What to expect when you’re expecting: do you expect environmental toxins?

Earth Day was first celebrated in 1970 and is meant to bring awareness to environmental protection. Ironically, since then, the amount of chemicals (i.e., insecticides, pesticides, manufacturing) used in the environment has increased. US industries make and import around 80,000 chemicals with an average of seven new chemicals approved each day. Of the top 20 chemicals discharged into the environment, nearly 75% are known or suspected to be toxic to the developing human brain.

A 2005 EWG study identified 287 different chemical in umbilical cord blood. 180 are known to cause cancer in humans and animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or abnormal development in animal tests.

A 2005 EWG study identified 287 different chemical in umbilical cord blood. 180 are known to cause cancer in humans and animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or abnormal development in animal tests.

This increase in exposure to toxic chemicals in the environment, including the home, can have drastic effects on children. Kids are more vulnerable to the effects of toxins than adults. Their ability to detoxify is not as well-developed as an adult’s. Kids also have more risk of toxic exposure from water, food, and air. This is because, pound-for-pound, kids drink, eat, and breathe more than adults. Kids also touch the ground more often and engage in more hand-to-mouth behaviors, making the risk even greater.

Exposure to toxic chemicals begins in the womb. The Environmental Working Group (EWG) ordered a study in 2004 to identify industrial chemicals, pollutants, and pesticides in human umbilical cord blood. The study, printed in 2005, found 287 different chemicals in the cord blood. Of these, 180 are known to cause cancer in humans and animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or abnormal development in animal tests.

Research has also found that acute leukemia is significantly linked with home and garden insecticide and fungicide use during pregnancy and childhood. Phthalates, substances added to plastics to increase flexibility, have been associated with increased allergies in children. Prenatal exposure to phthalates has also been linked to autistic behaviors. There have been reports that DDT exposure is associated with early menarche and shortened menstrual cycles. The National Academy of Sciences has also determined that environmental factors contribute to 28% of developmental disorders in children.

Industrial pollutants and toxins have become abundant in our environment, and prenatal and childhood exposure to these toxins is increasing. The total body burden of toxins should be kept as low as possible to support optimal health. Removal of toxins is important, including staying hydrated to flush out toxins as well as regular bowel movements. Maximizing children’s antioxidant reserves can also be beneficial to support their ability to detoxify. Neurotransmitter testing can also be of benefit to identify imbalances in the nervous system that may be due to toxic chemicals. Above all, the most important aspect is to minimize toxin exposure.

References:
Bornehag, CG., et al (2004). The Association between Asthma and Allergic Symptoms in Children and Phthalates in House Dust: A Nested Case-Control Study. Environ Health Perspect, 112(14): 1393-7.
Houlihan, J., et al. (2005). Body Burden: The Pollution in Newborns. Environmental Working Group. http://www.ewg.org/research/body-burden-pollution-newborns.
Menegaux, F, et al. (2006). Household exposure to pesticides and risk of childhood acute leukaemia. Occup Environ Med, 63: 131-4.
Miodovnik, A, et al. (2011). Endocrine disruptors and childhood social impairment. Neurotoxicology, 32(2): 261-7.
Ouyang, F, et al. (2005). Serum DDT, age at menarche, and abnormal menstrual cycle length. Occup Environ Med, 62: 878-84.
Posted in Immunology | Tagged , , , , , , , , , , | Leave a comment

Flu bugs aren’t the only infection that cause stomach problems: Viruses may worsen IBD

As Easter approaches and kids eagerly wait for candy from the Easter Bunny, parents will be watching to make sure they don’t eat too much at once and get a stomachache.  All of us have experienced stomach upset from time-to-time and regardless of what caused it, it was an unpleasant experience. Unfortunately, unpleasant GI experiences occur on a much more frequent basis for individuals with Crohn’s disease or ulcerative colitis.

Crohn’s disease and ulcerative colitis are both inflammatory bowel diseases (IBD) that cause inflammation of the lining of the digestive tract. Resulting inflammation can lead to abdominal pain, severe diarrhea, and even malnutrition. In Crohn’s disease, the inflammation often spreads deep into the layers of the affected tissue and can affect various areas of the digestive tract1. Ulcerative colitis, on the other hand, tends to only affect the colon and rectum2.

While the initial cause of IBD remains unclear, some literature suggests that viral infections are associated with the onset and aggravation of IBD. Of these viral infections, cytomegalovirus (CMV) is of particular interest to the development and worsening of the conditions. Mucosal injury, or damage to the intestinal tract, is also a component of the chronic nature of these diseases3.

Figure 1. IBD, CMV infection, and mucosal injury can all contribute to symptoms that plague patients.

Figure 1. IBD, CMV infection, and mucosal injury can all contribute to symptoms that plague patients.

IBD, CMV infection, and mucosal injury can all contribute to the symptoms that plague patients(Figure 1).

  • Patients with IBD are often treated with immunosuppressive medications to reduce symptoms.  These patients may also suffer from poor nutrition due to damaged intestinal tissues.  The combination of immunosuppressive medications and poor nutrition make it easier for CMV to infect or re-infect a host.
  • IBD can also worsen mucosal injury.  Inflamed mucosa may play a crucial role in inducing and sustaining CMV reactivation as epithelial cells can serve as permissive hosts for CMV during inflammatory responses.  This means they could possibly create a friendly environment for CMV reactivation and replication which in turn enhances the chance of chronic viral infection. This process can result in an increase in CMV infections over time.
  • CMV infection may be a result of mucosal injury, but it may also be a cause.  Reactivation of or new CMV infection is thought to cause severe colitis, particularly in patients with ulcerative colitis that are treated with immunosuppressive agents.

In addition to the physical symptoms IBD and CMV infection can cause, poor nutrient absorption by the damaged intestinal tract can also lead to malnutrition. This lack of nutrients may mean that the necessary building blocks for neurotransmitters and hormones are insufficient.  This deficiency can lead to symptoms like anxiousness, sleep difficulty, or fatigue. Identifying and addressing neurotransmitter and hormonal imbalances with targeted support may help ease a patient’s secondary symptoms.

Guest author: Rachel Rixmann is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in gastroenterology and nutrition.

References:
  1. http://www.mayoclinic.org/diseases-conditions/crohns-disease/basics/definition/con-20032061
  2. http://www.mayoclinic.org/diseases-conditions/ulcerative-colitis/basics/definition/con-20043763
  3. Cytomegalovirus (CMV)-Specific Perforin and Granzyme B ELISPOT Assays Detect Reactivation of CMV Infection in Inflammatory Bowel Disease.  Nowacki, Tobias M et. al.  Cells 2012, 1, 35-50; doi:10.3390/cells1020035.
Posted in Immunology | Tagged , , , , , , , , | 1 Comment

Carpe diem! Can you seize the day if seizures are contributing to your low mood?

Epilepsy is a brain disorder in which seizures occur as a result of abnormal neuron signaling.

Epilepsy is a brain disorder in which seizures occur as a result of abnormal neuron signaling.

Epilepsy is a brain disorder in which seizures occur as a result of abnormal neuron signaling. This irregular signaling may briefly alter a person’s consciousness, movements, or actions. However, having a seizure does not necessarily mean that a person has epilepsy. People are considered to have epilepsy when they have had two or more unprovoked seizures. Seizure symptoms can include convulsions, loss of consciousness, blank staring, lip smacking and/or jerking movements of the arms and legs.

One of the most-studied neurotransmitters that plays a role in epilepsy is GABA. Many of the drugs used to treat epilepsy affect GABA. These drugs alter the amount of GABA in the brain or change how the brain responds to it.

Another area of study in relation to epilepsy is depression. It’s estimated that 22% of epileptics have depression compared to 12% of the general population. This is believed to be due to the effect chronic epilepsy has on the hypothalamic-pituitary-adrenal (HPA) axis, specifically cortisol. Activity in the hippocampus leads to higher cortisol levels secreted from the adrenal glands. Elevated cortisol levels and hyperactivity of the HPA axis impair serotonin 5-HT1A receptors. This leads to decreased serotoninergic activity in the hippocampus. The resulting deficit in serotonergic activity can lead to the development of depression.

For patients with epilepsy, neurotransmitter and adrenal assessments can provide an important look at which neurotransmitters and hormones are out of balance and potentially contributing to the seizures or associated symptoms. Providing therapy that targets individual imbalances can help to improve symptoms and quality of life for a patient.

References:
http://www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm
E Pineda, D Shin, R Sankar, A Mazarati. (2010). Comorbidity between epilepsy and depression: Experimental evidence for the involvement of serotonergic, glucocorticoid and neuroinflammatory mechanisms. Epilepsia, 51.
M Mula, B Schmitz. (1990). Depression in epilepsy: mechanisms and therapeutic approach. Ther Adv Neurol Disord, 2(5): 337-344.
Posted in Neurology | Tagged , , , , , , , , , | 1 Comment

Epigenetics: more than “there’s a gene for that”

As we increasingly look to our personal electronic devices for help with our daily tasks, we’ve been assured they can help us address nearly any issue we may encounter. Companies like Apple that there is no problem they cannot address with their’s trademark mantra, “There’s an app for that.”  With the decoding of the human genome, which was expected to shed light on health issues ranging from weight to depression or addiction to the continuing rise of autism and other disorders, the medical community has taken a similar approach, being driven by the belief, “There’s a gene for that.”

Figure 1: The flow of information from DNA to protein is largely influenced by regulatory factors acting on the processes of transcription and translation. Environmental factors also influence protein expression.

Figure 1: The flow of information from DNA to protein is largely influenced by regulatory factors acting on the processes of transcription and translation. Environmental factors also influence protein expression.

While in many cases there may be “a gene for that”, this may not be the end of the story. Until recently, it was believed that our genes were the primary determining factors in how we look, think, and behave. Within the past decade however, this paradigm has shifted. It is increasingly apparent that the expression and function of our genes are largely influenced by a network of regulatory and environmental factors. Exploration into how internal regulation and environmental factors influence the expression of genes has given rise to a new field called epigenetics.

Epigenetic studies provide insight into how a person’s genetic makeup interacts with environmental, dietary, and lifestyle factors. The application of these insights has led to a new paradigm in medicine known as functional genetics. The fundamental tenet of this emerging field is that environmental triggers play a major role in whether a particular gene is expressed in a way that favors sickness or health, ease or disease.

The insight into human heredity has come a long way from Mendel’s discoveries in 1866 to the completion of the reference sequence for the human genome in 2003. Advances in current technology allow for studies that look deeper into our genetic code. These advances help determine how our genes are regulated and how they interact in response to various environmental factors. The enormous amounts of data obtained from these studies give us the potential to create truly personalized approaches to managing our well-being.

Guest author: Curtis Christian is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in genetics.

References:
Baranov, V. S. (2009). Genome paths: A way to personalized and predictive medicine. Acta Naturae, 3, 70-80.
Becker, F., van El, C. G., Ibarreta, D., Zika, E., Hogarth, S., Borry, P… Cornel, M. C. (2011). Genetic testing and common disorders in a public health framework: How to assess relevance and possibilities. European Journal of Human Genetics, 19, S6-S44.
Knight, J. C. (2009). Genetics and the general physician: Insights, applications and future challenges.  Q J Med, 102, 757-772. doi:10.1093/qjmed/hcp115
Rose, M. R., Mueller, L. D., & Burke, M. K. (2011). Anecdotal, historical and critical commentaries on genetics: New experiments for an undivided genetics. Genetics Society of America
Young, E., & Alper, H. (2010). Synthetic biology: Tools to design, build, and optimize cellular processes. Journal of Biomedicine and Biotechnology, 2010, 130781. doi:10.1155/2010/130781
Posted in Genetics | Tagged , , , , | 1 Comment

DNA, RNA, SNP – alphabet soup or an introduction to genetics?

Blue eyes or brown? Short or tall? Blond, redhead, or brunette? All the information that guides development of physical traits as well as the other aspects of the human body is encoded in long sequences of deoxyribonucleic acid (DNA). Sections of DNA, known as genes, tell the body how to develop and function. The human genome is made up of about three billion building blocks called nucleotides, which code for around 20,000 genes located on 23 chromosomes. Humans have two copies of each chromosome and thus two copies of each gene. Each parent donates one copy of a gene– one from the mother and one from the father.

Figure 1: The Central Dogma of Biology was coined by Francis Crick in 1953 to illustrate the flow of genetic information. First, DNA is used as a template to create a complimentary strand of ribonucleic acid (RNA) through a process called transcription. This RNA template is then used to create a protein by stringing together amino acids in a process called translation.

Figure 1: The Central Dogma of Biology was coined by Francis Crick in 1953 to illustrate the flow of genetic information. First, DNA is used as a template to create a complimentary strand of ribonucleic acid (RNA) through a process called transcription. This RNA template is then used to create a protein by stringing together amino acids in a process called translation.

Genes consist of specific DNA sequences which use four different nucleotides: adenine (A), cytosine (C), guanine (G), and thymine (T). The DNA sequence is used to create protein via a two- step process, transcription and translation (Figure 1). The resulting protein performs the function coded by the gene.

Figure 2: A SNP is a change in the genetic code of an individual where a single nucleotide is replaced by another in the DNA sequence. Nucleotides: adenine (A), cytosine (C), guanine (G), and thymine (T).

Figure 2: A SNP is a change in the genetic code of an individual where a single nucleotide is replaced by another in the DNA sequence. Nucleotides: adenine (A), cytosine (C), guanine (G), and thymine (T).

Of the three billion nucleotides that make up the human genome, the majority (~99.7%) remain the same from person-to-person. The remainder can vary in a number of different ways. The most common variation is a single nucleotide polymorphism (SNP – pronounced ‘Snip’). A SNP occurs when a nucleotide at a specific position in the DNA sequence gets replaced with a different nucleotide (Figure 2). Thus far, approximately 10 million SNPs have been identified. Most SNPs are found in non-protein coding regions of DNA. However, SNPs in sections coding for genes can result in changes to the transcription/translation process. This can result in a slightly different protein, which may not function in the typical manner.

In some cases, individuals may never notice the change in the protein function. In others, the change could lead to symptoms such as anxiousness, poor bone health, and reactions to various environmental stimuli. Identification of SNPs in specific genes for use in guiding lifestyle and treatment choices to improve overall health and wellness is known as Functional Genetics.

Guest author: Curtis Christian is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in genetics.

References:
Koonin, E. V. (2012). Does the central dogma still stand? Biology Direct, 7(27).
Shakya, K., O’Connell, M. J., & Ruskin, H. (2012). The landscape for epigenetic/epigenomic biomedical resources. Epigenetics, 7(9): 982-986.
Tishkoff, S. A., & Kidd, K. K (2004). Implications of biogeography of human populations for race and medicine. Nature Genetics, 36(11): S21-S27.
Young, E., & Alper, H. (2010). Synthetic biology: Tools to design, build, and optimize cellular processes. Journal of Biomedicine and Biotechnology, 130781. doi:10.1155/2010/130781.
Posted in Genetics | Tagged , , , , , , , , , , , | 1 Comment

T3 and reverse T3: Slight differences, considerable clinical consequences

Thyroid disorders are fairly commonplace in medical practice. Most people have either heard of or know an individual that has hyperthyroidism (e.g. Grave’s disease) or hypothyroidism (e.g. Hashimoto’s disease).

Figure 1. T4 can be converted into either T3 or rT3. Conversion to rT3 is increased by stress, inflammation, and dieting.

Figure 1. T4 can be converted into either T3 or rT3. Conversion to rT3 is increased by stress, inflammation, and dieting.

The thyroid gland is a butterfly-shaped gland in the throat. The main hormone it produces is thyroxine (T4). T4 is produced in large amounts, has a low potency, and converts to triiodothyronine (T3). T3 is produced in small amounts from T4 and has a high potency in the body. T4 has four iodine molecules attached to a tyrosine molecule, but T3 only has three (Figure 1). However, if the iodine molecules are arranged a different way, T3 becomes reverse T3 (rT3).

Some rT3 is always created in the body, but the conversion of T4 to rT3 can be increased due to factors such as stress (high cortisol), inflammation (pro-inflammatory cytokines), and dieting. rT3 is an inactive byproduct that blocks T3 receptors. Even if levels of T3 are adequate, they may not be able to exert their function if rT3 is blocking too many T3 receptors. Elevations in rT3 may compete with otherwise normal T3 and T4 levels and impair health.

Reverse T3 is a valuable marker for identifying hypothyroidism when traditional lab work shows normal T3 levels. Make sure to include rT3 in your thyroid assessments to insure you are getting the most complete evaluation of your patient’s symptoms.

References:

http://nahypothyroidism.org/

van den Beld, AW, et al. (2005). Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab, 90(12): 6403-9.

Posted in Endocrinology | Tagged , , , , , , , | 1 Comment

Tetrahydro…what? It’s essential to understand the whole neurotransmitter pathway

Last week’s post covered the effect oxidative stress can have on the tryptophan pathway and potential decreases in serotonin synthesis. This week we will discuss how oxidative stress can also have a drastic effect on catecholamine (epinephrine, norepinephrine, and dopamine) synthesis.

Figure 1. BH4 is a necessary cofactor for the conversion of tryptophan to 5-HTP, phenylalanine to tyrosine and tyrosine to L-DOPA.

Figure 1. BH4 is a necessary cofactor for the conversion of tryptophan to 5-HTP, phenylalanine to tyrosine and tyrosine to L-DOPA.

Tetrahydrobiopterin (BH4) is an essential cofactor in the synthesis of the monoamine neurotransmitters (Figure 1). BH4 is necessary for the conversion of phenylalanine to tyrosine, tyrosine to L-DOPA, and tryptophan to 5-HTP. However, BH4 is highly sensitive to oxidation and becomes irreversibly degraded to dihydroxyanthopterin (XPH2). Under conditions of oxidative stress, BH4 is rapidly destroyed and BH4-dependent enzymes are unable to perform their function. As a result of the decreased amount of BH4 available to act as a cofactor, lower levels of monoamines can be seen.  When BH4 is decreased, the body may not be able to properly convert precursors because their enzymes can’t function without BH4. This can lead to lower levels of monoamines such as dopamine, norepinephrine, epinephrine, and serotonin. Deficiencies in these neurotransmitters have been associated with a myriad of clinical complaints such as depression, fatigue, attention difficulties, insomnia, and anxiety. Understanding the connections between oxidative stress and neurotransmitters is extremely important. These connections have the potential to impact a patient’s response to therapy if there is inflammation or oxidative stress affecting neurotransmitter levels. Assessing both neurotransmitter levels and immune activity is essential to ensure that you are utilizing the most clinically effective approach for symptom relief.

