrosative stress. A study published in Neuroendocrinology Letters demonstrates how normalization of the antibody responses to LPS not only ameliorates but can predict the clinical outcome in chronic fatigue syndrome (CFS). The authors state:
“There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome (CFS).”
They investigated this by measuring serum concentrations of IgA and IgM to LPS of several gram-negative enterobacteria CFS patients, both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, while consuming a leaky gut diet during 10-14 months. They also measured corresponding result with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and after 10-14 months on the NAIOSs.
Good clinical response to lowered IgA and IgM
The improvement in CFS scores that they documented was very gratifying:
“Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).”
The authors’ comments on their data can hardly be overemphasized for clinicians participating in case management of chronic fatigue and fibromyalgia:
“The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.”
High IgA response to normal gut bacteria fires up inflammation in CFS
An interesting study published in the Journal of Affective Disorders documents how LPS from commensal gut bacteria that translocates into the GALT provokes inflammation that drives CFS. The authors note:
“Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by a) systemic IgA/IgM responses against the lipopolysaccharides (LPS) of commensal bacteria; b) inflammation, e.g. increased plasma interleukin-(IL)1 and tumor necrosis factor (TNF)α; and c) activation of cell-mediated immunity (CMI), as demonstrated by increased neopterin.”
These authors investigated the IgA/IgM responses to the LPS of 6 different enterobacteria by measuring serum IL-1, TNFα, neopterin, and elastase in 128 patients with ME/CFS and chronic fatigue (CF). When they correlated with biomarkers for inflammation, CMI and the symptoms of ME/CFS the results were noteworthy:
“Serum IL-1, TNFα, neopterin and elastase are significantly higher in patients with ME/CFS than in CF patients. There are significant and positive associations between the IgA responses to LPS and serum IL-1, TNFα, neopterin and elastase. Patients with an abnormally high IgA response show increased serum IL-1, TNFα and neopterin levels, and higher ratings on irritable bowel syndrome (IBS) than subjects with a normal IgA response. Serum IL-1, TNFα and neopterin are significantly related to fatigue, a flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability.”
This is extremely important in clinical practice due to the great functional significance of both systemic inflammation and autonomic nervous system regulation. The authors conclude:
“The findings show that increased IgA responses to commensal bacteria in ME/CFS are associated with inflammation and CMI activation, which are associated with symptom severity. It is concluded that increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients.”
Autoimmune attack on serotonin production
Another fascinating paper also published in the Journal of Affective Disorders reveals that bacterial translocation through the gut barrier into immune lymphoid tissue can provoke antibodies that attack 5-HT, the precursor of serotonin, contributing to chronic fatigue and depression. The authors state:
“Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation.”
The examined 117 patients with ME/CFS for autoimmune activity against 5-HT, measuring plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria. This was correlated with the fibromyalgia and chronic fatigue syndrome rating scale. Their data show a strong association:
“The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.”
This is very significant for clinicians involved in case management of fatigue, depression, chronic pain and autonomic dysregulation. The authors sum it up:
“The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions…These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.”
Leaky gut, LPS and depression
Yet another study in the same journal investigated increased IgA and IgM antibodies aimed at gut commensal bacteria specifically in depression. The authors measured antibodies directed against Hafnia alvei, Pseudomonas aeruginosa, Morganella morganii, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae in depressed patients and normal controls, and found a very significant correlation to symptoms of depression and fatigue:
“The prevalences and median values of serum IgM and IgA against LPS of these commensals were significantly higher in depressed patients than in controls. The IgM levels directed against the LPS of these commensal bacteria were significantly higher in patients with chronic depression than in those without. The immune responses directed against LPS were not associated with melancholia or recurrent depression. There was a significant correlation between the IgA response directed against LPS and gastro-intestinal symptoms.”
The treatment of chronic fatigue and depression demands a holistic, multidisciplinary approach. A core feature with a number of potential contributing causes that can vary in each case is up-regulation of immune pathways driving inflammation in the brain and against elements in neurotransmitter production. The authors highlight these considerations in their discussion:
“The results indicate that increased bacterial translocation with immune responses to the LPS of commensal bacteria may play a role in the pathophysiology of depression, particularly chronic depression…The findings suggest that “translocated” gut commensal bacteria activate immune cells to elicit IgA and IgM responses and that this phenomenon may play a role in the pathophysiology of (chronic) depression by causing progressive amplifications of immune pathways.”
Compounds that modulate neuroinflammation induced by LPS
A wide range of therapeutic resources are available to the functional practitioner to employ, depending on the individual case, that can ameliorate autoimmune inflammation triggered by reactions to the LPS of bacteria translocated through a leaky gut. By way of one example among many, a paper published in Neurochemistry International shows that anthocyanins (polyphenolic compounds imparting a blue color, found in vegetation such as blueberries) can ameliorate inflammation triggered by reactions to LPS.
“Several studies provide evidence that reactive oxygen species (ROS) are key mediators of various neurological disorders. Anthocyanins are polyphenolic compounds and are well known for their anti-oxidant and neuroprotective effects. In this study, we investigated the neuroprotective effects of anthocyanins (extracted from black soybean) against lipopolysaccharide (LPS)-induced ROS-mediated neuroinflammation and neurodegeneration in the adult mouse cortex.”
This benign intervention produced a gratifying result:
“The immunoblotting and morphological results showed that anthocyanins treatment significantly reduced LPS-induced-ROS-mediated neuroinflammation through inhibition of various inflammatory mediators, such as IL-1β, TNF-α and the transcription factor NF-kB…Anthocyanins also prevent overexpression of various apoptotic markers, i.e., Bax, cytosolic cytochrome C, cleaved caspase-3 and PARP-1. Immunohistochemical fluoro-jade B (FJB) and Nissl staining indicated that anthocyanins prevent LPS-induced neurodegeneration in the mouse cortex.”
Of particular note to the clinician:
“Our results suggest that dietary flavonoids, such as anthocyanins, have antioxidant and neuroprotective activities that could be beneficial to various neurological disorders.”
Mood disorders and thyroid autoimmunity are linked by aberrant levels of hematopoietic/neuronal growth factors in an excellent study just published in PLOS One (Public Library of Science). Their fascinating data show how, even before hypothyroidism has developed, and also in relatives of thyroid autoimmunity subjects, growth factors necessary for healthy brain function are at levels associated with a range of mood disorders including bipolar, depression and psychosis. They also include an important reminder that antibodies can predict clinical disease years in advance.
Hypothyroidism predicted years in advance
The authors state:
“Autoimmune hypothyroidism is characterized by a combination of clinical features, elevated serum TSH with reduced free T4 (FT4) levels, the presence of serum antibodies against thyroid antigens, and reduced echogenicity of the thyroid sonogram. It is the most common organ-specific autoimmune disorder with an estimated prevalence of 2%, with a higher prevalence in women and depending on iodine intake. Thyroid peroxidase (TPO) is the major autoantigen and TPO antibodies (TPO-Abs) are present in almost all patients with autoimmune hypothyroidism and precede the clinical phase of autoimmune hypothyroidism by many years. Subclinical autoimmune hypothyroidism (the presence of TPO-Abs with raised TSH and normal FT4 levels) is even more prevalent and affects about 9% of the population. In the Whickham follow-up study, women with TPO-Abs had an eight-fold higher risk of developing clinically overt hypothyroidism over 20 years than did antibody-negative women.”
And family members have a pronounced risk of thyroid autoimmunity showing up down the road:
“In our own studies on the Amsterdam AITD [autoimmune thyroid disease] cohort (euthyroid females with at least one first or second degree relative with a documented autoimmune hyper- or hypothyroidism) TPO-Ab positivity at the start of the study also represented a higher risk to develop overt hypothyroidism in a follow-up of 5 years. In addition, there was a higher conversion rate from TPO-Abs negativity to positivity, showing a familial proneness for thyroid autoimmune reactivity.”
And in another earlier study normal thyroid relatives showed a slew of abnormalities including a ‘background’ higher inflammatory state:
“We concluded that euthyroid females within AITD families show a characteristic pattern of abnormalities in serum levels of growth factors, chemokines, adhesion molecules and cytokines, suggesting an already compromised thyroid-immune system interaction in the euthyroid family members. Also, pre-seroconversion stages might be predicted using serum analytes pointing to a higher inflammatory state.”
