Suicide and biomarkers of gastrointestinal inflammation

Suicide and gastrointestinal inflammation

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

Most attempting suicide have an illness associated with neuroinflammation

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

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

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

Biomarkers of gastrointestinal inflammation are frequently increased in neuropsychiatric disorders.

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

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

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

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

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

Elevated IL-6

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

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

Gluten and brain inflammation

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

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

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

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

Pathogens and loss of immune tolerance

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

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

Significant link found

Association between suicide and markers of GI inflammation

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

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

Predicting risk and protecting patients

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

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

The authors conclude:

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

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

Mood disorders and thyroid autoimmunity

PLOS ONEMood 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 patients with 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

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.”

Earlier diagnosis

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.”

Moreover…

“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.”

Clinical Note

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.

Migraine, depression, Alzheimer’s and lipid metabolism

NeurologyMigraine, with its variety of symptoms associated with aberrant neuronal activation, is linked to abnormal metabolism of a class of bioactive lipids in an important study just published in the journal Neurology. Sphingolipids are involved in a variety of functions in mammalian systems including cell membrane formation, signaling, apoptosis, energy balance and inflammation. The authors set out to assess the levels of sphingolipids in circulation in women migraneurs between migraine attacks compared to control subjects. Their data show that altered sphingolipid metabolism clearly distinguished those with episodic migraine (EM) from controls:

Total ceramide (EM 6,502.9 ng/mL vs controls 10,518.5 ng/mL) and dihydroceramide (EM 39.3 ng/mL vs controls 63.1 ng/mL) levels were decreased in those with EM as compared with controls. Using multivariate logistic regression, each SD increase in total ceramide (odds ratio [OR] 0.07) and total dihydroceramide (OR 0.05) levels was associated with more than 92% reduced odds of migraine. Although crude sphingomyelin levels were not different in EM compared with controls, after adjustments, every SD increase in the sphingomyelin species C18:0 (OR 4.28) and C18:1 (OR 2.93) was associated with an increased odds of migraine. Recursive portioning models correctly classified 14 of 14 randomly selected participants as EM or control.”

Brain-liver axis and migraine

SphingolipidsThese interesting results shed light on a topic that deserves more attention: the role of the brain-liver axis in neuroinflammatory, neurodegenerative and neuropsychiatric disorders including migraine. This may be extended to include metabolism of lipids and other bioactive agents on a cellular level. The authors conclude in regard to sphingolipid metabolism and migraine:

“These results suggest that sphingolipid metabolism is altered in women with EM and that serum sphingolipid panels may have potential to differentiate EM presence or absence…This study provides Class III evidence that serum sphingolipid panels accurately distinguish women with migraine from women without migraine.”

Clinical note: for practitioners using medicines from the TCM (traditional Chinese medicine) and Ayurvedic systems the ‘brain-liver axis’ encompasses not just the visceral entity but consonant functions distributed throughout the organism.

Dementia, multiple sclerosis, obesity, and pain

Beyond migraine, a commentary on the study in Medscape Medical News states:

“The authors, led by B. Lee Peterlin, DO, from Johns Hopkins University School of Medicine, Baltimore, Maryland, note that neurologic disorders that are the result of severe deficiencies in enzymes that regulate sphingolipid metabolism have long been described (eg, Gaucher disease), and recent studies have suggested that even subtle changes of sphingolipid balance may be involved in dementia, multiple sclerosis, obesity, and pain…Now they also are reporting a study showing changes in sphingolipid levels in patients with migraine, implicating in particular two sphingolipid subtypes: ceramide and sphingomyelin…“Taken together, our findings suggest it is possible that migraine is a neurologic disorder of ‘minor’ sphingolipid dysmetabolism,” they conclude.”

Depression and anxiety

BBA - Molecular and Cell Biology of LipidsAlso in addition to migraine, a fascinating paper recently published in Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids reviews the function of neuronal membrane lipids including sphingolipids as a barrier and signaling medium in the brain and their role in depression and anxiety.

“Brain lipids determine the localization and function of proteins in the cell membrane and in doing so regulate synaptic throughput in neurons. Lipids may also leave the membrane as transmitters and relay signals from the membrane to intracellular compartments or to other cells. Here we review how membrane lipids, which play roles in the membrane’s function as a barrier and a signaling medium for classical transmitter signaling, contribute to depression and anxiety disorders and how this role may provide targets for lipid-based treatment approaches. Preclinical findings have suggested a crucial role for the membrane-forming n-3 polyunsaturated fatty acids, glycerolipids, glycerophospholipids, and sphingolipids in the induction of depression- and anxiety-related behaviors.”