References:
Haroon, E, et al. (2011). Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior. Neuropsychopharmacology, 1-28.
Neurauter, G., et al. (2008). Chronic immune stimulation correlates with reduced phenylalanine turnover. Curr Drug Metab, 9: 622-7.
Sprener-Unterweger, B., et al. (2014). Immune changes and neurotransmitter: Possible interactions in depression? Neuro-Psychopharmacology & Biological Psychiatry, 48: 268-76.
Posted in Immunology, NeuroImmune, Neurology | Tagged , , , , , , , , , , , , | Leave a comment

Is oxidative stress stealing your serotonin?

In recent posts, we’ve discussed oxidative stress and the innate systems the body uses to control free radical levels. When these systems are not functioning properly or free radicals are being produced too quickly for the body to keep up, problems start to arise. For example, an increase in free radical levels can affect immune activity and neurotransmitter levels by influencing neurotransmitter synthesis.

Free radicals can stimulate the adaptive immune response. This shift in immune activity can have a drastic effect on the tryptophan pathway and serotonin synthesis.

Figure 1. Immune upregulation can shunt tryptophan away from the serotonin pathway and into the kynurenine pathway.

Figure 1. Immune upregulation can shunt tryptophan away from the serotonin pathway and into the kynurenine pathway.

During the adaptive immune response, there is an increase in pro-inflammatory cytokines. One of the functions of these immune messengers is to increase activity of the enzyme indoleamine 2,3-deoxygenase (IDO) (Figure 1). The increase in IDO activity shunts tryptophan away from the serotonin pathway and into the kynurenine pathway. One purpose of this shift is to convert kynurenine to kynurenic acid, which is neuroprotective. However, kynurenine can also be converted to quinolinic acid, which is neurodegenerative.

A possible result of shunting tryptophan down the kynurenine pathway is lower serotonin levels. When IDO activity is increased, there’s less tryptophan available for making serotonin. Low serotonin levels have been associated with clinical symptoms such as depression, insomnia, and anxiety.

As these connections show, it is important to consider the interactions between systems when designing interventions. Assessing neurotransmitter levels and immune activity can help identify a patient’s unique imbalances to help create personalized therapies. Be sure to check back next week to learn how oxidative stress affects catecholamine (norepinephrine, dopamine, and epinephrine) synthesis.

References:
Anisman, A. (2009). Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. J Psychiatry Neurosci, 34(1): 4-20.
Korbecki, J, et al. (2013). The effect of reactive oxygen species on the synthesis of prostanoids from arachidonic acid. J Physiol Pharmacol, 64(4): 409-21.
Sutti, S, et al. (2013). Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology, Epub ahead of print.
Wichers, M., Maes, M. (2004). The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. J Psychiatry Nerosci, 29(1): 11-17.
Posted in Immunology, NeuroImmune, Neurology | Tagged , , , , , , , , , | 2 Comments

Do you have a radioactive intruder in your home?

Radon is a natural radioactive gas derived from decaying radium and uranium, which are common environmental toxins. Human exposure to radon has been linked to increased risk of lung cancer and can lead to oxidative stress and inflammation. In fact, the World Health Organization lists radon as the leading cause of lung cancer, in many countries, after smoking.

The most common exposure to radon occurs simply by breathing it in. What makes radon especially dangerous is that it cannot be seen, tasted, or smelled and can be found in any environment, including our homes. In fact, radon gas is more concentrated indoors than outdoors. The level of environmental radon indoors depends on the amount of uranium in the surrounding rocks. Radon gas naturally gets released by the earth and enters our home through cracks, holes, and joints in the house.

Figure 1. Radon gives off alpha particles, which can contribute to oxidative stress.

Figure 1. Radon gives off alpha particles, which can contribute to oxidative stress.

Radon causes oxidative stress by giving off alpha particles, which are a highly charged form of particle radiation (Figure 1). They have two protons and two neutrons but no electrons. As these particles are given off, they tend to “stick” to the first surface they meet. This collision causes physical damage to body tissue by disrupting the bonds that hold molecules together. More specifically, DNA may be damaged by electron displacement as well as structural changes in interacting DNA molecules.

As particle radiation damage occurs, an inflammatory response begins. Inflammation then induces oxidative stress and impairs antioxidant capacity in cells. Oxidative stress creates an influx of reactive oxygen species which can further lead to mutation and DNA damage. The damage that occurs to DNA can lead to the development of many disorders including cancer.

Radon particles usually enter through the mouth and nose as free gas particles or attached to dust particles. Because alpha particles usually enter the body through the respiratory tract, radon exposure is highly correlated to lung cancer. In fact, the Environmental Protection Agency considers radon as the number one cause of lung cancer in non-smokers.

So, what can we do to eliminate or reduce radon exposure in our homes? The best way to lower exposure to radon is improve ventilation and eliminate cracks and holes that allow radon to enter into the home. The increased air flow and blocked entrance may help prevent dense pockets of radon gas from forming. Further, checking radon levels regularly and avoiding high risk areas would be good first steps to take to reduce radon induced damage.

Guest author: Brett Tuominen is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in environmental toxins.

References:
http://www.epa.gov/radon/
Appleton, D. J. (2005). Radon in air and water. In O. Selinus, B. Alloway, J. A. Centeno, R. B. Finkelman, R. Fuge, U. Lindh, & P. Smedley (Eds.), Essentials of medical geology—impacts of the natural environment on public health (pp. 227–262). London: Elsevier Academic Press.
Turner, M.C., Krewski, D., Chen, Y., et al. (2011). Radon and Lung Cancer in the American Cancer Society Cohort. Cancer Epidemiol Biomarkers Prev, 20:438-448. Published OnlineFirst January 6, 2011.
Posted in Immunology | Tagged , , , , , , | Leave a comment

Did “Rain Man” teach you everything you know about autism?

Autism, by definition, is a behavioral/developmental disorder characterized clinically by delays and qualitative differences in communication and social interaction as well as repetitive behaviors and restricted interests.

Figure 1. The evolution of the proposed cause of autism.

Figure 1. The evolution of the proposed cause of autism.

In the movie “Rain Man” Dustin Hoffman’s character, Raymond, is an adult with autism.  Throughout the movie certain classic symptoms of autism are portrayed such as high intelligence, repetitive behavior, and limited eye contact.  However, the movie is not able to explain the reason behind the disorder – that exact reason has escaped researches for some time, but it is becoming more and more apparent that there are many contributing factors.

The proposed cause of autism has changed over time. Today’s theory of the pathophysiology of this disorder is rooted in the many biochemical and systemic factors that can affect the brain (Figure 1).

Figure 2. Many factors and various immunological and neurological components can affect a patient’s presentation.

Figure 2. Many factors and various immunological and neurological components can affect a patient’s presentation.

To help identify the various factors that can contribute to the presentation of autism, one could ask the following questions:

1)     Is this individual’s body and brain getting what it needs to function optimally?  This can include vitamins; minerals; omega-3 fatty acids; and healthy, clean foods.

2)     Is something present in this individual’s body and brain that interferes with the ability to function optimally?  This can include internally- or externally-derived toxins, free radicals, or cytokines.  Intestinal dysbiosis, or the disruption of a normally-functioning GI system, can severely disrupt a patient’s health and is an emerging point of intervention (Figure 2).

Figure 3. “Background noise” factors can have an opposing relationship with a patient’s signal strength.

Figure 3. “Background noise” factors can have an opposing relationship with a patient’s signal strength.

The net effect these immunological factors can have on the body has been called background noise in a recently described “signal-to-noise” ratio paradigm.  This model explains that when background noise increases (poor nutrition, oxidative stress, etc.) the body’s signal strength (brain transmission) decreases.  This may mean that the body’s neurotransmitters have become depleted or they may simply be unable to be heard over the background noise (Figure 3).

Providers can come to understand how better to treat autism by learning how the disorder may be caused.  The root cause is now believed to lie within multiple biochemical factors.  Decreasing exposure to potentially harmful factors and ensuring the body’s various systems are in good working order can result in beneficial outcomes.

Guest author: Rachel Rixmann is the manager of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in gastroenterology and nutrition.

References:
Compart, Pamela J. (2013). The Pathophysiology of Autism. Global Adv Health Med,2(6): 32-37.
MacFabe, Derrick. (2013). Autism: Metabolism, Mitochondria, and the Microbiome. Global Adv Health Med, 2(6): 52-66.
Posted in Immunology, Neurology | Tagged , , , , | Leave a comment

Ahh, the Superbowl: a championship game, new commercials, the half-time show…and cholesterol risk?

Many of us just recently enjoyed a Superbowl Sunday indulging in delicious food like sausages, chips, dips, wings, and more. While enjoying all these foods, did you stop to think about how they may impact your cholesterol levels?  This post discusses cholesterol and how elevated levels can impact overall health.

What is Cholesterol?

Cholesterol is a waxy, fat-like substance required for cell membrane permeability and fluidity. It is found within all cells and is necessary for your body to make certain steroid hormones and vitamin D as well as substances such as bile acids that help to digest foods. Your body actually makes all the cholesterol you need. Out of your total cholesterol levels, three-fourths is produced naturally and the other fourth comes from your diet. The dietary portion serves as a surplus of cholesterol and is obtained from animal products such as meat, eggs, and dairy.

Cholesterol flows through the bloodstream in small packages known as lipoproteins. It is unable to dissolve in the blood, so these transport proteins carry it to its destination. The lipoproteins carry cholesterol via low-density lipoproteins (LDL) and high-density lipoproteins (HDL). LDL is commonly referred to as the “bad” cholesterol, while HDL is considered the “good” cholesterol.

Figure 1: As blood flows through the arteries, LDL cholesterol can store itself in the artery walls. A plaque forms over time and can burst suddenly, causing a blood clot.

Figure 1: As blood flows through the arteries, LDL cholesterol can store itself in the artery walls. A plaque forms over time and can burst suddenly, causing a blood clot.

Bad Cholesterol

As LDL circulates throughout the bloodstream, some of it can be deposited into the wall of arteries. While LDL collects in the artery, white blood cells swallow and digest LDL, converting it to a toxic, oxidized form. Macrophages (a type of white blood cell) migrate to this area in the artery causing progressive inflammation. Over time, build up occurs in the artery wall creating plaque that can block the artery and impair proper blood flow, which leads to atherosclerosis. At any time, a sudden rupture of the plaque can occur, causing a blood clot to form on the ruptured area (Figure 1). This can lead to a heart attack if the clot breaks free and travels to the heart. Higher levels of LDL in the blood put patients at greater risk of stroke and heart attack.

Good Cholesterol

HDL, on the other hand, scavenges the bloodstream, removing harmful cholesterol (LDL) from where it doesn’t belong. HDL transports LDL to the liver where it undergoes reprocessing (kind of like recycling). HDL is essential for keeping the inner walls of arteries clean and healthy, which reduces the risk of atherosclerosis. Higher levels of HDL reduce the risk for heart disease while lower levels increase the risk.

Managing Your Cholesterol

Having your cholesterol levels checked regularly is important, especially if you have cardiovascular disease. Cholesterol can be affected by a wide variety of factors such as your age, gender, diet, and genetics. For patients with abnormal cholesterol levels, pharmaceuticals that help normalize cholesterol levels are an option. Lifestyle changes such as smoking cessation, regular exercise, and reduced dietary fat intake can also make a significant difference. Using these suggestions to maintain healthy cholesterol levels is always advised when it comes to living a happy and healthy life. You can help control your cholesterol levels with a little effort put towards a healthy lifestyle.

Guest author: Adam Westman is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in cardiology.

Posted in Cardiology | Tagged , , , , , , , , , , , | 1 Comment

Neutralizing the threat of excess free radicals – your body’s natural defense system

In a previous post, we discussed the concept of oxidative stress and the association that it can have with numerous health concerns. It is also important to understand how the body controls free radicals and prevents oxidative stress from occurring. To review – we know that oxidative stress is the burden on the body as a result of an overproduction of free radicals. This occurs when the control mechanisms of the body that counter free radicals aren’t able to maintain a proper balance. The cause of this imbalance is often attributed to a stressor such as an immune reaction or environmental exposure. It is important to note that free radicals do not always have negative effects on the body; a problem only arises when the amount of free radicals is high enough to outweigh the body’s normal antioxidant defenses.

Figure 1: SOD converts free radicals to hydrogen peroxide. Catalase then degrades hydrogen peroxide into water and oxygen with the help of a variety of other enzymes and vitamins.

Figure 1: SOD converts free radicals to hydrogen peroxide. Catalase then degrades hydrogen peroxide into water and oxygen with the help of a variety of other enzymes and vitamins.

The body has several ways to deal with an excess of free radicals. The first line of defense includes the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase, and catalase. These enzymes help rid the body of free radicals by converting them into water and oxygen (Figure 1). After oxygen becomes a free radical, SOD converts it into hydrogen peroxide, then catalase and glutathione peroxidase continue the conversion into water and oxygen.

The enzymes discussed above are the first line of defense against free radicals. Their optimal function is dependent on certain antioxidants and mineral cofactors derived from the diet. Polyphenols, vitamins E and C, coenzyme Q10, and glutathione support the antioxidant enzymes. The body makes every effort to minimize the negative effects of free radicals by relying on its own enzymes, as well as antioxidants from the diet. Deficiencies in either of these defense systems can lead to a wide variety of oxidative stress-related clinical symptoms and conditions.

 Guest author: Deanna Fall is currently a scientific writer and research analyst for NeuroScience, Inc. and holds a bachelor’s degree in biology from Ferris State University in Big Rapids, Michigan and a master’s degree in health informatics at the University of Minnesota.  Deanna joined NeuroScience in 2009 with experience in pharmaceutical research and development in the field of neurotoxicology.

References:
Muller, FL, et al. (2007). Trends in oxidative aging theories. Free Radic Biol Med, 43(4): 477-503.
Posted in Immunology | Tagged , , , , , , , , , | 1 Comment

When you hear “craving,” do you think sweet, salty…or serotonin?

We all experience cravings from time to time – a piece of fudge, one more handful of potato chips, or another slice of that heavenly apple pie. These cravings might not be due to the temptation of all the goodies we have gotten used to over the holiday season. They might be due to the neurotransmitters involved in food cravings, including serotonin, dopamine and glutamate.

chocolateSerotonin is involved in appetite and hunger.  When carbohydrate-rich foods are consumed, insulin raises brain tryptophan levels, which increases the rate of production and release of serotonin.1 Low serotonin levels can trigger carbohydrate cravings, which uncontrolled may lead to weight gain. Supporting serotonin may help decrease carbohydrate cravings.1

In a previous entry, we discussed glutamate and dopamine as part of the pleasure/reward pathway. As part of the pleasure/reward pathway, dopamine and glutamate are associated with cravings.

When we eat something delicious, dopamine is released from the ventral tegmental area (VTA) of the brain and sent to the nucleus accumbens. The size of this dopamine release is measured and glutamate instructs the prefrontal cortex to remember which foods produced more of a dopamine release. Since a burst of dopamine creates pleasure, the body then is wired to crave the food that increased the dopamine level. This is how cravings begin.2

One specific addiction seen frequently, especially in America today, is compulsive eating. Foods we typically find ourselves craving include those that contain a lot of sugar. In fact, sugar has addictive properties similar to opioids and psychostimulants.3 Acting on these cravings may lead to unwanted weight gain.

Imbalances in serotonin, dopamine and glutamate may be making it more difficult to make the right food choices. Correcting these imbalances can help control cravings and potentially aid in weight loss efforts. If cravings are a chief concern, balancing neurotransmitters is a vital first step on the way to feeling happier and healthier.

Guest author: Tricia Walz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in metabolic issues.

References:
(1). Wurtman, RJ., Wurtman, JJ. (1995). Brain Serotonin, Carbohydrate-Craving, Obesity and Depression. Obes Res. 3(4):477S-480S.
(2). Kalivas PW, Volkow ND. (2005). The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry, 162(8):1403-13.
(3). Gold, MS., et al. (2009). Food addiction? J Addict Med. 3: 42-45.
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Patients with low mood all have unique neurotransmitter patterns

Depression is a common illness, approximately 1 in 10 people report symptoms of depression (http://www.cdc.gov/features/dsdepression/). Imbalances in monoamine neurotransmitters, especially serotonin and norepinephrine, are commonly indicated in depression.   Despite this knowledge, therapies addressing serotonin and norepinephrine imbalances are often ineffective.  This may be due to a broad range of other imbalances contributing to depressive symptoms.  If serotonin imbalances are being addressed, but serotonin imbalance is not the cause of the depression, symptom alleviation may not occur.

Recent research has uncovered other neurotransmitters are involved in depressive symptoms.  Researchers have found a correlation between the blockade of the NMDA (glutamate) receptor, using an NMDA antagonist, and the alleviation of depressive symptoms in some patients.   Another neurotransmitter with known involvement is dopamine; this is known due to dopamine reuptake inhibition leading to symptom alleviation in some patients.

Why is this important?

With so many potential imbalances within the neurotransmitters contributing to depression and mood disorders, determination of the appropriate treatment is difficult.  Looking at baseline neurotransmitter values may be a valuable tool in determining which direction to take when addressing imbalances.

To illustrate this, below are urinary neurotransmitter results for 3 patients with depressive symptoms and /or mood issues:

Figure 1 depicts results from 3 different patients suffering from depression.  Figure 1a. Patient who may be experiencing depression symptoms due to a serotonin imbalance.  Figure 1b. A patient with depleted epinephrine and norepinephrine, which may be indicative of low adrenal function and may cause depressive symptoms.  Figure 1c. A patient with elevated glutamate, which may be a cause of depression.

Figure 1 depicts results from 3 different patients suffering from depression. Figure 1a. Patient who may be experiencing depression symptoms due to a serotonin imbalance. Figure 1b. A patient with elevated glutamate, which may be a cause of depression. Figure 1c. A patient with depleted epinephrine and norepinephrine, which may be indicative of low adrenal function and may cause depressive symptoms. 