Mood disorders and AITD
The emerging evidence shows that depression in association with autoimmune thyroid disease is caused by more than lower thyroid hormone in the brain. Just the presence of anti-thyroid antibodies while thyroid hormone levels are still normal is associated with increased risk of anxiety and mood disorders.
“Autoimmune hypothyroidism is commonly accompanied by depressive symptoms. A large epidemiological Danish nationwide, prospective cohort study showed that various autoimmune diseases including AITD, are associated with subsequent lifetime mood disorder diagnosis (e.g. bipolar affective disorder, unipolar depression, psychotic depression and other remaining mood disorders). In hypothyroid patients the lack of thyroid hormone in the brain is likely an important determinant for these mood disturbances. However, a deficit of thyroid hormone may not be the only cause, as even subjects with TPO-Abs with normal thyroid function have a higher risk to develop anxiety disorders and mood disorders.”
And further evidence supports the assertion of a shared pathogenesis for autoimmune thyroid disease and mood disorders:
“Also offspring of patientswith a bipolar affective disorder have a higher prevalence of TPO-Abs, even if they are not affected by the psychiatric disorder. In addition, a higher prevalence of TPO Abs and autoimmune hypothyroidism has been reported in patients with bipolar affective disorder, irrespective of the usage of lithium. Taken together, these associations might imply a shared immune pathogenesis for both AITD and mood disorders.”
Brain growth factors and AITD
To explore this relationship the authors examined data for 64 TPO-Ab-negative females with relatives with AITD. 32 of these subjects did and 32 did not seroconvert to TPO-Ab positivity in their 5-year follow-up. These were compared with 32 healthy controls (HCs). Importantly, they measured serum levels of brain-derived neurotrophic factor (BDNF), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF) and IL-7.
“We therefore additionally determined, in the sera used in the previous study, 5 growth and differentiation factors that have repeatedly* been shown to be abnormally expressed in the circulation of mood disorder patients and that are capable of influencing both immune and/or neuronal cell growth, i.e. SCF, IGFBP-2, EGF, BDNF and IL-7. In addition we studied the inter relationship of these factors with the previously determined factors using a cluster analysis to study patterns of TPO-Ab seroconversion.”
* Authors’ emphasis.
Even relatives of AITD patients are at higher risk of mood disorders
Their data showed an eye-opening correlation:
“BDNF was significantly lower (8.2 vs 18.9 ng/ml, P<0.001), while EGF (506.9 vs 307.6 pg/ml, P = 0.003) and IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028) were significantly higher in relatives than in HCs. Relatives who seroconverted in the next 5 years had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017). In a cluster analysis with the previously published growth factors/cytokines SCF clustered together with IL-1β, IL-6 and CCL-3, of which high levels also preceded seroconversion.”
Serum levels of growth and differentiation factors in healthy controls (C), Seroconverting (SC) and Non-Seroconverting (NSC) family members.
In other words, abnormal levels of growth factors necessary for brain health and higher levels of biomarkers for inflammation were both observed. Bear in mind that BDNF(brain derived neurotrophic factor) in particular has been identified as important for neurogenesis, plasticity and synaptic transmission. BDNF deficiency is associated with disorders of mood, cognition and memory. And an increase in BDNF is though to be a mechanism by which exercise (and certain medications) exert a beneficial effect on brain-based conditions.
“It is of note that the 5 studied factors have been highlighted as serum biomarkers for major mood disorders in several studies and are involved in neurogenesis, neuroprotection and hematopoietic differentiation. This is in particular known for BDNF. Neurotrophic factors, like BDNF, play an important role in neuronal plasticity, modulating not only axonal and dendritic growth and remodeling, but also neurotransmitter release and synapse formation.”
This makes striking the finding that even euthyroid (normal thyroid) relatives of autoimmune thyroid subjects are at higher risk of mood disorders with markedly lower levels of BDNF.
“The present study shows that euthyroid females, who are relatives of AITD patients and at risk of developing AITD, have an aberrant serum level of 4 of the 5 tested hematopoietic/neuronal growth and differentiation factors, i.e. of BDNF, IGFBP-2, EGF and SCF. BDNF levels were significantly lower and IGFBP-2 and EGF higher expressed in sera of the relatives of the AITD patients (in both SCs and NSCs) than in healthy controls. IL-7 levels were normal. We also found in the healthy relatives, who converted in the following 5 years to TPO-Ab positivity, significantly higher serum levels of SCF than in relatives who did not.”
This certainly underscores the clinical significance of predictive (low levels of) anti-thyroid antibodies. It also invites the possibility of even earlier diagnoses and interventions as stated by the authors:
“This study and the previous one therefore underscore the widespread changes in immune-neuro-endocrine molecular networks that apparently precede the appearance of TPO-Abs, which opens avenues for developing assays for the detection of individuals at risk for thyroid autoimmunity.”
“We assume that the generally low expression in NSCs in cluster A reflects an immune suppressive state preventing autoimmunity, while a rise of these pro-inflammatory compounds precedes a conversion to TPO-Ab positivity and thus may reflect a very early stage of thyroid auto reactivity.”
This presents the tantalizing possibility of very early diagnosis and the opportunity to intervene in thyroid and mood disorders at the earliest possible stage when easiest to treat. Meanwhile, clinicians should be attentive to even low levels of anti-thyroid antibodies.
The authors summarize:
“We conclude that subjects at risk for AITD show changes in growth and differentiation factors in serum, which are both active as neuronal and hematopoietic growth and differentiation factors and are abnormally expressed in patients with mood disorders. This suggests that shared growth and differentiation defects in both the hematopoietic and neuronal system may underlie both thyroid autoimmunity and mood disorders.”
Colleagues interested in our practice model incorporating predictive antibodies and bioidentical (human recombinant) low dose BDNF are welcome to contact.
Depression 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
Chronic 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:
Bottom line here is that circadian misalignment promotes a proinflammatory state.
Bright Light Therapy—Not Just For Seasonal Affective Disorder
Commenting 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.”
More 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 Newsquotes 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
Closing 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.”
This 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
Exercise 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.”
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.
Insulin resistance (IR) is central to type 2 diabetes and a contributing cause to cardiovascular and neurodegenerative disorders, chronic kidney disease (CKD), a number of cancers and more. A study recently published in BMC Endocrine Disorders the ratio between neutrophils and lymphocytes (neutrophil-lymphocyte ratio, NLR) is a valuable and inexpensive predictive marker for insulin resistance. The authors note:
“Insulin resistance (IR) is a reduction in reaction or sensitivity to insulin and is considered to be the common cause of impaired glucose tolerance, diabetes, obesity, dyslipidemia, and hypertensive diseases….several studies have confirmed the relationship between systemic inflammation and insulin resistance, in which an altered immune system plays a decisive role in the pathogenesis of DM. The immune response to various physiological challenges is characterized by increased neutrophil and decreased lymphocyte counts, and NLR is often recognized as an inflammatory marker to assess the severity of the disease.”
“Scholars have rarely investigated the relationship between IR and NLR. This study aims to evaluate the relationship between IR and NLR, and determine whether or not NLR is a reliable marker for IR.”
Mean neutrophil-lymphocyte ratio (NLR) values of the groups. Group 1 is diabetic w/o IR, Group 2 is diabetic with IR.
So they investigated the neutrophil-lymphocyte ratio in 413 patients with T2DM, 310 of whom had a HOMA-IR value (fasting plasma glucose (mmol/L) multiplied by fasting serum insulin (mIU/L) divided by 22.5) of > 2.0, indicating insulin resistance. They were compared to a control group of 130 healthy subjects and found a strong association:
“The NLR values of the diabetic patients were significantly higher than those of the healthy control, and the NLR values of the patients with a HOMA-IR value of > 2.0 are notably greater than those of the patients with a HOMA-IR value of ≤ 2.0. Pearson correlation analysis showed a significant positive correlation of NLR with HOMA-IR. Logistic regression analysis showed that the risk predictors of IR include NLR, TG and HbA1c. NLR levels correlated positively with IR. The IR odds ratio increased by a factor of 7.231 (95%) for every one unit increase in NLR.”
