The Role of Zinc and Copper in Autism Spectrum Disorders

Acta Neurobiol Exp 2013 2Children with Autism spectrum disorders (ASDs) appear to be at risk for zinc (Zn) deficiency, copper (Cu) toxicity, have often low Zn/Cu ratio, and often disturbed metallothionein (MT) system functioning. The evidence presented in this paper suggests that providing Zn to autistic children may be an important component of a treatment protocol, especially in children with Zn deficiency. It is important to monitor and follow the values for both Cu and Zn together during Zn therapy, because these two trace elements are both antagonists in function, and essential for living cells. 

The review article by Geir Bjørklund is published in Acta Neurobiologiae Experimentalis (2013; 73 (2): 225–236). This peer-reviewed journal is published by Nencki Institute of Experimental Biology in Warsaw, Poland.

 

Geir Bjørklund

The role of zinc and copper in autism spectrum disorders

Acta Neurobiol Exp (Wars) 2013; 73 (2): 225-236 

 

ABSTRACT

Autism spectrum disorders (ASDs) are a group of developmental disabilities that can cause significant social, communication and behavioral challenges. Several studies have suggested a disturbance in the copper (Cu) and zinc (Zn) metabolism in ASDs. Zinc deficiency, excess Cu levels, and low Zn/Cu ratio are common in children diagnosed with an ASD. The literature also suggests that mercury accumulation may occur as a cause or consequence of metallothionein (MT) dysfunction in children diagnosed with an ASD, which may be one of the causes of Zn deficiency. MTs are proteins with important functions in metal metabolism and protection. Zinc and Cu bind to and participate in the control of the synthesis of MT proteins. Studies indicate that the GABAergic system may be involved in ASDs, and that Zn and Cu may play a role in this system.

 

Exposure to high pollution levels during pregnancy may increase risk of having child with autism

AutismWomen in the U.S. exposed to high levels of air pollution while pregnant were up to twice as likely to have a child with autism as women who lived in areas with low pollution, according to a new study from Harvard School of Public Health (HSPH). It is the first large national study to examine links between autism and air pollution across the U.S.

“Our findings raise concerns since, depending on the pollutant, 20% to 60% of the women in our study lived in areas where risk of autism was elevated,” said lead author Andrea Roberts, research associate in the HSPH Department of Social and Behavioral Sciences.

The study appeared online June 18, 2013 in Environmental Health Perspectives.

Exposure to diesel particulates, lead, manganese, mercury, methylene chloride and other pollutants are known to affect brain function and to affect the developing baby. Two previous studies found associations between exposure to air pollution during pregnancy and autism in children, but those studies looked at data in just three locations in the U.S.

The researchers examined data from Nurses’ Health Study II, a long-term study based at Brigham and Women’s Hospital involving 116,430 nurses that began in 1989. Among that group, the authors studied 325 women who had a child with autism and 22,000 women who had a child without the disorder. They looked at associations between autism and levels of pollutants at the time and place of birth. They used air pollution data from the U.S. Environmental Protection Agency to estimate women’s exposure to pollutants while pregnant. They also adjusted for the influence of factors such as income, education, and smoking during pregnancy.

The results showed that women who lived in the 20% of locations with the highest levels of diesel particulates or mercury in the air were twice as likely to have a child with autism as those who lived in the 20% of areas with the lowest levels.

Other types of air pollution—lead, manganese, methylene chloride, and combined metal exposure—were associated with higher autism risk as well. Women who lived in the 20% of locations with the highest levels of these pollutants were about 50% more likely to have a child with autism than those who lived in the 20% of areas with the lowest concentrations.

Most pollutants were associated with autism more strongly in boys than girls. However, since there were few girls with autism in the study, the authors said this finding should be examined further.

Senior author Marc Weisskopf, associate professor of environmental and occupational epidemiology at HSPH, said, “Our results suggest that new studies should begin the process of measuring metals and other pollutants in the blood of pregnant women or newborn children to provide stronger evidence that specific pollutants increase risk of autism. A better understanding of this can help to develop interventions to reduce pregnant women’s exposure to these pollutants.”

 

Reference

Roberts AL, Lyall K, Hart JE, Laden F, Just AC, Bobb JF, Koenen KC, Ascherio A, Weisskopf MG. Perinatal air pollutant exposures and autism spectrum disorder in the children of Nurses’ Health Study II participants. Environmental Health Perspectives, online June 18, 2013.

 

Chemical Brain Drain (Lecture)

Brain development can be damaged by mercury and other environmental chemicals.