It has been illustrated here that a variety of neurotransmitter imbalances may contribute to depression.  It is also important to remember common underlying causes of neurotransmitter imbalances, such as diet, lifestyle, environment, psychological health, and the immune and endocrine systems.  While these imbalances may be addressed with specific therapies, it is always important to identify the root cause of the imbalance when trying to address the system as a whole.

Guest author: Jennifer Farley is a member of the Medical Education Department at NeuroScience, Inc. and one of the resident experts in psychiatric disorders.

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Genetic control of methylation can affect your health

With the holiday season ending so does a peak travel period, as friends, family, and coworkers return from holiday getaways. In addition to stories of family celebration or tropical paradises visited, the travel experience can also bring stories of layovers, cancelled flights, and lost luggage. As annoying as such experiences can be, it is quite profound how much actually goes right during these chaotic times given the amount of information that needs to be kept straight. A series of tickets, tags, scanners, and check points coordinate information to transport millions of people and their belongings all around the world.

The body has a similar information system to instruct molecules where they should be, when they should be there, and what they should be doing. One part of this system involves methylation. The methylation pathway, which is the result of close communication between the methionine, folate, and biopterin cycles, plays a vital role in many biological processes (Figure 1).

Figure 1. Methylation biochemistry is the result of close communication between the methionine, folate, and biopterin cycles and plays a role in many biological processes.

Figure 1. Methylation biochemistry is the result of close communication between the methionine, folate, and biopterin cycles and plays a role in many biological processes.

The methylation pathway affects inflammation, detoxification, DNA and cellular repair, as well as maintenance of proper levels of neurotransmitters which can influence energy levels, mood, and cognitive function. This is due, in part, to the effect of methylation on gene expression. Proper function of the methylation cycle is needed for gene expression, as methyl groups on regions of DNA serve as markers for when to turn a gene on and off.  Different methylation patterns in a variety of genes can result in many poor physical and mental health outcomes, including cardiovascular and metabolic issues, as well as depression, psychiatric disorders, and other mental health conditions. DNA methylation is also becoming increasingly important in understanding the pathology of many types of cancer, as tumor cells may shift methylation patterns in a way that favors inactivation of tumor suppressor genes.

Since methylation plays such an important role in gene expression, mutations in genes within the methylation cycle can alter normal biological processes. One important gene in this cycle is for the enzyme methylenetetrahydrofolate reductase (MTHFR). This gene is responsible for an important step in the metabolism of folate (a B-Vitamin). A variety of mutations in the MTHFR gene can interfere with this process.

A common variant in this gene includes the C677T polymorphisms. These polymorphisms result in an amino acid substitution that causes a significant decrease in enzymatic function at elevated temperatures. Mutations like this in the MTHFR gene can interact with other genetic or environmental components and possibly contribute to a variety of conditions, including Alzheimer’s disease, Parkinson’s disease, autism, diabetes, arthritis, cardiovascular issues, chronic fatigue, and many types of cancer.

As many of us return from our holiday travels, we transition from feasting to considering New Year’s Resolutions that often include improvements in our health.  The good news is that we may not have to struggle as much with these goals as we have in the past.  It is now possible to test our genes for mutations that increase our risk for many health conditions.  Gaining this insight into which genes we actually carry and how to best support proper function of these genes can help ensure we experience many more happy holiday travels to come.

Guest author: Curtis Christian is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in genetics.

References:
Bai, J. L., Zheng, M. H., Xia, X., Ter-Minassian, M., Chen, Y. P., & Chen F. (2008). MTHFR C677T polymorphism contributes to prostate cancer risk among Caucasians: A meta-analysis of 3511 cases and 2762 controls. European Journal of Cancer, 45, 1443-1449.
Botto, L. D., & Yang, Q. (2000). 5, 10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A huge review. American Journal of Epidemiology, 151(9), 862-877.
Carvalho, D. D., et al. (2012). DNA methylation screening identifies driver epigenetics events of cancer cell survival. Cancer Cell, 21, 655-667.
Coppede, F. (2014). Epigenetics biomarkers of colorectal cancer: Focus on DNA Methylation. Cancer Letters, 342, 238-247.
Phillips, T. (2008). The role of methylation in gene expression. Nature Education, 1(1), 116.
Szyf, M. (2013). DNA methylation, behavior and early life adversity. Journal of Genetics and Genomics, 40, 331-338.
Wu, Y. L., Ding, X. X., Sun, Y. H., & Sun, L. (2013). Methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson’s disease: A meta-analysis. Journal of Neurological Sciences, 335, 14-21.
Wang, W. Hou, Z., Wang, C., Wei, C., Li, Y, & Jiang, L. (2013). Association between 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and congenital heart  disease: A meta-analysis. Meta Gene, 1, 109-125.
Yang, S., Zhang, J., Feng, C. & Huang G. (2013). MTHFR 677 T variant contributes to diabetic nephropathy risk in Caucasian individuals with type 2 diabetes: A meta-analysis. Metabolism Clinical and Experimental, 62, 586-594.
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Norepinephrine: responsible for focus, mood, energy…and sleep?

Recently, we had a post about the importance of GABA, serotonin, and melatonin in sleep circuitry.  These calming markers are not the only factors important for sleep, however.

Figure 1. Light is absorbed through the retina and signals down the pathway to the superior cervical ganglion which uses norepinephrine to signal the pineal gland to synthesize melatonin. Image from Stehle, 2011. Abbreviations: RET-retina, RHT-retinohypothalamic tract, SCN-suprachiasmatic nuclei, PVN-paraventricular nuclei, IMC-intermediolateral column of the spinal cord, SCG-superior cervical ganglion, NE-norepinephrine, PIN-pineal gland, MEL-melatonin

Figure 1. Light is absorbed through the retina and signals down the pathway to the superior cervical ganglion which uses norepinephrine to signal the pineal gland to synthesize melatonin. Image from Stehle, 2011.
Abbreviations: RET-retina, RHT-retinohypothalamic tract, SCN-suprachiasmatic nuclei, PVN-paraventricular nuclei, IMC-intermediolateral column of the spinal cord, SCG-superior cervical ganglion, NE-norepinephrine, PIN-pineal gland, MEL-melatonin

Did you know that norepinephrine, a neurotransmitter commonly seen as excitatory, is an important part of the sleep pathway?  In fact, healthy levels of the sleep hormone melatonin depend on norepinephrine.

Melatonin is primarily secreted by the pineal gland in both day-active (diurnal) and night-active (nocturnal) animals during darkness.  The photoperiod is responsible for melatonin synthesis as well as its secretion.  The pathway from light perception to melatonin synthesis also included norepinephrine.

The retina of the eye absorbs light (Figure 1) and a signal passes through the retinohypothalamic tract to the suprachiasmatic nuclei.  From there the signal passes to the paraventricular nuclei, then onto the intermediolateral column of the spinal cord, and finally to the superior cervical ganglion.  The superior cervical ganglion then uses norepinephrine to signal the pineal gland to synthesize melatonin from serotonin.

Even though norepinephrine is classified as an excitatory neurotransmitter, it has a very important role in the synthesis of melatonin, and, therefore, in sleep.  However, sleep depends on optimal norepinephrine levels.  Too little norepinephrine can lead to lowered melatonin synthesis and sleep issues and too much norepinephrine, as it is excitatory, can keep you awake.  If sleep is an issue, make sure to consider norepinephrine and not just calming neurotransmitters.

References
Challet, E. (2007). Minireview: Entrainment of the Suprachiasmatic Clockwork in Diurnal and Nocturnal Mammals. Endocrinology, 148(12): 5648-55.
Conti A, et al. (2000). Evidence for melatonin synthesis in mouse and human bone marrow cells. Journal of Pineal Research, 28(4): 193-202.
Reiter, RJ, et al. (2010). Melatonin: a multitasking molecule. Progress in Brain Research, 18.
Stehle, JH, et al. (2011). A survey of molecular details in the human pineal gland in the light of phylogeny structure function and chronobiological diseases. J. Pineal Res, 51: 17-43.
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Is peace on earth evading you this Christmas season?

Last week’s blog post discussed fatigue during the holidays.  While some people can be worn out by the whirlwind of holiday activities, others can become overstimulated or anxious. The difference in response is due to neurotransmitters.

Figure 1. Stimulating neurotransmitters (e.g. norepinephrine, glutamate, and epinephrine) increase in response to stress.  In a healthy response, compensatory neurotransmitters (e.g. GABA, serotonin, and glycine) should increase to compensate for the increase in stimulating neurotransmitters.

Figure 1. Stimulating neurotransmitters (e.g. norepinephrine, glutamate, and epinephrine) increase in response to stress. In a healthy response, compensatory neurotransmitters (e.g. GABA, serotonin, and glycine) should increase to compensate for the increase in stimulating neurotransmitters.

Neurotransmitters are generally categorized as excitatory or compensatory.  Excitatory neurotransmitters include epinephrine, norepinephrine, and glutamate.  They stimulate the nervous system and are important for focus, energy, and mood.  However, an excess of these neurotransmitters can lead to anxiousness and overstimulation.  Compensatory neurotransmitters, like serotonin and GABA, calm the nervous system down by suppressing the activity of excitatory neurotransmitters.  Metaphorically, an increase in excitatory neurotransmitters causes stimulation, like stepping on the gas pedal in a car.  Compensatory neurotransmitters slow the nervous system, like the brakes of a car.

Ideally, excitatory and compensatory neurotransmitter activity would be balanced.  However, during times of stress, excitatory neurotransmitter activity increases (Figure 1).  If the nervous system is functioning properly, compensatory neurotransmitter activity should also increase in order to reduce excitatory activity.  The body uses this mechanism to restore balance.

Problems can occur when compensatory neurotransmitters aren’t able to compensate for the rise in excitatory neurotransmitters.  As the excitatory and compensatory systems become dysregulated due to chronic stress, many symptoms can begin to occur.  Anxiousness and overstimulation are two common symptoms resulting from the excess of stimulating neurotransmitters compared to compensatory neurotransmitters.

If anxiousness or overstimulation is a problem, neurotransmitter assessment can provide insight into which neurotransmitter imbalances may be contributing to clinical symptoms as well as help determine an individualized therapy program.

References:
Cryan, JF, et al. (2005). Don’t worry ‘B’ happy!: a role for GABAb receptors in anxiety and depression. TRENDS in Pharmacological Sciences, 26(1): 36-43.
Nikolaus, S, et al. (2010). Cortical gaba, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders-results from in vivo imaging studies. Reviews in the neurosciences, 21(2): 119-39.
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Do you have enough energy to rock around the Christmas tree?

Family, food, gifts, and fun are all part of the joy of the holidays for most people.  For many, fatigue is also a part of the holiday season.  Staying up late for holiday parties or the stress of finding a last minute gift can wear a person down; but what if the tired and worn out feelings persist beyond the holidays?  In cases like this, a busy schedule may not be to blame.  It may be adrenal fatigue.

Figure 1. Early-stage adrenal fatigue is characterized by elevated levels of adrenal neurotransmitters and hormones.

Figure 1. Early-stage adrenal fatigue is characterized by elevated levels of adrenal neurotransmitters and hormones.

Adrenal fatigue occurs when the adrenal glands can no longer produce enough adrenal hormones and neurotransmitters for optimal function.  This happens when stress has been constant.

Adrenal fatigue can be divided into three stages:

Figure 2. Mid-stage adrenal fatigue is characterized by dysregulated levels of adrenal neurotransmitters and hormones.

Figure 2. Mid-stage adrenal fatigue is characterized by dysregulated levels of adrenal neurotransmitters and hormones.

  1. Early-stage:  This stage is the body’s normal response to stressful events such as hosting a holiday party or finding the perfect gift for that difficult family member.  Early-stage (Figure 1) is characterized by elevated levels of epinephrine, norepinephrine, cortisol, and DHEA, and serotonin levels may be optimal or imbalanced.  Often, the clinical presentation in early stage includes overstimulation, anxiousness, sleep disturbances, trouble focusing, and feeling stressed.  In a healthy situation, the body will be able to recover with a little relaxation.  However, when stress is chronic, like the difficult family member moves in next door, adrenal fatigue can progress to mid-stage.

    Figure 3. Late-stage adrenal fatigue is characterized by depleted levels of adrenal neurotransmitters and hormones.

    Figure 3. Late-stage adrenal fatigue is characterized by depleted levels of adrenal neurotransmitters and hormones.

  2. Mid-stage: DHEA, epinephrine, and norepinephrine can appear variable in the mid-stage of adrenal fatigue and serotonin starts to become depleted in this stage (Figure 2).  Cortisol is dysregulated as shown by any of several patterns, including an “L-shaped” curve where levels are low in the morning and elevated in the evening.  Clinically, individuals in mid-stage adrenal fatigue are often “wired and tired” (indicating both anxiousness and fatigue) and have low mood.
  3. Late-stage: In late-stage adrenal fatigue, DHEA, cortisol, epinephrine, norepinephrine and serotonin levels are typically low (Figure 3).  Symptoms common in late-stage adrenal fatigue include fatigue/exhaustion, difficulty dealing with stress, cognitive decline, and weight management difficulties.

Adrenal fatigue occurs over time.  Addressing issues in the early stages is helpful, and lifestyle changes to reduce stress are also beneficial.  Testing adrenal hormone and neurotransmitter levels can help a practitioner determine what therapy will be most beneficial to support adrenal activity as opposed to just treating symptoms.

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Hormonal changes in menopause: Is it all downhill from here?

The last several weeks, this blog has discussed hormones during the reproductive cycle  as well as neuro-endo connections (e.g.  serotonin, estradiol, testosterone, dopamine, progesterone, and GABA).  This week we will look at hormonal changes approaching menopause.

Figure 1. As women  age, ovarian reserve falls, eventually leading to hormone fluctuations and the onset of menopause.

Figure 1. As women age, ovarian reserve falls, eventually leading to hormone fluctuations and the onset of menopause.

Around age 38 the ovarian reserve declines rapidly significantly decreasing fertility (Figure 1).  At this point, there are far fewer follicles that can be recruited and, as a result, less egg maturation and release.  This ovarian depletion results in hormonal fluctuation.  All of this eventually leads up to a woman’s final menstrual period, which is on average around age 51.

The first hormone to begin decreasing during perimenopause is progesterone (Figure 2).  As the number of follicles decreases, ovulation and the resulting corpus luteum formulation occurs less frequently. This significantly decreases the amount of progesterone produced. As progesterone levels begin to fall, gonadotropin releasing hormone (GnRH) increases, and as a result, follicle stimulating hormone (FSH) increases in an attempt to recruit a follicle. At the onset of menopause, when ovarian reserve is almost completely diminished, estradiol levels decrease dramatically and estrone becomes the most abundant type of estrogen in the body.

Figure 2. Progesterone is the first hormone to decrease during perimenopause followed by an increase in FSH and then a decrease in estradiol (E2).

Figure 2. Progesterone is the first hormone to decrease during perimenopause followed by an increase in FSH and then a decrease in estradiol (E2).

Although progesterone and estrogen levels fall drastically, hormone synthesis doesn’t stop altogether during menopause. When the ovarian reserve is depleted, and the ovaries are no longer producing hormones, other tissues in the body become the main producers of hormones. The adrenal glands are one of these tissues. They produce progesterone and androstenedione, the precursor to testosterone. Some of this testosterone converts into estrogen.

Adrenal fatigue or burnout can cause additional issues for women in perimenopause as exhausted adrenals cannot synthesize as many hormones as healthily functioning adrenals. Adipose (fat) tissue also produces estrogen. Individuals with higher body mass indexes (BMIs) and more adipose tissue have higher circulating hormone levels.

While it is natural for hormone levels to change throughout perimenopause and menopause, patients entering menopause with healthy adrenal gland activity and normal adipose stores have any easier transition with fewer symptoms. It is also important to keep in mind that with hormonal changes neurotransmitter activity also changes adding another layer to supporting a healthy transition to menopause.

References:
Nussey, Stephen, and Saffron Whitehead. Endocrinology: An Integrated Approach. Oxford: BIOS Scientific, 2001.
Widmaier, et al. (2008). Vander’s Human Physiology; Eleventh Edition.
Posted in Endocrinology | Tagged , , , , , , , , , , | 2 Comments

Oh baby! Did you know immune function can affect fertility?

Unexpected resultFertility issues can cause a lot of heartache for couples who are having difficulty conceiving.  According to the CDC, about 10% of reproductive-age women are infertile.  Infertility, however, is not always simply an endocrine imbalance.  Chronic stress and immune system status are two factors that can affect fertility and are often overlooked.

Infertility can be separated into male and female factor infertility.  Male factor infertility is more easily diagnosed, identified by changes in the count, mobility, and shape of the sperm. Female factor infertility is typically more difficult to assess.  Most cases are caused by ovulatory problems including irregular or absent menstrual cycles, Polycystic Ovary Syndrome (PCOS) or endometriosis. Other risk factors for female factor infertility include poor diet, athletic training, and being under/overweight.  However, immune system imbalances and chronic stress can affect fertility and contribute to conception issues, as well.

Figure 1. During the luteal phase and during pregnancy, the immune system should be biased toward a Th2 response.

Figure 1. During the luteal phase and during pregnancy, the immune system should be biased toward a Th2 response.

During the luteal phase of a woman’s cycle and during a healthy pregnancy, the body’s regulation of Th1/Th2 immune balance changes.  To promote pregnancy, the body increases Th2 immune activity and naturally suppresses T cell Th1 activity (Figure 1) and decrease the release of pro-inflammatory cytokines.   This is important because too much Th1 activity may lead to rejection of an embryo.  In fact, heightened Th1 activity has been noted in women with recurrent pregnancy loss and implantation failure.  Examples of Th1 activity include the cytokines TNF-alpha, IL-2, and INF-gamma and are commonly seen with chronic inflammation.  A rise in Th1 activity can also be the result of adrenal fatigue.

Adrenal fatigue is an indicator of stress.  Stress is a broad-spectrum risk factor for infertility.  Many things can lead to additional stress on the body including damaged GI tract, underlying inflammation, environmental toxin exposure, adrenal fatigue, disrupted thyroid function, or sympathetic dysfunction.