Diabetes, cancer and cardiovascular diseases
In relation to their confirmation of NLR as a predictor for insulin resistance the authors observe…
“Many epidemiological studies have determined that DM is associated with chronic inflammation, which may contribute to the acceleration of diabetic microangiopathy and the development of macroangiopathy; IR is a characterized of T2DM, whereas the exact molecular action leading to IR is not yet understood, several studies have associated IR with inflammation, experimental studies have demonstrated a link between chronic inflammation and insulin resistance through mechanisms involving obesity and atherosclerosis. NLR has been recently defined as a novel potential inflammation marker in cancer and cardiovascular diseases. NLR can easily be calculated using the neutrophil-lymphocyte ratio in peripheral blood count. Calculating NLR is simpler and cheaper than measuring other inflammatory cytokines, such as IL-6, IL-1β, and TNF-α.”
Diabetes and chronic inflammation
These findings highlight the relationship between chronic inflammation, insulin resistance and type 2 diabetes.
“he pathological activation of innate immunity leads to inflammation of the islet cells, resulting in a decrease in pancreatic beta-cell mass and impaired insulin secretion. Patients with T2DM are in a state of low-degree chronic inflammation that induces hypersecretion of inflammatory factors, such as CRP, IL-6, TNF-α, and MCP-1, which results in a constantly elevated neutrophilic granulocyte count. One mechanism by which increased levels of neutrophils could mediate IR may be through augmented inflammation. The increase in NLR appears to underlie the elevated levels of pro-inflammation, as evident from the persistent neutrophil activation and enhanced release of neutrophil proteases with T2DM.”
NLR tracks HgbA1c and triglycerides
Glycation of hemoglobin (HgbA1c) and triglycerides (TG) both go up as insulin resistance progresses along with the neutrophil-lymphocyte ratio.
“A logistic regression analysis of the following risk factors was conducted: NLR, TG and HbA1c. In our study, in conjunction with the rising of the level of HbAlc, the degree of IR increased significantly. HbA1c showed an association with early-phase insulin secretion assessed by insulinogenic index. Heianza et al. reported that elevated HbA1c levels of above 41 mmol/mol (>5.9%) were associated with a substantial reduction in insulin secretion and insulin sensitivity as well as an association with β-cell dysfunction in Japanese individuals without a history of treatment of diabetes. Increased accumulation of TG has been observed in human muscle tissue of obese and type 2 diabetic subjects, and associated with IR, which is in agreement with the present study. IR reduces the inhibition effect of lipolysis in adipose tissue, resulting in the increase of the free fatty acid (FFA) level in plasma.”
NLR is a superior biomarker
Although susceptible to modification by dehydration, elevated PSA or catecholamine release induced by exercise, the NLR is more sensitive than the neutrophil count alone or CRP levels.
“NLR represents a combination of two markers where neutrophils represent the active nonspecific inflammatory mediator initiating the first line of defense, whereas lymphocytes represent the regulatory or protective component of inflammation. NLR is superior to other leukocyte parameters (e.g., neutrophil, lymphocyte, and total leukocyte counts) because of its better stability compared with the other parameters that can be altered by various physiological, pathological, and physical factors. Thus, as a simple clinical indicator of IR, NLR is more sensitive compared with the neutrophilic granulocyte count and CRP levels, which are widely used as markers of IR.”
Clinical bottom line
Practitioners should not fail to make use of this significant, inexpensive biomarker that is under our noses every day. The authors sum it up:
“…in the present study, NLR serves an important function in predicting the risk of IR. IR in diabetic patients is related to chronic inflammation, and NLR may be helpful in assessing the prognoses of these patients…We recommend that the NLR values of diabetic patients be calculated as NLR is a cheap, predictive, and prognostic marker for IR. High NLR values were independently related to IR.”
In a richly valuable paper published recently in Frontiers in Cellular Neuroscience the authors describe the ways in which systemic inflammation causes neurodegeneration in the brain associated with cognitive decline and a host of neuropsychiatric disorders. In the short term this manifests the anorexia, malaise, depression, and decreased physical activity known as sickness behavior (SB) that occurs with inflammation due to infection. Permanent cognitive and behavioral changes due to neurodegeneration occur when inflammation is chronic. Discerning and targeting the causes of inflammation offers opportunities for treatment.
The nervous system senses inflammation directly and can exert control through the vagus nerve:
“The efferent axis of neuroimmune control is better understood after the cholinergic anti-inflammatory pathway (CAP), a cholinergic reflex system that regulates inflammation via the vagus nerve that stimulates the splenic nerve to release noradrenaline. Noradrenaline in turn stimulates a subset of acetylcholine (ACh)-producing splenic T-cells (CD4+CD44hiCD62Llo) to release ACh, which binds to α7 nicotinic receptors on the surface of macrophages, resulting in down-regulation of TNF by blocking the nuclear translocation ofnuclear factor kappa B (NF-κB). Thus far, this is a unique scenario in which an immune cell acts as interneuron in a reflex system. Electrical as well as chemical stimulation of the CAP have been shown to decrease the inflammatory burden and increase survival of experimental sepsis.”
The a cholinergic response expressed through the vagus nerve can wind down inflammation and protect against neurodegeneration.
Transient inflammation, such as associated with a cold or flu, produces behavioral symptoms of the same character as those which persist with the chronic systemic inflammation that can drive neurodegeneration.
“The acute effects of systemic inflammation upon cognition and behavior are not limited to the elderly or the critically ill. As we have witnessed in ourselves and those near us, even a minor and self-limited common cold induces a transient syndrome known assickness behavior (SB)marked by fatigue, depression, lack of drive, malaise, sleep disturbances, decreased physical activity, and social interactions, as well as cognitive impairment. Healthy volunteers develop anxiety, depression, and memory impairment in response to a low dose of lipopolysaccharide (LPS), and the development of such clinical scenario correlates with TNF secretion.”
And patients with chronic infections such as tuberculosis, human immunodeficiency virus (HIV), hepatitis B virus (HVB), and hepatitis C virus (HCV) can have cognitive and behavioral problems due to the persistent inflammatory response.
“This supports the role of large loads of inflammatory cytokines in inducing and sustaining brain dysfunction. Experimentally, NADPH oxidative activity andnitric oxide synthase (iNOS) are induced in the brain shortly after systemic inflammation, potentially leading to NMDA-dependent neurotoxicity”
Sepsis and severe trauma
An overwhelming load of pathogens or severe trauma can unleash an immune inflammatory response that results in neurodegeneration.
“Under normal conditions, inflammation is a well-orchestrated response with constant fine-tuning. Once microorganisms have breached the skin and mucosal barriers, innate immunity is critical in preventing further invasion by launching inflammation. After the infection source has been cleared, the inflammatory response also plays an important role in tissue repair and functional healing. When the source of damage has been controlled, the same mechanisms that initiated and regulated inflammation will dampen the response. Large loads of pathogens, or infection by highly virulent pathogens, can trigger an en-masse systemic response that leads to sepsis and multiple organ failure…The nervous system is particularly vulnerable to damage in response to systemic inflammation.”
Brain milieu changes in response to systemic inflammation
“Inflammation-induced infiltration of immune cells and mediators into the brain leads to profound structural and functional changes. As a consequence, up to 81% of septic patients develop sepsis-associated delirium (SAD), with elderly patients being at particularly high risk. In the elderly, severe sepsis is sufficient to trigger new cognitive decline of sufficient importance as to profoundly interfere with quality of life…Neonatal sepsis is also marked by abnormalities of the white matter (66% of infants in one cohort), and white matter lesions correlate to poorer mental and psychomotor development at 2 years.
“…clearing the trigger of sepsis does not prevent the appearance of persistent brain damage…in a model of endotoxemia in aged rats, a single systemic injection of LPS induced brain inflammation that lasted for at least 30 days…This suggests that even transient bouts of systemic inflammation of only limited significance can cause sustained brain damage.”
Traumatic inflammation also promotes neurodegeneration:
“Severe trauma, as well as surgery can lead to large loads of endogenous pro-inflammatory molecules (damage-associated molecular patterns (DAMPs) being released. A few DAMPs have been shown to induce brain dysfunction in vivo. Of those, TNF and IL-1 can mediate long-standing cognitive and behavioral changes and, in experimental settings, interfering with the effect of TNF reduces the effect of trauma in the formation of contextual memory.”