This opens the door to a class of treatment options…

“These polyunsaturated fatty acids also offer new treatment options such as targeted dietary supplementation or pharmacological interference with lipid-regulating enzymes. While clinical trials support this view, effective lipid-based therapies may need more individualized approaches. Altogether, accumulating evidence suggests a crucial role for membrane lipids in the pathogenesis of depression and anxiety disorders; these lipids could be exploited for improved prevention and treatment.”

Alzheimer’s disease

Journal of Alzheimer's DiseaseA review in the Journal of Alzheimer’s Disease discusses the metabolism and the presence in biofluids of sphingolipids and other lipids in Alzheimer’s disease (AD):

“With the difficulties of studying the brain directly, it is hoped that identifying the effect of AD on the metabolite composition of biofluids will provide insights into underlying mechanisms of pathology…Sphingolipid, antioxidant, and glutamate metabolism were found to be strongly associated with AD and were selected for detailed investigation of their role in pathogenesis. In plasma, two ceramides increased and eight sphingomyelins decreased with AD, with total ceramides shown to increase in both serum and cerebrospinal fluid. In general antioxidants were shown to be depleted, with oxidative stress markers elevated in a range of biofluids in patients suggesting AD produces a pro-oxidative environment. Shifts in glutamate and glutamine and elevation of 4-hydroxy-2-nonenal suggests peroxidation of the astrocyte lipid bilayer resulting in reduced glutamate clearance from the synaptic cleft, suggesting a excitotoxicity component to AD pathology; however, due to inconsistencies in literature reports, reliable interpretation is difficult.”

In addition to defective clearance of amyloid beta, tau proteins and glutamate, altered sphingolipid metabolism emerges as a significant factor.

“The present review has shown that metabolite shifts in biofluids can provide valuable insights into potential pathological mechanisms in the brain, with sphingolipid, antioxidant, and glutamate metabolism being implicated in AD pathology.”

Sphingolipids in food

Journal of NutritionSphingolipids are in a variety of foods and, though not known to be an ‘essential’ nutrient, have functional effects as discussed in a paper published in the The Journal of Nutrition. The authors state:

“There is no known nutritional requirement for sphingolipids; nonetheless, they are hydrolyzed throughout the gastrointestinal tract to the same categories of metabolites (ceramides and sphingoid bases) that are used by cells to regulate growth, differentiation, apoptosis and other cellular functions…both complex sphingolipids and their digestion products (ceramides and sphingosines) are highly bioactive compounds that have profound effects on cell regulation. This article reviews the structures of sphingolipids, their occurrence in food, digestion and metabolism, biochemical functions and apparent roles in both the etiology and prevention of disease.”

Sphingolipids and cell regulationIn regard to their functional role:

“Studies with experimental animals have shown that feeding sphingolipids inhibits colon carcinogenesis, reduces serum LDL cholesterol and elevates HDL, suggesting that sphingolipids represent a “functional” constituent of food. Sphingolipid metabolism can also be modified by constituents of the diet, such as cholesterol, fatty acids and mycotoxins (fumonisins), with consequences for cell regulation and disease. Additional associations among diet, sphingolipids and health are certain to emerge as more is learned about these compounds. “

The authors offer a table showing sphingolipid levels in various foods.

Stunning discovery links brain and immune system

NatureLong established scientific dogma asserts that there is no direct connection by vessels between the brain and immune system, yet the link between systemic inflammation, brain inflammation and neurodegeneration is vividly evident in clinical practice (see Systemic inflammation drives brain neurodegeneration and numerous related posts). Now investigators report in the prestigious journal Nature the stunning discovery of a central nervous system lymphatic system connecting the brain and immune system in a paper entitled Structural and functional features of central nervous system lymphatic vessels.

“One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes.”

Changes the landscape of neuroimmunology

Brain inflammation, a key factor in neuropsychiatric and neurodegenerative disorders, is linked directly to systems-wide immune function.

The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.”

Neuroinflammation’s mechanism re-defined

Neuroscience NewsAutism and bipolar disorder, Alzheimer’s and MS, and every other neuroinflammatory brain based disorder must be considered in this light. A commentary entitled Researchers Find Missing Link Between the Brain and Immune System in Neuroscience News states:

“That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer’s disease to multiple sclerosis.”

Quoting lead author Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA’s Center for Brain Immunology and Glia (BIG):

“Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels…It changes entirely the way we perceive the neuro-immune interaction…We believe that for every neurological disease that has an immune component to it, these vessels may play a major role.

Metabolic purpose of sleep

ScienceThe discovery of lymphatic vessels providing brain drainage reminds of the remarkable research entitled Sleep Drives Metabolic Clearance from the Adult Brain, published in the competing journal Science, that brilliantly demonstrates the metabolic purpose of sleep. The authors state:

“The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.”

