NeuroImmune Transmitters: Histamine

It’s allergy season, and that means antihistamines will be flying off drugstore shelves.  Antihistamines are often one of the first-line therapies used by allergy sufferers.  These histamine receptor antagonists, work by blocking histamine activity and signaling.  Histamine is best known for being released by mast cells during inflammatory responses, especially allergic reactions.  It is known that histamine synthesis and release is influenced by cytokines (IL-1, IL-3, IL-12, IL-18, TNF-α), but histamine’s role in immunoregulation is not completely understood.  Conditions at the cellular level, including receptor types, influence histamine activity on the immune system.  Below is a sampling of the interaction between histamine and immune system activity.

• O’Mahony et al. (2011) identified some of the effects histamine receptors had on the immune system.  Histamine 1 receptor (H1R) activation, a major player in immediate hypersensitivity, is preceded by upregulation of IL-3, IL-4 and histamine itself.  H2R can antagonize H1R effects and is found in the central nervous system (CNS).  However, too little histamine can result in the downregulation of H2R, leading to poor immune modulation.  H3R, also found in the CNS, is responsible for histamine’s role in the sleep-wake cycle, cognition, and inflammation regulation.  H3R deficiencies result in increased expression of macrophage inflammatory protein 2, IFN-10, and CSCR3 by T cells.  The authors also stress that healthy histamine levels are very important as both excess and deficiency are indicative of immune issues.
• Elevated histamine levels are associated with functional gastrointestinal (GI) disorders.  An article by Akhavein, et al (2012), found that high levels of histamine were associated with high levels of mast cells found in biopsies of the stomach, small bowel, and colon of individuals presenting with abdominal pain, early satiety, and nocturnal awakening.

Histamine is strongly associated with upregulated immune activity, especially of mast cells.  When you see an imbalance in urinary histamine levels, make sure to consider possible immune issues.

References

Akhavein, M.A., et al. (2012). Allergic mastocytic gastroenteritis and colitis: an unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterol Res Pract, Epub ahead of print (March 12).

O’Mahony, L., et al. (2011). Regulation of the immune response and inflammation by histamine and histamine receptors. J Allergy Clin Immunol, 128(6): 1153-62.

Another Autoimmune Success Story

Check out this case review by Dr. Peterson using stimulated cytokine testing!

Reblogged from Living Wellness

Several years ago I went to the ER because the tip of my finger turned blue.  The doctor said I had Raynauds, an autoimmune condition that affects the circulation in your hands and a positive blood test for Scleroderma…..my world began to fall apart.

Over the next few years I had numerous tests:  blood, urine, a barium swallow, an arteriogram of my upper extremities, doppler flow studies, stress testing, and the list goes on.  I was evaluated by the top rheumatologist in town who is expert in the field of Scleroderma.  I was also evaluated by a microvascular hand surgeon because not only did I have Reynaud’s but the arteriogram showed I was missing half the arteries in my hands and forearms (congenital defect).  The vascular insufficiency coupled with the autoimmune condition, landed me in the operating room on three different occasions for sympathectomies….a peeling away of the sympathetic nerve chain from the artery to improve blood flow.  My surgeon told me that my autoimmune system had turned on and was not able to turn off.  Without the surgery I could lose my finger.

The autoimmune symptoms in my hands were severe….both hot and cold would trigger the symptoms…..my fingers would turn white, blue or purple…..the ischemic pain was severe, it was like having a heart attack in my fingers. I developed ischemic ulcers resulting in tissue death and would have to have surgery to stop the ulcers from growing.  During autoimmune flare-ups (cytokine storms) my acrylic overlays would not bond to my nails.  A manicure that should last for two weeks only lasted five days for me.  There were times during my cytokine storms that some of my fingernails would partially detach from my nail beds.  I also began developing similar vascular symptoms in my feet waking up in the middle of the night with severe cramps.

My Rheumatologist said that although I have a positive blood test for Scleroderma and also Reynaud’s I did not have all the diagnostic criteria for the disease.  I asked how could that be and she said unfortunately there are probably a lot of people like me walking around with the same problem.  I left with no answers to my questions feeling scared, frustrated, and sick.  I felt like I was chasing my tail.  It seemed as though every time I left a doctor’s office they were scratching their head with a puzzled look on their face and I felt hopeless.

Thankfully, I met Dr. Peterson!!!!  He has given me answers, but more importantly HOPE!  Dr Peterson is an expert in autoimmune diseases. He was able to identify the root cause of my condition, develop a treatment plan, and today I can say that my autoimmune system is quiet and I feel good.  My ischemic symptoms are improving, my nails are reattaching, and the ulcers have repaired on their own and recently have stopped appearing. I no longer have cramps at night, and have not had to see the surgeon in over a year.  I no longer feel scared and desperate. Thanks to Dr. Peterson, his knowledgeable staff, and my ability to understand how to care for my autoimmune condition I feel in control of my life again.

Before & After Lab Testing

Fig. 1: Stimulated Cytokine panel during Autoimmune flare-up. Red = Immune Stimulation, White = Normal, Blue = Immune-suppression

We see changes not only in her hands. But in her lab testing as well. In Fig. 1, there is a overall “Base” – line TH1, TH2 & TH17 immune stimulation.  There is a “PHA” TH1, TH2 & TH17 immune stimulation when exposed to Lectins. In addition to “LPS” TH1, TH2 & TH17 immune stimulation when exposed to bacteria. The three types of immune stimulation made it impossible to escape or get any relief from her insensate cytokine storms. She didn’t mention the extreme vertigo she was experiencing in her story at this time. She was suffering from Cytokine-Induced Sickness Behavior where her body was shutting down as a ineffective means of protection.

Fig. 2: Stimulated Cytokine panel six months after cytokine storms have subsided. See the After Hand above. Red = Immune Stimulation, White = Normal, Blue = Immune-suppression

In Fig. 2, her “Base” immune response in normal, and her “PHA” & “LPS” immune response are immune suppressed. The immune suppression is controlling her immune response to lectin and bacteria exposure. She was diligent in taking the nutritional support for the cytokine storm, in addition to strictly following the gluten free, lectin free, & dairy free diet. This does not occur over night as you can see this was an eleven month struggle with many ups and downs during the first four months.

She has found that something as insignificant as emotional distress among other things can cause slight dizziness or for her hands to burn. When this occurs, she has learned to control her emotional response and increases her maintenance dosage of the cytokine storm nutritional support until the storm subsides.

Autoimmune cytokine storms in time with proper nutritional support and diet can be managed. Allowing suffers to maintain a more normal lifestyle through diet and exercise with minimal nutritional supplementation.

If you are looking for help in managing your Autoimmune condition, call 636.227.4949 today. One of our professional healthcare managers will be happy to triage your questions. Visit our Website: stlwa.com

Recreational substance use and neurotransmitters

Nervous system imbalances can lead to cravings, such as the desire to abuse recreational substances.   However, engaging in recreational substance use can also lead to changes in nervous system function and ultimately nervous system imbalances.

A number of neurotransmitters have been implicated in patients who engage in recreational substance use.   Glutamate, dopamine, serotonin, acetylcholine and norepinephrine have all been shown to contribute to cravings and urges through their respective roles in the pleasure and reward pathways of the nervous system.

It is important to recognize that recreational substance use can impact neurotransmitters, and psychological and physiological effects of recreational substance use are mediated by changes in the nervous system.  A brief overview of  some of the effects on neurotransmitter systems is listed here and additional resources can be found below.

Alcohol

• Binds GABA receptors as an agonist
• Blocks glutamate receptors ( antagonist)
• Increases dopamine release

Cannabis (marijuana)

•  THC (tetrahydrocannabinol) binds to cannabinoid receptors and interferes with neurotransmitter systems
• Decreased compensatory neurotransmitter release and leads to increased dopamine release

Cocaine

• Strong central nervous system(CNS) stimulation through inhibition of catecholamine (dopamine, norepinephrine, epinephrine) reuptake
• Dramatically increases extracellular dopamine concentrations
• Interferes with serotonin and norepinephrine reuptake

Heroin

• Metabolizes to morphine and interacts with opioid receptors
• Prevents compensatory control of dopamine resulting in increased dopamine release
• Reduces norepinephrine release

Ketamine

• Blocks NMDA (N-methyl-D-aspartate) glutamate receptor (antagonist)
• May activate opioid receptors
• Increases CNS glutamate levels
• Increases norepinephrine and dopamine activity and prevents dopamine reuptake
• Inhibition of cholingeric transmission

LSD

• Binds serotonin receptor as a partial agonist
• Binds dopamine and norepinephrine receptor as an agonist
• Increases central norepinephrine release

MDMA (Ecstasy)

• Taken up by serotonin transporters and alters transporter function
• Increases synaptic serotonin
• Neurotoxic to serotonin-producing neurons
• Mild stimulatory effect by inhibiting reuptake of serotonin, dopamine, and norepinephrine

Methamphetamine

• Increases synaptic dopamine, norepinephrine, and serotonin levels
• Resembles dopamine and is taken up through reuptake transporters forcing high amounts of dopamine out of the cell and into the synapse

For more information on how recreational substance use can impact the nervous system, please view these helpful links:

Mouse Party (http://learn.genetics.utah.edu/content/addiction/drugs/mouse.html)

Drugs and Human Performance Fact Sheet (http://www.nhtsa.gov/people/injury/research/job185drugs/index.htm)

U.S. Department of Justice, DEA 2008 Annual Report (http://www.deadiversion.usdoj.gov/nflis/2008annual_rpt.pdf)

National Institute on Drug Abuse:  The Science of Drug Abuse and Addiction  (http://www.drugabuse.gov/drugs-abuse)

National Survey on Drug Use and Health:  Findings  (http://www.oas.samhsa.gov/nsduh/2k8nsduh/2k8Results.pdf)

MedLinks MIT Student Health Pharmacology Reference (http://ocw.mit.edu/ans7870/SP/SP.236/S09/lecturenotes/drugchart.htm)

Additional References

Schobel S. Chaudhury N.H. Khan U.A.  Paniagua B. Styner M.A. Asllani I. Inbar B.P.  Corcoran C.M. Lieberman J.A. Moore H. Small S.A.  Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver.  Neuron. 2013;78:81-93.

The Truth about Low Mood and Urinary Serotonin Levels

Last week’s post about serotonin and the immune connection got me thinking about the clinical utility of evaluating urinary serotonin levels. I have recently been fielding calls from practitioners questioning the value of urinary serotonin measures for patients with depression. 

I find urinary serotonin measures to be very valuable for patients suffering from depression and other mood disorders.  Just over a year ago a study was published in the respected journal Analytical and Bioanalytical Chemistry by Nichkova, et al. at Pharmasan Labs entitled, “Evaluation of a novel ELISA for serotonin:  Urinary serotonin as a potential biomarker for depression.”  This original research demonstrated a significant link between depression and low urinary serotonin levels.

In fact, Psychology Progress (a forum to alert the scientific community of breaking journal articles considered to the best in psychology research) recently featured this Pharmasan Labs publication as a significant contributor in the study of depression.  A full text copy of the article is available here.

The Pharmasan Labs study reviewed serotonin concentrations in urine for 60 depressed individuals and 60 healthy controls.  The depressed population was found to have significantly lower levels of urinary serotonin as compared to the control population.

Furthermore, the study evaluated the clinical utility of using urinary serotonin measures to monitor the efficacy of serotonin-focused treatments.  46 depressed patients were evaluated based upon three treatment classes:  5-hydroxytryptophan (5-HTP) supplementation, selective serotonin reuptake inhibitor (SSRI) usage, or a combination therapy (both 5-HTP and SSRI).  Urinary serotonin measures were significantly higher in treatment groups when compared to the control group. The authors concluded that urinary serotonin measures can be effectively used to evaluate and guide treatment for depressed patients.

Peer-reviewed literature supports the clinical utility of urinary serotonin levels for evaluating and guiding treatment for depressed patients as well as monitoring the efficacy of these treatments.  The research and development team at Pharmasan Labs works tirelessly to offer high-quality research-supported laboratory testing.  Future publications will reveal additional Pharmasan Labs’ efforts in the R & D arena.  Their comprehensive test menu and wide-ranging services are tailored to support the needs of research institutions and healthcare businesses.  Pharmasan Labs, Inc. is certified by the Clinical Laboratory Improvement Amendments program (CLIA) and the New York State Department of Health.