In this context antioxidants can have neuroprotective effects.
“Experimentally, preemptive administration of the free radical scavenger endarvone before sepsis induction resulted in reduced neuronal damage and blood–brain barrier (BBB) permeability. Administration of the antioxidants N-acetylcysteine and deferoxamine shortly after murine sepsis induction has shown long-term neuroprotective effects.”
Systemic inflammation disrupts brain networks
The human brain connectome
The brain is characterized as a ‘small-world’ network with two levels of connection that are susceptible to disruption by inflammation.
“Biological systems, such as the neuronal network of the human brain have “small-world” properties. Small-world networks have two levels of organization. On the local level, groups of neurons specialized in a specific task form functional modules with high short intramodular connectivity. On the global level, different modules are connected through long intermodular connections. The advantage of the latter type of connections is enhanced computational efficiency through parallel processing of information. Anatomically, long intermodular connections are formed by axonal fiber tracts in the white matter. Long fibers are characterized by high energetic “wiring costs”. To provide the energy for the maintenance of these long fibers the brain is relying on a constant energy supply. Recent findings have elegantly identified oligodendrocyte-derived lactate as the main energetic substrates for axonal maintenance. Consistently, disruption of this oligodendrocyte-neuronal metabolic coupling triggered neurodegeneration. Systemic inflammation poses dramatic challenges to the energetic supply of the brain.”
The brain requires a constant stream of nutrients to maintain its ‘wiring’
Autoimmune driven neuroinflammation, among other insults, can disrupt the delivery of nutrients to neurons and contribute to mitochondrial dysfunction.
“To cover its wiring costs the brain is highly reliant on a constant nutrient supply. Nutrient supply through blood vessels can be compromised through vascular pathologies associated with systemic inflammation…Autoimmune disorders have a chronic course of vascular pathology with acute flares. The most common vascular pathology is the autoantibody-associated antiphospholipid syndrome. Patients with antiphospholipid syndrome display cognitive deficits. MRI studies found diffuse infarctions and white matter lesions in these patients…In line with the concept of high “wiring costs” imposed on the brain by long intermodular connections,Hans Lassmann argues that inflammation in MS causes mitochondrial damage and inability of the brain to maintain neuronal processes. The source of mitochondrial damage is radicals formed as a consequence of inflammation in MS.”
Energy crisis for the brain
Systemic inflammation damages connectivity and fuels mitochondrial dysfunction…
“Taken together these findings indicate that systemic inflammation leads to an energy crisis of the brain that reduces its connectivity. Oxidative stress might be the main mediator of this pathology. Thus, inflammation-induced changes in the brain resemble hallmarks of the aged brain where oxidative damage leads to decreased expression of genes associated with synaptic plasticity and increased expression of stress-response genes. Likewise, the brain during systemic inflammation shows hallmarks of neurodegenerative diseases where oxidative stress and mitochondrial damage have consistently been found.”
Normally astrocytes and neurons talk to each other to keep activation of brain immune cells in check. But this can get out of hand in response to a pathogen resulting in serious damage. Balance is maintained, partly by accepting a certain degree of tolerance for pathogens:
“Brain-resident microglia and peripheral immune cells maintain immune surveillance of brain parenchyma, CSF, and perivascular space for infectious agents or damage-associated milieu changes. In the case of brain infection, complete eradication of some invading pathogens can only be achieved at the cost of irreparable damage to brain tissue. To prevent such damage, the immune system has established active mechanisms of pathogen tolerance. Examples for coexistence-prone pathogens are herpes simplex virus type I or Cryptococcus gattii. A growing body of evidence indicates that not only immune tolerance but also resolution of neuroinflammation is a tightly regulated active immunological process. Taken together, anti-inflammatory brain milieu, pathogen tolerance, and resolution of neuroinflammation require a balanced action between different branches of the immune system.”
There are a number of mechanisms by which dysregulated systemic inflammation promotes neuroinflammation and neurodegeneration. These in include activation of apoptosis through the inflammasome (inflammation signalling chains):
“Apoptosis is one of the main drivers of neurodegeneration. Apoptosis and cell death constantly occur under physiological conditions throughout the human body and cell debris is cleared by immune cells mostly without induction of chronic inflammation. However, during systemic inflammation, apoptosis of stressed cells might further exacerbate the underlying pathology. Activators of apoptosis lead to direct or indirect activation of caspases…inflammatory caspases are crucial for the activation of the innate immune system through the inflammasome…Activation of the innate immune system through the inflammasome is a driver of pathology in age-associated and autoimmune neurodegenerative disorders…these finding show an intricate relationship between inflammation and activation of apoptosis”
Microvesicles (MVs) packed with inflammatory messengers are secreted by peripheral and brain immune cells contribute to neurodegeneration:
“Cellular components of innate immunity can pack and secrete inflammatory messengers in microvesicles (MVs). Peripheral macrophages, as well as brain microglia can secrete inflammasome components (caspase-1, IL-1β, and IL-18) in MVs, and the presence of extravesicular inflammatory inducers (e.g., astrocitic ATP) is sufficient to induce the neurotoxicity by the inflammatory load of MVs.”
This correlates with disease activity in multiple sclerosis and also a significant role in Alzheimer’s disease (AD):
“Recent evidence suggest that MVs play a critical role in the spectrum of AD as well. MVs released by activated microglia participate in the neurodegenerative process of AD by promoting the generation of highly neurotoxic soluble forms of β-amyloid. Based on this collective evidence, it is now clear that EVs produced by peripheral myeloid cells, as well as immune brain cells, are novel and potentially critical biomarkers for neuroinflammatory conditions by providing a link between inflammation and neurodegeneration.”
Inflammation to neurodegeneration
Immune cells and mediators drive neurodegeneration
Immune cells in both the periphery and the brain can cause neuronal apoptosis through multiple pathways that can be targeted for therapy:
“Various triggers of apoptosis have been described with respect to the brain. Neuronal apoptosis can be directly induced by ROS, pro-inflammatory cytokines or activated immune cells…Additionally, damaged mitochondria are a major source of ROS and mediators of apoptosis. Conversely, inactivation of ROS has anti-apoptotic effects. The inflammatory cytokine TNFα and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) directly induce neuronal apoptosis. Additionally, intracerebroventricularly injected TNFα was shown to induce depression-like symptoms. Cytokine mediated induction of apoptosis was also observed by IL-1β.”
Immune cells in the brain and the periphery cause neurodegeneration, with evidence that antiinflammatory interventions can oppose neuronal death.
“Sources of cytokines under systemic inflammation are brain resident, paravascular or peripheral immune cells. Furthermore, activated immune cells can directly induce neuronal cell death. Brain-resident microglia convey neuronal toxicity through various mechanisms including secretion of neurotoxic factors, as well as through activation of cyclooxygenase/prostaglandin E2 (COX/PGE2) pathways. In fact, blocking the COX/PGE2 pathway by experimentally deleting the prostaglandine receptor EP2 increases mitochondrial degradation of β-amyloid, potentially opening a new therapeutic avenue for AD.”
When there is systemic inflammation immune cells in the periphery in the body can gain access to the brain through the blood-brain barrier:
“Peripheral immune cells can penetrate the BBB under conditions of systemic inflammation and contribute to brain pathology. Cytotoxic T-cells were shown to be directly neurotoxic in autoimmune and aging-associated neurodegenerative disorders of the CNS. Co-localization of T-cells with neurons and neuron-specific cytotoxicity of T-cells was shown in vivo and in vitro.”
Identification of anti-brain antibodies is a key clinical finding that practitioners in a wide range of disciplines should be alert for.
“B-cell-derived anti-brain antibodies have been identified as drivers of brain pathology in various diseases. In the last decade, an increasing number of anti-brain antibodies has been detected that can affect cognition and behavior…Under pathological conditions, antibodies may penetrate the BBB through different mechanisms including local and systemic inflammation, or antigen mediated endocytosis.”
Anti-NMDA antibodies have been receiving much scrutiny for neuropsychiatric and neurodegenerative disorders.