In other words, they demonstrated that brain cells shrink during sleep to increase the interstitial space by a whopping 60%, and further showed that this results in marked increase drainage of toxic metabolites through the ‘glymphatic‘ system. This paper was published before the stunning discovery of the brain’s own lymphatic system.

Proteins linked to neurodegenerative diseases, including β-amyloid (Aβ), α-synuclein, and tau, are present in the interstitial space surrounding cells of the brain. In peripheral tissue, lymph vessels return excess interstitial proteins to the general circulation for degradation in the liver. Yet despite its high metabolic rate and the fragility of neurons to toxic waste products, the brain lacks a conventional lymphatic system. Instead, cerebrospinal fluid (CSF) recirculates through the brain, interchanging with interstitial fluid (ISF) and removing interstitial proteins, including Aβ. The convective exchange of CSF and ISF is organized around the cerebral vasculature, with CSF influx around arteries, whereas ISF exits along veins. These pathways were named the glymphatic system on the basis of their dependence on astrocytic aquaporin-4 (AQP4) water channels and the adoption of functions homologous to peripheral lymphatic removal of interstitial metabolic byproducts. Deletion of AQP4 channels reduces clearance of exogenous Aβ by 65%, suggesting that convective movement of ISF is a substantial contributor to the removal of interstitial waste products and other products of cellular activity. The interstitial concentration of Aβ is higher in awake than in sleeping rodents and humans, possibly indicating that wakefulness is associated with increased Aβ production. We tested the alternative hypothesis that Aβ clearance is increased during sleep and that the sleep-wake cycle regulates glymphatic clearance.”

The convective movement of brain interstitial fluid that they describe is only enhanced by lymphatic vessels that drain the brain. Sleep is the time when the brain ‘takes out the trash’.

Tremendous clinical significance

Cranial therapy that restores the amplitude and symmetry of the rhythmic expansion and contraction the skull associated with the circulation of cerebrospinal spinal fluid (CSF) and lymphatic exchange in the brain can be appreciated in this context along with the immunological implications. Further commenting in Neuroscience News:

“The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer’s disease. “In Alzheimer’s, there are accumulations of big protein chunks in the brain,” Kipnis said. “We think they may be accumulating in the brain because they’re not being efficiently removed by these vessels.” He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there’s an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist.”

Maps of the lymphatic system

Systemic inflammation drives brain neurodegeneration

Frontiers in Cellular NeuroscienceIn 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.

Neuroimmune modulation

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 of nuclear 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.

Sickness behavior

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 as sickness 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 and nitric 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

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.

Moreover…

“…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

Human brain connectome

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.”

Balancing act

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.”

Dysregulation causing systemic inflammation drives neurodegeneration

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 leads to 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.”

Anti-brain antibodies*

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.”

*Note: Transglutaminase-6 antibodies are included in the Wheat/Gluten Proteome Reactivity & Autoimmunity array from Cyrex Laboratories.

Neuropsychiatric illness, autoimmunity and the role of microbes

Current Opinion in RheumatologyNeuropsychiatric illness often involves brain inflammation for which there may be an autoimmune origin. The authors of a paper* recently published in Current Opinion in Rheumatology set out to…

“…illustrate how microbes might participate in the pathogenesis of neuropsychiatric illness by triggering the production of autoantibodies that bind to brain targets.”

They describe the science emerging on underlying mechanisms behind the observations that both exposure to infectious agents and autoantibodies without evidence of pathogens can cause brain disorders…

“…….evidence accumulates to support the idea that dysregulated cross-talk between the brain and the immune system is an important contributor to the pathogenesis of conditions as diverse as schizophrenia, mood disorders, autism spectrum disorders (ASDs), obsessive-compulsive disorder (OCD), Tourette syndrome and other tic disorders, attention-deficit hyperactivity disorder (ADHD), anorexia nervosa, narcolepsy, posttraumatic stress disorder and myalgic encephalomyelitis/chronic fatigue syndrome (CFS). In addition, intriguing new evidence lends support to the possibility that not only the microbes associated with infectious episodes but also the bacteria of the gut microbiome can foster the production of brain-reactive autoantibodies, and that these microbe-induced antibodies provide the critical link between infection and neuropsychiatric disorders.”