This is a lecture by Professor Philippe Grandjean who works at the University of Southern Denmark and Harvard School of Public Health in the United States. He tells in the presentation that there are 201 environmental chemicals currently identified as harmful for the brain. These toxic substances can cause the so-called brain drain, which means that the population’s skills decrease with more mental health problems and fewer highly intelligent people.

Grandjean also shows the magnetic resonance scanning of the brain when children make different finger movements. In children with high mercury levels are both right and left brain active instead of just one in children with low mercury load. This shows that the nerve impulses in mercury affected brains are not functioning optimally.

Omega-3 Intake Heightens Working Memory in Healthy Young Adults

University of Pittsburgh researchers publish first-ever Omega-3 study on a population at the “top of its cognitive game”. 

While Omega-3 essential fatty acids—found in foods like wild fish and grass-fed livestock—are necessary for human body functioning, their effects on the working memory of healthy young adults have not been studied until now.

In the first study of its kind, researchers at the University of Pittsburgh have determined that healthy young adults ages 18-25 can improve their working memory even further by increasing their Omega-3 fatty acid intake. Their findings have been published online in PLOS One.

“Before seeing this data, I would have said it was impossible to move young healthy individuals above their cognitive best,” said Bita Moghaddam, project investigator and professor of neuroscience. “We found that members of this population can enhance their working memory performance even further, despite their already being at the top of their cognitive game.”

Led by Rajesh Narendarn, project principal investigator and associate professor of radiology, the Pitt research team sought healthy young men and women from all ethnicities to boost their Omega-3 intake with supplements for six months. They were monitored monthly through phone calls and outpatient procedures.

Before they began taking the supplements, all participants underwent positron emission tomography (PET) imaging, and their blood samples were analyzed. They were then asked to perform a working memory test in which they were shown a series of letters and numbers. The young adults had to keep track of what appeared one, two, and three times prior, known as a simple “n-back test.”

“What was particularly interesting about the presupplementation n-back test was that it correlated positively with plasma Omega-3,” said Moghaddam. “This means that the Omega-3s they were getting from their diet already positively correlated with their working memory.”

After six months of taking Lovaza—an Omega-3 supplement approved by the Federal Drug Administration—the participants were asked to complete this series of outpatient procedures again. It was during this last stage, during the working memory test and blood sampling, that the improved working memory of this population was revealed.

“So many of the previous studies have been done with the elderly or people with medical conditions, leaving this unique population of young adults unaddressed,” said Matthew Muldoon, project coinvestigator and associate professor of medicine at Pitt. “But what about our highest-functioning periods? Can we help the brain achieve its full potential by adapting our healthy behaviors in our young adult life? We found that we absolutely can.”

Although the effects of Omega-3s on young people were a focus, the Pitt team was also hoping to determine the brain mechanism associated with Omega-3 regulation. Previous rodent studies suggested that removing Omega-3 from the diet might reduce dopamine storage (the neurotransmitter associated with mood as well as working memory) and decrease density in the striatal vesicular monoamine transporter type 2 (commonly referred to as VMAT2, a protein associated with decision making). Therefore, the Pitt researchers posited that increasing VMAT2 protein was the mechanism of action that boosted cognitive performance. Unfortunately, PET imaging revealed this was not the case.

“It is really interesting that diets enriched with Omega-3 fatty acid can enhance cognition in highly functional young individuals,” said Narendarn. “Nevertheless, it was a bit disappointing that our imaging studies were unable to clarify the mechanisms by which it enhances working memory.”

Ongoing animal modeling studies in the Moghaddam lab indicate that brain mechanisms that are affected by Omega-3s may be differently influenced in adolescents and young adults than they are in older adults. With this in mind, the Pitt team will continue to evaluate the effect of Omega-3 fatty acids in this younger population to find the mechanism that improves cognition.

Other Pitt researchers involved in the project include William G. Frankle, professor of psychiatry, and Neal S. Mason, research assistant professor of radiology.

 

Reference

Narendran R, Frankle WG, Mason NS, Muldoon MF, Moghaddam B. Improved working memory but no effect on striatal vesicular monoamine transporter type 2 after omega-3 polyunsaturated Fatty Acid supplementation. PLoS One. 2012;7(10):e46832. doi: 10.1371/journal.pone.0046832. Epub 2012 Oct 3.