For additional information on some infertility connections, see Module 3 of the Reproductive Endocrinology Curriculum: Hormones throughout the Life Cycle: Cycling Females (log-in required).

References:
Joon Yun, et al. (2004). Autonomic dysfunction may be an under-recognized cause of female fertility disorders.  Medical Hypotheses, 63(1):172-7.
Kwak-Kim JY, et al. (2003). Increased T helper 1 cytokine responses by circuating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod, 18(4):767-73.
Makhseed, M, et al. (2001).Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions. Hum Reprod, 16 (10): 2219-2226.
Polgar K, et al. (1996). Immune interferon gamma inhibits translational mobility of a plasma membrane protein in preimplantation stage mouse embryos: a T-helper 1 mechanism for immunologic reproductive failure.  Am J Obstet Gynecol, 174(1 Pt 1):282-7.
Posted in Endocrinology, Immunology | Tagged , , , , , , , , , , , , | 3 Comments

Progesterone and neurotransmitters: the under-recognized relationship

Hormones and the nervous system are linked in ways that may not be obvious. In recent weeks, we’ve explored the connections between estrogen and serotonin and testosterone and dopamine. Progesterone is another hormone that has many implications in the nervous system.

Figure 1. During the follicular phase, estradiol peaks around day 12, this estradiol peak and subsequent dropoff signal LH secretion. This sequence of events allows ovulation to occur around day 14. After day 14, during the luteal phase, the corpus luteum secretes progesterone.

Figure 1. During the follicular phase, estradiol peaks around day 12, this estradiol peak and subsequent dropoff signal LH secretion. This sequence of events allows ovulation to occur around day 14. After day 14, during the luteal phase, the corpus luteum secretes progesterone.

Normally, progesterone is recognized for its role in the luteal phase of the menstrual cycle (Figure 1). During the luteal phase, progesterone levels increase, signaling an egg has been released from the ovary. However, the increase in progesterone has effects beyond reproduction. The luteal rise of progesterone is thought to be the cause of many pre-menstrual syndrome (PMS) symptoms including bloating and irritability and when progesterone levels decline, anxiety and insomnia become more common. This occurs because progesterone has a calming effect.

Figure 2. Allopregnanolone, a metabolite of progesterone, enhances GABAA receptor activity.

Figure 2. Allopregnanolone, a metabolite of progesterone, enhances GABAA receptor activity.

Progesterone’s calming effect is due to its metabolite allopregnanolone, which enhances GABAA receptor activity1. gamma-Aminobutyric acid (GABA) is a calming neurotransmitter. Poor GABA activity has been linked to premenstrual dysphoric disorder (PMDD)2 as well as low mood, anxiety, and sleep disorders. When progesterone levels decrease, GABAA receptor activity also declines (Figure 2). This decrease in GABA receptor activation results in increased nervous system excitability, which frequently results in sleep disturbances and anxiousness.

Figure 3. Progesterone increases MAO activity which increases the degradation of monoamine neurotransmitters, leading to a decrease in these neurotransmitters.

Figure 3. Progesterone increases MAO activity which increases the degradation of monoamine neurotransmitters, leading to a decrease in these neurotransmitters.

Another contributing factor is progesterone’s effect on monoamine oxidase (MAO).3  Progesterone has been shown to increase MAO activity. The result is lower levels of the stimulating monoamine neurotransmitters norepinephrine and dopamine. Serotonin, however, is also a monoamine neurotransmitter, and healthy levels are important for sleep. (Figure 3). Too much progesterone could actually add to sleep difficulties by decreasing the serotonin levels.

Progesterone also plays a role in neurotransmission. In the central nervous system, progesterone is made by glial cells and supports neuronal signaling. Researchers are also exploring progesterone’s role in myelin formation during nerve regeneration.4

While progesterone is known for its role in embryo implantation and the maintenance of pregnancy, it also has essential nervous system functions. For more information on the assessment of neuroendocrine connections, check out the Reproductive Endocrinology Curriculum (health care provider login required).

Guest author: Megan Geitz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in endocrinology and women’s issues.

References:

  1. Follesa, P., et al. (2000). Allopregnanolone synthesis in cerebellar granule cells: roles in regulation of GABAA  receptor expression and function during progesterone treatment and withdrawal. Molecular Pharmacology, vol 57; no. 6:1262-1270.
  2. Cunningham, J.,et al. (2009). Update on research and treatment of premenstrual dysphoric disorder. Harv Rev Psychiatry, 12(2):120-137.
  3. Luine,V.N., et al. (1983). Gonadal hormone regulation of MAO and other enzymes in hypothalamic areas. Neuroendocrinology.36(3):235-241.
  4. Schumacher, M., et al. (2012). Progesterone synthesis in the nervous system: implications for myelination and myelin repair. Frontiers in Neuroscience, 6:10. 
Posted in Endocrinology, Neurology | Tagged , , , , , | 5 Comments

What do you do when counting sheep just doesn’t cut it? Look at neurocircuitry!

Most of us can attest to having trouble getting a good night’s sleep from time-to-time. We lie awake worrying about something that happened during the day, or the room is the wrong temperature or a scary movie we just watched seems a little too plausible. These little disturbances are common, but if you have trouble sleeping most nights there may be a more serious problem. According to the Centers for Disease Control and Prevention (CDC), 70 million Americans suffer from chronic sleep problems.  Sleep is a complex process influenced by many neurotransmitters and hormones.

Figure 1.  A simplified representation of sleep-wake neurocircuitry shows the major brain centers and neuroendocrine parameters involved.  Thick arrows represent active pathways during sleep.  The absence of daylight leads to a net inhibition of excitatory efferent projections to central and peripheral systems active during wakefulness.  Green arrows are excitatory pathways, red are inhibitory pathways.  Abbreviations: 5-HT-Serotonin, Ach-Acetylcholine, ACTH-Adrenocorticotropic hormone, AD-Adrenaline (Epinephrine), Cort-Cortisol, CRF-Corticotropin-releasing factor, DA-Dopamine, DMH-Dorsal medial hypothalamus, DRN-Dorsal raphe nucleus, GABA-Gamma-aminobutyric acid, Glut-Glutamate, HA-Histamine, HCRT-Hypocretin (orexin) neuropeptide precursor, LC-Locus ceruleus, LH-Lateral hypothalamus, Mela-Melatonin, MRN-Medial raphe nucleus, NE/NA-Norepinephrine/Noradrenaline, PVN-Paraventricular nucleus, RVLM-Rostral ventrolateral medulla, SCN-Hypothalamic suprachiasmatic nucleus, TMN-Tuberomammillary nucleus, VLPO-Ventral lateral preoptic area, VTA-Ventral tegmental area

Figure 1. A simplified representation of sleep-wake neurocircuitry shows the major brain centers and neuroendocrine parameters involved. Thick arrows represent active pathways during sleep. The absence of daylight leads to a net inhibition of excitatory efferent projections to central and peripheral systems active during wakefulness. Green arrows are excitatory pathways, red are inhibitory pathways.
Abbreviations: 5-HT-Serotonin, Ach-Acetylcholine, ACTH-Adrenocorticotropic hormone, AD-Adrenaline (Epinephrine), Cort-Cortisol, CRF-Corticotropin-releasing factor, DA-Dopamine, DMH-Dorsal medial hypothalamus, DRN-Dorsal raphe nucleus, GABA-Gamma-aminobutyric acid, Glut-Glutamate, HA-Histamine, HCRT-Hypocretin (orexin) neuropeptide precursor, LC-Locus ceruleus, LH-Lateral hypothalamus, Mela-Melatonin, MRN-Medial raphe nucleus, NE/NA-Norepinephrine/Noradrenaline, PVN-Paraventricular nucleus, RVLM-Rostral ventrolateral medulla, SCN-Hypothalamic suprachiasmatic nucleus, TMN-Tuberomammillary nucleus, VLPO-Ventral lateral preoptic area, VTA-Ventral tegmental area

During the day, wake-promoting brain centers in the brain such as the hypothalamic suprachiasmatic nucleus (SCN), tuberomammillary nucleus (TMN) or locus ceruleus (LC) use excitatory neurotransmitters such as glutamate, histamine, and norepinephrine to keep us awake (Figure 1).  Sleep is the result of a signal cascade that starts when the brain senses a lack of sunlight to the eye.  When the brain senses darkness, inhibitory neurotransmitters and hormones including GABA, serotonin, and melatonin reduce the activity of the wake-promoting brain centers.

Imbalances in neurotransmitters and hormones can lead to excessive activity in the wake-promoting brain centers.  This can contribute to sleep difficulties.  Neurotransmitters and hormones can become imbalanced by a number of different factors including stress, poor diet, infections, toxins, and hypersensitivities.

If your patients are not getting their healthy dose of quality sleep each night, assessing their neurotransmitter and hormone imbalances can provide the information required to develop personalized treatments for their sleep difficulties.

References:
Black, J, et al. (2005). Sleep and Wakefulness: Neurophysiologic Pathways and Pharmacologic Targets. A CME-Certified Monograph.
Chou, TC, et al. (2003). Journal of Neuroscience, 23(33):10691-702.
Freeman, DA, et al. (2007). Behav Neurosci, 121(40):689-97.
Lechin, F, et al. (2002). Neurocircuitry and Neuroautonomic Disorders: Reviews and Terapeutic Strategies. Basel (Switzerland): S. Karger AG.
Pace-Schott, EF, et al. (2002). Chapter 128: Basic Mechanisms of Sleep, In Davis, KL, et al (Eds.), Neuropsychopharmacology: The Fifth Generation of Progress (1859-1877).
Saper, CB, et al. (2005). Nature, 437(27):1257-63.
Simonneaux, V, et al. (2003). Pharmacol Rev, 55(2):352-95.
Posted in Endocrinology, Neurology | Tagged , , , , | 1 Comment

Dopamine and testosterone – two important pieces of the neuroendocrine puzzle

Figure 1. Testosterone plays many different roles in the body.

Figure 1. Testosterone plays many different roles in the body.

Barry Bonds, Marion Jones, Roger Clemons, Manny Ramirez…the list of athletes that have made the news for taking performance enhancing drugs is long and seems to grow daily. These news stories put hormones such as testosterone in a negative light, but this hormone is essential to human health.

Testosterone is the principal anabolic and sex hormone that plays a wide variety of roles in the body including sexual desire and function, muscular hypertrophy, densification of bones, and hair growth. Although testosterone is largely responsible for those traits and characteristics considered “masculine,” both sexes require it for proper sexual and physical development1. Testosterone also has effects on other systems in the body (Figure 1), including the nervous system.

The previous neuro-endocrine connection blog discussed the interactions between estrogen and serotonin; this time, the relationship between testosterone, prolactin, and dopamine will be discussed.

Dopamine and Testosterone

Dopamine and testosterone have a direct relationship. Dopamine, a neurotransmitter, plays a role in many different functions including cognition, movement, and feelings of pleasure and reward2. The relationship between dopamine and testosterone stems from the interaction both have with prolactin.

Figure 2. Dopamine increases testosterone levels by decreasing prolactin secretion from the pituitary.

Figure 2. Dopamine increases testosterone levels by decreasing prolactin secretion from the pituitary.

Prolactin is a hormone that has many different roles including breast milk production and sexual gratification. The release of prolactin from the pituitary gland is ultimately controlled by pituitary releasing hormone (PRH) produced by the hypothalamus. The increase in prolactin leads to a decrease in testosterone production in the leydig cells of the testes.

The activity of PRH is countered by dopamine, which is also released from the hypothalamus. An up-regulation of dopamine stimulates the release of prolactin inhibitory factor (PIF). PIF inhibits the pituitary from releasing prolactin. Because prolactin inhibits gonadotropin-releasing hormone (GnRH) secretion, the inhibition of prolactin caused by dopamine, increases the secretion of GnRH, therefore increasing the secretion of testosterone 3 (Figure 2).

This is yet another example of the connections between the endocrine and nervous systems.  By understanding these relationships, clinicians can more effectively determine the root cause of clinical symptoms and select more effective treatment options for patients.

Guest author: Megan Geitz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in endocrinology and women’s issues.

References:
1. Horstman, Astrid M., et al. (2012). The role of androgens and estrogens on healthy aging and longevity. J Gerontol A Biol Sci Med Sci, 67(11):1140-52.
2. Dalley J.W. and Everitt B.J. (2009). Dopamine receptors in the learning, memory and drug reward circuitry. Semin. Cell Dev. Biol. 20:403-10.
3. Zeitlin, S.I., et al. (2000). Hyperprolactinemia and erectile dysfunction. Rev Urol, 2(1):39-42.
Posted in Endocrinology | Tagged , , , | 6 Comments

Senile ovaries? There must be a better explanation…

Remember, radiation may not be the best choice to treat menopause!

Remember, radiation may not be the best choice to treat menopause!

Did you know in menopause the ovaries become senile?  According to this 1950s women’s health tutorial, posted on Huffington Post, they do.  Back then, they also recommended using radiation to treat “the menopause”.  Thankfully, we’ve come a long way since then and realized that interactions between the endocrine and nervous systems can contribute to and exacerbate menopausal symptoms.

For more information on the role neurotransmitters can play in hot flashes, please view the webinar “The Science of Being Hot: Clinical Neuroendocrinology for Hot Flashes and Night Sweats” on the NeuroScience YouTube channel and previous posts: Temperature fluctuations: due to weather seasons or seasons of change within you and Thought you knew everything about estrogen? What about its effects on the nervous system?

 

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Temperature fluctuations: due to weather seasons or seasons of change within you?

The changeThe seasons have just changed and temperatures have dropped.  Everyone feels comfortable at different temperatures, and right now in Wisconsin, it’s not uncommon to see some people wearing winter jackets while others are wearing shorts.  During menopause, a woman’s temperature comfort range changes and is the main cause of hot flashes.  Hot flashes are commonly blamed on the sudden change in hormone levels, but neurotransmitters also play a major role in hot flashes and temperature regulation.

One of the most significant connections is estradiol and serotonin.  Serotonin and estrogen receptors are present together in many of the same tissues throughout the body.  Activation of the estradiol receptor E2-β increases the number of the serotonin receptor 5-HT2A.  This is important because the 5-HT2A receptor is involved in mood, cognitive function, and temperature regulation.

Figure 1. At reproductive age, the temperature range that women feel comfortable is wide because of the abundance of serotonin and estradiol.  As women age, estrogen levels decrease, leading to a smaller comfort range for temperatures.  The smaller comfort range can easily lead to hot flashes.

Figure 1. At reproductive age, the temperature range that women feel comfortable is wide because of the abundance of serotonin and estradiol. As women age, estrogen levels decrease, leading to a smaller comfort range for temperatures. The smaller comfort range can easily lead to hot flashes.

5-HT2A receptors found in the hypothalamus regulate body temperature and work in conjunction with estradiol to influence the thermoregulatory set point (Figure 1).  For example, a pre-menopausal, “healthy” individual should have an abundance of estradiol and serotonin in circulation leading to estrogen binding and an upregulation of 5-HT2A receptors and a wide thermoregulatory set point.  As women age estrogen levels decline, resulting in less 5-HT2A receptors and a narrowing of the thermoregulatory set point.  This narrowing of the temperature range at which women feel comfortable is thought to be a change that leads to hot flashes.

So when you look to open a window when others reach for a sweater, consider your estrogen and serotonin levels. For more information on the role neurotransmitters can play in hot flashes, please watch the webinar “The Science of Being Hot: Clinical Neuroendocrinology for Hot Flashes and Night Sweats” on the NeuroScience YouTube channel.

References:
Blum I, et al. (1996). The effect of estrogen replacement therapy on plasma serotonin and catecholamines of postmenopausal women. Isr J Med Sci, 32:1158-62.
Roepke, T, et al. (2011). Front Biosci, 16:125-34.
Rybaczyk, LA, et al. (2005). An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology. BMC Women’s Health.
Posted in Endocrinology | Tagged , , , | Leave a comment

Tick bites: Scarier than ghosts and goblins

We hope you have a happy and safe Halloween!

We hope you have a happy and safe Halloween!

This Halloween when you see vampires and zombies, remember that nature can be the best at being gross.  A recent post in the New York Times includes a video that helps explain how the ticks that carry Lyme disease are able to attach and remain on the skin for days with their unique, saw-like mouthparts.  You can read the full article and see the video here.

For more information on Lyme disease testing, check out Pharmasan Labs’ iSpot Lyme test at www.ispotlyme.com.

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Thought you knew everything about estrogen? What about its effects on the nervous system?

Fatigue, weight gain, irritability, sleep issues, and depression are all issues we’ve dealt with either ourselves, or experienced by someone close to us. Many people associate these symptoms with hormone imbalances, but what might not be so obvious is that these symptoms can also be linked to neurotransmitter imbalances. Likewise, the difference in rates of psychiatric disorders between genders suggests that hormones play an important role in conditions commonly associated with nervous system imbalances (Figure 1)1.

Figure 1. This table, published in the Journal of Abnormal Psychology, depicts the incidence of psychiatric disorders between women and men 1.

Figure 1. This table, published in the Journal of Abnormal Psychology, depicts the incidence of psychiatric disorders between women and men (1).

These interactions demonstrate that the nervous and endocrine systems are intricately coupled, and both are involved in almost every bodily function including cognition, mood, reproduction, sleep, and temperature regulation. The correct balance of neurotransmitters and hormones is critical to preventing symptoms, as well as supporting overall health.

Hormones play an active role in brain function and affect neurotransmitter levels. For example, many women going through menopause experience depression, anxiety, and insomnia, which can also be correlated to neurotransmitter imbalances.  The interactions between estrogen and serotonin illustrate this point quite well.

Estradiol supports serotonin levels

Estradiol supports serotonin levels through two different mechanisms (Figure 2). Estradiol increases tryptophan hydroxylase, the rate limiting enzyme in the synthesis of serotonin2. Additionally, estradiol inhibits the enzyme monoamine oxidase (MAO), which degrades monoamine neurotransmitters such as serotonin 3.

Figure 2. Estradiol increases tryptophan hydroxylase which will increase the synthesis of serotonin. 2 Estradiol decreases MAO activity, which decreases the rate of monoamine neurotransmitter degradation, leading to increased levels of these neurotransmitters (3).

Figure 2. Estradiol increases tryptophan hydroxylase which will increase the synthesis of serotonin (2). Estradiol decreases MAO activity, which decreases the rate of monoamine neurotransmitter degradation, leading to increased levels of these neurotransmitters (3).

