Vitamin B6 deficiency enhances the noradrenergic system, leading to behavioral deficits
Tokyo Metropolitan Institute of Medical Science, May 27, 2021
Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as apathy and lack of emotion, and cognitive impairment. We have reported that VB6 (pyridoxal) levels in peripheral blood of a subpopulation of patients with schizophrenia is significantly lower than that of healthy controls. More than 35% of patients with schizophrenia have low levels of VB6 (clinically defined as male: < 6 ng/ml, female: < 4 ng/ml). VB6 level is inversely proportional to severity score on the positive and negative symptom scale (PANSS), suggesting that VB6 deficiency might contribute to the development of schizophrenia symptoms. In fact, a recent review has shown the decreased VB6 in patients with schizophrenia as the most convincing evidence in peripheral biomarkers for major mental disorders. Additionally, we recently reported that high-dose VB6 (pyridoxamine) was effective in alleviating psychotic symptoms, particularly the PANSS negative and general subscales, in a subset of patients with schizophrenia. Although a link between lower VB6 level and schizophrenia is widely hypothesized, the mechanism behind this remains poorly understood.
VB6 is not synthesized de novo in humans, but is primarily obtained from foods. In the present study, to clarify the relationship between VB6 deficiency and schizophrenia, we generated VB6-deficient (VB6(-)) mice through feeding with a VB6-lacking diet as a mouse model for the subpopulation of schizophrenia patients with VB6 deficiency. After feeding for 4 weeks, plasma VB6 level in VB6(-) mice decreased to 3% of that in control mice. The VB6(-) mice showed social deficits and cognitive impairment. Furthermore, the VB6(-) mice showed a marked increase in 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brain, suggesting enhanced NA metabolism in VB6(-) mice. We confirmed the increased NA release in the prefrontal cortex and the striatum of VB6(-) mice through in vivo microdialysis. These findings suggest that the activities of NAergic neuronal systems are enhanced in VB6(-) mice.
Furthermore, VB6 supplementation directly into the brain using an osmotic pump ameliorated the hyperactivation of the NAergic system and behavioral abnormalities. indicating that the enhanced NA turnover and the behavioral deficits shown in the VB6(-) mice are attributed to VB6 deficiency in the central nervous system. In addition, the ?2A adrenergic receptor agonist guanfacine also improved the hyperactivated NAergic system in the frontal cortex and behavioral disorders. These results show that the behavioral deficits in VB6(-) mice may be caused by an enhancement of NAergic signaling.
Schizophrenic patients with VB6 deficiency, who account for more than 35% of all patients, present with relatively severe clinical symptoms and treatment resistance. Our findings suggest that a new therapeutic strategy targeting the NAergic system might be effective for these patients. They will also provide evidence based on pathophysiology for a new therapeutic strategy called “VB6 treatment for schizophrenia,” which we are currently conducting clinical research on.
Families with a child with ADHD can benefit from mindfulness training
Radboud University Medical Center (Netherlands), May 27, 2021
Children with ADHD are generally treated with medication and/or behavioral treatments. However, medication-alone is insufficient in a quarter to a third of the children. For that reason, the scientists investigated whether a mindfulness-based intervention (MBI) would have a positive effect on children who did not respond sufficiently to other ADHD treatments. MBIs can elicit positive effects on psychological symptoms and behavior of children and parents.
In the study, two groups of children between the ages of eight and sixteen were compared. One group received only regular care (CAU, care-as-usual), and the other group also received MYmind, the mindfulness-based intervention (MBI) with at least one parent. They did this training for a period of eight weeks.
A striking result was that parents especially benefited from this training. There was an increase in mindful parenting, self-compassion and an improvement in mental health among the parents. These effects were still visible six months after the end of the training. In the children, there were some effects on ADHD symptoms, anxiety, and autistic traits, but effects were small. Yet, a subgroup appeared to benefit: One in three children reliably improved on self-control following MYmind, whereas only one in ten improved when following only regular care.
Professor of Environmental Sensitivity in Health and psychologist Corina Greven of Radboudumc, the Donders Institute and Karakter says that usual interventions for children with ADHD typically do not target mental health of parents, although they often struggle with parenting stress, anxiety or own ADHD symptoms. “While effects in children were small, we still found effects in the parents. Interviewing families , our team also discovered that many families reported important improvements in family relationships and insight in and acceptance of ADHD. We need to go broader than just looking at whether an intervention reduces symptoms, and include additional outcomes that families find important.” The study was conducted in collaboration with the Radboud Center for Mindfulness.