Evidence of Parallels Between Mercury Intoxication and the Brain Pathology in Autism

Although there may be genetic or developmental components to autism, the evidence in this current review of the brain findings in autism clearly indicates the reality of brain injury in Autism Spectrum Disorders (ASD); moreover, the brain injury symptoms which characterize autism closely correspond to those seen in sub-acute mercury (Hg) intoxication. The evidence presented in this paper is consistent with Hg being identified as either causal or contributory, working synergistically with other compounds or pathogens in producing the brain pathology observed in those diagnosed with ASD.

Their review article is published in Acta Neurobiologiae Experimentalis (2012; 72 (2): 113-153). This peer-reviewed journal is published by Nencki Institute of Experimental Biology in Warsaw, Poland. 

 

Janet K. Kern, David A. Geier, Tapan Audhya, Paul G. King, Lisa K. Sykes, and Mark R. Geier

Evidence of parallels between mercury intoxication and the brain pathology in autism

Acta Neurobiol Exp (Wars) 2012; 72 (2): 113-153 

 

ABSTRACT

The purpose of this review is to examine the parallels between the effects mercury intoxication on the brain and the brain pathology found in autism spectrum disorder (ASD). This review finds evidence of many parallels between the two, including: (1) microtubule degeneration, specifically large, long-range axon degeneration with subsequent abortive axonal sprouting (short, thin axons); (2) dentritic overgrowth; (3) neuroinflammation; (4) microglial/astrocytic activation; (5) brain immune response activation; (6) elevated glial fibrillary acidic protein; (7) oxidative stress and lipid peroxidation; (8) decreased reduced glutathione levels and elevated oxidized glutathione; (9) mitochondrial dysfunction; (10) disruption in calcium homeostasis and signaling; (11) inhibition of glutamic acid decarboxylase (GAD) activity; (12) disruption of GABAergic and glutamatergic homeostasis; (13) inhibition of IGF-1 and methionine synthase activity; (14) impairment in methylation; (15) vascular endothelial cell dysfunction and pathological changes of the blood vessels; (16) decreased cerebral/cerebellar blood flow; (17) increased amyloid precursor protein; (18) loss of granule and Purkinje neurons in the cerebellum; (19) increased pro-inflammatory cytokine levels in the brain (TNF-alppha, IFN-gamma, IL-1beta, IL-8); and (20) aberrant nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). This review also discusses the ability of mercury to potentiate and work synergistically with other toxins and pathogens in a way that may contribute to the brain pathology in ASD. The evidence suggests that mercury may be either causal or contributory in the brain pathology in ASD, possibly working synergistically with other toxic compounds or pathogens to produce the brain pathology observed in those diagnosed with an ASD.

 

Antioxidant may disrupt Alzheimer’s disease process

According to new study published in the Journal of Alzheimer’s Disease

Alzheimer’s disease (AD) is now the sixth leading cause of death among Americans, affecting nearly 1 in 8 people over the age of 65. There is currently no treatment that alters the course of this disease. However, an increasing amount of evidence suggests that changes in the way the body handles iron and other metals like copper and zinc may start years before the onset of AD symptoms. A new study shows that reducing iron levels in blood plasma may protect the brain from changes related to AD.

In the current study a group of investigators from led by Dr. Othman Ghribi, PhD, Associate Professor, Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, rabbits were fed a high-cholesterol diet which caused them to accumulate plaques of a small protein called beta-amyloid (Aβ). These plaques are toxic to neurons and central to the development of Alzheimer’s disease. The rabbits also developed changes in tau protein, which is part of the skeleton of neurons. When this protein becomes heavily phosphorylated, the ability of neurons to conduct electrical signals is disrupted. Following treatment with a drug called deferiprone (an iron chelator), the iron level in the rabbits’ blood plasma was reduced and the levels of both beta-amyloid and phosphorylated tau in the brain were returned to normal levels.

Another degenerative process in AD involves the production of reactive oxygen species (ROS) that can damage neurons in the brain. Deferiprone is also thought to suppress this reactive oxygen damage caused by free iron in the bloodstream, however in this study there was no difference in reactive oxygen species in the treated group. It appears that iron in the AD brain is located in the wrong places – in particular it accumulates to very high levels in the cores of beta-amyloid plaques and is very reactive in this setting.

According to Dr. Ghribi, “Our data show that treatment with the iron chelator deferiprone opposes several pathological events induced by a cholesterol-enriched diet…Deferiprone reduced the generation of Aβ and lowered levels of tau phosphorylation.” While there was no effect on ROS levels, he comments that “It is possible that a higher dose of deferiprone, or combination therapy of deferiprone together with an antioxidant to prevent ROS generation would more-fully protect against the deleterious effects of cholesterol-enriched diet that are relevant to AD pathology.”

