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.

Brain health is maintained by immune system activity

the-scientistDramatic advances in understanding how brain health is maintained by the immune system are described in an excellent article published recently in The Scientist that accompanies the brief video presentation by neuroscientist Michal Schwartz shown below. Only recently has it been recognized that brain immune function is integrated with the systemic immune system.

Until recently, the brain and the spinal cord were considered immune-privileged sites, strictly cordoned off from immune cells unless something went terribly wrong. Researchers knew, for example, that multiple sclerosis (MS) was caused by T cells that breach the selective border called the blood-brain barrier (BBB), enter the CNS, and attack the myelin sheath covering neurons. Even microglia, specialized macrophage-like immune cells that scientists had recognized as normal CNS residents since the 1960s, were mainly studied in the context of disease.”

Now the pervasive role of the immune system in brain function and maintenance is being observed:

“But over the past two decades, researchers have recognized that the entire immune system is very much a part of a functional CNS, with vital roles in cognition, injury repair, neurodegenerative disease, and sensory systems. Microglia pervade the CNS, including the white and gray matter that constitute the organ’s parenchyma. Other immune cells, including T cells, monocytes, and mast cells, reside in the brain and spinal cord’s outer membranes, known as the meninges, and circulate in cerebrospinal fluid (CSF).”

Immune cells in the brain help repair damage

It was formerly thought that immune cell activity in the brain was only harmful.

Macrophages, for example, can damage neurons by secreting cytokines, proteases, or reactive oxygen species, but in rat and mouse models of spinal cord injury, they also produce transforming growth factor-beta (TGFβ), which promotes wound healing,5 and interleukin 10 (IL-10) which helps resolve inflammation. By the late 2000s, researchers recognized that different subtypes of macrophages can benefit neuronal growth in rodents, and that some were critical to recovery. Views also began to change on the clinical side after the 2004 Corticosteroid Randomization After Significant Head Injury (CRASH) study showed that corticosteroids didn’t help brain injury patients recover, but increased their risk of disability and death.”

Cells of the adaptive immune system residing in the tissue lining of the ventricles can also assist in repair.

Her team also showed that T cells present in this lining, called thechoroid plexus, secrete cytokines such as interferon gamma (IFNγ), which allows selective passage of CD4+ T cells and monocytes from the blood into CSF within the ventricles.  In a model of spinal cord bruising, mice deficient for the IFNγ receptor had reduced immune cell trafficking across the choroid plexus and poor recovery of limb movement. And last year, Kipnis’s team reported that IL-4 produced by CD4+ T cells in the CNS signals neurons to regrow axons after spinal cord or optic nerve injury.”

Immune cells in the brainAn intact blood-brain barrier (BBB), however, is essential:

“His team also found that microglia reinforce the BBB, which is composed of endothelial cells, pericytes, and astrocytes. Microglia fill in spaces left by astrocytes killed or damaged during injury. Without a robust barrier, McGavern says, unwanted immune cells may flood the parenchyma and do more harm than good.”

Immune cells residing in the CSF and choroid plexus

Immune cells residing in the CSF and choroid plexus

Brain needs both anti-inflammatory and pro-inflammatory activity for cognition

Neuroinflammation is well known to be a core feature of neurodegenerative disorders, but inflammatory immune activity is also required for healthy cognition.

“…Rivest used two-photon microscopy to monitor monocytes in blood vessels of living mouse brains, and he watched as the cells migrated toward and cleared amyloid-β deposits within veins. When the researchers selectively depleted monocytes, the mice developed more amyloid-β plaques in the cortex and hippocampus. And when they knocked out the innate immune signaling protein MyD88, which mediates signals from several monocyte-activating receptors, the mice also experienced more amyloid-β accumulation, accompanied by accelerated cognitive decline.”