In the case of infection, it may not even matter so much what the infectious agent is…

“A complication in delineating the relationship of a particular pathogen to a particular neuropsychiatric disorder is that even if the link is real, it may nonetheless be nonspecific, both in terms of the type of infectious agent capable of inducing brain dysfunction, as well as in the neurobehavioral features that follow. An expanding body of studies using animal models of infection-related developmental disorders reports persistent effects on offspring brain development and behavior following prenatal or early postnatal exposures to noninfectious agents that mimic actual infection with influenza virus, such as polyinosinic:polycytidylic acid (poly I:C, a form of synthetic, double-stranded RNA), or a bacterium, such as lipopolysaccharide (LPS, or bacterial endotoxin), illustrating the importance of maternal immune responses as modifiers of postinfectious sequelae in the offspring. Findings from these studies suggest that CNS damage requires the presence of innate immune and inflammatory molecules that disrupt brain development.”

Noting that shifts in maternal immune activation toward an autoimmune and allergic phenotype predisposed offspring to autism-like behaviors which were subsequently abolished by bone marrow transplantation to modify immune expression…

“In addition to this overlap in neurodevelopmental consequences after prenatal and postnatal virus-like and bacteria-like exposures, exposure of infant mice to environmental contaminants such as the organic compound, toluene, is associated with upregulated expression of cytokine genes in hippocampus. Thus, increasing evidence suggests that it is the presence of innate immune molecules, as opposed to direct infection of neurons and glial cells, that mediates these effects.”

While breaching of the blood brain barrier (BBB) immunoreactive agents into the privileged space of the central nervous system, it may not always be necessary for the manifestation of neuropsychiatric symptoms:

“Another study that focused on GAS [group A streptococcus]-related, CNS-directed autoimmunity raised the intriguing suggestion that alternate transport systems may exist for entry of certain immunoglobulin isotypes or subclasses into the CNS. Zhang et al. injected naïve mice with anti-GAS IgM monoclonal antibodies, without the use of an adjuvant to breach the BBB, and found increased stereotypic behaviors…Transcellular mechanisms that obviated the need to compromise BBB integrity were postulated to facilitate the entry of these IgM antibodies into the CNS.”

Pathogens aren’t the only microbes that can incite autoimmune activity. As noted in earlier posts, the ‘normal’ commensal microbiota can also participate in loss of immune tolerance:

“Recent evidence suggests that both pathogenic and commensal microbes play a role in the pathogenesis of a subset of neuropsychiatric disorders through induction of brain-reactive autoantibodies. Whereas infection with certain pathogens can trigger autoantibody production through molecular mimicry, commensal bacteria that comprise the gastrointestinal microbiota probably set the stage for the development of autoimmune responses by skewing immune responses toward overproduction of Th17 cells and reduction in numbers and function of Tregs.”

The authors also note the role of antioxidants and depletion of the antoxidant system, particularly glutathione:

Increased oxidative stress with diminished glutathione impairs Tregs, increasing autoimmunity.

Increased oxidative stress with diminished glutathione impairs Tregs, increasing autoimmunity.

Failed uptake of antioxidant precursors in the terminal ileum, influenced by differences in tryptophan degradation capacity of the microbiota and related factors, may also contribute to a skew toward autoimmunity by reducing levels of Tregs and increasing levels of autoimmunity-provoking Th17 cells.”

The link between schizophrenia and Toxoplasma gondii infection is illustrative:

“There is also evidence that the microbial infection itself is not likely to be as important in pathogenesis as the presence of antibodies to the microbe, as well as the isotype and binding characteristics (cross-reactivity, affinity and avidity) of these antibodies. Anti-toxoplasma antibodies may also be more prevalent in individuals with bipolar disorder, type 1.”

Moreover…

“In individuals with schizophrenia, antibodies directed against food antigens, including bovine milk casein and wheat-derived gluten, are correlated with the presence of antibodies to T. gondii…In a separate study, increased levels of anti-gliadin antibodies were found in individuals with schizophrenia. Furthermore, the interactomes of nine neuropsychiatric disorders, including multiple sclerosis, Alzheimer’s disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson’s disease, ADHD and ASD, but not anorexia nervosa or myalgic encephalomyelitis/CFS, showed significant overlap with the interactome of T. gondii, and has been closely associated with a number of autoimmune diseases.”

Interestingly, autoimmunity with loss of tolerance to gluten may involve reduced antioxidant capacity:

“The relationship of anti-toxoplasma antibodies to anti-gliadin antibodies in some neuropsychiatric disorders may relate to reduced antioxidant capacity in the terminal ileum. Gliadin, a major protein component of wheat that is associated with celiac disease, also appears able to dysregulate redox balance in peripheral blood mononuclear cells, triggering allergic-type responses that include specific enhancement of IL-4-mediated IgE production…A clearer understanding of these processes may uncover unique strategies for intervention with less potential for toxicity, including antioxidants, prebiotics, probiotics and transplantation of fecal microbiota.”