Sweet cherry anthocyanins support liver health
Zhei-Jang University (China), June 1, 2021
Anthocyanins from sweet cherries may protect against diet-induced liver steatosis, or excessive amounts of fat in the liver’s tissue, says a new study with rats.
The study , published in the journal Nutrition, built upon the abundant existing literature on the beneficial role anthocyanins have as an antioxidative, anti-inflammatory, and anti-hyperlipidemic component.
Specifically, the cyanidin-3-glucoside variant “[has] been reported to ameliorate hepatic steatosis and adipose inflammation,” the researchers wrote. The condition known as liver steatosis is a common non-alcoholic fatty liver disease usually treated with drugs, but according to the researchers, some drug used for treatment “are usually accompanied by some adverse effect.”
For 15 weeks, the researchers investigated the effects of sweet cherry anthocyanin supplementation have on alleviating high-fat diet-induced liver steatosis in rodents to explore the possibility of a none-drug treatment for the liver condition.
Preparing the mice and the sweet cherry anthocyanins
The sweet cherry anthocyanin was extracted and pulverized, with one mg of the anthocyanin measured to contain amounts of cyanidine-3-rutinoside and pelargonidin-3-rutinoside, among other things.
Thirty male rodents were used for the study. The animals were housed five per cage and randomly divided into three groups: 10 rodents fed a low-fat diet, 10 rodents fed a high-fat diet, and 10 rodents fed a high-fat diet supplemented with sweet cherry anthocyanins.
The supplementation was given in liquid form at 200 mg/kg orally at the same time daily for 15 weeks, and the body weights and food intakes were monitored weekly.
The mice were sacrificed at week 15 after a half-day fast. Blood samples were collected and livers collected, rinsed with cold saline, and then weighed.
An automatic biochemistry analyser was used to measure total cholesterol, triacylglycerol, alanine aminotransferase, aspartate aminotransferase, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.
They found that at week 15, mice fed a high-fat diet supplemented with sweet cherry anthocyanins “displayed a significant reduction in body weight, liver weight, and liver index” compared to the mice that were only given a high-fat diet without supplementation.
They also found the serum levels for tricylglycerol, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in high-fat diet mice to be substantially higher than those fed a low-fat diet, but the group supplemented with the anthocyanin resulted in a significant reduction in these serum parameters.”
According to the researchers, the results demonstrated how sweet cherry anthocyanins may be developed into a supplement to “protect from high-fat diet-induced hepatic steatosis in mice,”leading to a suggested potential for the anthocyanin’s application in the “treatment of hepatic steatosis and other obesity related metabolic disorders.”
Healthy lifestyle linked to better cognition for oldest adults — regardless of genetic risk
New study suggests importance of maintaining healthy lifestyle even after age 80
Duke University & Kunshan University (China), June 1, 2021
A new analysis of adults aged 80 years and older shows that a healthier lifestyle is associated with a lower risk of cognitive impairment, and that this link does not depend on whether a person carries a particular form of the gene APOE. Xurui Jin of Duke Kunshan University in Jiangsu, China, and colleagues present these findings in the open-access journal PLOS Medicine.
The APOE gene comes in several different forms, and people with a form known as APOE ε4 have an increased risk of cognitive impairment and Alzheimer’s disease. Previous research has also linked cognitive function to lifestyle factors, such as smoking, exercise, and diet. However, it has been unclear whether the benefits of a healthy lifestyle are affected by APOE ε4, particularly for adults over 80 years of age.
To clarify the relationship between APOE ε4 and lifestyle, Jin and colleagues examined data from 6,160 adults aged 80 or older who had participated in a larger, ongoing study known as the Chinese Longitudinal Healthy Longevity Survey. The researchers statistically analyzed the data to investigate links between APOE ε4, lifestyle, and cognition. They also accounted for sociodemographics and other factors that could impact cognition.
The analysis confirmed that participants with healthy lifestyles or intermediately healthy lifestyles were significantly less likely to have cognitive impairment than those with an unhealthy lifestyle, by 55 and 28 percent, respectively. In addition, participants with APOE ε4 were 17 percent more likely to have cognitive impairment than those with other forms of APOE.
A previous study suggested that in individuals at low and intermediate genetic risk, favorable lifestyle profiles are related to a lower risk of dementia compared to unfavorable profiles. But these protective associations were not found in those at high genetic risk. However, the investigation showed the link between lifestyle and cognitive impairment did not vary significantly based on APOE ε4 status which represented the genetic dementia risk. This suggests that maintaining a healthier lifestyle could be important for maintaining cognitive function in adults over 80 years of age, regardless of genetic risk.