Estrogen affects serotonin receptor expression

Both estrogen and serotonin receptors coexist in a variety of tissues. Estradiol activation of E2-beta receptors stimulates an increase in serotonin receptor sites (5HT2a). 5HT2a receptors are involved in mood, cognition, and the inhibition of pain2. By increasing the number of serotonin receptors, estradiol up-regulates serotonin activity.

This interaction plays a critical role during menopause, specifically in the incidence of hot flashes. Estrogen and serotonin influence the thermoregulatory set point through the hypothalamus 4. A pre-menopausal woman will have an abundance of estradiol and serotonin in circulation. This also means there will be binding of estrogen receptors and an up regulation of 5-HT2a receptors, leading to a wide thermoregulatory set point.

Figure 3. Estradiol and serotonin have been shown to work together in the hypothalamus to regulate the thermoregulatory set point.

Figure 3. Estradiol and serotonin have been shown to work together in the hypothalamus to regulate the thermoregulatory set point.

As aging occurs, estrogen levels decline, leading to a decline in serotonin receptors, and potentially serotonin stores. With this decline in serotonin activity, the thermoregulatory set point narrows. This is one mechanism that leads to hot flashes and night sweats in menopausal females (Figure 3).

Additionally, estradiol can act as a central analgesic, and pain sensation is inhibited by the activation of some serotonergic neurons. The up-regulation of the 5HT2a receptors in the brain might play a role in this pain inhibition2.

The interactions between estrogen and serotonin provide evidence that symptoms and conditions typically thought of as exclusively related to hormones can also be influenced by the nervous system.  In the next few weeks, we will be covering additional connections between the endocrine and nervous systems, including the interactions between dopamine and testosterone as well as progesterone and GABA.  For additional information on the connection between sex hormones and neurotransmitters, see Module 10 of the Reproductive Endocrinology Curriculum (log in required).

Guest author: Megan Geitz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident experts in endocrinology and women’s issues.

References:
1. Eaton, Nicholas R., et al. (2012). An invariant dimensional liability model of gender differences in mental disorder prevalence: evidence from a national sample. Journal of Abnormal Psychology. 121(1):282-289.
2. Rybaczyk, L.A., et al. (2005). An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology. BMC Women’s Health, 5:12.
3. Luine,V.N., et al. (1983). Gonadal hormone regulation of MAO and other enzymes in hypothalamic areas.  Neuroendocrinology.36(3):235-241.
4. Berendsen, Hemmie H.G. (1999). The role of serotonin in hot flushes. Maturitas. 36:155-164.
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The roller coaster of female hormones – are you enjoying the ride?

Figure 1. Neuroendocrine signaling of the female reproductive cycle. (a) The hypothalamus secretes gonadotropin releasing hormone (GnRH) which signals the anterior pituitary to secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH). (b) FSH levels peak around day 3 of the menstrual cycle, and LH spikes around day 14, which signals for ovulation to occur. (c) During the follicular phase, FSH stimulates the growth and development of the follicle.  Around day 14, the follicle ruptures, releasing the egg.  In the luteal phase, the ruptured follicle forms the corpus luteum which secretes progesterone. (d) During the follicular phase, estradiol peaks around day 12 and progesterone peaks on day 21 of the luteal phase.  (e) Estrogen secretion throughout the follicular phase causes the build-up of the endometrial lining.  In the luteal phase, progesterone prepares the uterus for embryo implantation.

Figure 1. Neuroendocrine signaling of the female reproductive cycle. (a) The hypothalamus secretes gonadotropin releasing hormone (GnRH) which signals the anterior pituitary to secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH). (b) FSH levels peak around day 3 of the menstrual cycle, and LH spikes around day 14, which signals for ovulation to occur. (c) During the follicular phase, FSH stimulates the growth and development of the follicle. Around day 14, the follicle ruptures, releasing the egg. In the luteal phase, the ruptured follicle forms the corpus luteum which secretes progesterone. (d) During the follicular phase, estradiol peaks around day 12 and progesterone peaks on day 21 of the luteal phase. (e) Estradiol secretion throughout the follicular phase causes the build-up of the endometrial lining. In the luteal phase, progesterone prepares the uterus for embryo implantation.

Every woman has probably experienced at some point the decreased patience or craving for chocolate that can occur once a month.  It is well known that women have a monthly cycle in which there are hormonal variations, but do you know what is happening throughout the month that can cause mood changes and other symptoms?  Here is a brief overview:

The average female cycle is 28 days long and is spilt into two main phases: the follicular phase, lasting from the onset of menses to ovulation, and the luteal phase, lasting from ovulation to the onset of menses.  The luteal phase is fixed at fourteen days long, and the follicular phase averages about 14 days but can be more variable.  This variability can occur because the follicular phase is dependent on estradiol reaching levels that can trigger the release of luteinizing hormone (LH).  The time it takes estrogen to reach the right amount can vary depending on each individual.

As explained in the previous post, sex hormones are controlled via mechanisms in the brain.  Follicle stimulating hormone (FSH) and LH are released from the pituitary, following a signal from the hypothalamus, and follow specific trends throughout the cycle.  FSH peaks first on about day 3 of the cycle and is responsible for recruiting a follicle.  As the recruited follicle matures, estradiol builds gradually until it peaks around day 13.  During this time, estradiol facilitates the growth of the endometrial lining.  The peak in estradiol stimulates an LH surge 12-24 hours after the estradiol peak, which induces ovulation.   After ovulation, the follicle forms the corpus luteum and progesterone levels begin to rise.  Progesterone peaks on day 21 of a regular cycle, or 7 days before the menses. If ovulation doesn’t take place progesterone will not increase and a peak will not be seen on day 21.  The cycle begins again when the drop in progesterone and estradiol cause the shedding of the endometrial lining, or menses.

As the female cycle is characterized by hormone patterns, dysregulated patterns can result in a variety of clinical symptoms which we will detail in a coming blog post.  More information on the hormone patterns associated with the female cycle can be found in Module 3 of the Reproductive Endocrine Curriculum found here (log in required).

References:
Nussey, S.S., Whitehead, S.A. (2001). Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers.
Widmaier, et al. (2008). Vander’s Human Physiology; Eleventh Edition. McGraw-Hill.
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It’s 4th and long…are you confident in your endocrine system?

Figure 1. Ernest Henry Starling, an English MD, coined the term “hormone” in 1905.

Figure 1. Ernest Henry Starling, an English MD, coined the term “hormone” in 1905.

In the game of football, a team’s ultimate goal each drive is to score a touchdown, but to get to this point, there are many lines of communication that must occur smoothly.  The coach relays plays to his players on the field, and those players implement the play calls to achieve their goal of scoring.  The endocrine system is like a team in that it utilizes signals (play calls) from the hypothalamus (the coach).  Effective communication between the players of the endocrine system can lead to balanced hormone production.  Balanced hormone production is important in managing patient symptoms and ineffective communication can potentially lead to improper levels of hormones being synthesized.

Ernest Henry Starling, an MD in London, coined the term “hormone” in a series of lectures given to the Royal College of Physicians in London in 1905.  Hormones are defined as “a regulatory substance produced in an organism and transported in tissue fluids such as blood or sap to stimulate specific cells or tissues into action.”  Hormones are substances that are produced by the endocrine system in the body and influence the way the body grows or develops.  The pituitary gland, located in the brain, is considered the “master control” of the endocrine system; however, the hypothalamus actually controls the pituitary and is the overarching control of the endocrine system.

Figure 2. Hormones, and the endocrine system itself, are controlled by the hypothalamus in the brain.  The hypothalamus sends signals to the pituitary, initiating a signal cascade to affect hormone synthesis and function.

Figure 2. Hormones, and the endocrine system itself, are controlled by the hypothalamus in the brain. The hypothalamus sends signals to the pituitary, initiating a signal cascade to affect hormone synthesis and function.

Figure 2 (above) illustrates the top-down control of the stimulation and production of endocrine hormones.  Hormone signaling and synthesis primarily begins in the hypothalamus with the hormones seen here: prolactin releasing hormone (PRH), thyrotropin releasing hormone (TRH), corticotropin releasing hormone (CRH), growth hormone releasing hormone (GHRH), and gonadotropin releasing hormone (GnRH).  Each elicit the release of subsequent hormones synthesized in the anterior pituitary and have endocrine targets, with the exception of prolactin.  The endocrine targets then secrete hormones that have effects in nonendocrine targets, such as the skin or heart.

In terms of the sex hormones, GnRH from the hypothalamus signals the anterior pituitary to secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH), the gonadotropin hormones.  FSH and LH signal to endocrine cells to secrete androgens or estrogens and progesterone for males and females respectively.  FSH and LH are also able to signal directly to the germ cells of the gonads to have a nonendocrine target effect.

Just like any football team trying to win a championship, if any part of endocrine communications is not functioning optimally, the system won’t work and the end goals are not achieved. During a regular sex hormone workup, do not overlook factors such as leptin, insulin, and thyroid hormones, which are affected by hypothalamic activity.  More information on the top-down control of sex hormones can be found in Module 2, Part A of the Reproductive Endocrinology Curriculum, which is available here (log in required).

References:
Nussey, S.S., Whitehead, S.A. (2001). Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers.
Widmaier, et al. (2008). Vander’s Human Physiology; Eleventh Edition. McGraw-Hill.
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Sorry Dracula, but blood isn’t the only way to test hormones

Figure 1.  Saliva and serum are both used to measure hormone in a clinical setting.

Figure 1. Saliva and serum are both used to measure hormone in a clinical setting.

Hormones are found in a variety of biological fluids including saliva, cerebral spinal fluid, blood, serum and urine.  Saliva and serum are the most popular forms for testing, although they represent different forms of hormones.  Saliva represents the free (unbound) or biologically active portion of hormones while serum measures total levels of bound and unbound hormones.

There are many arguments why a practitioner would choose to measure serum or salivary levels of hormones over the other, but validity of testing should not be one of them.  Literature has explored the significant correlation between serum and saliva for assessing hormone levels.

  • Worthman et al (1990) measured salivary and serum estradiol levels in women under ovulation-inducing therapy.  They found that free levels of estradiol in saliva and serum are strongly correlated (p<0.0001).
  • Figure 2.  Salivary and serum progesterone are significantly correlated in healthy women during the regular menstrual cycle.

    Figure 2. Salivary and serum progesterone are significantly correlated in healthy women during the regular menstrual cycle.

    De Boever (1986) found that there is a correlation between paired saliva and serum progesterone in healthy women during the regular menstrual cycle (p<0.001) (Figure 2).

  • Researchers found that salivary testosterone levels positively correlated with free serum testosterone in eugonadic men (r=0.92, p=0.0001) (Arregger 2007).  The results showed that salivary testing can be used as a noninvasive approach to the diagnosis of male androgen deficiency.

While the correlation between serum and salivary levels is strong, sex hormone binding globulin (SHBG) levels can affect the ratio between free and bound hormone levels.  It is not possible to accurately compare saliva and serum hormone levels in a patient with either low or high SHBG levels.  More information on the correlation and serum and salivary hormone levels can be found in Module 5 of the Reproductive Endocrinology Curriculum, which is available here (log in required).

References:
Worthman, CM, et al. (1990). Sensitive salivary estradiol assay for monitoring ovarian function. Clin Chem, 36:1769-73.
Boever, JD, et al. (1986). Direct solid-phase chemiluminescence immunoassay for salivary progesterone. Clin Chem, 32:763-7.
Arregger, AL, et al. (2007). Salivary testosterone: a reliable approach to the diagnosis of male hypogonadism. Clin Endocrinol (Oxf), 67(5): 656-62.
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What is oxidative stress?

Oxidative stress has become somewhat of a buzzword in healthcare today, but what exactly does oxidative stress refer to?

Figure 1. Oxidative stress is an imbalance between the amount of free radicals and antioxidants in the body.

Figure 1. Oxidative stress is an imbalance between the amount of free radicals and antioxidants in the body.

Simply put, oxidative stress refers to the burden on the body as a result of an over-production of free radicals (Figure 1).  Free radicals are unstable molecules produced by normal metabolism (such as from mitochondrial energy production) that are necessary for certain immune function, like neutrophil phagocytosis.  However, when there is an abnormally high amount, they can cause damage to cells and lead to a variety of health complications.  The body has certain defense mechanisms to mitigate the damage caused by free radicals such as superoxide dismutase, glutathione peroxidase, and catalase.  When these defenses fail to maintain proper balance, the resulting clinical effects can be significant.

Figure 2. Oxidative stress is associated with a number of diseases.

Figure 2. Oxidative stress is associated with a number of diseases.

When left unchecked, free radicals can stimulate the over-production of pro-inflammatory cytokines which contribute to autoimmune and cardiovascular disease, among others.  Oxidative stress has also been found to be related to most chronic and neuropsychiatric conditions including: autism, attention-deficit hyperactivity disorder, hypertension, arthritis, asthma, Alzheimer’s disease, Parkinson’s disease, diabetes, and psoriasis (Figure 2).

Oxidative stress is ubiquitous in many ill patients.  Based on correlations with neuropsychiatric and other conditions, identification of oxidative stress levels could be utilized to investigate clinical symptoms.  Monitoring and controlling oxidative stress has the potential to improve current health as well as prevent future clinical complaints.

References:
Li, Xinyuan, et al. (2013). Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol, 6:19.
Patel, VP, Chu, CT. (2011). Nuclear transport, oxidative stress, and neurodegeneration. Int J Clin Exp Pathol, 4(3):215-29.
Rommelfanger, KS, Weinshenker, D. (2007). Norepinephrine: The redheaded stepchild of Parkinson’s disease. Biochemical Pharmacology, 74:177-90.
Posted in Immunology, NeuroImmune, Neurology | Tagged , , , , , , , | 3 Comments

Psychoneuroimmunology: Where kynurenic acid fits

Psychoneuroimmunology. It’s a mouthful, but that’s to be expected when trying to find one word to describe the interaction of the nervous, endocrine, and immune systems and the impact this has on health and disease. Robert Ader, considered the founding father of this emerging medical paradigm, coined the term in the late 1970s. The role of the immune system in influencing behaviors is one of the most intriguing concepts in medical research as well as clinical practice. An upregulated immune system has significant effects on the tryptophan pathway, including increasing the level of kynurenic acid, and those effects lead to depressive-like behavior.

Figure 1.  The activated IDO enzyme shunts tryptophan dow the kynurenine pathway to kynurenic acid as well as increasing serotonin breakdown leading to depressive-like behavior.  Adapted from Corona 2013.

Figure 1. The activated IDO enzyme shunts tryptophan dow the kynurenine pathway to kynurenic acid as well as increasing serotonin breakdown leading to depressive-like behavior. Adapted from Corona 2013.

Indoleamine 2,3-dioxygenase (IDO) is an enzyme present in microglial cells of the nervous system. This enzyme, turned on by pro-inflammatory mediators, is responsible for the “tryptophan steal.” Inflammation activates microglia to release this enzyme. Once activated, IDO shunts the serotonin precursor tryptophan down the kynurenine pathway (Figure 1). This increases the ratio of kynurenine:tryptophan and may decrease serotonin synthesis.

IDO also metabolizes 5-hydroxytryptophan (5-HTP) as well as serotonin into 5-hydroxykynuramine. This means in the presence of immune activation, serotonin turnover is increased. This is characterized by a greater 5-HIAA:serotonin ratio. In fact, after administering an IDO inhibitor to mice whose immune systems were upregulated, depressive-like behavior lessened and there were also decreased ratios of 5-HIAA:serotonin and kynurenine:tryptophan.

A rapidly growing body of evidence supports the fact that inflammation has a notable effect on behaviors. More advanced tools, such as kynurenic acid, to assess the impact of inflammation on nervous system function will help manage behavioral disorders whose mechanism is rooted in immune modulation. This is psychoneuroimmunology in motion.

References:
Ader, R. (2007) Psychoneuroimmunology. Burlington, MA: Elsevier Academic Press.
Corona AW, Norden DM, Skendelas JP, et al. (2013). Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX3CR1)-deficient mice. Brain Behav Immun, 31:134-42.
http://www.journals.elsevier.com/brain-behavior-and-immunity/
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“Stressed” is “desserts” spelled backwards: Why weight gain is due to stress

The increased incidence of diabetes in society today is well-known.  According to the Centers for Disease Control and Prevention (CDC), more than one-third of U.S. adults are obese and 11.3% of U.S. adults have diabetes.  What is less known is the role that norepinephrine can play in insulin release and the development of metabolic syndrome and type 2 diabetes.

Figure 1. Normal function of a pancreatic beta cell involves insulin granules docking at the edge of the cell to release insulin in the extracellular space (Gribble, 2010).

Figure 1. Normal function of a pancreatic beta cell involves insulin granules docking at the edge of the cell to release insulin in the extracellular space (Gribble, 2010).

Normally, insulin granules are docked at the edge of pancreatic beta cells to release insulin in response to protein and glucose in the blood (Figure 1).  Insulin causes muscles and fat tissue to absorb glucose from the blood.  Too much glucose in the blood can be toxic and is a hallmark sign of diabetes and metabolic syndrome.

Some individuals have too many α2A-adrenergic receptors that norepinephrine binds to on the pancreatic beta cells that produce insulin (Figure 2). These additional receptors block the insulin granules from docking at the edge of the beta cells, which reduces the amount of insulin released.  Too much norepinephrine activity can lead to less insulin release in individuals who are genetically wired with too many receptors.  Less insulin released can’t regulate blood glucose, leading to higher glucose levels (hyperglycemia) and the development of adrenergic diabetes.  When α2A-adrenergic receptors are blocked by antagonists, insulin granules begin docking again and insulin release returns to normal.

Figure 2. The susceptible genotype for adrenergic diabetes has increased numbers of α2A-adrenergic receptors on pancreatic beta cells.  This inhibits the docking of insulin granules preventing the release of insulin (Gribble, 2010).

Figure 2. The susceptible genotype for adrenergic diabetes has increased numbers of α2A-adrenergic receptors on pancreatic beta cells. This inhibits the docking of insulin granules preventing the release of insulin (Gribble, 2010).