Even in the classic disease of neuroinflammation, MS, immune cell activity is necessary:

“Rivest’s team found that microglia-forming monocytes are beneficial in a model of MS, where microglia are found within the inflammatory lesions. Last year, the researchers reported that inhibiting monocytes from entering the CNS reduced the clearance of damaged myelin and impeded proper remyelination.”

Evidence for the immune system’s role in preventing neurodegeneration continues to mount:

“Schwartz has similarly found evidence for the immune system’s ability to protect against neurodegeneration. Last year, she and her colleagues reported that the choroid plexus epithelium was less permissive to immune cell trafficking in a mouse model of Alzheimer’s disease than in wild-type mice, due to anti-inflammatory signals produced by regulatory T cells (Tregs). They found that depleting Tregs in Alzheimer’s mice allowed macrophages and CD4+ T cells into the brain, reduced the number of amyloid-β plaques, and improved cognition. Similarly, blocking the T-cell checkpoint protein PD1, which normally supports Treg survival while suppressing the activity of other T cells, reduced amyloid-β plaques in mouse brains and improved the animals’ scores in a learning and memory water maze test.”

Clinicians should be alert to evaluate and support balance

Too much neuroinflammation is clearly adverse.

“But there’s a reason that scientists have believed that immune activity contributes to Alzheimer’s damage: microglia, perhaps best known for trimming back synapses, have the potential to become overzealous, and excessive synapse pruning can cause neural damage in a variety of CNS diseases. By blocking the cells’ proliferation in mice, Diego Gomez-Nicola of the University of Southampton in the U.K. has successfully alleviated symptoms of Alzheimer’s disease, amyotrophic lateral sclerosis, and prion disease. And earlier this year, Beth Stevens of the Broad Institute and her colleagues reported that inhibiting a protein that tags synapses for microglial pruning halted over-pruning and loss of synapse signaling strength in two mouse models of Alzheimer’s disease.”

Regulation of stress is critical

Stress has a major effect on which way the ‘two-edged sword’ swings.

“Kipnis says regulation of stress may be linked to T cells’ role in learning. Stress can signal macrophages to secrete proinflammatory cytokines, some of which block a protein called brain-derived neurotrophic factor (BDNF), which astrocytes need to support learning and memory. CD4+ T cells in the meninges make more IL-4 cytokine after mice have been trained in a water maze—a stressful exercise for the animals—suggesting the signaling molecule might let macrophages know when the brain is dealing with the stress of learning something new, not the stress of an infection. “They tell macrophages, ‘Don’t overshoot,’” says Kipnis. In mice whose meninges are depleted of CD4+ T cells and thus deficient for IL-4, macrophages secrete proinflammatory factors unchecked in times of stress, disrupting their ability to learn and form memories.”

But excess suppression of inflammatory activity in the brain could have unwanted consequences as in the case of mast cells:

“Best known for their involvement in allergic responses in the upper airway, skin, and gastrointestinal tract, mast cells have been found in the meninges as well as in perivascular spaces of the thalamus, hypothalamus, and amygdala. They are known to quickly recruit large numbers of other immune cell types to sites of inflammation, and to play a role in MS. But mast cells also release serotonin into the hippocampus, where the molecule aids neurogenesis, supports learning and memory, and regulates anxiety.”

A ‘goldilocks zone’ for immune activity in the brain

As in every condition clinical evaluation must embrace the whole context…

“Thus, like microglia, mast cells are a double-edged sword when it comes to neural health. It’s a reflection of the entire immune system’s love-hate relationship with the CNS, Kipnis says. “Saying the immune system is always good for the brain, it’s wrong; saying it’s always bad for the brain, it’s wrong. It depends on the conditions.”

Neuroscientist Michal Schwartz — Breaking The Wall Between Body and Mind

 

Leaky gut: inflammation, chronic fatigue and depression

Neuroendocrinology Letters--leaky gut and chronic fatigueLeaky gut‘ is abnormal intestinal 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

Journal of Affective DisordersAn 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.”