“Furthermore, NMDA-receptor-specific antibodies to the subunit 2 (GluN2) have been found in a subset of SLE patients with neuropsychiatric symptoms. These antibodies are cross-reactive to DNA…DNA–NMDA receptor antibodies preferentially bind the open configuration of the NMDA receptor and augment NMDA receptor-mediated excitatory postsynaptic potentials…Depending on the antibody concentrations, DNA–NMDA receptor antibodies can cause either neuronal dysfunction by transiently enhancing excitatory postsynaptic potentials or can result in neuronal cell death. This evidence could be of high relevance in terms of reversibility of symptoms…Furthermore, anti-brain antibodies were also shown to induce neuropsychiatric symptoms in patients with other autoimmune disorders such as celiac disease or inflammatory bowel diseases. Taken together, anti-brain antibodies were shown to cause neuropsychiatric pathology in different diseases presenting novel therapeutic options.”
Inflammation disrupts neurogenesis
Both generation of new neurons and the support of synaptic health and plasticity are adversely affected by inflammation and this too is an avenue for treatment.
“Neurogenesis is a central mechanism required for neuronal maintenance and adaptive plasticity in the healthy and diseased brain. Inflammatory mediators have various effects on neurogenesis. Impairment of neurogenesis was shown in neurodegenerative diseases such as AD and neuropsychiatric disorders such as depression. Interestingly, approved AD drugs and chronic antidepressant treatment induce neurogenesis. Inflammation and microglial activation is detrimental for neurogenesis that can be restored by anti-inflammatory treatment. Moreover, microglia are not only involved in the maintenance of the neurogenic niche but also in synaptic maintenance. Of interest, systemic immune cells were shown to be involved in regulation of neurogenesis. CD4+ T-cells were shown to promote while CD8+ T-cells impair proliferation of neural progenitor cells…one may speculate that neuropsychiatric symptoms elicited by chronic inflammation may be driven by detrimental changes of neuronal homeostasis. Thus, specific immune modulatory treatment might be beneficial.”
Inflammation is a core issue for brain health, cognition and mood
Case management of neuropsychiatric and neurodegenerative disorders requires discerning and treating the causes of chronic inflammation on an individual case basis. The authors conclude:
“Sustained systemic inflammation is a common feature of many autoimmune disorders, and is present in most sepsis survivors. Cognitive impairment is common in sepsis survivors, as well as patients suffering from chronic inflammatory conditions…Moreover, systemic inflammation occurring in a susceptible brain (e.g., patients with AD) may lead to even further disruption in quality of life and activities of daily living. Up to 95% of patients with SLE develop neuropsychiatric dysfunction…In patients with rheumatoid arthritis, the baseline vagal tone of is persistently low, suggesting a possible mechanism for persistent inflammation. Those examples indicate that the normal neuroimmune cross-talk in health can become deleterious during disease, particularly in a primed brain – one with preexistent damage. Recently, cellular, molecular, environmental, and genetic components have been linked to the persistent brain dysfunction of systemic inflammation. Here, we have discussed mechanistic evidence for the intricate interrelation between inflammation and neurodegeneration. Identification of druggable targets derived from these mechanisms holds the promise to prevent long-term disability and improve the quality of life in patients with chronic inflammatory conditions.”
Severe fatigue, associated with chronic fatigue syndrome (CFS) or another disorder, has as a core underlying cause chronic inflammation. A valuable paper recently published in BMC Medicine illuminates the role of immune activation and peripheral inflammation with subsequent neuroinflammation and mitochondrial damage as key clinical features. The authors state:
“The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.”
Fatigue triggered by acute infection or ongoing autoimmunity
In either case, immune cells in the brain are activated and persist as chronic neuroinflammation, the linchpin of fatigue.
“There is copious evidence establishing the causative role of peripheral immune activation and inflammation, evidenced by elevated levels of proinflammatory cytokines in the genesis of debilitating fatigue in neuro-inflammatory, autoimmune and inflammatory disorders. Activation of pathogen recognition receptors by pathogen associated molecular patterns leads to the production of nuclear factor NF-kappaB and subsequent production of proinflammatory cytokines by the myeloid differentiation primary response gene (88) (MYD88), which is a universal adapter protein that is used by almost all Toll-like receptors (TLRs) in dependent and independent pathways. Systemic inflammatory stimuli, resulting from the presence of proinflammatory cytokines in the peripheral circulation, enter the brain via a number of routes activating microglia and astrocytes inducing the production of proinflammatory cytokines and other neurotoxins leading to an environment of neuroinflammation. This sequence of events ultimately underpins the genesis of fatigue and other signs and symptoms associated with acute pathogen invasion. Many people suffering from a range of neuroimmune and autoimmune diseases also suffer from debilitating or intractable fatigue.
They point out that chronic immune activation and systemic inflammation are associated with debilitating fatigue in conditions as diverse as multiple sclerosis, Alzheimer’s and Parkinson’s disease, major depression, systemic lupus erythromatosis (SLE), Sjogren’s syndrome, and rheumatoid arthritis.
Elevated cytokines, oxidative and nitrosative stress (O and NS) and NF-kappaB
They note that viral and bacterial infections are not always the trigger, and that other factors including environmental toxins can promote chronic inflammation.
“One of the key drivers in the development of chronic immune activation in the absence of bacteria or virus infection is the development of chronic inflammation as evidenced by elevated levels of cytokines and oxidative and nitrosative stress (O and NS) and characterized by activated NF-kappaB. Indeed, the production of proinflammatory cytokines and other inflammatory molecules by macrophages and other sentinel cells, even in the absence of pathogen invasion, and the subsequent activation of NF-kappaB are early events in the genesis of chronic inflammation. Activation of this transcription factor leads to the upregulation of cytokines and O and NS. These players can engage in a feed-forward manner to maintain and amplify chronic inflammation and immune activation in a TLR radical cycle.”
In other words, in many conditions associated with fatigue there is a self-maintaining feedback loop of chronic inflammation that sustains activation of NF-kappaB (nuclear factor kappa beta), thus promoting chronic and persistent inflammatory damage. Hence the great clinical importance of the benign agents available to clinicians that help wind down NF-kappaB activity.
Damaging the intestinal barrier systems
Loss of barrier integrity of the intestinal mucosa (and the blood-brain and respiratory barriers) is a major contributor to the loss of immune tolerance and maintenance of chronic inflammation and associated fatigue.
“Chronically elevated levels of NF-kappaB, proinflammatory cytokines and O and NS, in turn, lead to a disruption of epithelial tight junctions in the intestine allowing translocation of gram-negative bacteria, containing lipopolysaccharides, into the circulation, which can further amplify the TLR-radical cycle by acting as a pathogen-associated molecular pattern (PAMP). Translocation of bacterial lipopolysaccharides (LPS) from the gut and engagement with TLRs, due to a state of increased intestinal permeability driven by the effector molecules of chronic inflammation is another cause of chronic immune activation that may play a role in major depression, CFS, neuro-inflammatory disorders and some systemic autoimmune disorders.”
See a brief animation of the TLR signaling chain in inflammation at the bottom. TLR activation is a key step in inflammation that produces fatigue:
“Given the established association between chronic inflammation and the genesis of incapacitating fatigue, the TLR-radical cycle can potentially explain the development of incapacitating fatigue in patients suffering from these and other illnesses. This association may be explained by chronically increased levels of proinflammatory cytokines and reactive oxygen and nitrogen species (ROS/RNS) produced by the TLR-radical cycle upon stimulation by PAMPs and DAMPs. We have reviewed previously that some proinflammatory cytokines, including IL-1β, TNF-α and IL-6, and increased O and NS processes may cause fatigue in some vulnerable individuals.”
Mitochondrial dysfunction and fatigue
Disruption of the capacity to produce energy at the cellular level and depletion of ATP further contribute to fatigue. Multiple sclerosis offers one example:
“Mitochondrial dysfunction likely plays a major role in the progression of MS. Electron transport chain (ETC) complex I, complex III and complex IV activity is grossly reduced in normal appearing gray matter and in normal tissue within the motor cortex in patients suffering from this illness. There is also direct evidence of globally impaired energy production and longitudinal depletion of ATP levels leads to increased levels of physical disability.”