One clinical result of excess α2A-adrenergic receptors is stress-induced hyperglycemia.  Stress-induced hyperglycemia is characterized by elevated blood glucose in response to stress.  This could be caused by increased norepinephrine being released as a response to stress decreasing the amount of insulin that would control blood sugar.  Genetic differences that cause varying levels of the α2A-adrenergic receptors aid our understanding why one patient may be susceptible to stress-induced hyperglycemia, while another may not.

Remember these connections the next time you or a patient is experiencing chronic stress and consider addressing a patient’s stress response as a primary therapy in cases of stress-induced hyperglycemia or as part of your comprehensive blood sugar management approach.  Excessive norepinephrine release from a stress response can lead to metabolic issues due to subsequent decreased insulin release.

References:
http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf
http://www.cdc.gov/obesity/data/adult.html
Gribble FM. Phil D.  (2010). a2A adrenergic receptors and type 2 diabetes.  New Eng J Med, 4: 361-362.
Kyrou I. Tsigos C. (2007). Stress mechanisms and metabolic complications.  Horm Metab Res, 39(6): 430-8.
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Lyme disease study from Pharmasan Labs selected as 2013 feature paper

Cells, a peer-reviewed, international, open access journal, has selected Pharmasan Labs’ research study entitled “An Enhanced ELISPOT Assay for Sensitive Detection of Antigen-Specific T-Cell Responses to Borrelia burgdorferi” as a Feature Paper of 2013.  Feature Papers are selected for their significant contributions to the science of cell biology, molecular biology and biophysics. The study is available at http://www.mdpi.com/2073-4409/2/3/607/.

Lead-authored by Chenggang Jin, MD, PhD, Head of Immunology at Pharmasan Labs, the study tested and validated a novel T cell-based assay for the detection of antigen-specific T cell response to Borrelia burgdorferi, the causative agent of Lyme disease. Through a clinical study of Lyme-positive patients, Dr. Jin’s team demonstrated that the new assay, called iSpot Lyme™, provides significantly higher specificity and sensitivity levels, compared with the Western Blot assay that is currently used as a diagnostic measure.

The publication comes on the heels of the Centers for Disease Control and Prevention’s announcement last month that Lyme disease is a full ten times more prevalent than previously thought. CDC estimates now place the number of infected patients at 300,000 people each year.

“We are honored to have our research selected for Cells’ Featured Papers of 2013,” said Pharmasan Labs’ Dr. Jin. “More importantly, we’re hopeful that our evaluation of both antibody response and T cell response to Borrelia infection will provide new insights into the pathogenesis, diagnosis, treatment and monitoring of Lyme disease, which is a potentially serious and increasingly common infection.”

Co-authored by Diana R. Roen of Pharmasan Labs, Dr. Gottfried H. Kellermann of NeuroScience, Inc. and Paul V. Lehmann of Cellular Technology Limited, the study received the Best Abstract Award from the American Association for Clinical Chemistry in July, and was presented at the 13th International Conference on Lyme Borreliosis and Other Tick-Borne Diseases (ICLB) in August.

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It’s all in your head: The neurocircuitry of addiction

According to the National Institute on Drug Abuse, abuse of tobacco, alcohol, and illicit drugs costs over $600 billion annually due to crime, lost work productivity, and healthcare expenses.  Brain chemistry can be one of the reasons why it is so difficult to conquer addictions.

Did you know that addictive drugs and normal learned behaviors stimulate the same neural pathways?  As such, the neurological reward and emotional sense of pleasure associated with the achievement of normal biological cues are also stimulated by addictive drugs.  The difference between the two is that drugs cause a much higher degree of neuronal pathway stimulation and neurotransmitter release.  This flood of neurotransmitters causes prolonged changes in the brains’ neurocircuitry responsible for sensing satisfaction and reward; and appears to play a key role in addiction.

There has been extensive research illustrating the neurotransmitters and neural adaptations involved in addiction.  Simply put, the development of addiction occurs when neuronal projections from the ventral tegmental area (VTA) increase dopamine signaling within the pleasure sensing nucleus accumbens.  This pathway is reinforced through repeated exposures to the substance, which causes the prefrontal cortex to learn and eventually repeat the behavior that led to the neurotransmitter release.

The neural circuits of the VTA, nucleus accumbens, and prefrontal cortex are critical in learning both natural and addictive behavior.

Here is a closer look at the neurocircuitry of addiction and how dopamine and glutamate are key neurotransmitters involved (Figure 1):

  1. Upon exposure to a naturally rewarding stimulus or a drug, there is an increase in
    Figure 1. Dopamine and glutamate are key players in the neurocircuitry of addiction.

    Figure 1. Dopamine and glutamate are key players in the neurocircuitry of addiction.

    dopamine signaling from the VTA to the nucleus accumbens.  The nucleus accumbens ‘perceives’ this dopamine signal and measures the ‘goodness’ of the reward based upon the size of the dopamine release.

  2. Glutamate projections from the nucleus accumbens instruct the prefrontal cortex to remember the environment and behaviors which lead to the occurrence of ‘goodness’.
  3. Excess signaling of glutamate neurons in the prefrontal cortex stimulates the nucleus accumbens, triggering addiction-seeking behaviors at the expense of naturally rewarding behaviors.

Addiction occurs as the result of dopamine signaling in the nucleus accumbens, and glutamate projections from the prefrontal cortex are key plays in drug seeking and relapse.  Glutamate and dopamine both play roles in addiction, and assessing imbalances can help successfully treat addictive behaviors.

Guest author: Jennifer Farley is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and one of the resident experts in psychiatric disorders.

References:
Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW. (2002). The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci, 22(20):9134-41.
Goldstein RZ, Volkow ND. (2002). Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry, 159(10):1642-52.
Kalivas PW, Volkow ND.  (2005). The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry, 162(8):1403-13.
Roberts AJ, Koob GF. (1997). The neurobiology of addiction: an overview. Alcohol Health Res World,  21(2):101-6.
http://www.drugabuse.gov/related-topics/trends-statistics
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Lyme disease infection rate ten times higher than previously reported

Lyme disease may be ten times more common than previously reported, the CDC says.

Lyme disease may be ten times more common than previously reported, the CDC says.

The Centers for Disease Control and Prevention (CDC) recently released preliminary results of three ongoing studies indicating Lyme disease infection is ten times higher than previous studies showed. In a press release on Monday, August 19, 2013, the CDC stated “Each year, more than 30,000 cases of Lyme disease are reported to CDC, making it the most commonly reported tick-borne illness in the United States. The new estimate suggests the total number of people diagnosed with Lyme disease is roughly 10 times higher than the yearly reported number. This new estimate supports studies published in the 1990s indicating that the true number of cases is between 3- and 12-fold higher than the number of reported cases.”

“We know that routine surveillance only gives us part of the picture, and that the true number of illnesses is much greater,” Paul Mead, M.D., M.P.H., chief of epidemiology and surveillance for CDC’s Lyme disease program, said in the press release. “This new preliminary estimate confirms that Lyme disease is a tremendous public health problem in the United States, and clearly highlights the urgent need for prevention.”

Adult ticks are approximately the size of a sesame seed.

Adult ticks are approximately the size of a sesame seed.

The enormity of the implications for health care in the United States led national media outlets (CBS, NBC, The Boston Globe, Fox News) to run this story. The New Yorker pointed out the 800-pound gorilla in the room, “underreporting of Lyme disease obscures the true burden of the illnesses, on individuals as well as on health-care systems.”

The CDC’s new projections indicate a much greater infection rate than most Lyme disease experts imagined. The startling aspect of the report is that this 10-fold rate increase only reflects reported cases of Lyme disease. It does not include individuals whose diagnosis may have been missed.

Current antibody-based testing for Lyme disease detects only 30-50% of cases. This means the rate of infection in people who have sought medical testing could, in fact, be 50-70% higher. The true number of people infected is probably even higher since not all people realize a tick has bitten them. New advances in Lyme testing hold great promise to better identify infected people.

The iSpot Lyme™ test detects Lyme disease more reliably. With a sensitivity of 84% and a specificity of 94%, you can be more confident in your diagnosis using iSpot Lyme. If you are not familiar with iSpot Lyme, go to Modern Health Care Professional Lyme Learning Center or read the article in Holistic Primary Care. This new CDC report has brought nation-wide attention to the health crisis of Lyme disease. Hopefully it will also bring about better options for those suffering from Lyme disease.

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Amino acids…how can diet affect mental health?

We all know we need food to survive. However, the type of food we eat enhances our survival. When we eat protein-containing foods, they are broken down into amino acids which are the building blocks for neurotransmitters.For example, tryptophan is a precursor to serotonin, and tyrosine is a precursor to the neurotransmitters dopamine, epinephrine, and norepinephrine.1 It is important to understand the role neurotransmitter precursors play, because neurotransmitters are critical for proper mental health. Imbalances in neurotransmitters can result in low mood, anxiousness, and compulsive behavior.2, 3, 4

Amino AcidsAmino acids are made when protein is broken down in the small intestines and within cells.3 There are two groups of amino acids (Table 1). Nonessential amino acids can be made by the body from protein or other amino acids. Essential amino acids can only be obtained through the diet. Low protein diets mean fewer amino acids are available for making neurotransmitters. In addition, it is important to eat adequate amounts of amino acids, because they must compete with other dietary proteins for intestinal absorption and transport across cell membranes and the blood-brain barrier (BBB).5, 6

Figure 1. The blood-brain barrier acts as a wall to protect the brain and keep harmful substances out.

Figure 1. The blood-brain barrier acts as a wall to protect the brain and keep harmful substances out.

The BBB (Figure 1) consists of the endothelial cells lining the blood vessels in the brain. These cells serve as a fortress that guards and protects the brain from foreign substances.7 The tight junctions of the BBB make it difficult for foreign materials in the blood to enter the brain.8 Because of this obstacle, amino acids are assigned to specific carriers or transporters that allow them to get through the BBB.8, 9

Optimal health is built on a solid foundation and amino acids are its primary building blocks. In turn, an optimal nervous system is built on a foundation of healthy neurotransmitter levels, which requires a steady supply of amino acids in the diet. These kinds of strong foundations are critical for good mental health.

Guest author: Rachel Rixmann is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in gastroenterology and nutrition.

References
1. Savelieva KV, Zhao S, Pogorelov VM et al. (2008). Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PloS ONE 3 (10): e3301.
 2. Delgado, P L, & Moreno, F A. (2000). Role of norepinephrine in depression. The Journal of clinical psychiatry, 61(1): 5−12.
 3. Nikolaus, S, Antke, C, Beu, M, et al. (2010). Cortical gaba, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders−−results from in vivo imaging studies. Reviews in the neurosciences, 21(2): 119−139.
 4. Moeller SJ, Tomasi D, Honorio J, Volkow ND, Goldstein RZ. (2012). Dopaminergic involvement during mental fatigue in health and cocaine addiction. Transl Psychiatry, Published online Oct. 23.
 5. Berg, J., et al. (2002). Biochemistry. 632-633.
 6. http://faculty.washington.edu/chudler/bbb.html
 7. Matthews, D.M., Leonard, L. (1965). Absorption of protein digestion products: A review. Gut.
 8. Pietz, J., et al. (1999). Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest, 103(8): 1169-1178.
 9. Feurté, S., Gerozissis, K., Regnault, A., Paul, F.M. (2001). Plasma Trp/LNAA ratio increases during chronic ingestion of an alpha-lactalbumin diet in rats. Nutr Neurosci, 4(5):413-8.
 10. Oldendorf,W.H., Szabo,J. (1976). Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am.J.Physiol, 230:94-98.
 11. http://www.sdmags.net/2012/01/breaching-the-blood-brain-barrier/
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Epinephrine: Ally or enemy in the fight against metabolic issues?

Our nervous system controls all of our bodily processes, including metabolism.  Communication within this system is vital to maintaining balance within the body and can be disrupted by metabolic syndrome.

What is metabolic syndrome?

Figure 1. Waist size, cholesterol, blood pressure, and blood sugar levels are all risk factors of metabolic syndrome.  Patients with metabolic syndrome typically have at least three of these risk factors. (Adapted from NIH)

Figure 1. Waist size, cholesterol, blood pressure, and blood sugar levels are all risk factors of metabolic syndrome. Patients with metabolic syndrome typically have at least three of these risk factors. (Adapted from NIH)

According to the American Heart Association, more than 47 million Americans have metabolic syndrome.  Metabolic syndrome is defined as a combination of conditions which include increased blood pressure, high blood sugar levels, excess body fat around the waist, and abnormal cholesterol levels. The combination of these conditions significantly increases the risk of heart disease, stroke, and diabetes (Figure 1).

Epinephrine correlations with metabolic syndrome

Healthy adrenal function, specifically healthy epinephrine levels can be protective against metabolic syndrome.  Ziegler and colleagues (2012) point out that low epinephrine production can be correlated with obesity in their recent publication on metabolic syndrome.

Historically, excess epinephrine has been viewed as part of the problem for individuals experiencing metabolic disturbances leading to hypertension and insulin resistance.  Ziegler, et al. note that the impacts of epinephrine on metabolism are much different in the short- and long-term.  The short-term effects of epinephrine are to raise systolic blood pressure and blood glucose.  Longer-term consequences of beta2 receptor stimulation by epinephrine however, are decreased peripheral vascular resistance, lower exercise blood pressure, and enhanced insulin sensitivity.

Our nervous system plays a major role in metabolic syndrome and epinephrine is not the only neurotransmitter involved.  Look for a forthcoming post detailing the effects norepinephrine has on stress, insulin release, and hyperglycemia.

Guest author: Tricia Walz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in metabolic issues.

References
 Baker, RG., et al. (2011). NF-κB, Inflammation, and Metabolic Disease. Cell Metab. 13(1): 11-22.
 Despres, JP., et al. (2008). Abdominal Obesity and the Metabolic Syndrome: Contribution to Global Cardiometabolic Risk. Arterioscler Thromb Biol. 28: 1039-49.
 Kyrou, I., Tsigos, C. (2007). Stress Mechanisms and Metabolic Complications. Horm Metab Res. 39(6):430-8.
 Ziegler, MG. (2012). Epinephrine and the Metabolic Syndrome. Curr Hypertens Rep. 14(1):1-7.
 http://www.nhlbi.nih.gov/health/health-topics/topics/ms/
 http://www.mayoclinic.com/health/metabolic%20syndrome/DS00522
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Hidden metals might be making you sick

What do processed cheeses, deodorants, toothpastes, astringents, and tattoos have in common?  Few people are aware that these items may contain aluminum in them.  For most people, this isn’t a problem, but it’s a different story for people with metal hypersensitivities. For those individuals, these exposures can cause an inflammatory response and symptoms such as chronic fatigue, pain, and headaches.

Often when metals are thought to be a problem, tests looking for toxic levels in the individual are performed.  These tests provide insight into toxicity levels and how much of a metal a patient currently has in their body will be used. Just looking at the amount of a metal in the body isn’t good enough for people with metal hypersensitivities though.  For individuals that have a hypersensitivity to a given metal, even trace amounts of exposure can be enough to cause a significant immune reaction and associated clinical symptoms.  There is no such thing as a “safe limit” of exposure for these individuals.

The MELISA® (Memory Lymphocyte Immunostimulation Assay) is different than tests measuring the level of a metal in the body.  It measures the response of the immune system when it encounters a particular metal (methodology information). It is for this reason that MELISA testing is a useful tool for determining the root cause of chronic clinical conditions.

Since even tiny amounts of metal can trigger an immune reaction, it is very important that people who are hypersensitive to a certain metal avoid all contact with it. This isn’t always easy in everyday life as there are many hidden sources of metals that may be surprising; for instance, aluminum in toothpaste or copper in wine.  The documents below list additional hidden sources of metals that could be causing an inflammatory response in patients with metal hypersensitivities.

MELISA is a registered trademark of the MELISA Medica Foundation.

Hidden sources of metal exposures can still trigger an immune reaction.

Download a PDF of the hidden metals resource sheet.

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Attention! Calling all neurotransmitters!

Inattention, trouble focusing, impulsivity, hyperactivity…  All children have trouble with these at some times, but for the 5-10% of school-age children with attention-deficit hyperactivity disorder (ADHD), these issues are a constant daily struggle.

ADHD is correlated with underlying biochemical imbalances

For many children, ADHD is correlated with an underlying biochemical imbalance.  Photo credit: Corbis

For many children, ADHD is correlated with an underlying biochemical imbalance. Photo credit: Corbis

Children with ADHD have been shown to have abnormalities in urinary excretion of the neurotransmitters β-phenylethylamine (PEA) and the catecholamines (epinephrine, norepinephrine, and dopamine).  Decreased PEA levels have been associated with inattentiveness, and research demonstrates that urinary PEA levels are significantly lower in ADHD patients.  Both decreased and increased levels of epinephrine and increased levels of a norepinephrine metabolite have also been observed in individuals with comorbid anxiety and ADHD.  This suggests that sympathetic adrenal function may be altered in subjects with ADHD.  Clinically, PEA, epinephrine, and norepinephrine affect attention, memory, focus, and energy.  Imbalances in any of these neurotransmitters correlate with the symptoms of inattention, focus issues, and hyperactivity commonly seen with ADHD.

Urinary neurotransmitter testing can help monitor ADHD treatment

Neurotransmitter testing can be a useful tool for monitoring ADHD treatment.  A study in 2002 by Kusaga et al found that responders to methylphenidate, a stimulant that inhibits the reuptake of norepinephrine and dopamine, had significantly increased urinary PEA levels.  Non-responders, however, did not demonstrate a significant change.  Methylphenidate increases urinary epinephrine and norepinephrine levels as well.  This example illustrates how changes in biomarkers can provide insight into the response of an individual patient to a particular intervention.

ADHD is a disorder that affects a significant number of children.  Urinary neurotransmitter testing can be beneficial in identifying the underlying biochemical imbalances present in children with ADHD.  Neurotransmitter testing can also be used to help monitor and adjust ADHD treatment regiments to suit a patient’s individual biochemistry; thus increasing treatment efficacy and improving clinical outcomes.

References:
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Mood, blues, and reuptake pathways: Why common interventions are not always effective

According to Harvard Health Blog, about 1 in every 10 Americans takes an antidepressant.  The most commonly prescribed class of antidepressants is Selective Serotonin Reuptake Inhibitors (SSRIs).