More information about urinary neurotransmitter measures can be found below.

www.pharmasan.com

https://www.neurorelief.com/index.php?p=testing

Neurotransmitters excreted in the urine as biomarkers of nervous system activity: Validity and clinical applicability

Studies on the immune response and preparation of antibodies against a large panel of conjugated neurotransmitters and biogenic amines: specific polyclonal antibody response and tolerance

Novel ELISAs for Screening of the Biogenic Amines GABA, Glycine, B-Phenylethylamine, Agmatine, and Taurine Using One Derivatization Procedure of Whole Urine Samples

NeuroImmune Transmitters: Serotonin

Have you ever been sick and irritable about every little thing, even toward those who are trying to help you feel better?  Low serotonin levels may be to blame.  Low levels of serotonin are associated with complaints such as mood issues/swings, anxiousness, sleep disturbances, or difficulty regulating temperature.  Interestingly, serotonin signaling is affected by chronic inflammation.  Serotonin levels drop in individuals with chronic inflammation due to the shunting of tryptophan into the “kynurenine pathway” (see Figure 1 below), which can contribute to symptoms associated with low serotonin.

Figure 1. Kynurenine Pathway. Tryptophan can be converted into 5-HTP or kynurenine. Pro-inflammatory cytokines can activate the enzyme indoleamine 2,3-dioxygenase (IDO) and shunt tryptophan away from conversion to 5-HTP into the kynurenine and quinolinic acid pathway.

• Dantzer et al. (2008) found that high levels of pro-inflammatory cytokines led to decreased serotonin synthesis by shunting tryptophan into the kynurenine pathway.
• Maes et al. (2011) also found that activation of IL-6, IFN-γ, TNF-α, and oxidative stress in the body can lead to activation of IDO, and an increased cortisol (which is also indicative of immune up-regulation) can increase the activity of tryptophan dioxygenase (TDO), both of which shunt tryptophan into the kynurenine and quinolinic acid pathways.  This leads to a reduction in endogenous serotonin synthesis.

Low serotonin levels, especially in combination with other signs of immune upregulation (see our previous NeuroImmune Transmitters posts, and watch for additional posts), can be an indicator of immune activation because of the shunting of tryptophan into the kynurenine and quinolinic acid pathways.  Be sure to consider possible immune triggers when addressing a low serotonin.

References

Dantzer, R., et al. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews, 9: 46-57.

Maes, M., et al. (2011). The new serotonin hypothesis of depression: Cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Progress in Neuro-psychopharmacology & Biological Psychiatry, 35(3): 702-21.

NeuroImmune Transmitters: Norepinephrine

It is becoming clear that neurotransmitters play a greater role in the immune system than previously thought.  Norepinephrine is a catecholamine with multiple roles including acting as a hormone and neurotransmitter.  It is best known for its role in the fight-or-flight stress response along with epinephrine, but its role in modulating neuroinflammation is just becoming better understood.  Below are reviews of studies that have uncovered some of norepinephrine’s immunomodulatory effects.

• Rommelfanger, et al. (2007) report that norepinephrine suppresses the expression of proinflammatory molecules, such as TNF- α and IL-1β, and elevates the expression of anti-inflammatory molecules, such as IκB, by signaling through α1-, α2-, and β-adrenergic receptors on astrocytes and glia.  This regulates expression of inflammatory genes and nitric oxide (NO), which are thought to contribute to neurodegenerative diseases.
• A study by Takayanagi, et al. (2012) has found that norepinephrine regulate intestinal mucosal immune responses.  Norepinephrine suppresses the production of IFN-γ and TNF-α in murine intestinal intraepithelial lymphocytes via the β1 adrenoceptor in murines.
• The 2003 review by Pavlov, et al. also discusses the impact of norepinephrine on the immune system.  A major noradrenergic center of the brain is the locus coeruleus (LC), which signals to sympathetic preganglionic cholinergic neurons in the spinal cord.  Some of these sympathetic nerve endings release norepinephrine, which has been found to have anti-inflammatory effects by interacting with the adrenoceptors expressed on lymphocytes and macrophages.  In this way, norepinephrine has activity at both ends of the pathway: initiating the signaling from the LC and interacting with the immune adrenoceptors to have an immunomodulatory effect.

Norepinephrine’s role in modulating the immune system and more specifically, neuroinflammation, should be considered when reviewing a urinary neurotransmitter test result.  It is not uncommon to see elevated urinary norepinephrine levels in patients with acute or chronic inflammation or with an active immune system.  Potential causes of inflammation should be considered when elevated norepinephrine levels are found, especially if a patient presents with persistently elevated levels.

References

Pavlov, V.A., Wang, H., Czura, C.J., Griedman, S.G., and Tracey, K.J. (2003). The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation. Molecular Medicine, 9(5-8):125-34.

Rommelfanger, K.S., Weinshender, D. (2007). Norepinephrine: The redheaded stepchild of Parkinson’s disease. Biochemical Pharmacology, 74(2):177-90.

Takayanagi, Y., Osawa, S., Ikuma, M., Takagaki, K., Zhang, J., Jamaya, Y., Yamada, T., Sugimoto M., Furuta, T., Miyajima, H., Sugimoto, K. (2012). Norepinephrine suppresses INF-γ and TNF-α production by murine intestinal intraepithelial lymphocytes via the β1 adrenoceptor. Journal of Neuroimmunology, 245(1-2):66-74.

Horror autotoxicus: The story of autoimmunity

Autoimmunity has become a well-known concept in our modern world, although it was not widely accepted in mainstream medicine until the 1950s and 1960s.   Many of us have a general idea what the term means or can list a number of autoimmune conditions.

Paul Erlich, German Immunologist

Diseases such as multiple sclerosis (MS), systemic lupus erythmatosis (SLE), type 1 diabetes, Hashimoto’s thyroiditis, Sjogren’s syndrome, rheumatoid arthritis (RA), Crohn’s disease and celiac disease are now widely recognized.  Over 23.5 million Americans have an autoimmune disease, and autoimmune diseases have been identified in virtually every organ system.

What is autoimmunity?  It literally means “immunity against self” or an immune system mistakenly attacking healthy tissue.  The German immunologist and Nobel Laureate, Paul Ehrlich (1845-1915), coined the term horror autotoxicus “the horror of self-toxicity” to describe the body’s aversion to immunological self-destruction.  Our bodies are equipped with powerful defenses against invading microorganisms like viruses and bacteria.   We have protective mechanisms directing the immune system to distinguish between “self” and “non-self,” preventing the immune system from attacking and destroying healthy tissue.

Factors that can contribute to autoimmune disease

During an autoimmune reaction, this recognition of “self” is impaired, resulting in an increased immune response.  While we all have a small degree of autoimmunity occurring within our bodies, autoimmune diseases develop when benign autoimmunity progresses to pathogenic autoimmunity.

The puzzling question of why our immune systems would initiate an attack on our own tissues is an area of ongoing research.  Autoimmunity has been attributed to a number of suspected causes including genetic susceptibility, environmental triggers, and immune dysregulation.  While these causes can overlap and interact, there is at this time no single causative factor.

Autoimmunity can contribute to a number of symptoms

Autoimmune disease symptoms wax and wane, and signs can vary greatly from patient, making diagnosis difficult.  Flare ups, or periods of worsening symptoms,  are often interspersed with periods of remission or few to no symptoms.  Initial autoimmunity symptoms include:  fatigue, unexplained rashes, abdominal pain, low grade fever, and malaise, among others.  A classic indicator of autoimmunity is inflammation, which may lead to redness, heat, pain or swelling of the affected tissue.

Autoimmunity can be identified by the presence of autoantibodies that are part of the immune reaction to “self.”

A number of lab test parameters are useful.  The chart below (click for larger image) provides a summary of autoantibody clinical correlations.

A summary of autoantibody clinical correlations

Combining clinical observations, general autoimmune lab tests and disease-specific markers, clinicians improve their chances to diagnose a patient’s autoimmune disease.

References:

Paul Erlich Image Source: Bildarchiv Bayerische Staatsbibliothek, Portrat-und Ansichtensammlung, Bild-Nr. port-003494

Bell, E. and Bird, E. (2005). Autoimmunity. Nature Reviews, 7042:583.

Johns Hopkins Autoimmune Research Center. (September 10, 2001). What is autoimmunity? Retrieved from: http://autoimmune.pathology.jhmi.edu/whatisautoimmunity.html

National Institutes of Health. (March 8, 2013). Autoimmune diseases. Medline Plus. Retrieved from: http://www.nlm.nih.gov/medlineplus/autoimmunediseases.html

Importance of methylation for neurotransmitter synthesis

Did you know that methylation plays a role in facilitating detoxification (especially in the liver), is important for proper functioning of the hypothalamic-pituitary-adrenal (HPA) axis, and helps determine which genes are expressed in your body? Methylation is a topic of great interest in the health care world today, as the addition of a methyl group is vital to a wide variety of biological processes.

A variety of factors including stress, nutritional deficits, certain diseases, and genetics can contribute to insufficient methylation.  Poor methylation can result in a reduced ability of the body to make monoamine neurotransmitters and to remove toxins and metabolic waste.  This can lead to a wide variety of symptoms including low mood, anxiousness, sleep issues, fatigue, and decreased cognition.  Regaining appropriate neurotransmitter synthesis by supporting methylation pathways can lead to increased health and the improvement of symptoms.

Let’s take a closer look at methylation processes in our body.

Methylation is important for neurotransmitter formation

Methylation is critical for the synthesis of all monoamine neurotransmitters as well as histamine.  For example, the enzyme that converts norepinephrine to epinephrine, phenylethanolamine N-methyltransferase, requires SAMe as a cofactor for activation.  The folate and biopterin (BH4) cycles (Figure 1) help ensure adequate monoamine neurotransmitter production.  Biopterin is necessary for the conversion of tryptophan to 5-hydroxytryptophan (5-HTP), phenylalanine to tyrosine, and tyrosine to L-DOPA (L-3,4-dihydroxyphenylalanine).

Figure 1. The methionine, folate, and biopterin cycles function coordinately to facilitate the production of methyl groups for key biomolecules and to drive the biosynthesis of a variety of neurotransmitters. Left: the methionine cycle is vital to the overall process of methylation. The derivative of methionine, SAMe, serves as the main methyl donor in the methylation pathways. The methionine cycle also facilitates the synthesis of homocysteine, which is an intermediate int he production of taurine and glutathione. Center: the folate cycle converts folate into 5-MTHF by utilizing MS, vitamin B12, as well as MTHFR. Right: the bipterin cycle also utilizes MTHFR as a reaction enzyme. BH4 is a cofactor involved in the production of the catecholamine neurotransmitters and serotonin.

Epigenetics affect methylation

Epigenetics is the study of heritable changes that occur without a change in the DNA sequence.  Waterland and Jirtle (2003) performed a study on agouti mice; mice that carry the agouti gene are ravenous, yellow, and prone to cancer and diabetes.  The study found that when the diet of the pregnant agouti mothers was supplemented with methyl donors (folic acid, vitamin B12, choline, and betaine) the deleterious agouti gene was dimmed in the offspring.  This made the offspring slender and mousy brown without their parents’ susceptibility to cancer and diabetes.

Oxidative stress affects methylation

A study by Panayiotidis and colleagues (2009) found that low and moderate levels of oxidative stress significantly decreased levels of SAMe in lung epithelial cells.  However, when oxidative stress was severe, concentrations of SAMe were increased, despite severe methionine depletion.  The researchers concluded that the high levels of SAMe released were probably an adaptive response to increased oxidative stress.

 

While each of these points highlights an aspect of methylation in health, the overall theme is that methylation is vital to a wide variety of biological processes. Without proper methylation, there can be impacts on neurotransmitter synthesis, metabolic activity, and gene expression.  Insufficient methylation can also lead to a wide variety of symptoms such as low mood, anxiousness, sleep issues, fatigue, and decreased cognition.  Supporting healthy neurotransmitter synthesis with methyl donors can lead to increased overall health as well as the improvement of symptoms.