Clinical note: Clearly practitioners must be alert to the role of autoimmunity in neuropsychiatric disorders and must discriminate between infection and loss of immune tolerance triggered by infection. It may not be so apparent that the indigenous commensal microbiota can play a role in autoimmunity, antimicrobial therapy may modify symptoms for a time but ‘dig the hole deeper’, and that caution must be observed in contemplating treatment for infections that expose the immune system to the lipopolysaccharides of disintegrating bacterial and fungal cells in the presence of active or latent loss of immune tolerance.

The authors conclude:

“Genetically susceptible individuals may generate brain-reactive autoantibodies when exposed to certain infectious agents or commensal organisms. Under inflammatory conditions that promote BBB disruption and facilitate trafficking into the CNS, binding of autoantibodies to cross-reactive epitopes may contribute to the cognitive and behavioral disturbances associated with these disorders by altering brain activity within key circuitry. This conceptual model views altered brain–immune signaling as a product of the interaction of immune response genes and microbial exposures at key points during prenatal and postnatal development, and provides a framework within which discordant findings across studies of different neuropsychiatric disorders may be better explained and through which novel pathways for improved therapeutics may be discovered.”

* The entire paper can be read in Medscape Family Medicine.

Lyme disease, neuropsychiatric symptoms and autoimmunity

As with other chronic infections, the most devastating effects of Lyme disease can occur from the immune system losing tolerance for normal tissue as it cross-reacts while attacking the pathogen. A paper just published in The Open Neurology Journal reviews the body of knowledge on the neuropsychiatric symptoms of Lyme disease and other infections as an immune mediated neurodegenerative disorder, enlarged by a wealth of citations. The author states:

“Disease progression of neuropsychiatric symptoms in Lyme/tick-borne diseases can be better understood by greater attention to psychoimmunology. Although there are multiple contributors that provoke and weaken the immune system, infections and persistent infections are significant causes of pathological immune reactions. Immune mediated effects are a significant contributor to the pathophysiological processes and disease progression.”

He expands on neurodegeneration and immune-mediated inflammation such as occurs in Lyme disease, depression and Alzheimer’s disease:

“When neurodegenerative diseases are progressive uncontrolled inflammation drives disease progression. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. It has been hypothesized that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. There is evidence with depression, Alzheimer’s disease (AD), schizophrenia and epilepsy to support this position. A meta-analysis of cytokines in major depression including 24 studies reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects. A meta-analysis of cytokines in AD which reviewed 86 studies strengthens the clinical evidence that AD is accompanied by an inflammatory response with particularly higher peripheral concentrations of IL-6, TNF, IL-1, transforming growth factor, IL-12 and IL-18 and higher CSF concentrations of transforming growth factor.”

Schizophrenia is included in the list of autoimmune neurodegenerative disorders:

Hundreds of studies of schizophrenic illness in adults have documented immunological abnormalities in these patients. First-episode psychosis in children is associated with evidence of increased inflammation. Increasing evidence now suggests that the glia, cerebral vasculature, and the BBB may be involved which support the inflammatory theory of schizophrenia that was formulated over a 100 years ago.”

Epilepsy, of course, is also included:

There is a rapidly growing body of evidence that supports the involvement of inflammatory mediators in epilepsy—released by brain cells and peripheral immune cells—in both the origin of individual seizures and the epileptogenic process. Aspects of brain inflammation and immunity were first described and subsequently, it was demonstrated how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death.”

The astute clinician must also bear in mind associated phenomena that support the autoimmune inflammatory process in Lyme disease and other neurodegenerative conditions:

“Oxidative stress and oxygen free radicals or activated oxygen has been implicated in diverse environmental stresses and appears to be a common contributor in neurodegenerative diseases…Excitotoxicity and inadequate remethylation leads to increased homocysteine levels which are excitotoxic [33]. Elevated C-reactive protein levels are linked to a decline in executive function and frontal lobe damage…Proinflammatory cytokines include Interferon alpha, IL-1-beta and IL-6. Cytokine activation has been associated with psychiatric symptoms. For example, IL-6 is elevated in the cerebrospinal fluid of suicide attempters and is related to symptom severity, memory deficits and aggressiveness and IL-1-beta is associated with self-inflicted aggressive behavior and fatigue.”