Clinical note

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

Neurochemistry InternationalA 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.”

Depression, inflammation and light therapy

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

Depression and inflammation

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

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

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

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

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

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

The author of this coverage in also notes:

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

Of course safer antiinflammatory agents are readily available.

Circadian misalignment increases inflammation

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

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

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

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

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

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

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

Bright Light Therapy—Not Just For Seasonal Affective Disorder

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

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

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

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

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

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

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

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

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

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

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

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

Circadian rhythms and inflammation in rheumatoid arthritis

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

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

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

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

Chronotherapy with bright light beats exercise for depression

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

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

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

The authors of the this study conclude:

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

Bottom Line

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

Pain chronic after injury, surgery due to neuroinflammation

Scandinavian Journal of PainPain is a protective physiological response to injury but it is dysfunctional when it persists after a normal period of repair. Research just published in the Scandinavian Journal of Pain describes how neuroinflammation due to dysregulated glial cells (immune cells in the central nervous system) cause chronic persistent neuropathic pain. The authors state:

“Acute pain in response to injury is an important mechanism that serves to protect living beings from harm. However, persistent pain remaining long after the injury has healed serves no useful purpose and is a disabling condition. Persistent postsurgical pain, which is pain that lasts more than 3 months after surgery, affects 10–50% of patients undergoing elective surgery…When established, this type of pain is difficult to treat and new approaches for prevention and treatment are needed.”

Activated glial cells promote chronic pain

They set out to investigate the role of inflammatory glial cell dysfunction based on observing…

“A possible contributing mechanism for the transition from acute physiological pain to persistent pain involves low-grade inflammation in the central nervous system (CNS), glial dysfunction and subsequently an imbalance in the neuron–glial interaction that causes enhanced and prolonged pain transmission.”

Their investigation brought these mechanisms to light:

“Immediately after an injury to a nerve ending in the periphery such as in surgery, the inflammatory cascade is activated and immunocompetent cells migrate to the site of injury. Macrophages infiltrate the injured nerve and cause an inflammatory reaction in the nerve cell. This reaction leads to microglia activation in the central nervous system and the release of pro-inflammatory cytokines that activate and alter astrocyte function. Once the astrocytes and microglia have become activated, they participate in the development, spread, and potentiation of low-grade neuroinflammation. The inflammatory activated glial cells exhibit cellular changes, and their communication to each other and to neurons is altered. This renders neurons more excitable and pain transmission is enhanced and prolonged.”

Clinical note

Neuroinflammation produced by dysregulated immune cell activation more easily occurs in a biological ‘terrain’ in which immune tolerance has already been compromised (latent autoimmunity). The authors consider a combination of endomorphin-1, ultralow doses of naloxone and levetiracetam, but a number of other strategies emerge when case management includes comprehensively targeting the underlying causes of loss of immune tolerance and chronic inflammation. The role of dysregulated inflammation and immune dysfunction in any chronic pain condition should be borne in mind.

The authors conclude:

“Surgery causes inflammation at the site of injury. Peripheral nerve injury can cause low-grade inflammation in the CNS known as neuroinflammation. Low-grade neuroinflammation can cause an imbalance in the glial–neuron interaction and communication. This renders neurons more excitable and pain transmission is enhanced and prolonged…Potentially, by targeting inflammatory activated glial cells and not only neurons, a new arena for development of pharmacological agents for persistent pain is opened.”

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

Magnesium protects against preeclampsia seizures

Pregnancy HypertensionPreeclampsia includes among its afflictions a tendency for seizures. A study just published in the journal Pregnancy Hypertension demonstrates magnesium raises the threshold for seizures in preeclampsia by reducing neuroinflammation. The authors state:

“The mechanism by which MgSO4 [magnesium sulfate] provides seizure prophylaxis in women with preeclampsia (PE) remains unclear, and may be multifaceted. Here, we investigated the effect of MgSO4 on seizure threshold, blood-brain barrier (BBB) permeability and neuroinflammation in a rat model of PE.”