 

References

Bottiglieri, T. (2002). S-Adenosyl-L-methionine (SAMe): from the bench to the bedside—molecular basis of a pleiotrophic molecule1–3. Am J ClinNutr., 76, 1151S–7S.

Deloughery, TG, Evans, A., Sadeghi, A., McWilliams, J., Henner, WD., Taylor, L.M. Jr., Press, R.D. (1996). Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease. Circulation., 94(12), 3074-8.

Krzystanek, M., Pałasz, A., Krzystanek, E., Krupka-Matuszczyk, I., Wiaderkiewicz, R., Skowronek R. (2011). [S-adenosyl L-methionine in CNS diseases]. Psychiatr Pol., 45(6), 923-31.

Levkovitz, Y., Alpert, J.E., Brintz, C.E., Mischoulon, D., Papakostas, G.I. (2011). Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. Eur Psychiatry., 136(3), 1174-8.

Panayiotidis, MI, Stabler, SP, Allen, RH, Pappa, A, White, CW. (2009). Oxidative stress-induced regulation of the methionine metabolic pathway in human lung epithelial-like (A549) cells. Mutat Res, 674(1-2), 23-30.

Pancheri, P., Scapicchio, P., Chiaie, R.D. (2002). A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Int J Neuropsychopharmacol., 5(4), 287-94.

Papakostas, G.I., Mischoulon, D., Shyu, I., Alpert, J.E., Fava, M. (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 167(8), 942-8.

Reynolds, E. (2006). Vitamin B12, folic acid, and the nervous system. The Lancet Neurology., 5(11), 949-960.

Waterland, RA, Jirtle, RL. (2003). Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol, 23(15), 5293-300.

Wurtman, RJ, Pohorecky, LA, Baliga, BS. (1972). Adrenocortical control of the biosynthesis of epinephrine and proteins in the adrenal medulla. Pharmacol Rev, 24(2), 411-26.

Additional Resources

Part of this blog post was based off the white paper “Methylation: Fundamental to a Healthy Nervous System”

NeuroImmune Transmitters: Glutamate

A common contributing cause of increased excitatory stimulation is elevated glutamate as a result of an overly active immune system. Glutamate is highly excitatory and is described as “excitotoxic” because elevated levels can damage neurons.  Elevated glutamate could be a root cause behind calming neurotransmitter (serotonin and GABA) imbalances and a consequence of imbalances in the immune system. Glutamate is highly influenced by the presence of both acute and chronic inflammatory responses. Glutamate is released upon over-activation of the kynurenine pathway by quinolinic acid (Figure 1) and from dendritic cells binding to antigens or dendritic cell maturation.  Glutamate binds directly to receptors on T cells and at concentration dependent doses affects their function to either enhance cytokine secretion (at mid to high glutamate concentration) or decrease cytokine secretion (at very high glutamate concentration).  Below, examples of glutamate’s association with the immune system will be explored

• 

  Figure 1. A peripheral inflammatory response is suggested to increase quinolinic acid from microglial cells, which is associated with increased glutamate release and decreased glutamate reuptake. (Image from Miller et al. 2009)

  Muller, et al., in 2007, described an integrated view of depression.  Activation of the kynurenine pathway by IL-2, IFN-γ, or TNF-α causes increases in indoleamine 2,3-dioxygenase (IDO) activation.  IDO is the enzyme responsible for the conversion of tryptophan to N-formylkynurenine, the start of the kynurenine pathway.  This increase in IDO activation leads to an increase of quinolinic acid in microglial cells, which can then overproduce glutamate in people with impaired astrocyte response to immune challenge causing an inflammatory response reaction.

• Steiner, et al. (2011) found that severe depression is associated with increased microglial quiolinic acid in subregions of the anterior cingulate gyrus and hypothesized that this could be evidence for immune-modulated glutamatergic neurotransmission.
• Franco, et al., (2007) describes the role of glutamate in T cell mediated immunity.  There are a number of glutamate receptors on resting T cells, including the ionotropic glutamate receptor 3 (iGlu3R) and metabotropic glutamate receptor 5 (mGlu5R).  Stimulation of iGlu3R promotes a pattern of adhesion and migration towards certain chemokines, and stimulation of mGlu5R impairs T cell activation.  Mature, glutamate-releasing dendritic cells in lymph nodes encounter patrolling naïve T cells and can promote T cell activation; however mGlu5R prevents excessive activation when dendritic cell signaling is not strong enough to promote activation.  When T cells become activated, the granzyme B they release degrades iGlu3R.  T cells also express metabotropic glutamate receptor 1 (mGlu1R), which promotes T cell activation partly by bypassing the mGlu5R-mediated inhibitory signal to potentiate T cell proliferation and enhancing the secretion of TNF-α, IFN-γ, and IL-6.  In this way, depending on the activation state of a T cell, glutamate can have an inhibitory or stimulating role on immune function.

Glutamate, in addition to acting as an excitatory neurotransmitter, also plays a role in immune function and modulation.  Increased glutamate is released in response to over-activation of the kynurenine pathway and quinolinic acid, which suggests evidence for immune-modulated glutamatergic neurotransmission.  Glutamate can also bind directly to T cell receptors to enhance or decrease cytokine secretion leading to immune modulation. When reviewing urinary neurotransmitter test results, it is important to keep in mind the immune system’s connection to glutamate. If patients are found to have elevated glutamate levels, root causes to immune system imbalances may need to be factored into differentials and further testing considerations.

References Franco, R., et al. (2007). The emergence of neurotransmitters as immune modulators. Trends in immunology, 28(9):400-7.

Miller, A.H., Maletic, V., Raison, C.L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry, 65(9):732-41.

Muller, N., Schwarz, M.J. (2007). The immune-mediated alteration of serotonin and glutamate: Towards and integrated view of depression. Molecular Psychiatry, 12(11):988-1000.

Steiner, J., et al. (2011). Severe depression is associated with increased microglial quiolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?. Journal of Neuroinflammation, 8:94.

Beneficial Properties of Licorice Root

We all have days where we feel a little low on energy and motivation; this is understandable when you take a look at the schedules people try to keep up with these days. After working nine hours, running errands, making sure kids get where they need to be, making dinner, cleaning up, enforcing homework time, and attempting to keep up with the housework, it’s really no wonder that some of us feel like we need a few more hours in a day! However, if this feeling of chronic tiredness seems to persist for more than a few days or when on relatively calm occasions, it may be caused by something more than just a hectic lifestyle.

Adrenal Fatigue
Dr. James Wilson coined the term “adrenal fatigue” to describe a chronic lack of energy (along with a variety of associated symptoms). According to Dr. Wilson, about 80% of people will experience this condition at some point in their lives. Here at NeuroScience we are passionate about researching ingredients that address specific imbalances within the body associated with adrenal fatigue.

Licorice Root
Our latest ingredient of interest is licorice root (glycyrrhizic acid). This ingredient works by inhibiting the conversion of cortisol to inactive cortisone; therefore, supporting adequate cortisol levels in patients with suboptimal levels due to the effects of adrenal fatigue.

Looking beyond the cortisol-supporting properties of licorice root, we would like to point out a few other benefits of this ingredient.  Licorice root has been used as a key herb in traditional Chinese medicine for over three thousand years. It was used as a treatment to rejuvenate the heart and spleen, aid in the treatment of ulcers, coughs, colds, and digestive complaints. In addition to supporting cortisol levels and adrenal function, here are a few other beneficial properties of licorice root that make it a valuable addition to a variety of patient protocols.

Licorice has anti-inflammatory properties
There have been a variety of studies that have investigated the anti-inflammatory and immuno-modulatory properties of licorice root (glycyrrhiza):

• Martin and colleagues (2008) performed a randomized, double-blind clinical trial for the use of glycyrrhiza in the treatment of recurrent aphthous ulcers (canker sores). They observed  that the group treated with glycyrrhiza reported lower pain levels as well as significantly reduced ulcer size.
• Messier and colleagues (2012) also reported on the potential beneficial effects of licorice on treating/preventing oro-dental diseases, such as dental cavities, periodontitis, and candidiasis. Wenyuan Shi, PhD, a micorbiologist at UCLA’s School of Dentristry states, “More studies are needed before it is proven that the compounds effectively fight cavities in humans. If further studies show promise, the licorice compounds could eventually be used as cavity-fighting components in mouthwash or toothpaste.”
• The Journal of Drugs in Dermatology July edition reports that licorice is effective for use in treatment of rosacea, atopic dermatitis, irritated skin, drug-induced skin eruptions, and psoriasis.

Licorice helps regulate blood sugar and may help counteract Type 2 Diabetes

• Glucocorticoids help regulate the activity of phosphoenolpyruvate carboxykinase (PEPCK), an enzyme that is used in the metabolic pathway of gluconeogenesis.  PEPCK is associated with the pathogenesis of metabolic syndrome when dysregulated.
• Researchers (Chia, 2012) noted that treatment with glycyrrizic acid led to a decrease in blood glucose, as well as reduced adipocytes in subcutaneous and visceral deposits.  They concluded that glycyrrizic acid may help counteract the development of type 2 diabetes mellitus by improving insulin sensitivity.

Licorice can be beneficial in cases of hypotension

• One of the symptoms of insufficient adrenal function is hypotension.  Licorice is known to support adrenal function and has also been shown to raise blood pressure (Al-Dujaili 2010). Due to this effect, patients that are prone to hypertension should not use licorice, or only do so under the guidance of a healthcare practitioner.

Hopefully this entry has given you some new and useful information about licorice root and reminded you of the effects of adrenal fatigue. Adrenal function plays a significant role in overall health and wellbeing, so if you find yourself or a patient experiencing symptoms that go beyond the effects of a jam-packed schedule, remember this ingredient as a possible intervention. As demonstrated above, licorice root is a very useful ingredient with a wide variety of beneficial properties including supporting healthy cortisol levels.

→ Testing for adrenal fatigue

References

Al-Dujaili, EA, et al. (2010). Liquorice and glycyrrhetinic acid increase DHEA and deoxycorticosterone levels in vivo and in vitro by inhibiting adrenal SULT2A1 activity. Mol Cell Endocrinol, 336(1-2), 102-9.
Chia, YY, et al. (2012). Amelioration of glucose homeostasis by glycyrrhizic acid through gluconeogenesis rate-limiting enzymes. Eur J Pharmacol, 677(103), 197-202.
Martin, MD, et al. (2008). A controlled trial of a dissolving oral patch concerning glycyrrhiza (licorice) herbal extract for the treatment of aphthous ulcers. Gen Dent, 56(2), 206-10.
Messier, C, et al. (2012). Licorice and its potential beneficial effects in common oro-dental diseases. Oral Dis, 18(1), 32-9.
Murphy S.C., Agger S., Rainey P.M. (2009). Too much of a good thing: a woman with hypertension and hypokalemia. Clin Chem, 55(12):2093-6.
Ploeger, B, et al. (2001). A Population Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Inhibition of 11-beta-Hydroxysteroid Dehydrogenase Activity by Glycyrrhetic Acid. Toxicology and Applied Pharmacology, 170, 46-55.
Zhang, Y, et al. (1999). Effects of glycyrrhizin on blood pressure and its mechanisms. Zhonghua NeiKe ZaZhi, 38(5), 302-5.

Restless Legs Syndrome and the dopamine connection

We’re nearing the summer solstice, and putting my kids to bed when it’s still light outside poses a definite challenge in my household. I’ve always wondered how parents living in places like Sweden or Iceland get their children to sleep when it’s light all night long…

Eventually the little ones do settle down and get a good night’s sleep. “Too bad that’s not the case for those who suffer from restless legs syndrome,” my NeuroScience colleague Deanna Fall told me. RLS, or Willis-Ekbom disease, is a neurological condition characterized by uncomfortable sensations of itching, burning, pulling, crawling, or creeping. This can affect not only the legs, but also the arms and other parts of the body. This sensation usually occurs at night, but really can happen during any period of inactivity.