Practitioners who are fuzzy on serotonin dynamics will appreciate their review of how infections by parasites and pathogens like Borrelia burgdorferi in Lyme disease pervert the metabolism of serotonin in such a way that serotonin support can worsen depression. Clinicians who attempt to modulate serotonin with either reuptake inhibitors or precursor therapy must be aware of the following:

“Inflammation provoked by parasites impacts the conversion of tryptophan into serotonin. The kynurenine pathway is a major route of L-tryptophan catabolism into serotonin with a number of metabolites that include—kynurenic acid which is an N-Methyl-D-aspartic acid (NMDA) antagonist (neuroprotective, unless excessive), quinolinic acid which is a NMDA agonist (neurotoxic). In an inflammatory state there is decreased serotonin & a shift to quinolinic acid rather than kynurenic acid. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan into kynurenine and which is stimulated by proinflammatory cytokines, is implicated in the development of interferon–induced depressive symptoms, first by decreasing the serotonin availability to the brain and second by the induction of the kynurenine pathway resulting in the production of neurotoxic metabolites. In persistent infections associated with persistent inflammation, chronic activation of TNF-alpha stimulates interferon-gamma, which overactivates IDO, the rate-limiting enzyme for catabolism of tryptophan in the brain. Overactivated IDO causes neurotoxicity, and immune suppression of cytotoxic T cells.”

So attempting to increase serotonin under these conditions is prone to backfire. Moreover…

“Underactivation of IDO is known to cause autoimmune reactions, but it has recently been discovered that overactivated IDO causes autoimmune B cell antibody production. CSF quinolinic acid is significantly elevated in a number of CNS infections including Borrelia burgdorferi (Bb), infection—dramatically in patients with CNS inflammation, less in encephalopathy. The presence of this known agonist of NMDA synaptic function; a receptor involved in learning, memory, and synaptic plasticity; may contribute to the neurologic and cognitive deficits seen in many Lyme disease patients.”

The author also comments on the polar character of the immune imbalance associated with Lyme disease:

“Some immune mediated pathophysiology seen in Lyme/Tick-Borne Diseases (LYD/TBD) is a failure to shift from Th1 to Th2. Persisting immune activation causes the cytokine storm in chronic Lyme. In these patients, the innate immune system is not turned off by a series of specific immune peptides…The magnitude of IL-6 in human serum and CSF has been shown to correlate with disease activity in neurologic Lyme disease. Elevated levels of IL-6 can cause symptoms of fatigue and malaise, common to many infectious conditions as well as Lyme disease. Borrelia species induce activation of IL-17 production. The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis CSF CXCL13 and can be used as a diagnostic marker for infection.”

Persistently elevated IL-17 is an insignia of autoimmunity.

Lyme disease neuropsychiatric phenomena are similar to psychiatric morbidities following strep infection:

“Paraneoplastic limbic encephalopathies and pediatric autoimmune diseases associated with strep (PANDAS) are good models to understand the effects of autoantibodies directed against intracellular neuronal antigens and the associated psychiatric symptoms. In paraneoplastic and nonparaneoplastic limbic encephalitis, voltage-gated potassium channel limbic encephalitis, Hashimoto’s encephalopathy, anti-NMDA and other glutamate receptor encephalitis, encephalitis associated with gamma-aminobutyric acid signaling and systemic lupus erythematosus neurons are excited to death by autoantibodies resulting in neurotoxicity. PANDAS is an interaction of a Streptococcal infection in a genetically susceptible individual at a young age which can result in obsessive compulsive disorder, tics and sometimes attention span difficulties. PANDAS is often comorbid with LYD/TBD and the broader categorization has been referred to as pediatric infection-triggered autoimmune neuropsychiatric disorders. Symptom flares follow a strep infection and correlate with increased antibody production.”

Specifically, antigens on the surface of Borrelia can trigger an immune inflammatory response that cross-reacts with the host’s neuronal tissues:

Lyme surface antigens can cause molecular mimicry and associated autoimmune symptoms. Bb spirochetes surface glycolipids may elicit cross-reactive antibodies and IgM Bb flagella antibodies cross-reacted with neuronal antigens. Anti-neural antibody reactivity has been demonstrated in patients with a history of Lyme borreliosis and persistent symptoms. Anti-neural antibody reactivity was found to be significantly higher in the Lyme patients with prior treatment and persistent symptoms (PLS) group than in the post-Lyme healthy and normal healthy groups. Immunohistochemical analysis of PLS serum antibody activity demonstrated binding to cells in the central and peripheral nervous systems. The presence of anti-neural antibody reactivity in patients with PLS demonstrates ‘objective immunologic abnormalities’ and underscores the pathophysiologic nature of PLS and discredits the psychosomatic theory advanced by some as the cause of persisting symptoms.”