Neuroinflammation and BBB permeability are both increased in preeclampsia

They subjected their pregnant (P) and preeclampsia (PE) study animals to seizures by infusions of pentylenetetrazol (PTZ) and while recorrding EEGs and the amount of PTZ required to elicit a seizure compared to a subset treated with magnesium. They measured blood brain barrier (BBB) permeability by quantifying passage of infused sodium fluorescein (NaFl) into the brain. Microglial activation was their metric for neuroinflammation, done by immunostaining for ionized calcium binding adapter molecule. This revealed a specific benefit of magnesium in preeclampsia:

“Seizure threshold was lower in PE compared to P rats that was reversed by MgSO4. BBB permeability was increased in PE, with more NaFl passing into the brain compared to P rats that was unaffected by MgSO4. PE rats had neuroinflammation, characterized by activated microglia that was reversed by MgSO4.”

Magnesium reduces neuroinflammation

Magnesium increases seizure threshold by reducing activation of microglia in preeclampsia.

Magnesium increases seizure threshold by reducing activation of microglia in preeclampsia.

Among its many virtues, this preeclampsia model highlights the ability of magnesium to reduce neuroinflammation, calming the brain’s immune cells (microglia). Also relevant for preeclampsia is magnesium’s benefit for hypertension. Alert practitioners note that suboptimal levels of magnesium are ubiquitous. The authors conclude:

“PE was associated with lower seizure threshold, potentially due to increased BBB permeability and neuroinflammation. MgSO4 increased seizure threshold in PE rats through a quiescent effect on microglia without affecting BBB permeability.”

Magnesium prevents high blood pressure in pregnancy

Gynecology and ObstetricsHere we can appreciate a study demonstrating that magnesium supplementation also prevents hypertension in the last weeks of pregnancy that was published in Gynecology and Obstetrics. The authors conducted a randomized placebo controlled trial by giving 300 mg magnesium as citrate or placebo from pregnancy week 25 in a randomised double-blind setup to a cohort of pregnant primagravida women with a marked result:

In the magnesium-supplemented group, the average diastolic blood pressure at week 37 was significantly lower than in the placebo group. The number of women with an increase in diastolic blood pressure of ≥15 mmHg was significantly lower in the magnesium group compared with the women who received placebo. There was an inverse relation between the urinary excretion of magnesium during pregnancy and the diastolic blood pressure.”

Preeclampsia: seizures and hypertension controlled by magnesium

Taken together this and similar data in the literature argue in favor of clinicians diligently considering magnesium supplementation for every pregnant woman at risk for preeclampsia. It’s hard to argue against this point, particularly considering the low cost and practically absent risk. The authors of the latter study conclude:

Magnesium supplementation prevented an increase in diastolic blood pressure during the last weeks of pregnancy. The relation between diastolic blood pressure and urinary excretion of magnesium suggests that magnesium is involved in the regulation of blood pressure and that the increase in diastolic blood pressure in pregnancy could be due to a lack of magnesium.”

ALS treatment: start long before clinical symptoms

Journal of Neurology, Neurosurgery & PsychiatryALS (amyotrophic lateral sclerosis), a devastating autoimmune disease of the central nervous system, has a long presymptomatic period during which neuroprotective interventions can be applied according to an important paper published in the Journal of Neurology, Neurosurgery & Psychiatry. The authors state:

“We propose that, in common with other neurodegenerations, the pathogenic mechanisms culminating in ALS phenotypes begin much earlier in life. Animal models of genetically determined ALS exhibit pathological abnormalities long predating clinical deficits. The overt clinical ALS phenotype may develop when safety margins are exceeded subsequent to years of mitochondrial dysfunction, neuroinflammation or an imbalanced environment of excitation and inhibition in the neuropil. Somatic mutations, the epigenome and external environmental influences may interact to trigger a metabolic cascade that in the adult eventually exceeds functional threshold. A long preclinical and subsequent presymptomatic period pose a challenge for recognition, since it offers an opportunity for protective and perhaps even preventive therapeutic intervention to rescue dysfunctional neurons.”