I asked Deanna to tell us more about RLS, and she summarizes her findings here.

RLS can cause a variety of social and psychological issues, and can create safety risks to sufferers and those around them. That’s because RLS can greatly impact sleep quality, and quality of life overall. More than 80% of individuals with RLS suffer from periodic limb movement during sleep that can interrupt the sleep cycle. RLS sufferers are more likely to drive while drowsy, and have reported that their performance at work has been affected by being late or making mistakes due to RLS-associated insomnia.

Who gets RLS? It’s been estimated that up to 10% of the population may be affected, especially in those over 65; while it occurs in both men and women, the incidence is about twice as high in women. Stress can make the symptoms of RLS worse. RLS is often associated with pre-existing conditions such as:

• obesity
• diabetes
• kidney disease
• anemia
• Parkinson’s disease
• rheumatoid arthritis
• pregnancy
• infection of the central and/or peripheral nervous system (and resulting inflammation)

There’s also a genetic component to RLS, with variants in several genes including BTBD9 and MEIS1, both of which are implicated in iron storage and metabolism.

It comes down (again) to biochemistry

“Are there biochemical imbalances in RLS?” I asked Deanna. After all, here at NeuroScience, we like to dig down to the biochemical basis of a health issue. Absolutely, she replied. There’s considerable support for the idea that RLS is related to dopamine dysregulation – a dysfunction in the brain’s basal ganglia circuits that utilize dopamine for the regulation and control of muscle activity. Insufficient iron availability can lead to deficiencies in the dopaminergic system as well, since dopamine synthesis is dependent on iron. Magnesium and folate deficiencies have also been implicated.

So when you’re trying to find the best way to manage the symptoms of RLS, laboratory evaluation of possible dopamine or mineral deficiencies can help determine the course of treatment. Providing dopamine support with precursors such as L‑DOPA or tyrosine, or a dopamine agonist, may help to restore appropriate dopamine levels and improve symptoms associated with a lack of neurotransmission. Iron, magnesium, and/or folate supplementation can also help, especially if testing shows deficiencies. Any intervention should be complemented with non-pharmaceutical approaches such as good sleep hygiene, stretching, moderate exercise, and avoidance of alcohol, caffeine, and nicotine.

If the midnight sun is keeping you up at night, why not spend those sleepless hours learning more about RLS from these selected references Deanna’s shared.

Restless Legs Fact Sheet. National Institute of Neurological Disorders and Stroke, NIH. http://www.ninds.nih.gov/disorders/restless_legs/detail_restless_legs.htm

Allen R.P., Earley C.J. The role of iron in restless legs syndrome. Mov Disord. 2007;22 Suppl 18:S440-8.

Connor J.R., Wang X.S., Allen R.P., Beard J.L., Wiesinger J.A., Felt B.T., Earley C.J. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain. 2009 Sep;132(Pt 9):2403-12. Epub 2009 May 25.

Ryan M., Slevin J.T. Restless legs syndrome. Am J Health Syst Pharm. 2006 Sep 1;63(17):1599-612.

Weinstock L.B., Walters A.S., Paueksakon P. Restless legs syndrome – Theoretical roles of inflammatory and immune mechanisms. Sleep Med Rev. 2011 Jan 16. [Epub ahead of print]

Yun C.H., Lee S.K., Kim H., Park H.K., Lee S.H., Kim S.J., Shin C. Association between irritable bowel syndrome and restless legs syndrome in the general population. J Sleep Res. 2012 Mar 29. doi: 10.1111/j.1365-2869.2012.01011.x. [Epub ahead of print]

Zintzaras E., Kitsios G.D., Papathanasiou A.A., Konitsiotis S., Miligkos M., Rodopoulou P., Hadjigeorgiou G.M. Randomized trials of dopamine agonists in restless legs syndrome: a systematic review, quality assessment, and meta-analysis. Clin Ther. 2010 Feb;32(2):221-37.

Just can’t get enough of the Autonomic Nervous System? Read and watch!

Just a little note to let you know that we just released a white paper to accompany our educational video outlining the neurocircuitry of top-down sympathetic autonomic nervous system control. We here at NeuroScience think this stuff is fascinating – and if you’re reading this blog, I bet you do, too!

Ethan Hunt! Your locus ceruleus is calling…

On a recent date night, my husband and I took in the latest Mission Impossible movie. “That Tom Cruise character,” I marveled, watching him shimmy up the tallest building in Dubai. “He’s definitely in sympathetic overdrive. Clearly a case of ANS imbalance.” My husband looked at me with a mixture of pity and admiration and called me a nerd, which I am, but that’s OK because he’s a scientist too. Here’s what’s on our minds these days at NeuroScience…

As we mentioned in a recent post, all involuntary bodily functions are controlled by the autonomic nervous system (ANS). Because of its extensive influence, when the ANS is out of balance, it can cause a range of health issues affecting sleep, energy levels, metabolism, gastrointestinal function, cardiovascular function, psychiatric issues, and more, resulting in a wide variety of symptoms that may differ among patients based on genetic predisposition and other factors.

For this reason, many institutions have come to recognize and endorse the importance of ANS assessment, including the American Heart Association, American Diabetes Association, the National Institutes of Health, and others.

Neurocircuitry research has revealed that a dysregulated ANS can often be traced to alterations in key areas of the brain that are critical for maintaining properly balanced sympathetic (SNS) and parasympathetic (PNS) tone (we described the concept of tone in our earlier post). Investigations have shown that various disorders can be successfully addressed by targeting specific brain nuclei with rationally selected pharmacological interventions based on neurotransmitters and metabolite measurements in urine and blood (Lechin et al., 1996).

In other words, ANS imbalances, while impacting peripheral organ systems and tissues, are likely governed by central brain regions. The following examples describe two opposing profiles of ANS imbalance that can be measured in urinary neurotransmitters – and the hypothesized central causes in the brain.

• Low urinary norepinephrine combined with elevated cortisol and epinephrine – This imbalance may result from upregulated activity of specific brainstem regions including the serotonergic dorsal raphe, noradrenergic locus coeruleus, and adrenergic rostroventral lateral medulla (or C1). The C1 is known to trigger the release of epinephrine and cortisol from the adrenal glandsinto the circulation (Lechin & van der Dijs, 2008). Increased activity of C1 has an opposing effect on the noradrenergic A5 area.
• Elevated urinary norepinephrine relative to cortisol and epinephrine -
  This profile may be due to upregulated activity of the serotonergic median raphe  and noradrenergic A5, resulting in decreased activity of the locus ceruleus, RVLM, and DR. Neurons in the A5 area stimulate an increased release of  norepinephrine into the circulation and may also  decrease the release of epinephrine and cortisol  (Lechin & van der Dijs, 2008). Sound like adrenal fatigue to you?

The locus ceruleus (LC) is emerging as a very important master controller in our brainstem, because – through norepinephrine signals – it  regulates the C1 and A5 areas, which have opposing effects on SNS tone. It effectively acts as a fulcrum to keep the effects of A1 and C5  in balance.

The locus ceruleus (LC) uses norepinephrine to signal the regulation of the C1 and A5 areas, which have opposing effects on SNS tone.

When this ‘fulcrum’ is functioning suboptimally, ANS imbalances can result. In our next post, we’ll discuss some ideas for maintaining proper LC function. Which should be perfect if you’re Ethan Hunt and insist on scaling tall buildings without any ropes.

Could your ANS be in free fall?

Will you be attending the Integrative Healthcare Symposium?

The IHS (Feb 9-11 in New York City) promises once again to be one of the premier events in integrative medicine. We’re extremely proud to be  a GOLD sponsor of this symposium, and if you’re coming too, here’s a few things I’d like to let you in on.

• If you HAVEN’T yet registered for the IHS – drop me a line (by commenting on this blog entry) with your email address and I will send you a link for 10% off your registration.
• If you’re coming to the IHS, be sure to stop by our booth 108.  If you bring a friend or associate along and you both sign up a new account, we’ll enter both of you for a prize drawing for a free neurotransmitter test profile!
• Be sure to attend Dr. Scott Theirl’s talk on Saturday morning. He’ll be presenting on “Assessing and Addressing Sleep Disturbances through the Lens of the Autonomic Nervous System.” Not only is Dr. Theirl one of the most engaging and knowledgeable speakers I know, he’ll also be providing the audience a special code for a second prize drawing for free testing. Be sure to check out Dr. Theirl’s website to learn more about him!

See you in New York!

2011 in review

The WordPress.com stats helper monkeys prepared a 2011 annual report for this blog.

Here’s an excerpt:

The concert hall at the Sydney Opera House holds 2,700 people. This blog was viewed about 13,000 times in 2011. If it were a concert at Sydney Opera House, it would take about 5 sold-out performances for that many people to see it.

Click here to see the complete report.

Announcing our latest peer-reviewed publication on urinary neurotransmitter (serotonin) testing!

Get happy... test your neurotransmitters with NeuroScience

It’s always exciting to be able to talk about a new publication from our team of brilliant and hard-working scientists. So I’m thrilled to tell you that our R&D team, led by Mikaela Nichkova and NeuroScience CEO & founder Gottfried Kellermann,  recently published a report titled “Evaluation of a novel ELISA for serotonin: urinary serotonin as a potential biomarker for depression“.

Here’s some key takeaways:

• Good correlation was observed between urinary serotonin levels measured by ELISA and liquid chromatography tandem mass spectrometry.
• There was a good correlation between “spot” urine collection (a urine sample collected two hours after waking) and pooled 24 hour urine.
• Serotonin levels detected in depressed patients were significantly lower (p < 0.001) than in nondepressed subjects.
• Urinary excretion of serotonin in depressed individuals significantly increased after antidepressant treatment by 5-hydroxy-tryptophan (5-HTP) and/or selective serotonin re-uptake inhibitor (SSRI) (p < 0.01).

The article appears in the December 9 issue of Analytical and Bioanalytical Chemistry.  Happy reading!

Could it be a metal hypersensitivity? The power of the MELISA test

At NeuroScience, our appreciation of the Neuro-Endo-Immune Supersystem makes it a priority for us to help healthcare practitioners understand the contribution of chronic immune activation (inflammation) to overall health. That’s why we offer an extensive suite of immune testing, including cytokine testing, Lyme testing (MY Lyme Immune I.D.), and NEI Nutrition’s food allergy testing and intestinal barrier assessment (Type IV food hypersensitivity testing). Here’s another important component of NeuroScience’s testing portfolio – the MELISA^®. I’m just going to cover some high points here; you can learn more at www.neuroscienceinc.com/melisa.

MELISA (pronounced me-LYE-za) stands for Memory Lymphocyte Immunostimulation Assay. As you can learn at the MELISA Medica Foundation’s website, the test was originally developed for the diagnosis of occupational allergies at Astra Pharmaceuticals (now AstraZeneca). Since that time, it has proved clinically useful in identifying metal hypersensitivities that can affect our overall health in many ways.

Could this be the cause of your health issues?

Let’s start by discussing what it means to have a metal hypersensitivity. All of us are exposed to metals in our daily lives, in sometimes unexpected ways. Metals can be found in the foods we eat (and not just contaminated fish!), dental amalgams, jewelry, medications, cigarette smoke, surgical implants, occupational exposure…the list goes on and on. In some exposed individuals, certain metals that enter our bodies modify our own proteins in such a way that we develop an immune response, or hypersensitivity, to these metal-modified proteins.

Patients with documented metal hypersensitivities have a wide array of symptoms, as you would expect from someone having an chronically activated immune system along with all the potential downstream effects on neurological and cognitive health. These include:

• Persistent fever
• Chronic headaches or migraines
• Unexplained rashes
• Thyroid disorders
• Lethargy
• Impaired cognitive function
• Chronic fatigue
• Musculoskeletal pain
• Fibromyalgia

The MELISA is a way of testing whether a person has such hypersensitivity, and to which metal(s). Here’s how the test works.