Figure 1. Mechanism of action for SSRI medications: serotonin is released from the pre-synaptic neuron to bind receptors on the post-synaptic neuron.  Normally, the serotonin is then reuptaken into the presynaptic neuron and repackaged.  SSRIs block the reuptake channels, keeping the serotonin in the synapse for longer to act on the post-synaptic neuron.

Figure 1. Mechanism of action for SSRI medications: serotonin is released from the pre-synaptic neuron to bind receptors on the post-synaptic neuron. Normally, the serotonin is then reuptaken into the presynaptic neuron and repackaged. SSRIs block the reuptake channels, keeping the serotonin in the synapse for longer to act on the post-synaptic neuron.

SSRIs block the removal of serotonin from the synapse, allowing serotonin to signal longer on the post-synaptic neuron (Figure 1).  The net effect is to allow serotonin signaling to occur following what would otherwise be an insufficient release of serotonin. It has been estimated that, at best, approximately 50% of patients using SSRI medications achieve positive clinical outcomes while some are effective for no more than 5% of patients.

Why don’t SSRIs work more often?

Lack of symptom improvement may be attributed to a number of things including: improper absorption, slow metabolic breakdown, and existing serotonin levels.  SSRIs do not create more serotonin and therefore require a certain circulating levels of serotonin to have its desired clinical effects. This can be observed through 2 common clinical outcomes:

  1. Patients taking SSRIs for depression experience reoccurrence of symptoms over time.
  2. Antidepressant efficacy can be improved when serotonin synthesis is supported.

People suffering from depression often begin with low serotonin stores and it is hypothesized that extended use of SSRI medications will deplete serotonin stores further, regardless of baseline levels.  It is well documented that serotonin support increases serotonin synthesis.  In the handful of published studies, serotonin support along with SSRIs have been shown to be safe, effective, and further highlight the need to manage serotonin stores in depressed patients.

Guest author: Jennifer Farley is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and one of the resident experts in psychiatric disorders.

References:
Delgado, PL., et al. (2000). Role of norepinephrine in depression. J Clin Psychiatry, 1:5-12.
Nelson, JC. (2000).  Augmentation strategies in depression. J Clin Psychiatry, 61:213-219.
vanPraag, HM. (1984). In search of the mode of action of antidepressants: 5-HTP/tyrosine mixtures in depression. Adv Biochem Psychopharmacol, 39:301-314.
vanPraag, HM. (1996). Serotonin precursors in the treatment of depression. Adv Biochem Neuropsychiatry Clin Neurosci, 8(2):168-71.
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NeuroImmune Transmitters: Glycine

Glycine is a neurotransmitter for which elevated levels have been observed to correlate with inflammation.  From the literature, it has been demonstrated that glycine has an immunomodulatory role – inhibiting, as well as stimulating, pro-inflammatory cytokine production and synthesis.  However, it is not clear which inflammatory processes stimulate the increased synthesis of glycine.  The studies below are a sampling of the research pertaining to glycine’s connection to the immune system.

Glycine can stimulate TNF-alpha production from macrophages.

Glycine can stimulate TNF-alpha production from macrophages.

  • Carmans, et al. (2010), discussed that glycine has been shown to modulate peripheral immune cell responses.  Glycine modulates macrophage effector functions implicated in central nervous system inflammation by stimulating TNF-α production by macrophages.  The authors also noted that glycine levels are increased in several neuroinflammatory disorders, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS).
  • Hasegawa, et al., (2010) found that glycine can inhibit NF-κB activation and IL-6 production in human arterial endothelial cells, suggesting that it may exhibit anti-inflammatory effects during endothelial inflammation.
  • It was reported by Almanza-Perez, et al., (2010) that glycine can regulate the production of inflammatory cytokines, including TNF-α and IL-6, through peroxisome proliferator-activated receptors (involved in energy balance) in adipocytes.

Glycine’s correlation with inflammation should be considered when examining a neurotransmitter report.  Identifying and ruling out potential immune contributions is an important aspect of determining the root cause of a patient’s symptoms and imbalances observed in urinary neurotransmitter tests.

References
Almanza-Perez, J.C., et al. (2010). Glycine regulates inflammatory markers modifying the energetic balance through PPAR and UCP-2. Biomed Pharmacother, 64(8): 534-40.
Carmans, S., et al. (2010). The inhibitory neurotransmitter glycine modulates macrophage activity by activation of neutral amino acid transporters. J Neurosci Res, 88(11): 2420-30.
Hasegawa, S., et al. (2010). Cysteine, histidine and glycine exhibit anti-inflammatory effects in human coronary arterial endothelial cells. Clin Exp Immunol, 167(2): 269-74.
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NeuroImmune Transmitters: Epinephrine

When encountering a highly stressful situation – for example, being chased by a bear in the woods – epinephrine is released by the adrenals to support the “fight or flight” response.  Epinephrine is integral to the stress response, but epinephrine also has an important place in immune responses as well.  Have you ever wondered why epinephrine autoinjectors are used to manage anaphylactic shock in severe allergies?

Epinephrine autoinjectors help avoid or treat anaphylactic shock by constricting blood vessels.  Epinephrine is also immunomodulatory and suppresses pro-inflammatory cytokines.

Epinephrine autoinjectors help avoid or treat anaphylactic shock by constricting blood vessels. Epinephrine is also immunomodulatory and suppresses pro-inflammatory cytokines.

Anaphylactic shock is usually characterized by systemic vasodilation that causes very low blood pressure.  Epinephrine autoinjectors help avoid or treat anaphylactic shock by constricting blood vessels.  In addition to being a vascular constrictor, epinephrine is immunomodulatory and suppresses the pro-inflammatory cytokine immune response.

A study by Oberbeck and colleagues in 2004 found that epinephrine, also known as adrenaline, binds to β-adrenergic receptors on immune cells.  By doing so, epinephrine signals to decrease circulating monocytes, B cells, T cells, and natural killer cells while also inhibiting pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α.  Optimal levels of epinephrine are very important, as extreme elevations can lead to significant immunosuppression, while levels that are depleted could contribute to runaway inflammation.

Epinephrine’s modulatory role in inflammation is an integral part of the body controlling the immune system response.  Balance is especially important, as either too high or too low levels can be problematic.  Urinary neurotransmitter testing can help determine if epinephrine are at appropriate levels to optimally modulate immune function.

References
Limsuwan, T., et al. (2010). Acute symptoms of drug hypersensitivity (urticaria, angioedema, anaphylaxis, anaphylactic shock). The Medical Clinics of North America, 94(4): 691-710.
Oberbeck, R., et al. (2004). Adrenergic Modulation of Survival and Cellular Immune Functions during Polymicrobial Sepsis. Neuroimmunomodulation, 11(4): 214-23.
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The Kynurenine Pathway: Implications for inflammation and mood

When you’re sick, the last thing you want to do is drag yourself to work and deal with your normal routine. Even socializing with friends does not sound pleasant anymore. You may experience low energy, sleep issues, low appetite, and low mood, to name a few. This “sickness behavior” shares many of the same symptoms as depression. This behavior is thought to have evolved to encourage people to slow down and rest when ill in order to maintain the resources needed to clear an infection1. In most cases, these symptoms will be short lived, and the body will return to normal once the infection has cleared. However, in instances of long term immune up-regulation, these symptoms may become more persistent and result in a long term depressive state. Over the years, a great deal of research has linked inflammation to depression, and many different theories regarding the mechanism by which this may occur have been proposed.

Figure 1. Neuropsychiatric side effects of immunotherapies based on the administration of pro-inflammatory cytokines.   Image from Schiepers 2005.

Figure 1. Neuropsychiatric side effects of immunotherapies based on the administration of pro-inflammatory cytokines. Image from Schiepers 2005.

Immune cells produce cytokines which help regulate immune responses in the body. The activities, as well as the classifications, of cytokines vary greatly. Typically cytokines are discussed in the context of pro-inflammatory and anti-inflammatory capacities. Pro-inflammatory cytokines activate the inflammatory response and anti-inflammatory cytokines dampen that response. Cytokines are suspected to access the brain by crossing the blood- brain barrier in vulnerable areas, being transported by active transport, as well as being produced directly in the brain by astrocytes and microglia3.

The link between pro-inflammatory cytokines and depressive symptoms was discovered by observing patients receiving immunotherapy. Certain pro-inflammatory cytokines are sometimes given as immunotherapy for disorders such as cancer, chronic hepatitis C, and multiple sclerosis (MS). This therapy has been shown to cause a variety of side effects in patients, many of which are similar to symptoms of depression3. Figure 1 shows the different cytokines given as immunotherapy and the neuropsychiatric effects they can have on patients3.

The exact mechanism by which pro-inflammatory cytokines cause depressive symptoms in patients is unknown; however, as stated previously, many different mechanisms have been proposed. Many researchers believe that both chronic stressors and the presence of pro-inflammatory cytokines in the central nervous system influence similar pathways and result in similar consequences. Some of these consequences include: increased corticotrophin releasing hormone (CRH) leading to increased glucocorticoid levels, variations in monoamine levels and activity, and alterations in different growth and anti-apoptotic factors leading to decreased neuroplasticity2. One of the most extensively studied consequences is the variation in monoamine levels and activity, specifically of serotonin.

Inflammation has been shown to affect serotonin through activation of the kynurenine pathway. Pro-inflammatory cytokines activate the enzyme indoleamine 2,3-dioxygenase (IDO). IDO shuttles tryptophan, the precursor to 5-hydroxytryptophan (5-HTP), down the kynurenine pathway rather than down the pathway that would result in the synthesis of serotonin (Figure 2). Activation of the kynurenine pathway can result in depletion of tryptophan and consequently, depletion of serotonin. Furthermore, 5-HTP and serotonin itself can be substrates for IDO leading to further depletions4.

Figure 2. Indoleamine 2,3-dioxygenase (IDO) degrades tryptophan through the kynurenine pathway. Image from Wichers 2004.

Figure 2. Indoleamine 2,3-dioxygenase (IDO) degrades tryptophan through the kynurenine pathway. Image from Dantzer 2008.

In addition to decreasing serotonin levels in the body, the kynurenine pathway also results in the synthesis of multiple metabolites that can have neurotoxic effects. These metabolites include 3-hydroxy-kynurenine (3-OH-KYN) as well as quinolinic acid. 3-OH-KYN exerts its damaging effects by increasing reactive oxygen species (ROS) in the brain. This increase in ROS leads to oxidative stress and possibly neuronal apoptosis4. Overproduction of ROS is linked to an increase in Monoamine oxidase (MAO) activity, which could deplete monoamine levels in the brain leading to a depressed mood4. Quinolinic acid is a potent N-methyl-D-aspartate (NMDA) receptor agonist. Overstimulation of these receptors leads to an increased calcium influx into target neurons resulting in neuronal damage4. Increased influx of calcium into cells may also lead to the generation of ROS4. Both metabolites have been found to be elevated in certain neurodegenerative disorders such as Huntington’s disease and Parkinson’s disease4.

The increase in IDO activity brought about by increased pro-inflammatory cytokine levels is just one way in which the immune system affects the nervous system. There are undoubtedly many other mechanisms to be investigated in which the immune system and nervous system can affect one another. For patients who present with depressive symptoms, it may be beneficial to investigate possible underlying inflammatory issues. Full symptom relief is unlikely to be achieved until the underlying inflammatory issue is controlled or resolved.

Guest author: Alyson Betcher is a member of the Clinical Support & Education Department at NeuroScience, Inc. and one of the resident experts in psychiatric disorders.

References:
  1. Anisman, A. (2009). Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. J Psychiatry Neurosci; 34(1): 4-20.
  2. Hayley, S., Poulter, M., Merali, Z., Anisman, H., (2005). The pathogenesis of clinical depression: stressor and cytokine – induced alterations of neuroplasticity. Neuroscience; 135: 659-678.
  3. Schiepers, O., Wichers, M., Maes, M., (2005). Cytokines and major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry; 29: 201-217.
  4. Wichers, M., Maes, M. (2004). The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. J Psychiatry Neurosci; 29(1): 11-17.
  5. Dantzer, R., et al. (2008). From Inflammation to Sickness and Depression: When the Immune System Subjugates the Brain. Nature Reviews Neuroscience, 9(1): 46–56.
Posted in Immunology, NeuroImmune, Neurology | Tagged , , , , , , , , , | 8 Comments

GABA and glutamate: The balancing act of the nervous system

As with most things in life, balance is key to an optimally functioning nervous system.  GABA and glutamate are the primary calming and excitatory neurotransmitters in the central nervous system (respectively) and serve opposing functions.  Despite their opposite roles, GABA and glutamate have many connections, including their existence in the same biological pathway (Figure 1).

Figure 1. Glutamate is the biological precursor for GABA.  Glutamate is synthesized from the nonessential amino acid glutamine, and glutamate is converted into GABA by the enzyme glutamate decarboxylase.  Glutamate decarboxylase uses Vitamin B6 as a cofactor.

Figure 1. Glutamate is the biological precursor for GABA. Glutamate is synthesized from the nonessential amino acid glutamine, and glutamate is converted into GABA by the enzyme glutamate decarboxylase. Glutamate decarboxylase uses Vitamin B6 as a cofactor.

Under normal physiological conditions, glutamate and GABA activity is in balance.  However, under stressful conditions, such as inflammation or immune upregulation, glutamate activity increases.  If the nervous system is functioning appropriately, GABA activity also increases to compensate for the excitation in an attempt to restore homeostasis.

Glutamate is the precursor to GABA, which means an increase in glutamate levels should cause a subsequent increase in GABA synthesis as well (Figure 2).  This “allostatic mechanism” is the body’s attempt to restore homeostasis and balance excitatory and compensatory activity.  Common symptoms of an imbalanced system in which glutamate levels are more elevated than GABA levels include anxiousness, overstimulation, sleep difficulties, and focus issues.

Figure 2. GABA should increase in activity to compensate for elevations in stimulatory neurotransmitters, such as glutamate, under stressful conditions.

Figure 2. GABA should increase in activity to compensate for elevations in stimulatory neurotransmitters, such as glutamate, under stressful conditions.

How do glutamate and GABA become out of balance though?  There are a variety of factors that can prevent glutamate from converting to GABA.  One of the most common is malnutrition or poor diet.  Without an adequate amount of Vitamin B6 in their diet, or poor absorption of B6 in the GI tract, there may not be enough necessary cofactor for the glutamate decarboxylase enzyme to facilitate the conversion to GABA.  Another possible contributor to inadequate conversion is gluten sensitivity.  Gluten sensitivity creates gliadin antibodies which specifically inhibit the glutamate decarboxylase enzyme.  Without the functional enzyme, GABA synthesis is compromised, which can lead to low GABA levels.

Regardless of the cause, imbalances between glutamate and GABA can lead to symptoms.  For a healthy and optimally functioning nervous system, GABA and glutamate balance is essential. Even though GABA is the most calming neurotransmitter in the central nervous system, and glutamate the most excitatory, they are irreversibly linked as part of the same biochemical pathway and balance is key.

References
Cryan, J.F., et al. (2005). Don’t worry ‘B’ happy!: a role for GABAb receptors in anxiety and depression. TRENDS in Pharmacological Sciences, 26(1): 36-43.
Dong, E., et al. (2012). Effects of microinjections of Group II metabotropic glutamate agents into the amygdala on sleep. Brain Res, 1452: 85-95.
Hadjivassi, R., et al. (2004). Gluten sensitivity: from gut to brain. Trends in Immunology, 11: 578-82.
Nikolaus, S., et al. (2010). Cortical gaba, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders-results from in vivo imaging studies. Reviews in the neurosciences, 21(2): 119-39.
Posted in Neurology | Tagged , , , , , , | 4 Comments

iSpot Lyme: A New Approach to Lyme Disease Testing

It looks like spring has finally arrived! Along with warmer weather, this means the return of ticks to certain regions and new cases of Lyme disease. The Centers for Disease control (CDC) reported approximately 32,500 new cases of Lyme disease in 20111. However, it is estimated that the actual number could be up to 10-fold higher2 due to the potential for misdiagnosis and underreporting.

Lyme disease is caused by the bacterium Borrelia burgdorferi. Lyme disease is a vector-borne disease transmitted by the Ixodes (blacklegged) tick, more commonly known as the deer tick (Figure 1).

Figure 1. Ixodes tick

Figure 1. Ixodes tick

Symptoms may include:

  • Observed tick bite
  • Bullseye rash
  • Flu-like symptoms
  • Lymphadenopathy
  • Joint pain
  • Neurological symptoms
  • Heart palpitations
  • Severe fatigue

How is Lyme Disease Diagnosed?

The current CDC guidelines for diagnosing Lyme disease involve a two-tiered approach that consists of antibody-based Enzyme Linked Immunosorbent Assay (ELISA) and Western Blot (WB) testing. These tests are serological assays that detect antibodies to B. burgdorferi. The low sensitivity of the two-tier tests (about 30% in early Lyme disease and 50% in late Lyme disease) and the significant seronegativity of Lyme patients (as many as 30% to 50% of cases) suggests that more sensitive cellular immune-based laboratory tests should also be developed3. A comprehensive evaluation for Lyme requires testing for both a humoral (WB) and an immune cell-mediated (ELISPOT) response to B. burgdorferi.

What is iSpot LymeTM?

Enzyme-linked immunosorbent spot (ELISPOT) is an effective method for assessment of T cell immunity by measuring stimulated antigen-specific T cells4,5. The ELISPOT method utilized in iSpot LymeTM is a highly sensitive technique for detecting immune cells that secrete signature proteins (such as a given cytokine). It is the most sensitive technology that accurately detects, measures, and performs functional analysis of these immune cells. iSpot Lyme has a sensitivity of 84% and specificity of 94% for the detection of B. burgdorferi; making it an excellent complement to the current two-tiered antibody methods.

How does this Test Detect Lyme Disease?

The iSpot Lyme detects a cellular immune response against Lyme antigens, which appears earlier in the disease process (2 weeks) than the antibody response detected by the traditional WB test (4-6 weeks)6. More importantly, iSpot Lyme can even detect antigen-specific T cell responses in seronegative patients7.

iSpot Lyme test results are produced by measuring interferon-gamma (IFN- γ) secreted by T cells in response to stimulation by the B. burgdorferi antigens DbpA, OspC, p100, and VisE-1 (Figure 2). This test measures frequency of antigen-specific T cells by measuring those that produce INF- γ in response to Lyme antigens.