This cross-sectional study emphasized the importance of a healthy lifestyle on cognitive health. While further research will be needed to validate these findings among different population, this study could help inform efforts to boost cognitive function for the oldest of adults.
In the next step, the team will explore this association using the AD polygenetic risk score (AD-PRS) and explore the interactive relationship between AD-PRS and lifestyle on cognition with the longitudinal data.
Study shows BPA exposure below regulatory levels can impact brain development
University of Calgary (Canada) June 1, 2021
BPA disrupts development of the mouse brain sleep centre (outlined), image on right. The change can impact behaviour. The control image on the left (“CON”) shows sleep centre without BPA. Credit: Kurrasch lab, published in Science Advances
Humans are exposed to a bath of chemicals every day. They are in the beds where we sleep, the cars that we drive and the kitchens we use to feed our families. With thousands of chemicals floating around in our environment, exposure to any number is practically unavoidable. Through the work of researchers like Dr. Deborah Kurrasch, Ph.D., the implications of many of these chemicals are being thoroughly explored.
“Manufacturers follow standards set by regulatory bodies, it’s not up to the manufacturers to prove the chemicals in consumer products are safe,” says Kurrasch, a researcher in the University of Calgary’s Hotchkiss Brain Institute (HBI) and Alberta Children’s Research Institute at the Cumming School of Medicine. “Scientists play a critical role and do the meticulous work of determining where the risks lie.”
Kurrasch’s research over the past decade has focused on a chemical that is broadly recognizable: Bisphenol A, also known as BPA. This chemical is commonly found in plastics, canned food linings, and even thermal receipts. Studies from Kurrasch’s lab contribute to the collective research that shows the harms of exposure to this industrial compound.
The latest study out of Kurrasch’s lab, published in Science Advances, suggests that continued vigilance is needed. A postdoctoral researcher in her lab, Dr. Dinu Nesan, Ph.D., examined the impact of low levels of BPA exposure to pregnant mice and the brain development of their offspring.
“Our goal was to model BPA levels equivalent to what pregnant women and developing babies are typically exposed to,” says Kurrasch. “We purposefully did not use a high dose. In fact, our doses were 11-times and nearly 25-times lower than those deemed safe by Health Canada and the FDA (U.S. Food and Drug Administration), respectively. Even at these low levels, we saw effects on prenatal brain development in the mice.”
Using this BPA exposure model, Nesan found striking changes to the brain region responsible for driving circadian rhythms, the suprachiasmatic nucleus, located in the hypothalamus. When prenatally exposed to these low levels of BPA, the suprachiasmatic nucleus failed to develop properly. This change can have implications for sleep, activity levels, and other behaviors.
“Previously we showed embryonic exposure to low-dose BPA can affect the timing of when neurons develop in zebrafish, but it was unclear whether a similar effect would be observed in a mammalian model with more similarities to humans,” says Nesan, first author on the study. When neurons develop, they rely on proper signals to guide them. If neurons develop too early, the cues they experience are different, which can lead to developmental errors such as migrating to the wrong location, becoming the wrong type of neuron, or forming inappropriate connections. These errors can lead to altered behaviors later in life.
“Our study shows that in pregnant mice, prenatal exposure to BPA affects the timing of neuron development in the fetal brain, which has lasting effects on behaviors. Offspring that are exposed to BPA during gestation are awake longer and exhibit hyperactivity. The prenatal BPA exposure seems to change the brain’s circadian cues, causing the animals to have elevated energy levels and spend less time resting,” says Nesan.
The researchers are hopeful their findings will add continued pressure on regulatory bodies to keep revisiting their determinations around safe levels of BPA.
“We think there’s an incredible abundance of data showing BPA exposure guidelines are not yet at the appropriate level, which includes even the EU (European Union) who is leading on this front, but their ‘safe’ levels are still twice the dose we used in our study” says Kurrasch, “We hope our research serves as a reminder that low dose BPA is still capable of causing changes that are measurable and significant.”
Her message of how to interpret this research is simple:
- Limit your exposure to BPA the best you can.
- Maintain smart practices with plastics in your kitchen, for example not heating them, and using glass or stainless steel when possible.
This research was conducted in collaboration with Dr. Michael Antle, Ph.D., professor of psychology and member of the HBI.