1. A patient sends a blood sample into the lab.
2. Their white blood cells (immune cells) are incubated for several days with individual metals.
3. If the patient has a hypersensitivity to a particular metal, their white blood cells contain T cells that react to that metal. When these T cells re-encounter that metal in the culture, they divide (proliferate), and so there are more cells at the end of the culture period compared to a control culture with no metal added. Conversely, if there has not been a past immune response to a given metal, there will be little or no proliferation.
4. Therefore, we can assess metal hypersensitivity by measuring how much T cell proliferation has occurred in response to that metal.

The basic premise of the MELISA test

The MELISA test is distinctive from other metal tests. For one thing, metal hypersensitivity is not the same as metal toxicity. Hypersensitivity can be caused by very low amounts of metal, well below the levels considered to be toxic as detected in tests that assess metal levels in hair, nails, and bodily fluids. In addition, some metals may not be excreted in hair or nails, leading to false negative results for these types of tests.

In addition, MELISA is less likely to generate false negative results compared to other methods that aim to detect a past immune response to foreign substances, such as Clifford Materials Reactivity Testing (CMRT) that looks for antibodies to such substances. There are two reasons for this:

• While the immune system retains a “memory” of a past exposure to a metal in the form of both memory T cells and antibodies, with time this memory “dims”, to the point where antibodies may become undetectable in a serological assay. In contrast, in the MELISA assay there’s a 5-day culture that gives any residual metal-reactive memory T cells time to proliferate and expand their numbers, making them more likely to become detectable.
• In some individuals, metal hypersensitivity may only involve the cellular component of our immune system and never stimulate antibody production.

Deciding whether someone with symptoms should receive a MELISA test may sometimes be a bit of a no-brainer if there are obvious clues, like recent dental work (amalgam removal, for instance), diets high in fish, or occupations with obvious metal exposure such as plumber, electrician, hairdresser, or dentist. But as I mentioned earlier, metal exposure can come from a wide variety of sources and isn’t always obvious. If you feel like you’ve ruled out other possible root causes for patient symptoms, don’t forget that a little metal can do a whole lot of harm.

View our webinar on our neuroscienceinc YouTube channel about clinical applications of MELISA testing!

To read research articles about metal hypersensitivity, visit our PubMed collection.

What are those neurotransmitter results REALLY telling you?

In the six years that I’ve been doing consults about NeuroScience‘s urinary neurotransmitter testing, I often hear healthcare practitioners state that their patient has a “nervous system imbalance”. Most believe that the “imbalance” is due to a disparity between excitatory and inhibitory neurotransmitters. This may superficially seem to be the case, but at a deeper level, nervous system imbalances reflect abnormalities in the tone, or activity level, of the various branches of the nervous system – specifically the autonomic nervous system.

The autonomic nervous system is comprised of two branches – the sympathetic (SNS) and parasympathetic (PNS). In stress situations, it is the SNS that is primarily active and results in a “fight or flight” response. The PNS is more active in non-stress settings, and controls “rest and digest” functions. It is the balance between the two branches of the autonomic nervous system – the SNS and PNS – that is crucial for maintaining homeostasis and overall good health.

More than Just Numbers

The regular idling activity or “tone” of the SNS and/or PNS has a major impact on organ system activity, and is reflected in the peripheral neurotransmitters which we can measure as biomarkers of nervous system health. Simply put, if a person’s SNS is operating at a suboptimal activity level or tone, it is common to see a corresponding reduced level of certain peripheral neurotransmitters. Likewise, an increase in sympathetic activity or tone results in elevated levels of these peripheral neurotransmitters.

In complex cases, we may observe a multitude of neurotransmitter biomarkers having an abnormal signature; addressing each individual neurotransmitter singly would require a treatment protocol consisting of five or more different interventions. Doesn’t sound too fun (or affordable) for the patient, does it?

Autonomic nervous system balance is important for overall health.

On the other hand, by appreciating neurocircuitry, we realize that while many of the symptoms are caused by a dysregulated autonomic nervous system, the issue goes deeper (and higher) than that. That’s because the dysregulation can often be traced to alterations in the central nervous system, particularly key areas of the brain critical for keeping the SNS and PNS tone in balance.

This insight helps us understand that our patients’ symptoms may not always respond to interventions that merely increase a depleted neurotransmitter or lower an elevated neurotransmitter. Those approaches may end up being merely band-aids that don’t address the root cause. In other words, peripheral neurotransmitter biomarkers collectively report dysregulation in the central control mechanisms that keep the PNS and SNS in balance.

Consequently, we are better off employing a “top-down” approach directed at the central control. This is likely to resolve multiple symptoms that all had a shared root cause, and therefore reduce the number of interventions while improving response rates.

It’s a Balancing Act

Neurotransmitter excesses and depletions may very well be driving patient symptoms, but autonomic nervous system balance is what is truly vital for long-term positive health outcomes. Homeostasis can only be achieved if the branches of the autonomic nervous system have a healthy tone. So, when you find yourself telling a patient that their nervous system is out of balance, keep in mind that the imbalance may go deeper – and higher – than simply a high or low neurotransmitter test result.

Can’t sleep? How neurocircuitry may help.

age-adjusted percentage of adults who reported 30 days of insufficient rest or sleep during the preceding 30 days (Source: CDC).

While I love my work at NeuroScience, I also love a three day weekend, especially for that additional bit of sleep I gain before getting back to the fast pace of the work week. Did you know that sleep disorders affect an estimated 10-40% of American adults, and according to the CDC, 25-39% of us get less than 7 hours a night of sleep, including yours truly? Chronic sleep disturbances can lead to impaired concentration, cognition, memory, and coordination, as well as a host of chronic health issues.

Frustratingly, there is no “magic bullet” that brings relief to all sufferers. If you think about the neurocircuitry of sleep, this shouldn’t be a surprise – there are many points in this circuitry when things can go out of balance. Here’s a quick review.

During wakefulness, the brain is kept active and alert by the actions of neurotransmitters that include acetylcholine, norepinephrine, serotonin, dopamine, and histamine. Norepinephrine contributes to elevated energy, mood, and vigilance. Histamine promotes wakefulness and arousal. In the absence of light, the brain’s wake-promoting centers are inhibited when sleep-promoting regions of the brain release gamma amino-butyric acid (GABA) as well as melatonin, resulting in a sleep-state.

Sleep is characterized by stages of non-rapid eye movement (NREM) and rapid eye movement (REM). Here too, neurotransmitters play a role in the transition between these stages; particularly the reciprocal actions of norepinephrine and serotonin (enhancing NREM sleep) and acetylcholine (which is involved in inducing REM sleep).

In recent years, researchers have made great strides toward understanding the neurocircuitry that controls sleep-wake states. As we’ve discussed previously in this space, neurocircuitry has helped us understand some of the possible causes of sleep difficulties, for example:

• Excess release of norepinephrine and histamine results in a state of wakefulness .
• Perturbations in neurotransmitter signaling can interfere with REM/NREM oscillations, leading to impaired sleep.

Circuit Board Butterfly #16 by Truda Glatz.

Understanding the neurocircuitry of sleep has allowed researchers to identify biomarkers that can be measured for example in urine. These biomarkers can help characterize patients’ individual biochemical imbalances, as well as help healthcare practitioners select and monitor therapeutic interventions. Several correlations between central brain activity and peripheral biomarkers have been reported, such as:

• Overactivity of certain wake centers in the brain can trigger the release of norepinephrine which is reflected in urinary norepinephrine levels. Therapeutic strategies that successfully regulate norepinephrine output may help promote sleep.
• Exercise-induced increase in epinephrine correlates with a delay in REM sleep onset (Netzer, 2001), and total REM sleep is lower following exercise. Accordingly, exercise has been shown to stimulate an increase in urinary epinephrine.

Data suggests that neurotransmitter imbalances that have been associated with neuropsychological disorders, such as insufficient serotonin and elevated glutamate, norepinephrine, dopamine, and epinephrine may also contribute to sleep disturbances.  Depression has been reported to be one of the strongest risk factors for current insomnia, but it has also been suggested that current insomnia is a risk factor for future depression. Interestingly, certain therapeutic interventions that target neuropsychological disorders have also been shown to improve sleep. For example, 5-hydroxytryptophan (5-HTP), the amino acid precursor to serotonin, has been reported to promote sleep quality in patients with insomnia.

Analysis of peripheral biomarkers may also help predict who will respond to various sleep medications and/or supplements, thereby simplifying the therapeutic protocol. For example, in a study of a sleep-inducing benzodiazepine, patients who had a favorable antidepressant response had significantly higher pretreatment urinary epinephrine and norepinephrine levels than control subjects, while no such difference was found among nonresponders.

Overall, it’s become clear that individuals with sleep disorders may exhibit a spectrum of different biochemical imbalances. Using neurocircuitry to define clinically relevant peripheral neurotransmitter and hormone biomarkers, we are beginning to characterize individual patients’ imbalances, thus customizing sleep aids for better likelihood of efficacy.

Frequent readers of this blog will notice the unusual absence of references in this post! That’s because it was adapted from the white paper we wrote earlier this year about the neurocircuitry of sleep. You can get a copy – and see all the references – by contacting me in the Comments section below. Thanks for your interest!

Marvelous melatonin

If you’re like me and thought melatonin is basically all about promoting sleep, get ready to look at melatonin in a whole new light. I’ve discovered that supporting sleep is only the tip of the iceberg when it comes to the many functions of melatonin, and thought I’d share my insights with our NeuroScience friends.

Studying the melatonin synthesis biochemical pathway may help you fall asleep.

Okay, so let’s start with sleep. Following the onset of darkness, there is a surge in melatonin secretion from the pineal gland that initiates the onset of sleep. Circulating pineal-derived melatonin continues to rise until the middle of the night and then falls again by morning. This nocturnal elevation is essential for sleep and for regulating the body’s circadian rhythm. Messing with this diurnal variation in melatonin output disrupts not only sleep, but numerous other biological processes that follow a circadian pattern as well.

In addition to promoting sleep onset, melatonin supports sleep quality by increasing levels of gamma-aminobutyric acid, or GABA, in the hypothalamus (Xu et al., 1995). Melatonin also reduces the negative effects of glutamate signaling (Kumar and Singh, 2009). Consequently, melatonin can reduce stress and anxiety. And by promoting restful, restorative sleep and reducing stress, melatonin can help prevent short-term cognitive deficits and inflammation.

Now let’s move beyond sleep. Melatonin’s well-documented antioxidant effects are at least as important as its sleep benefits. These effects are triggered by (1) its own intrinsic antioxidant activity; (2) upregulation of other antioxidant systems such as glutathione peroxidase, glutathione reductase, and superoxide dismutases; and (3) down-regulation of pro-oxidative enzymes (Hardeland and Pandi-Perumal, 2005; Kumar and Singh, 2009). Melatonin’s anti-oxidant benefits have many health implications, including in neurodegenerative diseases such as Alzheimer’s, Parkinsons disease, and amyotrophic lateral sclerosis (ALS) known to involve oxidative cell damage (Tan, 2010). [Melatonin may also benefit Alzheimer’s patients by preventing amyloid plaque formation in the brain (Paula-Lima, 2003) via favoring GABA over glutamate signaling (Das, 2008; Das, 2010)].

What can't melatonin do?

But the marvels of melatonin aren’t restricted to the brain. Melatonin can aid in digestion, helps heal gastric ulcers (Brzozowska, 2009), and may be useful in  managing constipation and other smooth muscle-related health issues (Pozo, 2010). Melatonin has also been found to enhance the effects of anti-hypertension therapies, perhaps primarily due to its antioxidant effects (Kedziora-Kornatowska, 2008). Melatonin has been found to significantly alleviate symptoms of chronic pain in patients with fibromyalgia and irritable bowel syndrome (Wilhelmsen, 2011), conditions that represent a clear unmet medical need. Many clinical trials are underway to assess the clinical benefits of melatonin in a wide array of disorders.

You may have noted that several conditions I’ve mentioned in this post occur more frequently with aging. Probably not coincidentally, nighttime melatonin production decreases as we get older. There is a growing body of evidence that melatonin may have a number of anti-aging effects. Melatonin supplementation suppresses middle-age fat deposition, at least in rats (Rasmussen, 1999; Wolden-Hanson, 2000). Melatonin may combat the aging of the immune system, or immunosenescence (Cardinali, 2008). And finally, the observation that calorie restriction can help prolong lifespan has recently been complemented by observations that hunger boosts gastrointestinal melatonin production (Bubenik and Konturek, 2011). Coincidence? Maybe, but given a choice between melatonin supplementation and feeling hungry every day…I’ll take the melatonin!