He also considers the autoimmune dimension of autism spectrum disorders (ASD):

“There has been recent attention to the association between chronic infections, LYD/TBD and autism spectrum disorders (ASD). Immune reactivity associated with these infections in the mother, fetus and child appear to adversely affect developing neural tissue and contribute to the pathophysiology associated with autism spectrum disorders. Possible pathophysiological mechanisms include both inflammatory processes as well as autoantibodies to developing neural tissueIndividuals with autism show increased pro-inflammatory cytokines in the brain, as well as activation of microglia. Additionally, antibodies that target brain tissues have been described in both children with autism and their mothers…Autoantibodies targeting brain proteins have been discovered in both children with autism and their mothers and circulating maternal autoantibodies directed toward fetal brain proteins are highly specific for autism…In addition, antibodies that react to the 36, 37, 39, 61 and/or 73 kDa bands on Western Blot testing are associated with provoking an immune reaction and contribute to causing autism. Reactivity to these bands is also associated with Borrelia burgdorferi and to a lesser degree to Bartonella henselae, Bartonella quintana, Mycoplasma, Chlamydia pneumonia and Streptococcus pneumoniae.”

Besides a reminder of factors that practitioners must bear in mind when managing Lyme disease or post-Lyme disease conditions, the author has covered important points for psychiatric disease in general. Readers may wish to see some of the 64 citations referenced in this paper by clicking on the link above. The author concludes:

“When looking at the clinical and basic science research on the subject articles it is apparent that persistent infection and associated inflammation and molecular mimicry mechanisms are associated with gradually increasing encephalopathy and gradually increasing mental symptoms. Cognitive symptoms begin as executive dysfunction and mild cognitive impairments and may gradually progress to dementia while emotional symptoms begin with insomnia, reduced frustration tolerance, irritability and dysthymia and may progress to anxiety disorders, depression, impulsivity and personality disorders and subsequently psychosis and/or suicidal and homicidal tendencies. Many of the neurological, cognitive and psychiatric symptoms associated with LYD/TBD appear to be mediated by immune mechanisms.”

OCD: an autoimmune disease

CellAn interesting study just published in the journal Cell demonstrates one mechanism by which immunological dysfunction causes obsessive-compulsive disorder (OCD). The authors show that microglia (the immune cells in the brain) when abnormal can cause compulsive behaviors in mice that correspond to OCD in humans:

“Mouse Hoxb8 mutants (with faulty microglia) show unexpected behavior manifested by compulsive grooming and hair removal, similar to behavior in humans with the obsessive-compulsive disorder spectrum disorder trichotillomania.”

They then showed that transplanting normal microglia eliminated their pathological OCD behavior.

Immunological dysfunctions have been associated with neuropsychiatric disorders…In this mouse, a distinct compulsive behavioral disorder is associated with mutant microglia.”

Science NowThe author of a report on this study published in Science Now comments:

“Previous studies have implied a link between the immune system and obsessive-compulsive disorder and other neuropsychiatric conditions, Capecchi says. “Here, we say there is a direct connection.”…The results raise the possibility of treating obsessive-compulsive disorder by targeting the immune system rather than the brain.”

Neuroscience LettersWhat other evidence might there be that OCD in humans is an autoimmune disease? A paper published a year and a half ago in Neuroscience Letters shows how an immune cytokine abnormality also contributes to OCD. The authors begin by observing:

Several lines of evidence support an immunologic involvement in obsessive-compulsive disorder (OCD): the increased prevalence of OCD in patients with rheumatic fever (RF), and the aggregation of obsessive-compulsive spectrum disorders among relatives of RF probands [affected persons studied in a genetic investigation]. Tumor necrosis factor alpha is a proinflammatory cytokine involved in RF and other autoimmune diseases…the goal of the present study was to investigate a possible association between polymorphisms within the promoter region of TNFA and OCD.”

They studied two polymorphisms of the genes for TNF-alpha and found that:

“Significant associations were observed between both polymorphisms and OCD.”

NeuropsychopharmacologyThe theme is carried forward in a paper more recently published in the journal Neuropsychopharmacology that reports the presence of anti-brain autoantibodies that derange excitatory neurotransmitters with OCD. The authors begin by observing:

“…serum autoantibodies directed against basal ganglia (BG) implicate autoimmunity in the pathogenesis of obsessive–compulsive disorder (OCD),…We examined this by investigating the presence of autoantibodies directed against the BG or thalamus in the serum as well as CSF of 23 OCD patients compared with 23 matched psychiatrically normal controls.”

Basal gangliaThey also measured several neurotransmitters including the most abundant excitatory neurotransmitter glutamate. What did their data show?

“There was evidence of significantly more binding of CSF autoantibodies to homogenate of BG as well as to homogenate of thalamus among OCD patients compared with controls. …CSF glutamate and glycine levels were also significantly higher in OCD patients compared with controls…”

Thus their conclusion:

“The results of our study implicate autoimmune mechanisms in the pathogenesis of OCD and also provide preliminary evidence that autoantibodies against BG and thalamus may cause OCD by modulating excitatory neurotransmission.”