Selenium plus CoQ10 intake associated with reductions in D-dimer and cardiovascular mortality
Linköping University (Sweden), June 2, 2021
Findings from a randomized, double-blind, placebo-controlled trial, published on April 17, 2021 in the journal Nutrients,revealed a reduction in D-dimer levels among older Swedish men and women who received selenium and coenzyme Q10 (CoQ10), as well as a lower risk of mortality from cardiovascular disease in individuals having higher D-dimer levels at baseline.
Coenzyme Q10 is an antioxidant involved in the mitochondria’s production of energy. It has been estimated that the body’s production of CoQ10 at the age of 80 years is approximately half that of someone who is 20 years old.
Selenium is a trace element necessary for normal function of human cells. Dietary intake of this mineral may be insufficient in areas of the world that have low soil selenium levels. Selenium also is necessary for the function of many antioxidant enzymes, including one which recycles CoQ10, and has anti-inflammatory activity.
D-dimer is a fragment of degraded fibrin and is commonly used to assess for the presence or degradation of potentially dangerous blood clots (venous thromboembolism or pulmonary embolism). It also reflects the activity of peripheral artery disease and has been shown to be associated with endothelial dysfunction and inflammation even in the absence of thromboembolism.
The current investigation included 213 men and women aged 70 to 88 years who did not have conditions known to influence D-dimer concentrations (e.g., atrial fibrillation, malignancies). Participants received a placebo or 200 micrograms selenium plus 200 milligrams CoQ10 daily for four years.
Blood samples collected from the subjects upon enrollment in the trial and at 48 months were analyzed for levels of D-dimer. Although D-dimer levels were not significantly different between groups at the beginning of the trial, it was noted to be significantly associated with age. At 48 months, a significantly lower level of D-dimer was found among those who received selenium and CoQ10 in comparison with the placebo, which was maintained after adjustment for co-variates that might influence D-dimer (such as C-reactive protein).
When participants with D-dimer levels that were above the median of all participants at baseline were analyzed, an association was found between intake of selenium and CoQ10 and a lower risk of cardiovascular mortality. Among those whose D-dimer levels were higher than 0.21 mg/L at the beginning of the study, one person among 53 who received selenium and CoQ10 died during a median 4.9-year follow-up period compared to 8 of the 52 who received a placebo. Mortality from all causes was also lower in the selenium and CoQ10 group; however, the reduction failed to reach statistical significance.
This group also reported a larger study, which didn’t exclude individuals having conditions known to increase D-dimer, finding that in the older Swedish citizens the combination of selenium and CoQ10 significantly increased heart systolic function, lowered NT-proBNP (which is elevated during heart failure) and decreased risk of cardiovascular mortality, defined as death from myocardial infarctions, cerebrovascular lesions, cardiac arrythmias, heart failure or aortic aneurysms.1
“[Intake of] selenium and coenzyme Q10 in a group of elderly low in selenium and coenzyme Q10 prevented an increase in D-dimer and reduced the risk of cardiovascular mortality in comparison with the placebo group,” concluded first author Urban Alehagen and his colleagues. “The obtained results also illustrate important associations between inflammation, endothelial function and cardiovascular risk.”
Effect of Korean Red Ginseng on Cognitive Function and Quantitative EEG in Alzheimer Patients
Seoul Medical Center (Korea) June 1, 2021
Researchers detail new data in Neurodegenerative Diseases. According to news reporting originating in Seoul, South Korea research stated, “Korean red ginseng (KRG) has a nootropic effect. This study assessed the efficacy of KRG on cognitive function and quantitative electroencephalography (EEG) in patients with Alzheimer’s disease (AD).”
The news reporters obtained a quote from the research from Seoul Medical Center, “Fourteen patients with AD (mean age, 74.93 years; 11 women and 3 men) were recruited and treated with KRG (4.5 g per day) for 12 weeks. Cognitive function was assessed by the Korean Mini-Mental State Examination (K-MMSE) and the Frontal Assessment Battery (FAB). EEG performed before and after treatment were analyzed with quantitative spectral analysis. The FAB score improved significantly after 12 weeks of treatment. In the relative power spectrum analysis performed according to responsiveness, alpha power increased significantly in the right temporal area of the responders. The increments of relative alpha power in the right temporal, parietal, and occipital areas were significantly higher in the responders than the nonresponders.”
According to the news reporters, the research concluded: “This study indicates the efficacy of KRG on frontal lobe function in AD, related to increasing relative alpha power.”