Figure 2: When peripheral blood mononuclear cells (PBMCs) from a B. burgdorferi-infected patient are exposed to B. burgdorferi protein antigens (A), B. burgdorferi-specific T cells are activated and secrete small proteins called cytokines (B). T cells that are not specific for B. burgdorferi do not become activated.  iSpot Lyme™ measures the cytokine IFN- secreted by the patient’s T cells. Cytokine proteins (IFN-gamma) are captured near the cells that secreted them and are then detected using a color reagent (C).

Figure 2: When peripheral blood mononuclear cells (PBMCs) from a B. burgdorferi-infected patient are exposed to B. burgdorferi protein antigens (A), B. burgdorferi-specific T cells are activated and secrete small proteins called cytokines (B). T cells that are not specific for B. burgdorferi do not become activated. iSpot Lyme™ measures the cytokine IFN-gamma secreted by the patient’s T cells. Cytokine proteins (IFN-gamma) are captured near the cells that secreted them and are then detected using a color reagent (C).

The iSpot Lyme test counts B. burgdorferi-sensitized T cells by capturing IFN-γ secreted by these T cells. More specifically, when IFN- γ is released, a “spot” of insoluble precipitate is formed at the site of the reaction. Evaluating the number of spot forming units (SFUs) provides a measurement of B.burgdorferi-sensitive effector/memory T cells in the peripheral blood. The SFU count correlates to a patient’s T cell reaction to B. burgdorferi.

In conclusion, the diagnosis and treatment of Lyme disease is controversial even as Lyme disease rates continue to increase. A more comprehensive approach to diagnosis can lead to faster treatment and better clinical outcomes. The very high sensitivity and specificity of the new cellular-based iSpot Lyme test combined with the traditional antibody-based western blot analysis improves Lyme disease diagnosis. This can benefit many people who are currently suffering from misdiagnosed or undiagnosed Lyme disease.

References
  1. http://www.cdc.gov/lyme/stats/chartstables/casesbyyear.html
  2. Yound JD. Underreporting of Lyme disease. N Engl J Med. 1998. 338(22):1629-1629.
  3. Lehmann PV, Zhang W. Unique Strengths of ELISPOT for T Cell Diagnostics. In: Alexander Kalyuzhny Ed. Handbook of ELISPOT: Methods and Protocols, Methods in Molecular Biology, vol. 792. 2nd Ed. New York, NY: Spriner Science+Business Media, LLC; 2012: 3-23.
  4. T-Spot.TB 96 [Package Insert]. Oxfordshire, UK: Oxford Immunotec Limited; 2009.
  5. Tary-Lehmann M, Hamm CD, Lehmann PV. Validating reference samples for comparison in a regulated ELISPOT assay. In: Uma Orabhakar and Marian Kelley Eds. Validation of Cell-Based Assays in the GLP Setting: A Practical Guide. 1st Ed. West Sussex, England: John Wiley & Sons. Ltd; 2008: 127-146.
  6. Ekerfelt C, Forsberg P, Svenvik M et al. Asymptomatic Borrelia-seropositive individuals display the same incidence of Borrelia-specific interferon-gamma (IFN-g)-secreting cells in blood as patients with clinical Borrelia infection. Clin Exp Immunol. 1999. 115: 498-502.
  7. Dattwyler RJ, Volkman DJ, Luft BJ, et al. Seronegatice Lyme Disease- Dissociation of Specific T- and B-Lymphocyte Responses to Borrelia burgdorferi. New England Journal of Med. 1988. 319(22): 1441-1446.

For more detailed information please see our White Paper: iSpot Lyme: A New Generation of Lyme Disease Testing

Guest authors: Chenggang Jin, MD, PhD, holds a PhD in immunology and has 10 years of experience in medical research at Princeton University, the University of Iowa Hospitals and Clinics, and Beth Israel Deaconess Medical Center/Harvard Medical School.  Dr. Jin also holds certification from the Educational Commission for Foreign Medical Graduates in the field of medicine.  His specialized training includes many years of technical and research experience in cellular immunology and molecular biology.  He is currently the director of laboratory immunology at Pharmasan Labs and led the creation of a new clinical laboratory assay, iSpot-Lyme, for Lyme disease.

Deanna Fall is currently a scientific writer and research analyst for NeuroScience, Inc. and holds a bachelor’s degree in biology from Ferris State University in Big Rapids, Michigan.  Deanna joined NeuroScience in 2009 with experience in pharmaceutical research and development in the field of neurotoxicology.  She is currently pursuing a master’s degree in health informatics at the University of Minnesota.

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NeuroImmune Transmitters: GABA

When considering neurotransmitters having an effect on immune function, GABA is not one that commonly comes to mind.  Yet, recent research has determined that GABA, the most calming neurotransmitter in the central nervous system, does have an effect on immune function.

Dendritic cells, along with macrophages and T cells, increase GABA production and secretion when activated.

Dendritic cells, along with macrophages and T cells, increase GABA production and secretion when activated.

A recent article, published by Bhat and colleagues in 2010, found that when dendritic cells, macrophages, and T cells are activated, there is an increase in the production and secretion of GABA by these cells.  GABA can inhibit the production of IL-1β and IL-6 from antigen presenting cells, and GABAergic agents also inhibit the production of IL-17 and IFN-γ, both of which are inflammatory cytokines.  GABA plays a role in immune system modulation to affect cytokine secretion, cell proliferation, phagocytic activity, and chemotaxis.  It also appears that GABA levels will increase during an inflammatory response.

When GABA is elevated on a neurotransmitter report, don’t forget to consider the possibility of an inflammatory response.  It’s possible that GABA is elevated to modulate immune system activity and additional support for GABA may still be warranted in some cases.

Reference
Bhat, R., et al. (2010). Inhibitory role for GABA in autoimmune inflammation. Proceedings of the National Academy of Sciences of the United States of America, 107(6): 2580-5.
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Trauma-related stress: What happens when neuro/endo/immune soldiers are still on active duty?

What is PTSD?

We’ve all heard the reports of soldiers and/or veterans coming back from active duty suffering from post-traumatic stress disorder (PTSD), but what does that entail?  PTSD can occur after someone has been through a traumatic or life-threatening event.  This could include soldiercombat exposure, physical or sexual abuse/assault, serious accidents (i.e. vehicular accidents), or natural disasters (i.e. flood, earthquake, fire, tornado).

Diagnostic criteria for PTSD includes previous exposure to a traumatic event and symptoms from each of the following four categories lasting longer than one month and resulting in clinically significant distress or impairment.

Four symptom types of PTSD from the Diagnostic and Statistical Manual (DSM)-IV:

  1. Re-experiencing: Flashbacks of the event in memories or dreams.
  2. Avoidance: Avoiding situations or people that trigger memories of the event as well as avoiding talking or thinking about the event.
  3. Numbing: Difficulty expressing feelings or disinterest in previously enjoyed activities.
  4. Hyperarousal: Feeling anxious, nervous, jittery, or always being on the alert for danger.

Neuroendoimmune correlations with PTSD

Alyson Betcher, one of our resident experts in psychiatric issues, recently looked into neuroendoimmune correlations with PTSD.  The signs and symptoms of PTSD seem to reflect a persistent and abnormal adaptation of neurobiological systems to a traumatic experience.  Research has generally assumed these changes occur as a result of trauma; however, more recently, researchers have acknowledged that these could be pre-existing and are simply “activated” by trauma.  There are several biochemical abnormalities correlated with PTSD that have been identified in the literature.

Table 1. Effects of biochemical alterations correlated with PTSD.

Table 1. Effects of biochemical alterations correlated with PTSD.

Imbalances in adrenal hormones and neurotransmitters are correlated with and can contribute to PTSD symptoms.  Chronic low-level inflammation has also been associated with PTSD.  Effective therapy for PTSD should include interventions that address individual imbalances as part of a comprehensive therapeutic approach.

References:
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Washington DC: American Psychiatric Association; 1994.
Gola, H., et al. (2013). Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells. BMC Psychiatry, 13: 40-8
Sherin, J.E., et al. (2011). Post-traumatic stress disorder: the neurobiological impact of psychological trauma. Dialogues Clin Neurosci, 13: 263-78.
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Great Scott! Could time travel be a movement disorder?

Who hasn’t seen “Back to the Future”?  A great movie about a kid named Marty McFly, played by Michael J. Fox, whose goal is to go back to the future after he repairs the damage he inadvertently caused when he is accidentally sent back in time.  Michael J. Fox would star in this movie and its two sequels and propel them to cult movie status, before he was diagnosed in 1991 with Parkinson’s disease, a degenerative neurological condition. Parkinson’s disease would eventually sideline him as a mainstream “on-screen” actor, and cause him to stick to voice-work as his main acting roles.

Parkinson’s disease, along with many other movement disorders is characterized by degeneration of neuron function in the central nervous system and physically presents itself in the form of decreasing muscle control in the patient.  In addition to this primary symptom, Parkinson’s disease patients can also experience other recurring symptoms, including depression, dementia, speech issues and poor sleep.

What is Parkinson’s disease at the base level? What causes the progressive loss of motor control in patients?  Recent research into the neurocircuitry of this disease has revealed quite a bit of information on the pathology of this disease and its progression.

The basis of Parkinson’s disease lies in the basal ganglia located in the forebrain, with many connections stretching out to other structures such as the thalamus and the cerebral cortex (Figure 1).  The basal ganglia are a group of functionally similar nuclei that work in conjunction with each other to convey output signals to targets such as the cerebral cortex, superior colliculus, and the lateral habenular nucleus.  Within these basal ganglia is where Parkinson’s disease develops.

Figure 1.  Basal ganglia and related structures of the brain.  Image from Henkel, 1998.

Figure 1. Basal ganglia and related structures of the brain. Image from Henkel, 1998.

The predominant feature of Parkinson’s disease is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), a primary input to the basal ganglia, which sends signals to the striatum.  It is this reduction in dopamine transmission that defines idiopathic Parkinson’s disease.

This decrease in dopamine signaling can be caused by reduced dopamine synthesis, altered dopamine release from neurons, or a problem with dopamine binding to post-synaptic neurons, preventing dopamine from causing an effect.  The loss in dopamine signaling in the basal ganglia is incredibly important due to their function as the motor control center of the brain.  When the frontal cortex sends a signal to the basal ganglia, such as “pick up the penny”, the basal ganglia send signals outward which decide “how to pick up the penny”; that is, what muscles need to contract and relax in order to pick up the penny.  This signal from the basal ganglia goes back to the cortex via the thalamus.  Interruptions in this signaling pathway can cause these messages to become corrupted, and the planned muscle movements to become distorted.

In a more technical sense, neurodegeneration of the SNc leads to changes within the basal ganglia nuclei that result in an overall increase in the output of the interior globus pallidus (GPi) and the substantia nigra pars reticulata (SNr).  The increased output of these two nuclei causes the inhibition of the ventral lateral thalamus (VL) and the ventral anterior thalamus (VA).  The VL and the VA signal to the motor cortices, which completes the regulatory circuitry of the basal ganglia.  Thus, it is specifically VA/VL inhibition which causes reduced motor control.

Figure 2. Thick lines indicate increased output, and thin arrows indicate decreased output patterns present in Parkinson’s disease. Black lines indicate inhibitory actions, and lines in red indicate excitatory actions.

The image above helps to visualize the previous concepts (Figure 2).  Thicker lines indicate increased output, and thin arrows indicate decreased output patterns present in Parkinson’s disease. Black lines indicate inhibitory actions, and lines in red indicate excitatory actions.  Note that, with loss of SNc function, the cascade of effects causes decreased VL/VA function, which leads to loss of motor control.

Decreased dopamine signaling in the basal ganglia can lead to a subsequent decrease in muscle control.  However, with recent treatment protocols and advances in modern medicine, this degeneration of muscle control can be slowed down leading to increased patient quality of life.  Treatment of this condition focuses around modulating the dopamine imbalance.  More dopamine leads to increased signaling in the SNc, which can provide patients of the disease with symptom relief.

For more information about monitoring of dopamine levels in patients, please check out this paper: Validation of an ELISA for urinary dopamine: applications in monitoring treatment of dopamine-related disorders.

Guest author: Ken Gorsegner is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in autoimmune disorders.

References:
Henkel, John (July-August 1998). “Parkinson’s Disease: New Treatments Slow Onslaught of Symptoms“. FDA Consumer: p. 17.
Oluigbo, Chima O, and Ali RRezai. (2011). Addressing neurological disorders with neuromodulation. IEEE Transactions on Biomedical Engineering, 58(7): 1907-17.
Wichmann, Thomas and Delong, Mahlon. (2002). Neurocircuitry of Parkinson’s Disease. Neuropsychopharmacology: The Fifth Generation of Progress.
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To Wheat or Not to Wheat: May is Celiac Disease Awareness Month

Celiac disease is a digestive condition elicited by the consumption of gluten.  Gluten is a protein found primarily in foods containing wheat, barley, or rye.  When a person with celiac disease consumes any of these foods, it causes an immune reaction in the small intestines causing damage and impacting absorption of nutrients.  In this entry we will discuss celiac disease in more detail, including what causes this condition and the clinical effects it has on those affected.

Who is affected by celiac disease?

Approximately 1 in 133 people in the United States are thought to be affected with celiac disease, a type of gluten sensitivity.  Most people who have the disease are not aware of it because symptoms are variable and are often thought to be due to a variety of other reasons.  Diagnosis of celiac disease may be missed or delayed, sometimes for years.1

What is gluten sensitivity?

The term “gluten sensitivity” is used to describe a variety of clinical complaints caused by the ingestion of gluten.  The most commonly known gluten sensitivity is celiac disease, or Common symptomsgluten sensitive enteropathy (GSE) with genetic predisposition.  GSE is an autoimmune disease of the small intestines whereby the ingestion of gluten results in inflammation and loss of villus structure (Figure 1).  Villi are the finger-like projections in the intestines that are responsible for the absorption of nutrients.  Loss of villi results in decreased area of the intestines leading to issues with absorption.  In celiac disease, the immune system overreacts to the presence of gluten, resulting in the production of antibodies to gliadin (one of the main protein groups in gluten) and tissue transglutaminase (an intracellular enzyme present in the endomysium and released upon cell damage).

Figure 1.  Biopsy specimen showing normal villi structure (A) and biopsy-proven changes of untreated celiac disease (B).  Villi are "flattened" and rudimentary in celiac disease (Adapted from Freeman, 2008).

Figure 1. Biopsy specimen showing normal villi structure (A) and biopsy-proven changes of untreated celiac disease (B). Villi are “flattened” and rudimentary in celiac disease (Adapted from Freeman, 2008).

A second type of gluten sensitivity is known as non-celiac gluten sensitivity.  This type of sensitivity also involves an inappropriate immune response to gluten and some of the same symptoms, but not the intestinal damage and antibody response.  It can occur in any individual and is typically induced by intestinal barrier distress and enhanced intestinal permeability.

What is celiac disease and what causes it?

Celiac disease is genetic, so people with a family history of celiac should be tested for the disease if symptoms are present to prevent long-term health issues that can result from undiagnosed celiac disease.  Many patients have celiac disease, but do not develop symptoms until the disease is triggered (becomes active for the first time) which can happen after stressful events such as surgery, pregnancy, childbirth, viral infection, or severe emotional stress.1

Alessio Fasano, in his article Surprises from Celiac Disease, has proposed “a trio of causes,” discussed in the graphic below, that may underlie celiac disease.  These include an environmental trigger (the consumption of gluten), a genetic susceptibility, and an unusually permeable gut.

A trio of causes

Figure 2. A trio of causes that may underlie celiac disease including an environmental trigger, a genetic susceptibility, and an unusually permeable gut.

How is celiac disease treated?

The only treatment available at this time is the total elimination of gluten-containing food from the diet.  This can be very difficult as gluten is found in many foods: bread, pasta, cookies, and can even be found in foods such as salad dressing.  Additional nutritional support, such as vitamin D supplementation, and regular laboratory testing of gliadin and transglutaminase antibodies should be performed to determine if gluten has been successfully removed from the diet and to monitor for accidental contamination.

Who should be tested for gluten sensitivity and celiac?

Tests for gluten sensitivity and/or celiac disease include markers such as gliadin, tissue transglutaminase, and endomysial antibody levels.  There are a number of individuals that can benefit from assessing possible gluten sensitivity or celiac disease including those with:

  • Common symptoms of celiac disease or unexplained GI conditions
  • A family history of celiac disease
  • Food testing results that indicate gluten sensitivity

Testing can monitor compliance to a gluten-free diet and can be helpful in evaluating the effectiveness of treatment.  Gliadin, tissue transglutaminase, and endomysial antibody levels should fall when gluten is removed from the diet.

Celiac disease can lead to other diseases

Celiac disease can lead to other diseases in which the immune system attacks the body’s healthy cells and tissues.  These can include the following:1-4

Other diseases

In addition to leading to other diseases, celiac disease and gluten sensitivity can act as immune stressors that may impact other systems in the body such as the nervous system, detoxification, adrenal system and metabolism.

Celiac disease or gluten sensitivity is a problem for a large number of individuals.  For patients whose symptoms seem resistant to other therapies, identification and elimantion of dietary stressors – such as gluten – may be beneficial.

Guest author: Rachel Rixmann is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in gastroenterology and nutrition.

References:
  1. National Institute of Diabetes and Digestive and Kidney Diseases. Sept. 2008. Publication No. 08-4269.
  2. NIH Consensus Statement on Celiac Disease. (2004). NIH Consensus and State-of-the-Science Statements, 21(1): 1-22.
  3. Kumar, V. Mount Sinai Medical Center (1996). Predictive Value of Serology Testing in Celiac Disease. http://www.enabling.org/ia/celiac/diag-tst.html.
  4. American Association for Clinical Chemistry – Lab Tests Online. March 2009.
  5. Fasano, A. (2009). Surprises from Celiac Disease. Scientific American, Inc., 301: 54-61.
  6. Freeman, H.J. (2008). Pearls and pitfalls in the diagnosis of adult celiac disease. Can J Gastroenterol, 22: 273-280.
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