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Multitasker field representative Ross Sutcliffe can talk, type, AND spend QT with his dog!

Here at NeuroScience, Inc. there’s no such thing as a summer lull. We never stop! I have to shove my folks out the door so they get a little R&R! I’m so proud to be part of such a dedicated group. But it also means, alas, that we’re a little behind on giving you a fresh blog post to enjoy. My colleague Jeannemarie has been doing some research on melatonin lately, and she’s agreed to sum up some fascinating details in a forthcoming entry – so look for that coming soon. I, for one, had no idea how multifaceted melatonin truly is.

In the meantime, let me selfishly use this space to let you know that we are running a brief survey for  healthcare practitioners. It will take literally only a minute of your time (hey, we know you’re busy too!) – and the responses will fundamentally inform some very exciting new features and services we’re looking to implement over the coming months.

So please, if you’re a healthcare provider and have an account with us,  check the Lab Updates email we sent you earlier this week to get the survey link, or ask your sales representative. And if you’re a patient, remind your HCP about this important opportunity to provide us some quick feedback to improve our service to our valued customers!

Enjoy your summer!

Food allergies in kids – the links to obesity and inflammation

Food allergies in kids is more frequent than previously thought.

While NeuroScience, Inc. is nestled in a bucolic pocket of Wisconsin’s St. Croix River Valley, we avidly stay abreast of the latest health and science news. As we pointed out in a recent blog post, a new study by Gupta and colleagues published in the journal Pediatrics concludes that childhood allergy is much more common than previously suspected. The study assessed the prevalence of childhood allergy to be 8% of all children, considerably higher than previously reported findings of approximately 4% (Liu 2010; Boyce 2010). This study also noted that about 39% of those with food allergies had experienced a severe reaction, while about 30% had multiple food allergies.

These troubling findings raise a number of questions. What can be causing this rise in childhood allergies? Are childhood allergies becoming more common, or are food allergies being diagnosed more often? These questions are very difficult to answer from a scientific standpoint. What I do know is that my daughter’s elementary school teacher shared with me that the number of children sitting at the reserved allergen table in the student cafeteria has significantly increased over the last 3-5 years. In fact, for the first time in the school’s history, two reserved allergen tables are required for some of the school’s lunch periods.

I speculate that there are a number of contributing factors: intestinal hyperpermeability, food quality, and obesity.

Download a larger copy by clicking on the image (3 MB)

Intestinal hyperpermeability increases the amount of allergenic proteins that make contact with components of the immune system (Heyman 2005; Hong 2011). Increased intestinal permeability has been linked to chronic inflammation, particularly elevations in the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) (Ginzberg 2004). Children with intestinal hyperpermeability and resulting inflammation have an increased risk of developing food allergies (IgE reactions).

The rise in consumption of low-quality foods (especially fast foods and processed foods), with a concomitant decrease in consumption of  fresh foods, has resulted in nutrient deficiencies, increased intestinal permeability, and likely an increase in food allergies. It is a sad fact that Americans now spend more than $110 billion annually on fast food, according to Eric Schlosser, author of Fast Food Nation.  For example, in Louisiana there are 13 fast food restaurants for every 100,000 residents, 33% of whom are obese (CDC Obesity Trends). Fast food may be inexpensive, but it is also has very poor nutritional content.

Image: FastFoodHealth.org via Babble.com

Then there’s obesity, which we know is directly related to food quality. It’s not surprising that the rapid rise in childhood obesity correlates with an apparent increase in food allergies (Wilders-Truschnig, 2007), considering that obesity is now considered a chronic inflammatory disease (Bastard 2006; Moschen 2010). Fifteen percent of all American children are obese, and it has been estimated that a third of children are carrying extra unnecessary weight (Ogden et al. 2010). Overweight children therefore are also suffering from chronic inflammation, which, as I pointed out earlier, sets them up for increased intestinal permeability.

All is not lost by any means, but it’s going to take hard work, commitment, and some serious lifestyle changes to save the next generation from a lifetime of morbidity. By addressing diets, increasing exercise, screening for food allergies/ sensitivities, and addressing intestinal hyperpermeability, many of the alarming health trends in our nation’s children can be reversed.

Kids (and everyone else) should eat plenty of fruits & vegetables

In the mean time, the news that food allergies are so alarmingly prevalent in our children is another good reason to screen every child for IgE food allergies (10 Foods IgE) and to evaluate them for intestinal permeability/IgG sensitivities (154 Foods IgG). Based on the results, elimination diets and intestinal permeability support should be added to any weight-loss program to further address sources of chronic inflammation.

Find out more at www.neinutrition.com!

Love creates pioneers (in medicine)

We here at NeuroScience, Inc. were struck in several ways by a recent article by Bainbridge and colleagues in last week’s Science Translational Medicine about a pair of twins, Noah and Alexis Beery, afflicted with a rare genetic disorder known as dopamine-responsive dystonia or DRD.

Bainbridge, et al.: June 16 Science TM cover article

Though as infants the twins were initially diagnosed as having cerebral palsy, their parents suspected that something else was at play (you can read more about their story at the Baylor College of Medicine’s website and National Public Radio’s blog). They doggedly questioned their doctors and pursued scientific leads from the literature, until, years later, DRD was fingered. This type of dystonia is caused by defects in the dopamine synthesis pathway, and indeed, treatment with L-dopa was effective for several years.

Unfortunately, when the twins reached their early teens their condition began to worsen, suggesting a more severe form of the disease.  To cut the story short, the twins’ genomes were sequenced and revealed additional gene defects that suggested additional enzymatic malfunctions that resulted not only in dopamine deficiency, but also a reduction in serotonin. Consequently, the twins’ condition has been stabilized by supplementing their L-dopa dosing with 5- hydroxytryptophan, the precursor to serotonin.

Baylor’s Human Genome Sequencing Center

Technologically speaking, this is a “cool” story because the twins’ molecular diagnosis was made using next-generation genome sequencing, indicating that the cost of this approach is falling to a level that will make it ever more accessible in the coming years (see the commentary by Kingsmore & Saunders).

But as a parent of twins myself, I find that the heart of the story is the persistence of these kids’ parents and some insightful doctors, who collectively refused to accept the obvious diagnosis, and used all available means to cure these children. It’s yet another example of how it is often patients and their families who are the ones who push the boundaries of medicine with their courage, perseverance, imagination, and refusal to accept facile diagnosis. Love creates pioneers.

We at NeuroScience, Inc. would humbly suggest that a low-cost analysis of peripheral neurotransmitters, such as we offer and run by the thousands each year, might have rapidly revealed the Noah’s and Alexis’ dopamine and serotonin deficiencies in an initial low-cost diagnostic step, guiding and complementing subsequent genomic analysis. We sincerely hope that forward-thinking clinical academicians and health care specialists will consider this simple approach to help guide their important work.

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IgE Testing: More than Once in a Lifetime

excerpted from: Gupta et al. (2011). "The Prevalence, Severity, and Distribution of Childhood Food Allergy in the United States."

We recently began offering IgE testing here at NeuroScience, Inc., and just about the same time an interesting, but disturbing study about allergies hit the newswire. It appears, based on a survey of nearly 38,000 children, that the prevalence of childhood allergies is about 1 in 12, or twice what we previously thought (you can read additional commentary in this article in the Huffington Post).  The underlying causes remain unclear, but the health effects of allergies can, of course, be quite serious.  We’ll discuss this interesting study in a future post.

While I think we’re all fairly aware of the situation of food allergies in kids, I’m surprised by how often I hear healthcare providers tell me that they don’t feel the need to test their adult patients for allergies to foods and inhalants such as pollens and pet dander, because most of their patients have already had skin prick testing done previously in their lives.

On the contrary, there are several reasons why it is important to test for IgE allergies more than once and in some cases frequently throughout life. For example, our gastric acid levels can fluctuate over the years. Low gastric acid has been found to be a causative mechanism in the induction of IgE-mediated allergy (Pali-Schöll 2010; Riemer 2010). The stomach uses pepsin, a gastric protease, to partially destroy dietary proteins, a process essential for oral tolerance to foods. Low gastric acid levels can occur due to regular usage of antacids and proton pump inhibitors (e.g. Prilosec, Prevacid, and Zegerid), or inherently low gastric acid production (aka hypochlorhydria).

In addition, a patient’s sensitivity to foods and inhalants can change over time, leading to worsening or alteration of symptoms (Kewalramani 2010). This progressive change has been coined the “allergic march” or “atopic march”, which has been well-documented in the progression of atopic dermatitis to allergic rhinitis and asthma (Zheng 2011).

How can we best determine whether a patient has Type I (IgE-mediated) hypersensitivities? Skin prick testing (SPT) has been used by allergists for years as the primary allergy diagnostic approach. While certainly a valuable tool in the allergy testing armamentarium, it may not identify all IgE allergies and therefore may provide an incomplete picture of a patient’s allergies. In addition, SPT does not evaluate Type III delayed-type (IgG-mediated) hypersensitivities, and is unable to quantify sensitization in patients (Kamdar 2010; ACAAI 2006).

Mast cells, chock-full of histamine, etc. just waiting to be released following IgE stimulation.

In contrast, specific IgE serum testing is accurate, highly specific, and provides quantifiable measurements of Type I hypersensitivity (Eigenmann 2009; Jung 2010; Sampson 2001). Quantifiable IgE test results enable healthcare practitioners to identify allergy sensitization prior to major symptom eruption and to evaluate therapeutic interventions.

Due to the connection between IgE allergic responses and increased intestinal permeability, everyone testing positive for IgE reactions should also undergo gastrointestinal nutritional support (Perrier and Corthésy 2011; Hauk 2008). Nutritional supplements designed to improve a patient’s intestinal permeability and gut microecology have been shown to prevent allergic conditions such as asthma and irritable bowel disease (del Giudice 2006; Hong 2011). NEI Nutrition offers the 6-week GI Repair System™ to simplify process of healing the GI tract for doctors and patients alike.

In conclusion, it’s a good practice to test, and re-test, patients for IgE allergies if they have reduced stomach acid, have allergic symptoms, suffer from intestinal hyper-permeability, or have only been tested using SPT.

Might cats also be allergic to humans? Follow @neuroscienceinc on Twitter and we'll let you know if we find out.

Immune aging and NK cells – oh, and let’s clear up a few things about CD57

Natural Killer cells. (Science Photo Library)

As I mentioned in my previous entry, aging of the immune system – or immunosenescence – affects many kinds of immune cells. Since I recently discussed natural killer (NK) cells, I’ll add a few comments about immunosenescence regarding these cells specifically. (For a good review, see the paper by Gayoso et al., 2011 – I am happy to send it to anyone who writes me.)

First, a quick primer.

• NK cells are critical to innate immunity (those rapid, nonspecific immune responses). They can tell “self” from “non-self” which lets them recognize virus-infected cells and certain cancer cell types.
• NK cells can be divided into two main subsets.
  • CD56(bright) NK cells that produce cytokines which activate and enhance the actions of other white blood cells
  • CD56(dim) NK cells that are primarily known for their ability to lyse and kill “non-self” cells, also known as cytotoxicity.
• There is a continuum of NK cell differentiation (e.g. from CD56(bright) to CD56(dim). At the far end of this continuum is the CD56(dim)CD57+ NK cell subset that is highly differentiated, probably terminally so. Keep in mind that “terminal” here doesn’t mean that CD57+ NK cells are dying – just that they will no longer differentiate into any other functional subset. (Here I want to kindly thank my former colleague Dr. Lewis Lanier for his insights and point you to a recent paper from his lab about CD57+ NK cells (Lopez-Verges, 2010).)