Noted expert on metals metabolism research on AD Ashley Bush, MD, PhD, Mental Health Research Institute, Melbourne, Australia, adds that “this research highlights the role of metal ions as key modulators for the toxic interactions of risk factors for Alzheimer’s disease, in this case cholesterol. Drugs targeting these metal interactions hold promise as disease-modifying agents.”

 

Reference

Prasanthi JR, Schrag M, Dasari B, Marwarha G, Kirsch WM, Ghribi O. Deferiprone Reduces Amyloid-β and Tau Phosphorylation Levels but not Reactive Oxygen Species Generation in Hippocampus of Rabbits Fed a Cholesterol-Enriched Diet. J Alzheimers Dis. 2012 Mar 9. [Epub ahead of print]

 

Vitamin C May Enhance Radiation Therapy for Aggressive Brain Tumours

Person receiving radiation therapy

Recent research by the University of Otago, Wellington has shown that giving brain cancer cells high dose vitamin C makes them much more susceptible to radiation therapy.

The study, carried out in association with Wellington’s Malaghan Institute was recently published in Free Radical Biology and Medicine.

Lead author Dr Patries Herst together with Dr Melanie McConnell investigated how combining high dose vitamin C with radiation affected survival of cancer cells isolated from glioblastoma multiforme (GBM) brain tumours, and compared this with the survival of normal cells.

They found that high dose vitamin C by itself caused DNA damage and cell death which was much more pronounced when high dose vitamin C was given just prior to radiation.

Herst says GBM patients have a poor prognosis because the aggressive GBM tumours are very resistant to radiation therapy. “We found that high dose vitamin C makes it easier to kill these GBM cells by radiation therapy”.

She says there has long been debate about the use of high dose vitamin C in the treatment of cancer. High dose vitamin C specifically kills a range of cancer cells in the laboratory and in animal models. It produces aggressive free radicals in the tumour environment but not in the environment of healthy cells. The free radicals damage DNA, which kills the cells, but the high concentration necessary to kill cancer cells can only be achieved by intravenous injection.

However, these promising findings have so far not been validated in clinical studies. “If carefully designed clinical trials show that combining high dose vitamin C with radiation therapy improves patient survival, there may be merit in combining both treatments for radiation-resistant cancers, such as glioblastoma multiforme,” says Dr Herst.

 

Reference 

Herst PM, Broadley KWR, Harper JL, McConnell MJ. Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free Radical Biology and Medicine 2012; 52 (6). Available online 2 February 2012.

 

Zinc Regulates Communication Between Brain Cells

– Zinc has been found to play a critical role in regulating communication between cells in the brain, possibly governing the formation of memories and controlling the occurrence of epileptic seizures.

A collaborative project between Duke University Medical Center researchers and chemists at the Massachusetts Institute of Technology has been able to watch zinc in action as it regulates communication between neurons in the hippocampus, where learning and memory processes occur – and where disrupted communication may contribute to epilepsy.

“We discovered that zinc is essential to control the efficiency of communication between two critical populations of nerve cells in the hippocampus,” said James McNamara, M.D., senior author and chair of the Department of Neurobiology at Duke. “This addresses a longstanding controversy in the field.”

The study appeared in Neuron Journal online on Sept. 21.

McNamara noted that zinc supplements are commonly sold over the counter to treat several different brain disorders, including depression. It isn’t clear whether these supplements modify zinc content in the brain, or modify the efficiency of communication between these nerve cells. He emphasized that people taking zinc supplements should be cautious, pending needed information on the desired zinc concentrations and how oral supplements affect them.

More than 50 years ago scientists discovered that high concentrations of zinc are contained in a specialized compartment of nerve cells, called vesicles, that package the transmitters which enable nerve cells to communicate. The highest concentrations of brain zinc were found among the neurons of the hippocampus, the center of learning and memory.

Zinc’s presence in these vesicles suggested that zinc played some role in communication between nerve cells, but whether it actually did so remained controversial.

To address this controversy, McNamara and his colleagues at Duke teamed up with Dr. Steve Lippard and colleagues in the Department of Chemistry at the Massachusetts Institute of Technology.

The Lippard team synthesized a novel chemical that bound zinc far more rapidly and selectively than previously available compounds. Use of this chemical let the Duke team rapidly bind the zinc released by nerve cells, taking it out of circulation and preventing enhanced communication.

The Duke team went on to confirm that eliminating zinc from the vesicles of mutant mice also prevented enhanced communication. They also found that increases in the transmitter glutamate seemed to increase zinc-mediated enhancement of communication.