Progress In Neuro-Psychopharmacology & Biological PsychiatryThis post would not be complete without including the recognized association of OCD with Tourette’s disorder (TD). The authors of this clinically useful study published not long ago in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry linked TD and OCD in their investigation of the cytokines promoting the autoimmune attack on brain tissue:

“This study examined the potential role of cytokines, modulators of the immune system. We hypothesized that children with TD would have increased levels of tumor necrosis factor (TNF)-α, interleukin (IL)-12, IL-1β and IL-6, and decreased IL-2. We also explored whether comorbid [happening together] obsessive compulsive disorder (OCD) had an effect on the cytokine profile of TD patients.”

They found that both TD and OCD had abnormal elevations of cytokines associated with their immune dysfunction, only those who had OCD comorbid with TD had significantly elevated IL-12.

“Findings suggest a role for IL-12 and IL-2 in TD, and that the TD+OCD subgroup may involve different neuroimmunological functions than the TD−OCD subgroup.”

Their conclusion confirms both the autoimmune etiology and that each patient must be precisely evaluated and treated as in individual for their autoimmune disorder.

How well can you smell: autoimmunity & neuropsychiatric disorders

Clinical ImmunologyThere is a connection between how well you can smell, brain damage from autoimmune inflammation, and psychiatric disease. Consider this fascinating paper published in the journal Clinical Immunology in which the authors discuss the inter-relationship between olfactory impairment, autoimmunity and neurological/psychiatric symptoms in several diseases affecting the central nervous system (CNS) such as Parkinson, Alzheimer’s disease, autism, schizophrenia, multiple sclerosis and neuropsychiatric lupus erythematosus. We suggest that common manifestations are not mere coincidences. Current data from animal models show that neuropsychiatric manifestations are intimately associated with smell impairment, and autoimmune dysregulation, via autoantibodies…”

Autoimmunity ReviewsIn another paper published in the journal Autoimmunity Reviews the authors note that “Research in the field of immunology as well as in various brain illnesses is beginning to indicate the increasing relevance of smell in pathophysiology.” They further state “…evidence exists that there may be something unique about the olfactory system that is inextricably related to immunological function. In addition, accumulating evidence confirms the existence of olfactory dysfunction in brain disease, much of which appears at early stages including multiple sclerosis, Alzheimer’s Disease, Parkinson’s Disease, schizophrenia and depression…under certain circumstances, olfactory abnormalities may be associated with autoimmune conditions. Since the organization of the olfactory system is so sensitive, impairment may be noted at an early stage. This may become important in the prediction of certain brain illnesses.”

International Journal of NeuroscienceThis paper recently published in the International Journal of Neuroscience focuses specifically on the link between olfaction, autoimmunity and Parkinson’s Disease. They first describe “the immune alterations observed in PD patients…the increase in the innate immune components including complement and cytokines within their substantia nigra and cerebrospinal fluid (CSF). These alterations extended to the adaptive immune response with the elevation of T cells and autoantibodies…in the peripheral blood and CSF of PD patients.” (Just the kinds of things we test for in the functional medicine approach.) They then describe the link between PD, autoimmunity and olfaction: Smell deficit is one of the earliest signs of PD and a unique observation suggesting olfactory declines to be a consequence of autoimmune mechanisms.”

AutoimmunityAnd the authors of this study published recently in the journal Autoimmunity observe that Psychiatric diseases are often associated with mild alterations in immune functions (e.g., schizophrenia) as well as autoimmune features. Recent evidence suggests that autoimmune diseases (AD) demonstrate a higher prevalence of psychiatric disorders, such as depression and psychosis, than in the normal population. Patients with AD often have an olfactory impairment as well, based on smell studies… ” They report that olfactory gene receptors have brain functions in addition to smell, and go on to describe the genetic polymorphisms (variations) that link autoimmunity, psychiatric disorders and smell impairment.

Israel Medical Association JournalThe paper that concludes this post is tantalizingly entitled Olfaction—A Window to the Mind. Published not long ago in The Israel Medical Association Journal, it is available here in its entirety. The authors comment that “The sense of smell can provide a natural window to the brain. This window provides an opportunity to examine neural mechanisms and brain function in a non-invasive way.” They then undertake a fascinating review of the field of olfactory studies encompassing aspects ranging from autoimmunity and neuropsychiatric disease to sexual function, addiction, social behavior and the discrimination of self from non-self. Their conclusion is worth bearing in mind: “…assessment of the sense of smell and olfactory impairments is usually overlooked by patients and their clinicians. Given the clinical data reviewed here, clinicians should be encouraged to screen for olfactory impairments, which can help in the early diagnosis of CNS diseases such as Parkinson, dementia and schizophrenia, as well as CNS-autoimmune diseases such as neuropsychiatric lupus.”