Inflammatory and oxidative damage to mitochondria also figures in chronic fatigue and major depression:
“Multiple lines of evidence demonstrate the existence of mitochondrial dysfunction in many, but by no means all, patients afforded a diagnosis of CFS. These abnormalities include loss of mitochondrial membrane integrity and oxidative corruption of translocatory proteins. Other findings include abnormal muscle mitochondrial morphology and defective aerobic metabolism uncharacteristic of muscle disuse. There is also accumulating evidence that inflammation and subsequent mitochondrial dysfunction drive the symptoms of major depression.”
Mitochondial dysfunction and glutathione depletion in autoimmunity
Fatigue in autoimmune disorders occurs from neuroinflammation and when the capacity to produce energy is derailed.
“Localized or global mitochondrial dysfunction is also an invariant feature of autoimmune diseases. Persistent mitochondrial membrane hyperpolarization and increased O and NS production combined with depleted levels of glutathioneand ATP is an invariant characteristic of T cells in SLE. The release of DAMPS into the systemic circulation, consequent to necrosis, acts as a mechanism by which localized mitochondrial pathology can lead to self-perpetuating systemic inflammation which, in turn, amplifies mitochondrial dysfunction in a vicious feed-forward loop. The association between chronic oxidative stress, systemic inflammation and mitochondrial dysfunction and chronic oxidative stress is also firmly established in Sjogren’s syndrome. There is also evidence of widespread nitric oxide (NO)-induced inhibition of complex III and V of the ETC in patients with rheumatoid arthritis. The causative role of chronic inflammation and oxidative stress and mitochondrial dysfunction is explained by the presence of elevated levels of ROS and RNS in such environments. These entities cause damage to proteins, DNA and lipid membranes. NO and peroxynitrite have the capacity to inhibit crucial enzymes within the ETC and can inactivate crucial enzymes in the tricarboxylic acid cycle leading to, often critical, reductions in the generation of ATP. Peroxynitrite, in particular, also has a destructive influence on the mitochondrial membrane leading to the loss of potential difference between the outer and inner membrane needed to manufacture ATP. The products of lipid peroxidation driven by elevated levels of ROS are also toxic to mitochondrial membranes. It is noteworthy that inhibition of the ETC leads to the formation of even higher concentrations of oxygen radical species which, in turn, leads to further impairment of mitochondrial function.”
Chronic fatigue syndrome
CFS has multiple causes that combine in varying ways for each individual.
“Pathological levels of fatigue unrelated to activity and not relieved by rest is a mandatory requirement for a diagnosis of chronic fatigue syndrome under the current internationally accepted diagnostic guidelines. The original diagnostic criteria contained another mandatory element, namely a clinical picture whereby the patient’s global symptoms represent a unitary illness with a single pathogenesis and pathophysiology. It is more likely that a diagnosis of CFS represents a spectrum of illnesses where different pathophysiological processes converge to produce a very similar phenotype.”
Immune dysregulation and present with different types of imbalances with chronic fatigue:
“Numerous research teams have reported a wide range of peripheral immune abnormalities in people afforded a diagnosis of CFS…now data reveal that while some patients present with a Th2 profile and a preponderance of anti-inflammatory cytokine production, others present with a Th1 or possibly Th17 profile, with the synthesis of proinflammatory cytokines being dominant…We have reviewed previously that patients with CFS and Myalgic Encephalomyelitis (ME) show different cytokine profiles, for example, a Th1-like pattern, with increased levels of IFN-γ, IL-2, IL-12 and IL-2 receptor, or a Th2-like pattern, with increased levels of IL-10, IL-4 and IL-5, or combinations thereof. Two recent studies reported evidence of activated TLR4 receptors. The causative relationship between chronic inflammation and the development of fatigue is perhaps strongest in patients afforded a diagnosis of CFS, with many studies demonstrating a significant positive correlation between surrogate markers of inflammation, oxidative stress and symptom severity.”
And addressing these causal patterns can afford relief:
“Miwa and Fujita (2010) demonstrated that a rapid decline in inflammation and oxidative stress of patients corresponded with a decline in severity of fatigue and amelioration of their entire symptom profile.”
Major depression and fatigue
It is now well established that major depression is a disorder characterized by chronic neuroinflammation:
“The existence of increased levels of circulatory proinflammatory cytokines in these patients is now a textbook truism…Fatigue of variable severity occurs in practically 100% of people with a diagnosis of depression. It is worthy of note, however, that a systematic review reported that almost 80% of patients still experienced chronic debilitating levels of exhaustion following treatment of their depression. This is perhaps to be expected given that several studies have now demonstrated that antidepressants have no positive modulatory effects on fatigue.”
Chronic inflammation, oxidative damage, intestinal barrier permeability and mitochondrial dysfunction all can contribute to depression:
“There is copious evidence of chronically activated T cells with Th1, Th2 and Th17 patterns of differentiation…Chronic systemic inflammation and oxidative stress play a major role in the etiology of depression. Elevated levels of redox-damaged DAMPs, including oxidized low density lipoprotein, oxidized phospholipids, and malondialdehyde (MDA)-adducts are also consistently found in patients suffering from this illness. Compromised epithelial barrier integrity is also a finding in depression and the resulting bacterial translocation into the systemic circulation is intimately involved in the pathogenesis of the disease. Mitochondrial dysfunction affects neuronal function, synaptic plasticity, energy metabolism and neurotransmitter release and, hence, it is not surprising that there is increasing evidence that mitochondrial dysfunction and inflammation drive the symptoms of major depression. Gardner and Boles highlighted the fact that research has failed to confirm a consistent relationship between serotonin levels and depression and that compromised bioenergetics should become a focus of research into the pathogenesis of the illness.”
Inflammation in the periphery can fire up inflammation in the brain
There is cross-talk between the rest of the body and the central nervous system that promotes neuroinflammation and fatigue. As this continues the pathways become primed to maintain dysfunctional inflammation even in the absence of the original triggering stimuli.
“There is now copious evidence that chronic or intermittent inflammation…can worsen or trigger neuroinflammatory or neurodegenerative processes via the induction of primed microglia. Briefly, prolonged or intermittent peripheral inflammation and immune activation act to prime microgliawhich thereafter become exquisitely sensitive to future inflammatory stimuli. Once microglia have achieved this sensitized status, subsequent peripheral inflammation and proinflammatory cytokine production mediated by a number of insults (for example, biotoxin exposure or pathogen invasion) provokes an exaggerated response from microglia and the production of excessive concentrations of neurotoxic molecules, such as nitric oxide, peroxinitrite, prostaglandins, cyclo-oxygenase 2 and cytokines. The secretion of these neurotoxins and alarmins leads to the activation of astrocytes and the combined activation of these glial cells provokes dysregulation of brain homeostasis, development of chronic neuroinflammation and neurotoxicity.”
Neuronal (vagal) and cytokine signaling from the periphery to the brain are involved, with disruption of the blood-brain barrier….
“Both humoral and neuroendocrine routes mediate proinflammatory signaling to the brain. The neural route operates via the dorsal motor nucleus of the afferent vagus nerve. The humoral route is facilitated by circulating proinflammatory cytokines that communicate their presence to the brain via direct and indirect routes. Such pathways involve engagement with specific transporters in the blood brain barrier (BBB)…The cumulative effects of proinflammatory cytokines and activated astrocytes cause disruption of the BBB allowing abnormally high numbers of activated T cells and B-cells to circulate between the peripheral immune system and the brain, acting as more channels of communication between the peripheral and central immune system. It should be noted that cytokines are able to diffuse from the CNS into the bloodstream as well.”
Gender, hormones and inflammation
There are important sex-related differences in autoimmune predilection associated with the immunomodulatory roles of sex hormones.
“An increased incidence rate in women is observed in most autoimmune disorders…Estrogen, progesterone and testosterone play important immunomodulatory roles and influence the quantity and pattern of cytokine secretion by antigen presentation cells and T lymphocytes and immunoglobulin production by B cells. Sex hormones also regulate the Th1/Th2 balance of the immune system, the production of regulatory T cells and the functionality of granulocytes and natural killer cells.”
Clinicians should remember that, while estrogens are neuroprotective at physiological levels, they can promote autoimmune inflammation when excessive.
“…Thus, excessive estrogens but less androgens may favor activation of B cells, a Th2-like response and increased numbers of autoimmune cells and, thus, autoimmune responses.”