Interestingly, the nerve cells in which the high concentrations of zinc reside are critical for a particular type of memory formation. Excessive enhancement of communication by the zinc-containing nerve cells occurs in epileptic animals and may worsen the severity of the epilepsy.

“Carefully controlling zinc’s regulation of communication between these nerve cells is critical to both formation of memories and perhaps to occurrence of epileptic seizures,” McNamara said.

McNamara also noted that the scientific collaboration between the Duke and MIT scientists was critical to the success of this work. The availability of the novel chemical provided a critical tool that allowed the neuroscientists to unravel the puzzle.

 

Reference

Pan E, Zhang X, Huang Z, Krezel A, Zhao M, Tinberg CE, Lippard SJ, McNamara JO. Vesicular Zinc Promotes Presynaptic and Inhibits Postsynaptic Long-Term Potentiation of Mossy Fiber-CA3 Synapse. Neuron 2011; 71 (6): 1116-1 126.

 

To Ditch Dessert, Feed The Brain

Brain reward regions are activated when glucose falls below normal levels (blue). In lean people -- but not obese people -- the prefrontal cortex which is involved in decision making and regulating impulses is activated (red) when glucose levels are normal.

If the brain goes hungry, Twinkies look a lot better, a study led by researchers at Yale University and the University of Southern California has found.

Brain imaging scans show that when glucose levels drop, an area of the brain known to regulate emotions and impulses loses the ability to dampen desire for high-calorie food, according to the study published online September 19 in The Journal of Clinical Investigation.

“Our prefrontal cortex is a sucker for glucose,” said Rajita Sinha, the Foundations Fund Professor of Psychiatry, and professor in the Department of Neurobiology and the Yale Child Study Center, one of the senior authors of the research.

The Yale team manipulated glucose levels intravenously and monitored changes in blood sugar levels while subjects were shown pictures of high-calorie food, low-calorie food and non-food as they underwent fMRI scans.

When glucose levels drop, an area of the brain called the hypothalamus senses the change. Other regions called the insula and striatum associated with reward are activated, inducing a desire to eat, the study found. The most pronounced reaction to reduced glucose levels was seen in the prefrontal cortex. When glucose is lowered, the prefrontal cortex seemed to lose its ability to put the brakes upon increasingly urgent signals to eat generated in the striatum. This weakened response was particularly striking in the obese when shown high-calorie foods.

“This response was quite specific and more dramatic in the presence of high-calorie foods,” Sinha said.

“Our results suggest that obese individuals may have a limited ability to inhibit the impulsive drive to eat, especially when glucose levels drop below normal,” commented Kathleen Page, assistant professor of medicine at the University of Southern California and one of the lead authors of the paper.

A similarly robust response to high-calorie food was also seen in the striatum, which became hyperactive when glucose was reduced. However, the levels of the stress hormone cortisol seemed to play a more significant role than glucose in activating the brain’s reward centers, note the researchers. Sinha suggests that the stress associated with glucose drops may play a key role in activating the striatum.

“The key seems to be eating healthy foods that maintain glucose levels,” Sinha said. “The brain needs its food.”

 

Reference

Page KA, Seo D, Belfort-Deaguiar R, Lacadie C, Dzuira J, Naik S, Amarnath S et al. Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. J Clin Invest 2011 Sep 19. [Epub ahead of print]

 

Vaccines and Brain Development (Lecture)

Centers for Disease Control and Prevention (CDC) officials claim vaccines are safe and effective. Is that true? If vaccines are safe, why did the incidence of autism increase from one case of autism in 10,000 American children to one case of autism in 150 American children after the massive childhood vaccination program began? If childhood vaccines are safe, why are 560,000 vaccinated children afflicted with autism while nonvaccinated Amish and Mennonite children rarely have the disease? Why has the incidence of asthma, allergies, autoimmune disease, Type I diabetes, and neurologic conditions dramatically increased in vaccinated children?

Why do obstetricians give pregnant women influenza vaccines that contain a toxic dose of mercury? Why do newborn children receive Hepatitis B vaccine in the nursery when there is no medical justification for the immunization?

Dr. Russell Blaylock (born 1945) is a board certified neurosurgeon, author and lecturer. He is a former clinical assistant professor of neurosurgery at the University of Mississippi Medical Center and is currently a visiting professor in the biology department at Belhaven College. His discussion addresses those, and many other, issues. If you are concerned about your health, and the health of your family, you must watch this video.

This lecture was given in October 2008 at the Radio Liberty Seminar.