As offered by NeuroScience, Inc., tests can assess people’s NK cell status by (1) counting them, and (2) by measuring their cytotoxic activity. As we discussed last time, immunosenescence doesn’t necessarily track with chronological age. Healthy centenarians have exhibit an overall increase in their NK cell count, and no decrease in NK cell cytotoxic activity. In contrast, unselected elderly populations (i.e., all comers, regardless of health status) show evidence of reduced NK cell count and cytotoxic activity. This can be a predictive biomarker of overall health risk, with at least one report indicating that individuals with a low NK cell count have an increased mortality risk compared to individuals with high NK cell count (Remarque & Pawelec, 1998, as cited in Gayoso et al.). Evidence similarly points to the association of low NK cell activity with infections and degenerative diseases such as atherosclerosis (Bruunsgaard, 2001).

We are beginning to understand the reason for these differences: During immunosenescence, an important shift in NK cell subsets occurs – there is a decline in cytokine-producing CD56(bright) NK cells, and an increase in cytotoxic CD56(dim)CD57+ NK cells.

How this contributes to overall immunosenescence, and increased health issues, is that the loss of cytokine-producing CD56(bright) NK cells likely means a reduction in the cytokine signals that are critical for activating other immune cells, such as macrophages, dendritic cells, and T cells. This could result in a reduced ability to effectively conquer infectious microbes.

A final comment regarding CD57: I urge anyone who orders CD57 tests on their patients to take the patient’s age into consideration when interpreting the results. Since it is a general marker of NK cell terminal differentiation, I’ll also wager that there is nothing pathogen-specific about a CD57 count! It cannot and should not be used to diagnose Lyme disease, XMRV, or any other specific infection, though I don’t reject the possibility that an extremely low CD57+ NK cell count may indicate some sort of pathology.

Is your immune system feeling old?

As part of our growing focus on healthy aging at NeuroScience, Inc., here’s what’s on our radar: Immunosenescence, which is a fancy way of saying “aging of the immune system”.

While you might not give immunosenescence a second thought (because all biological systems age, right?), several interesting findings suggest that immunosenescence is not strictly associated with chronological age. There are very old people out there with youthful-looking immune systems, and on the other hand, premature immunosenescence has been observed in the under-fifty set.

View my collection, “Immunosenescence” from NCBI

Immunosenescence is definitely cause for concern.  Unilever’s Steve Wilson and Dawn Mazzatti note that “the production of high levels of pro-inflammatory cytokines and alterations in immunity … are thought to underlie the progression of chronic degenerative diseases of aging, such as atherosclerosis, Type 2 diabetes and Alzheimer’s disease.” UCLA’s Rita Effros writes, “Aging of the immune system is a major factor responsible for the increased severity of infections, reduced responses to vaccines, and higher cancer incidence in the elderly.” Provinciali et al. concur, reviewing data indicating that persistent inflammation increases the risk of cancer and its progression.

Senescence: the change in the biology of an organism as it ages after its maturity. (Wikipedia)

What does immunosenescence look like? Research is showing us that an aging immune system is characterized by a number of functional alterations and cellular characteristics, in what is collectively termed an ‘immune risk profile’, or IRP, by Evelyna Derhovanessian and her colleagues. Larbi et al. summarized many of the changes in T and B cell function in this table from their 2008 paper, and here are the findings by other investigators:

• Decreased numbers of T cells (perhaps particularly CD4+ T helper cells) and B cells
• Decreased functionof immune cells, including
  • T cells – impaired delayed-type hypersensitivity
  • B cells –  reduced ability to generate antibody responses, which is why vaccinations are often not as effective in the elderly
  • Natural killer cells – reduced cytolytic activity and interferon-gamma production (we’ve discussed NK cells in an earlier post)
  • Macrophages and neutrophils – decreased phagocytosis, which is an important means whereby these innate immune cells “eat” pathogens and dying cells
  • Dendritic cells – decreased responsiveness to microbial signals that is often the first step in kicking off an immune response (Panda et al., 2010; Rosenstiel et al., 2008)
• A shift in the expression of particular lymphocyte cell surface markers, including the loss of CD28-expressing cells, and an increase in cells expressing CD95 and/or the terminal differentiation marker CD57.
• Elevated proinflammatory cytokines and CRP levels indicative of a chronic state of low-grade inflammation
• Seropositivity for viruses such as CMV
• Low intracellular zinc content
• Elevated cortisol, and perhaps especially an elevated cortisol/DHEA ratio

NeuroScience, Inc. is excited to begin offering an Immunosenescence test profile effective July 1. You’ll hear more from me about immunosenescence, including possible causes and what we might be able to do to reverse it, in future posts.

Don’t forget to follow @neuroscienceinc on Twitter!

Natural killer cells – Canaries in the immunological coal mine

NeuroScience, Inc. offers testing that assesses both natural killer cell count (5079), NK cell activity (3014), or both (5067). Now let’s say you run one of these tests on your patient and the results indicate abnormal NK cell count or activity –  how can you use this information?

First, a few words about natural killer cells (arguably the coolest-sounding immune cells, and quite pretty as well!). NK cells basically function by distinguishing “self” (our healthy cells) from “non-self” (self-cells that are virally-infected or cancerous, or bacteria). NK cells (1) lyse (kill)  “non-self” cells, as well as (2) produce cytokines (small protein messengers) that promote helper T cell (Th1) and cytotoxic T cell mediated immunity. Bottom line, NK cells are vital players in the immune response.

Here, I’ve summarized some of the underlying reasons why your patient might have non-normal NK cell counts or function. A bit of a laundry list, but I hope that in the context of your patient’s  history and symptoms, it can help you can isolate the possible root causes and design appropriate therapeutic interventions (we’ll discuss what sorts of interventions may be able to boost NK cell activity in a future post).

Low NK cell function or count – what does that tell me?

Individuals with low NK cell activity are at greater risk of severe or persistent infections and associated morbidity. Low NK cells can also result in endometriosis in women.

• Stress has been reported to lower NK cell activity, while laughter and stress reduction programs have been shown to increase NK cell activity.
• PTSD is associated with lower NK cell activity.
• Some, though not all, studies on depression suggest that it is correlated with reduced NK cell function, even as other immune parameters may be activated.
• In CFIDS (chronic fatigue immune dysfunction syndrome), NK cell activity correlates inversely with clinical severity. A number of other studies such as this one agree that NK cell activity is reduced in chronic fatigue syndrome (CFS), though NK cell count may not be different from normal controls.
• Some reports indicate that NK cell activity decreases with age, while others suggest that this is not per se the case, but that low NK activity with aging predicts impending morbidity.
• Micronutrient deficiencies in zinc or vitamins A, C, and D can negatively affect NK cell function (Wintergerst, 2006; Erickson, 2000).
• A diet rich in long-chain polyunsaturated fatty acids can reduce NK cell count.
• Exposure to toxic chemicals can harm NK cell activity.
• Stroke is followed by low NK cells.
• Pregnancy is accompanied by low NK cell activity (consider that the fetus is partially “non-self” and doesn’t need the scrutiny of ever-vigilant NK cells!)
• Exercise, particularly high-intensity and/or high-frequency resistance exercise, can depress NK cells (Kawada, 2010).
• Obesity and smoking are associated with decreased NK cell count and activity.
• Cancer is frequently associated with lowered NK cell activity, which some studies is correlated with poor prognosis.
• Short-term steroid (e.g. prednisolone) dosing; opioids and anesthetics used in surgery
• Angiotensin II (AngII) inhibitors may suppress NK cells
• Genetic immunodeficiency is perhaps the most rare cause of low NK count or activity, but is also the toughest to address since it is least likely to respond to interventions.

Elevated NK cell function or count – where does that come from?

Some of the consequences of elevated NK cell activity may include inflammation, for example in the gut, as well as exacerbated autoimmunity. Also, women with elevated NK cell activity and count are at risk of repeated miscarriages.

• Of course, your first suspect should be viral and bacterial infections that trigger normal NK cell activation, especially early in the course of the immune response.
• In certain autoimmune disorders such as Behçet’s disease and Sjögren’s syndrome, the number of activated NK cells activity is higher in active disease compared to inactive disease or healthy controls.
• In contrast to adults, stress may enhance NK cell function in children.
• Supplements that provide micronutrients such as zinc, vitamin C, and vitamin A may elevate NK cells (Erickson, 2000; Ahmad, 2009).
• Certain probiotics, such as Lactobacillus casei strain Shirota, enhance NK cell activity.
• Lithium enhances NK cell activity, as may selective serotonin reuptake inhibitors (SSRI’s).

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Th1/Th2? That’s so 1990′s…

Sometimes I feel like I’m in a time warp.

Back when I was a grad student in the early ‘90s, immunologists were vigorously expanding upon Tim Mosmann and Bob Coffman’s seminal insight that helper T cells were actually comprised of functionally distinct Th1 and Th2 T helper cells.  (Helper T cells are an important type of white blood cell involved in the adaptive immune response. They “help” B cells make antibodies, but are also responsible for cell-mediated immune responses.) Since that initial discovery, over 16,000 journal articles about Th1 and Th2 cells have been published, and many disorders like inflammatory bowel diseases, psoriasis, allergies and asthma have been found to be associated with a predominantly Th1 or Th2 type of immune response.

But nothing is ever simple, and this dichotomous view of helper T cells is not the complete picture. Another helper T cell subset, Th17, appears to play a role in the pathology of autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis, but also has been proposed to protect against infectious agents, particularly extracellular bacteria and fungi, and to contribute to protection of mucosal sites such as the gut and lungs.

Indeed, the story doesn’t even stop there; immunologists now speak not only of Th1, Th2, and Th17 cells, but also of regulatory T cells and most recently, Th9 and Th22 subsets!

Th cells may look alike, but have distinct functions!

I’ll discuss the clinical relevance of Th17 and regulatory T cells a bit more in future posts, but for now, let me only comment that I feel as though I’m back in the 1990’s when I hear self-proclaimed didacts continuing to adhere to the simplistic Th1/Th2 paradigm. True, the discovery of additional helper T cell subsets can be bewildering and their precise contributions to host protection and pathology are still unfolding, but we must keep stride with research discoveries if we are to nimbly leverage them in our continuing quest to improve our diagnosis (and intervention) of perplexing and debilitating health issues.

This is why you will find IL-17 among the cytokines assessed in several of NeuroScience’s Stimulated Cytokine profiles. If a patient’s white blood cells express elevated levels of IL-17, it helps narrow down possible root causes underlying the patient’s symptoms, such as immune activation in the gut, a fungal infection, or an autoimmune disorder in which Th17 cells have been implicated.

It’s not necessarily an instant diagnosis, but it sheds light where previously there was none.

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Stimulated Cytokine testing: Biomarkers of Immune Status

Why test immune cytokines?
At NeuroScience, Inc., we always strive to raise awareness about the complex interplay of the neurological, endocrine, and immune subsystems that constitute the NEI Supersystem©. Because of this interconnectedness,  symptoms such as fatigue, low mood, anxiousness, or insomnia may be due to any number of contributors, not least of which is inflammation. Potential root causes of inflammation include infections, autoimmune disorders, environmental toxins, or disrupted gut microbiota. Even psychosocial stress can result in inflammation!

During inflammation, there is increased production of certain cytokines (small messenger proteins) by white blood cells and other cell types. This can impact neurological and endocrine functions in a number of ways, including the litany of symptoms described above which are sometimes collectively termed “sickness syndrome” or the “sickness response”, an adaptive state that “minimizes risk by limiting normal behavior and social interactions and forcing recuperation” (Chapman et al., 2008).

Not only are these cytokines players in the pathology of a given disorder, they are also reporters of immune imbalance. That’s where Stimulated Cytokine testing comes in.

What is Stimulated Cytokine testing?
Stimulated Cytokine testing is intended to assess whether an individual’s symptoms could be attributable to an imbalanced immune response. Our goal is to understand as best we can where to target therapeutic interventions, minimizing empiricism and guesswork in the therapeutic protocol.

In the test, white blood cells (which include many immune cells) are isolated from a sample of the patient’s blood. These cells are then placed in culture, either without stimulation (defined as baseline), or stimulated with phytohemagglutinin (PHA, a potent stimulator primarily of T cells) or lipopolysaccharide (LPS, principally a powerful stimulator of innate immune cells such as monocytes/macrophages and dendritic cells). After 24 hours, levels of cytokines are measured in the culture medium and compared to the normal range observed in asymptomatic individuals.