Inter-related mechanisms produce fatigue
Clearly, a systems biomedicine perspective is required to grasp the dynamics, and peripheral inflammation plays a key role.
“It is of interest that levels of peripheral inflammation, oxidative stress and TNF-α also display a positive correlation with objective markers of disease activity and disability levels and that levels of proinflammatory cytokines correlate positively with levels of fatigue. The existence of gray matter atrophy before the advent of white matter abnormalities, and the existence of metabolic abnormalities before the advent of gray matter pathology, rather argues against the proposition that the chronic peripheral immune activation and oxidative stress seen in early disease is secondary to the release of inflammatory mediators from the CNS. These observations, coupled with data demonstrating that the severity of neuro-inflammation depends on the level of peripheral immune activation and that inflammation drives the development of disease, emphasizes the likely causative role of peripheral pathology. The strong association between the severity of fatigue and disability and the level and geographical distribution of glucose hypometabolism and gray matter hypoperfusion strongly indicates that these elements are driven by generic rather than disease specific pathology…There is also evidence demonstrating that the severity of fatigue is associated with the degree of white matter hyperintensities in people with SLE and evidence that the neuropathology in Sjogren’s syndrome is immune mediated. The widespread mitochondrial dysfunction seen in people with autoimmune diseases could also make a significant contribution to the development of fatigue…Given that many such patients also display evidence of peripheral immune activation, oxidative stress, gray matter pathology, glucose hypometabolism, hypoperfusion and metabolic abnormalities in the prefrontal cortex, basal ganglia and elsewhere, it would seem reasonable to investigate all such patients for the presence of these abnormalities. Standard MRI is unlikely to be helpful but other approaches discussed in the main body combined with serum measures of immune activation and oxidative stress may well bear fruit.”
Clinical bottom line
Practitioners need to view the complex and dynamic interactions at play for case analysis and treatment planning.
“..the multifactorial triggers that cause secondary fatigue by activating the networks/pathways in those disorders, including viral and bacterial infections, bacterial translocation, psychosocial stressors, exposure to adjuvants, nicotine dependence, sex- and gender-related factors, and so on. Towards this end, a systems biomedicine approach is essential to delineate the genetic and molecular signature of fatigue in these disorders and the non-linear interactions between the many pathways, networks, and trigger and genetic factors that underpin secondary fatigue.”
And the authors conclude by mentioning a short list from among the varied therapeutic resources already in use:
“Multi-targeting these interlinked dysfunctions may show benefit in these diseases. For example, a number of antioxidant compounds have demonstrated efficacy in modifying pathways leading to chronic inflammation, oxidative stress and immune dysregulation at relatively high doses for a long duration. N-acetyl-cysteine is an example of a multi-target therapeutic approach having the capacity to decrease the levels of ROS/RNS, increase the levels of cellular antioxidants, such as reduced glutathione, and normalize the production of proinflammatory cytokines and immune cell functions. This supplement has demonstrated the capacity to improve fatigue and disease activity in SLE, CFS and major and bipolar depression. Omega-3 polyunsaturated fatty acids (PUFAs) and zinc are also very effective antioxidants and anti-inflammatory compounds and supplementation has produced clinical benefit in patients diagnosed with depression and chronic fatigue syndrome…Curcumin, another nutraceutical with anti-inflammatory and antioxidative effects, is useful in the treatment of depression and rheumatoid arthritis. Coenzyme Q10 is another powerful antioxidant and anti-inflammatory compound which also has positive effects on mitochondrial function and which displays disease modifying effects in Parkinson’s disease and produced clinical benefit in patients with a diagnosis of CFS. Other approaches aimed at upregulating antioxidant defenses include N acetylcysteine, methylfolate and dimethyl fumarate, with the latter displaying disease modifying properties in MS . Methylfolate produces a similar quantum of benefit in MDD as antidepressants and can often be effective in treatment-resistant depression.”
Of course for these and many more therapies clinicians should shun a ‘try this, try that’ approach and employ the abundant objective laboratory resources to target specific needs on an individual case basis. The authors conclude:
“It is concluded that there are sufficient robust multiple lines of evidence to support the proposition that the severe fatigue and profound disability experienced by people with the neurodegenerative, neuro-immune and autoimmune diseases discussed here is largely driven by peripheral immune activation and systemic inflammation either directly or indirectly by inducing mitochondrial damage.”
Perinatal brain injury involves neuroinflammation with consequences for neuropsychiatric disease extending into adult life as reported in a paper recently published in Nature Reviews Neurology. The authors state:
“Inflammation is increasingly recognized as being a critical contributor to both normal development and injury outcome in the immature brain. The focus of this Review is to highlight important differences in innate and adaptive immunity in immature versus adult brain, which support the notion that the consequences of inflammation will be entirely different depending on context and stage of CNS development.”
Preterm birth gets a head start with neuroinflammation
Inflammation plays a role in the incidence of preterm birth occurring in the first place:
“Perinatal brain injury can result from neonatal encephalopathy and perinatal arterial ischaemic stroke, usually at term, but also in preterm infants. Inflammation occurs before, during and after brain injury at term, and modulates vulnerability to and development of brain injury. Preterm birth, on the other hand, is often a result of exposure to inflammation at a very early developmental phase, which affects the brain not only during fetal life, but also over a protracted period of postnatal life in a neonatal intensive care setting, influencing critical phases of myelination and cortical plasticity.”
A risk factor for adult neuropsychiatric disorders
The authors’ conclusion reminds practitioners to consider perinatal brain injury as an etiologic factor in adult disorders:
“Neuroinflammation during the perinatal period can increase the risk of neurological and neuropsychiatric disease throughout childhood and adulthood, and is, therefore, of concern to the broader group of physicians who care for these individuals.”
Traumatic brain injury(TBI) even in it’s milder forms can initiate a process of chronicneuroinflammation that causes a range of chronic neurodegenerative disorders. The authors of a paper just published in Neuropsychiatric Disease and Treatment detail the secondary injury cascades that exacerbate the damage and can lead to chronic traumatic brain injury.
“Mild TBI, sometimes referred to as concussion, is the most prevalent TBI. Although TBI has been traditionally considered an acute injury, accumulating clinical and laboratory evidence has recognized the chronic pathology of the disease. Indeed, TBI can manifest many symptoms of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease…Accumulating laboratory and clinical evidence has implicated neuroinflammation in both acute and chronic stages of TBI, suggesting this secondary cell death pathway may be the key to the disease pathology and treatment…”
Neuroinflammation in traumatic brain injury stands out as a target of inquiry:
“Here, we focus on neuroinflammation, which closely manifests immediately after TBI onset, and equally important, it persists in the chronic stages of the disease, making it an appealing target for understanding TBI pathology and its treatment.”
Mild traumatic brain injury may cause a variety of symptoms to persist
Clinicians need to be alert to a range of possible symptoms long after the original injury.
“Most patients fully recover in a couple hours or days, although it may take a couple of weeks. However, depending on the severity of the injury, there are some cases in which victims do not recover and the symptoms persist for years….Clinical manifestations of mild TBI consist of a combination of physical and neuropsychiatric symptoms, which include behavioral and cognitive disorders…Of the physical symptoms of TBI, headaches are the most common, with around 25%–90% of post–mild TBI patients reporting it. Dizziness and nausea are other common symptoms, along with fatigue, sleep disruption, hearing problems, and visual disturbances. As a result of damage to the frontal or temporal lobe, TBI patients are also prone to seizures, which may present a challenge for diagnosis and treatment (ie, differential diagnosis between TBI and epilepsy).”
Chronic cognitive and behavioral disorders from mild traumatic brain injury
The cascade of neurodegenerative effects stemming from mild traumatic brain injury are tragically life altering.
“Cognitive disorders after TBI primarily include attention deficit, memory problems, and executive dysfunction. Attention deficit is very common and interferes with other functions, making daily tasks harder than before…These include irritability, mood changes, aggression, impulsivity, self-centered behavior, and poor persistence.Other symptoms related to TBI are depression (sadness, low energy and motivation, not liking oneself, hopelessness), anxiety, and posttraumatic stress disorder. In addition, as noted earlier, TBI may increase the risk of developing Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative diseases in the long term.”