Biological changes starting decades earlier

The authors postulate a lengthy evolution in the development of ALS and other neurodegenerative diseases:

“Symptom onset in adult neurodegenerations, including ALS, typically occurs in mid-life to late life. In Alzheimer’s disease (AD) and Parkinson’s disease (PD), pathological changes precede clinical disease by years, if not decades…It has previously been suggested that ALS may have a prolonged preclinical period, but, generally, it is assumed that the clinical onset of ALS is coincident with, or starts shortly after, the onset of the pathological process underlying the disease…However, absence of detectable change found by these tests of lower motor neuron function does not necessarily equate with normal functioning of anterior horn cells; abnormality of upper motor neuron functioning has clearly been demonstrated to precede clinical deficit in ALS. More likely, there is bio-molecular dysfunction at a cellular level that cannot presently be detected, which is insufficient to cause clinical features, but potentially present and building for years or decades prior to onset of clinical disease. In SOD1 ALS mouse models, pathological changes are evident shortly after birth, predating the first clinical abnormalities by 2–3 months. In human genetically-linked ALS (FALS), expression of the disease-causative proteins, or other metabolic defect, must be evident even during embryonic life. Similarly, in sporadic ALS, biological abnormalities reflect a long-lasting morbid process progressing over years, or potentially even decades, before the first symptoms become apparent.

Early mutations in both hereditary and sporadic ALS

Both familial and acquired genetic mutations can start the process that becomes symptomatic years later.

Inherited mutations, applicable to the 29 nuclear genes that have presently been identified to be associated with hereditary ALS, have the highest risk of disease, since all cells carry the mutant gene. However, spontaneous gene mutations associated with cell division during embryogenesis and early development are also potentially disease-inducing. Spontaneous mutations blur the difference between hereditary and sporadic ALS. In sporadic ALS, spontaneously arising ‘at risk mutations’, occurring early in development, would carry only a slightly lower risk relative to hereditary ALS...it is likely that mutations of only a few of the numerous genes guiding developmental programming and network formation and function will add to the overall burden of risk for developing ALS later in life.”

Perinatal and rapid developmental periods are particularly vulnerable

These are phases of increased susceptibility to mitochondrial and genetic damage:

“Neural network development begins at conception, and continues into adolescence and young adulthood. However, it is the prenatal and perinatal periods that are associated with the greatest metabolic activity. This is required for neurogenesis, neuronal proliferation and neural differentiation and migration…The added metabolic demand increases oxidative stress and must be countered by antioxidant production and redox-sensing systems sufficient to control reactive oxygen species (ROS) production, and remove damaged mitochondria. During these periods, spontaneous mutations may cause subtle abnormalities in central nervous system (CNS) wiring, connectivity and network formation inducing vulnerability for late-in-life neurodegeneration, including ALS. Postnatally, the process of synaptic proliferation continues through middle childhood and is followed by programmed elimination of synapses. Substantial refinement of brain structure and function occurs during adolescence, again a period of potential susceptibility for disease in later life.”

Even in hereditary ALS environmental factors play a large role

“Neurodegenerative diseases with Mendelian inheritance and diseases including familial ALS are associated with genetic variants present from the time of conception, even though they do not present clinically until mid to late adulthood. This implies either that these genes are not ‘switched on’ until later life, or that there are decades of progressive cellular compromise eventually culminating in the catastrophic decline manifesting as presentation of clinically overt ALS. Heritability studies suggest that about 60% of the risk of ALS is genetically determined, and the remaining 40% environmentally determined.”