Why not just measure serum cytokines?
Many practitioners wonder why they should run a Stimulated Cytokine test; wouldn’t measuring serum cytokines give the same results? The answer is “not necessarily”. That’s because serum cytokine testing can have issues related to reliability and reproducibility, as summarized by de Jager et al. (2009), that are not encountered with stimulated cytokine testing. These issues pertain to sample handling and storage, as well as interference of endogenous plasma proteins.

Another thing to consider is that, unless the patient has a serious case of systemic inflammation, cytokine concentrations in the serum may be too low to detect. In contrast, stimulated cytokine testing first cultures white blood cells over a 24-hour time period, so any cytokines that are secreted in that time frame are concentrated in a small volume of culture medium. Furthermore, being able to stimulate the patient’s white blood cells with PHA and LPS provides a means to expand the dynamic range of the cytokines, while provocation is of course not possible when testing serum cytokines.

What do stimulated cytokine results tell us?
There are a few key proinflammatory cytokines, such as TNF-α and interleukin-1β, for which we know a fair amount about how they may impact the NEI Supersystem. For example, IL-1β has been documented to activate the HPA axis, increase norepinephrine release in the hypothalamus, and increase metabolism of 5-hydroxytryptophan toward excitatory quinolinic acid, at the expense of serotonin.

However, at the same time it’s important to recognize that even a test that measures up to 17 cytokines, as NeuroScience, Inc.’s Stimulated Cytokines Comprehensive panel does, is far from actually being “comprehensive”, considering that over 100 cytokines have been described to date! Scientists still do not understand the precise function of many of these cytokines, and partly as a consequence, commercial detection assays do not include them (though this will certainly evolve over the coming years).

Therefore, we need to stay humble and realize that the cytokines we can test for today are unlikely to give us the whole story about what is going on in an individual. Imagine you were trying to understand someone who was speaking in a language for which you only knew 17 words! Nonetheless, if you heard the words “danger”, “help”, and “fire”, you would have a decent idea as to the meaning of the message. Similarly, perturbations in the cytokines that we are able to commercially assess are extremely useful as indicators of the patient’s immune status, or to use the more formal lingo, they are biomarkers of the immune system. (We previously discussed the biomarker concept in an earlier blog entry about NeuroScience, Inc.’s Lyme test.)

Thus ends Part 1 of my commentary on cytokine testing – In an upcoming entry, I’ll walk through a couple of Stimulated Cytokine test cases and provide some interpretative guidelines to apply in practice! Remember, in order to appropriately target interventions, we need to understand whether immune imbalances are an underlying issue.

 

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Mapping Neural Connections: The NeuroCircuitry Model

As we mentioned in our previous blog post, NeuroScience, Inc. is developing a NeuroCircuitry model to gain a deeper understanding of central nervous system (CNS) function.

This model maps neural connections, based on peer-reviewed literature and systems biology databases, and allows us to implement peripheral (urinary and plasma) neurotransmitter biomarker measurements to identify the central pathways that are altered in various disease states (Elfering et al., 2008; Yu et al., 2008).

The concept of the NeuroCircuitry model owes a debt to a pioneer in the field, Fuad Lechin. Dr. Lechin has focused much of his research on understanding the crosstalk between the CNS and the peripheral nervous system (PNS) (Lechin et al., 2002). Through the examination of over 30,000 patients, Dr. Lechin and his colleagues have assessed circulating neurotransmitters before and after various types of challenges, including orthostasis testing, exercise, oral glucose tolerance testing, and the administration of peripherally and centrally acting drugs. He has proposed innovative methods to treat various disorders by targeting specific CNS nuclei with pharmacological interventions, guided by measurements of circulating neurotransmitters, hormones, and metabolites present in urine, platelets, and plasma (Lechin et al., 1996). His work has afforded researchers a better understanding of pharmacological and supplemental interventions to correct the effects of exogenous (environmental factors) and endogenous (inflammation, genetic, disease) variables that can alter CNS and PNS activity.

Dr. Fuad Lechin.

As we mentioned in our last post, although some question the ability of peripheral markers to indicate central function due to the transport-limiting effects of the blood-brain barrier, research has clearly illustrated that crosstalk does occur. Therefore, neural circuits that mediate this crosstalk provide sound insight into CNS function through the measurement of peripheral biomarkers.

In upcoming blog posts, we’ll show some case studies demonstrating how the NeuroCircuitry model can use peripheral neurotransmitter measurements to assess altered CNS functions as well as the effectiveness of pharmaceutical and dietary supplement interventions.

 

Urinary Neurotransmitters as Biomarkers

Brainbow, by Lichtman, Livet, & Sanes (2008)

Happy New Year, everyone! In a previous post, we talked about using cytokines as biomarkers. In this post,  NeuroScience‘s David T. Marc, BS, Gottfried H. Kellermann, PhD & J. Fernando Bazan, PhD discuss the utility of urinary neurotransmitters as biomarkers.

In medicine, biomarkers are a powerful means to guide effective treatments; for instance, high cholesterol may identify patients at risk of cardiovascular events, and screening for HER2 expression helps pinpoint those breast cancer patients who are most likely to benefit from Herceptin treatment. While biomarkers are well-accepted in cardiovascular disease and oncology, neurological disorders lag in the availability of clinical biomarkers, notwithstanding that medications that alter neurological actions are widely used.

The few available neurological biomarkers are met with some with opposition, because most are not measured directly in the brain, but rather in blood, urine, and cerebrospinal fluid (CSF) (Fisar & Raboch, 2008). A common misconception is that the peripheral and central nervous systems (PNS and CNS) are dissociated (Elenkov et al., 2000) and therefore circulating neurotransmitters cannot be considered biomarkers of brain activity.

However, evidence suggests that there is significant molecular cross-talk between the PNS and CNS (Lechin, 2009; Salome et al., 2006). The brain-gut connection is a great example of this linkage. Nerves allow communication from the gut to the brain to signal satiety in the hypothalamus (Wang et al., 1998; Barrachina et al., 1997). Likewise, nerves leading from the brain to the gut can elicit changes in digestion (Janig & Morrison, 1986). Given these and other examples of PNS-CNS cross-talk, it’s clear that (1) neurotransmitters in the CNS can manipulate peripheral neurochemistry, and vice-versa (Berthoud & Neuhuber, 2000), and (2) CNS activity can arguably be inferred from peripheral neurotransmitter biomarker levels (Lechin et al., 1996).

The advantages of measuring neurotransmitters in urine, as compared to blood or CSF, include non-invasive specimen collection, stability of the sample, and over 60 years of documented clinical utility (Rosano et al., 1950). Early attempts to establish urinary neurotransmitters as biomarkers focused on the diagnoses of depression, anxiety, and attention-deficit-hyperactivity disorder (Pliszka et al., 1994; Zametkin et al., 1985; Kopin, 1984; Koslow et al., 1983). In our recent comprehensive review by Marc et al. in Neuroscience and Biobehavioral Reviews, we summarized peer-reviewed studies that clearly demonstrate the correlation of urinary neurotransmitters with clinical conditions and their ability to predict treatment outcomes, which can have a huge impact for managing patient care.

Many neurotransmitter-related disorders, as well as clinical interventions, affect neurotransmitter levels. Unfortunately, due to the spectral nature of these disorders, as well as frequent comorbidity, treatment success is difficult to achieve (Benazzi, 2006; Nemeroff, 2007). Comprehensive assessment of urinary neurotransmitters allows health care practitioners to improve health outcomes by better guiding the selection of specific interventions (Schwarz & Bahn, 2008; Le-Niculescu et al., 2008).

In an upcoming blog post, we’ll delve deeper into the idea that urinary neurotransmitters are biomarkers that reflect CNS activity, and introduce the concept of NeuroCircuitry. Briefly, NeuroCircuitry uses peer-reviewed literature and emerging systems biology databases and tools to model pathways by which PNS-CNS crosstalk occurs. The NeuroCircuitry model enhances the utility of peripheral neurotransmitter biomarkers in assessing CNS function and predicting responses to intervention, thus offering an even greater opportunity to guide individualized treatment selection.

The powers of prickly pear in restoring gastrointestinal health

The most recent snowstorm has left four-foot drifts here at NeuroScience, and we find ourselves fantasizing wistfully about warmer climes. The riches of the desert never cease to amaze, and their benefits show up in the unlikeliest places. Did you know, for example, that the prickly pear cactus (Opuntia ficus indica)  contains high levels of soluble and insoluble fiber, which is ideal for slowing down the release of dietary sugars into the bloodstream? This fact was recently highlighted by Dr. Oz in his program, The 7 Wonders of the Natural World (go to the 2:00 mark in his video).

How does the cactus fit into what we do at NeuroScience? The benefits of prickly pear, it turns out, are manifold. Ever vigilant in identifying innovative, natural products to improve GI health, the folks in NeuroScience’s NEI Nutrition™ division were among the first to recognize its value in healing the damaged GI tract.

It all begins with our appreciation that imbalances in the Neuro-Endo-Immune Supersystem^© can often be traced back to disturbances in the GI tract. The intestinal mucous layer is a vital protective barrier that acts a molecular “sieve”, keeping out large molecules, food antigens, and pathogens while still allowing for the passage of vital nutrients. The mucous layer also supports symbiotic microflora (or “good” bacteria) so essential to our health. Damage to either the mucous or epithelial layer results in an increase in intestinal permeability or “leaky gut”, an altered microflora milieu, and ultimately disturbances in the NEI Supersystem^© with health implications that transcend the gut.

Prickly pear leaves contain a combination of carbohydrate-containing polymers as well as fiber to supply a healing mixture of mucilage and pectin. In addition, prickly pear increases the activity of goblet cells, specialized cells in the GI tract that produce protective mucus. We have found that prickly pear supports mucosal tissues better than other ingredients in the marketplace, and that is why you’ll find certified organic prickly pear cactus in our GI Barrier Repair product, part of our 6-week GI Repair System.

As a bonus, research suggests that prickly pear cactus also supports healthy blood lipids as well as control carbohydrate metabolism, as highlighted by Dr. Oz.

If you think prickly pear cactus is innovative, take a look at the rest of NEI Nutrition’s approach to GI health!

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Welcome to the NEI Connection!

Hello, and welcome to the inaugural blog post from the research and clinical experts at NeuroScience, Inc.! We are passionately committed to improving human health through a better understanding of what we call the NEI Supersystem^©.  As such, this blog is a dialogue with health care practitioners, researchers, and advocates about what’s going on at NeuroScience, and the scientific and clinical concepts that drive our work.

Let’s start by defining the NEI Supersystem. Rather than viewing the Neurological, Endocrine, and Immune systems as isolated entities, there is an emerging paradigm that they are all interconnected in a single, dynamic supersystem. Neurotransmitters, cytokines, hormones, and other biomolecules “speak” across this entire supersystem. Consequently, imbalances in any one part of the NEI Supersystem affect the other parts as well.

At NeuroScience, our mantra is “assess and address” – we assess NEI imbalances in patients to help practitioners understand the basis of anxiousness, low mood, aggression, fatigue, sleep issues, and other maladies. Understanding the root cause of such symptoms helps us advise practitioners how to effectively address the underlying imbalances to help restore patients to better health.

By realizing that the neurological, endocrine, and immunological systems are all interconnected, practitioners are able to have a more expansive understanding of possible root causes of some of today’s most challenging health concerns. Here’s a very simple example: when a person has the flu, he or she may experience brain fog, lack of motivation and fatigue, and even symptoms resembling depression. Of course, a doctor wouldn’t give this patient antidepressants – because we know that the root cause is an infection!

More generally, this example drives home another point, neurological manifestations may have non-neurological root causes such as chronic infection, metal sensitivity, reactivity to environmental toxins, etc. Understanding the root cause is critical to recommending the most appropriate, effective intervention. Not only will you be more successful at resolving the symptoms, you’re also more likely to achieve better health.

Again, welcome. We look forward to bringing you the latest NeuroScience, Inc. information through the NEI Connection.

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