Primary and secondary waves of injury
Both short and long term cascades of damage occur when the brain is subject to trauma.
“The initial insult first leads to a primary injury caused by the mechanical damage from shearing, tearing, and/or stretching of neurons, axons, glia, and blood vessels…The primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes. This occurs within seconds to minutes after the traumatic insult and can last for days, months, or years. It often leads to progressive neurodegeneration and delayed cell death, exacerbating the damage from the primary injury. The secondary wave is mainly detected in the injury site and surrounding tissue, although neurodegeneration in brain areas located far from the primary impact has recently been recognized…
The secondary wave consists of excitotoxicity, oxidative stress, mitochondrial dysfunction, blood–brain barrier (BBB) disruption, and inflammation. All these processes contribute to neurological deficits separately, but at the same time, these cell death processes interact, worsening the progressive outcome of TBI.”
Excitotoxicity in traumatic brain injury
Substances released by damaged neurons cause brain cells to be stimulated to death.
“…injured nerve cells secreting large amounts of intracellular glutamate into the extracellular space…overstimulates the AMPA and NMDA receptors of surrounding nerve cells. These receptors stay activated, allowing an influx of sodium and calcium ions into the cell. The high concentration of calcium ions in the cytosol leads to the activation of protein phosphatases, phospholipases, and endonucleases. Eventually, the DNA is fragmented, and structures and membranes of the cell are deteriorated. This results in cell death through a hybrid form of apoptosis and necrosis. The overstimulation of glutamate receptors also results in the increased production of nitric oxide, free radicals, and pro-death transcription factors.”
ROS in traumatic brain injury
A damaging increase in free radical reactive oxygen species (ROS) and reactive nitrogen species (RON), which are normally kept at a low level in the brain by antioxidants and enyzmes, also contributes to neuronal cell death.
“After TBI, a significant increase in ROS and impairment of antioxidants that lower the levels is seen. When the generation of ROS/RON is too large, it leads to major cell dysfunction, as its oxidative capabilities damage all biomolecules. ROS cause lipoperoxidation of the cell membrane, which results in the dysfunction of many structures and organelles, such as the mitochondria and oxidizing proteins that affect membrane pores. It may also fragment DNA, causing mutations. ROS are also related to the infiltration of neutrophil, which induces an inflammatory response that, in turn, increases the generation of ROS. Overall, oxidative stress cascade results in large neuronal cell death.”
Mitochondrial dysfunction in mild TBI
Mitochondrial dysfunction, typically a contributing factor to neurodegeneration in general, also plays a role in neuronal cell death and chronic loss of brain function following traumatic brain injury.
“After TBI, the stabilizing mechanisms of levels of ROS become impaired, resulting in increased concentrations. Lipid peroxidation-mediated oxidative damage to the mitochondrial membrane negatively affects its structure and function. The mitochondria also works as a calcium ion buffer, releasing and absorbing the ions as needed to maintain homeostasis. However, when the calcium ion load becomes too large from excitotoxicity, the function of the mitochondria becomes impaired. The mitochondrial permeability transition pore, associated with the mitochondrial inner membrane, is a calcium ion-dependent pore. With the excess calcium ions, the pore stays active, disrupting the mitochondrial membrane potential. Without a membrane potential, the mitochondria is unable to produce ATP, and the ATP synthase may actually consume ATP instead of producing it. With mitochondrial break down, toxins and apoptotic factors are released into the cell, activating the caspase-dependent apoptosis. This causes the cell to commit suicide.”
Blood-brain barrier disruption
Loss of blood brain barrier (BBB) integrity also contributes to brain cell death following TBI.
“BBB dysfunction is related to neuronal cell death and cognitive decline and limits the effectiveness of therapies. Its dysfunction triggers many other secondary injuries, including cell death, oxidative stress, and inflammation, causing the brain to swell, with higher intracranial pressure and ischemia. The primary injury disrupts the tight junctions, allowing an influx of peripheral immune cells and circulating factors (albumin, thrombin, and fibrinogen). These events affect the interaction between BBB endothelial cells and astrocytic glial cells, further contributing to the effects of BBB dysfunction by increasing its permeability. One of the underlying mechanisms regarding BBB dysfunction after TBI is the up-regulation of protein matrix metallopeptidase 9 (MMP-9). This digests the tight junctions, disrupting its proper function. BBB breakdown also allows an influx of larger molecules such as leukocytes that increase the osmotic force in the brain. This results in edema and higher intracranial pressure, which are directly related to ischemia and further cell death.”
Neuroinflammation, the ‘big enchilada’
Red line = damaging neuroinflammation, Green solid = pro-survival inflammation, green dotted = treatment, arrow = initiation of treatment.
Brain inflammation may be the leading contributor to accelerated loss of brain cells in most forms of neurodegeneration. In traumatic brain injury it is triggered immediately after impact and can continue for many years.
“After the initial injury, an endogenous inflammatory response is triggered to defend the injury site from invading pathogens and to repair the damaged cells. The complement is activated to perform these functions and recruits inflammatory cells into the intrathecal compartment. The activation of the complement is also accompanied by the infiltration of neutrophils, monocytes, and lymphocytes across the BBB. These secrete prostaglandins, free radicals, proinflammatory cytokines, and other inflammatory mediators that, in turn, up-regulate the expression of chemokines and cell adhesion molecules. This results in immune cells and microglia mobilizing into the brain parenchyma.”
While the microglial cells perform important positive functions that limit damage and sequester the injured tissue, they fire up neuroinflammation by over-reacting. This is particularly true of the M1 phenotype of glial cells.
“…microglial activation in TBI is excessive, and proinflammatory cytokines such as tumor necrosis factor (TNF)- , IL-1 , IL-6, IL-12, and interferon are released. The up-regulation of these cytokines increases the permeability of the BBB by higher expression of cell adhesion molecules in the endothelial cells and by an increased production of chemokines. This results in an increased inflammatory response. Sustained microglial activation also produces neurotoxic molecules and free radicals, which lead to other mechanisms of secondary cell death…In addition, activated microglial cells increase the expression of major histocompatibility complex class II (MHCII ), which is directly correlated to neurodegeneration.”
Astrocytes too exert beneficial effects by increasing brain-derived neutrophilic factors (BDNF) and regulating extracellular glutamate to reduce excitotoxicity. However…
“…when the presence of astrocytes is too large and they become overactivated, it can lead to detrimental effects in the brain. The astrocytes secrete inhibitory extracellular matrix, building a dense physical and chemical barrier surrounding the injury site (glial scar), which encapsulates and isolates the axons. This protects the remaining healthy brain from the neurotoxic environment of the injury site, but it also interferes and prevents the regeneration and repair of the damaged tissue.”
What to do?
A rational treatment plan should include the various remedial measures that target all of these processes:
Wind down glutamate excitotoxicity
Oppose oxidative stress
Support mitochondrial function
Help repair the blood-brain barrier
These processes play a role in neurodegeneration from other causes besides traumatic brain injury. The clinician should have a repertoire of remedial measures at hand to address them. Past and future posts report on advances in treatment. Calming neuroinflammation plays a premiere role.”
“It takes considerably more time for the inflammatory cells to reach the injured brain and contribute to the secondary cell death damage than it takes other secondary death mechanisms, such as glutamate excitotoxicity. This delayed onset provides an extended window of opportunity in which treatments can be administered, greatly increasing the chances of a successful intervention and preventing further damage.”
One cardinal point must be kept in mind: there is a beneficial ‘housecleaning’ side to neuroinflammation so antiinflammatory therapies should not be overdone.
“Immune cells, astrocytes, cytokines, and chemokines are all necessary components for brain repair, and it is their excessive levels that contribute to the secondary cell death damage in TBI…When considering treatments for neuroinflammation in TBI, it is important to note that inflammation has both beneficial and detrimental effects. Prior studies have shown that high doses of antiinflammatory agents actually lead to worse outcomes. In addition to inhibiting the detrimental effects of neuroinflammation, these robust treatments may also retard the beneficial ones.”
Judicious application of natural anti-inflammatory agents to minimize side-effects along with other measures guided by objective measurements is a standard for treating traumatic brain injury that can be applied to other neurodegenerative disorders as well.