Modifiable risk factors years in advance

There are significant points for early intervention that can be targeted by appropriate tests:

“Environmental exposure to toxins, smoking, excessive physical activity, occupation, dietary factors and changes in immunity all increase the risk of developing sporadic ALS. These factors may drive epigenetic changes over many years, which then induce disease onset and progression. There is a significant association with smoking; prolonged exposure and current smoking increase ALS risk by twofold to threefold. Exposure to pollutants is one mechanism that may trigger and can chronically perpetuate neuroinflammation…Nevertheless, neuronal damage from oxidative stress may continue throughout life by accumulation of environmental, occupational, dietary and lifestyle exposures. Neuroepidemiological studies of risk factors for ALS suggest that exposure must occur several years before disease onset, implying that an environmental trigger may be active for years before clinical disease develops.”

Biological 'seeds' of ALS

Biological ‘seeds’ of ALS. Motor neurons and supporting glia are susceptible to many potential insults, such as neuroinflammation, excitotoxicity, mitochondrial dysfunction, excessive oxidative stress and environmental risk factors. Epigenetic influences may further determine individual sensitivity and susceptibility. Environmental risk factors continue to exert their influence throughout life.

Neuroinflammation and male predominance in ALS

They note the fascinating observation that physical aggression in boys predicts reduced anti-inflammatory cytokines:

“During development, microglia contribute to the formation of the neural network by stimulating vascularisation and assisting in pruning excess neurons and synapses, as well as facilitating cell differentiation. Throughout life, there is a balance between microglia-derived protective anti-inflammatory cytokines, which are maximum in early development and childhood, versus pro-inflammatory cytokines, which accumulate with ageing and are associated with a chronic inflammatory state. A shift toward pro-inflammatory cytokines contributes to increased susceptibility and neurodegenerations. Physical aggression in boys during childhood is a predictor of reduced anti-inflammatory cytokines in early adulthood, raising the intriguing speculation that the male predominance of ALS might partly be related to reduction of anti-inflammatory cytokines early in life. This may tie in with the findings that patients with ALS have a lower second-to-fourth digit ratio, consistent with higher prenatal circulating levels of testosterone, and possibly a prenatal influence of testosterone on motor neuron vulnerability in later life.”

Clinical note

Practitioners should make appropriate use of the array of laboratory tests already available to investigate early undifferentiated neuronal autoimmunity, excessive oxidative stress, dysregulated inflammation and its contributing causes, and defects in mitochondrial function along with deficiencies in key co-factors that can be targeted well in advance of clinical symptoms for both hereditary and sporadic ALS.

The authors conclude:

“We postulate that ALS shares commonality with other neurodegenerative disorders in which there is a compelling body of evidence to indicate that the onset of clinical symptoms is preceded by a long presymptomatic period. Such a period may last for years or possibly decades, with downstream events that exceed the threshold for the emergence of clinical symptoms becoming evident only years after the pathobiological disease process commenced…We suggest that many different biomolecular events may impact normal development in such a way that the disease only becomes clinically apparent when intrinsic compensatory mechanisms break down, perhaps decades after their onset. The processes involved are complex, interactive and progressive. The clinical syndrome of ALS becomes evident when neuronal and also possibly astroglial metabolism is overwhelmed by the accumulation of biological abnormality, especially involving energy kinetics, until a ‘tipping point’ is reached.”

Imperative to intervene early

“It therefore follows that the current failure of therapies to effectively modify ALS may largely reflect the long time elapsed between the onset of the pathological process and the onset of overt symptomatic disease. It therefore becomes imperative to identify the primary targets of disease-causing proteins in this preclinical stage…A lengthy presymptomatic period with compromised cellular and associated neural network dysfunction, possibly arising in the perinatal period, opens a potentially important window for neuroprotective intervention that might allow rescue of dysfunctional but not yet dead neurons. It is even possible that many of the agents previously trialled, which have failed to show benefit in overt ALS, if given very early, may have neuroprotective properties.”