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Category: brain

Published on Leave a comment on DASH Diet Linked To Lower Rate of Depression

A number of recent studies and articles have discussed the effectiveness of diet in treating or preventing depression with the main conclusion that yes, it helps. Now an observational study (that will be presented in April) found that elderly people following the DASH diet most closely were 11% less likely to become depressed over time than those that did not.

Researchers studying 964 elderly participants over six and a half years found that those who followed the DASH diet, which emphasizes whole grains, fruits, and vegetables, had lower rates of depression, while those who ate a traditional Western diet were more prone to depression. The DASH (Dietary Approaches to Stop Hypertension) diet also emphasizes low sodium (salt) to lower blood pressure, as well as foods rich in nutrients (such as potassium, calcium, and magnesium) that are thought to lower blood pressure.

The study's lead author L. J. Cherian (at Rush Medical Center in Chicago) said that "we need to view food as medicine”. Yes. Eating more fruits and vegetables, whole grains, legumes, seeds, nuts have many health benefits (such as cardiovascular benefits, improving the gut microbes) -  a win-win. From Science Daily:

Diet shown to reduce stroke risk may also reduce risk of depression

People who eat vegetables, fruit and whole grains may have lower rates of depression over time, according to a preliminary study that will be presented at the American Academy of Neurology's 70th Annual Meeting in Los Angeles, April 21 to 27, 2018. The study found that people whose diets adhered more closely to the Dietary Approaches to Stop Hypertension (DASH) diet were less likely to develop depression than people who did not closely follow the diet. In addition to fruit and vegetables, the DASH diet recommends fat-free or low-fat dairy products and limits foods that are high in saturated fats and sugar. Studies have shown health benefits such as lowering high blood pressure and bad cholesterol (LDL), along with lowering body weight.  ...continue reading "DASH Diet Linked To Lower Rate of Depression"

Published on Leave a comment on Heavy Drinking And Risk of Dementia

Study after study has found negative health effects from frequent heavy drinking of alcohol, including a number of cancers. On the other hand, light to moderate drinking seems to have some health benefits (here and here). Recently a large study conducted in France found that chronic heavy drinking, which has resulted in alcohol use disorders (alcohol abuse, alcohol dependence, or alcoholism), is the biggest risk factor for developing dementia, especially early onset dementia. Only people with alcohol use disorders which resulted in them being hospitalized were included in the study.

But the surprising thing was that lower levels of "chronic heavy drinking" doesn't seem so much - it's daily consumption of more than 60 grams of pure alcohol  for men, and more than 40 grams of pure alcohol for women. In the United States, a standard drink contains about 14 grams of alcohol - which is a 12 ounce (350 ml) glass of beer, a 5 ounce (150 ml) glass of 12% wine, or a 1.5 ounce (44 ml) glass of spirits. In other words, drinking 3 glasses of wine daily (or more) is heavy drinking for a woman. (Note: The Centers for Disease Control (CDC) views moderate drinking as 1 glass of wine daily for women, and 2 glasses of wine daily for men).  ...continue reading "Heavy Drinking And Risk of Dementia"

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Published on 1 Comment on A Little Alcohol Daily May Be Beneficial

Interesting new research found health benefits to the brain from daily low intake of alcohol (equivalent to about 2 1/2 drinks per day). The University of Rochester (in New York) researchers found that while low daily (chronic) levels of alcohol were beneficial to the brain's glymphatic system, higher daily levels or binge drinking was not. And the low daily levels of alcohol intake was also better for the glymphatic system than no alcohol at all (the control group). In 2015 this same research team described the glymphatic system as not just the brain’s “waste-clearance system,” but as potentially helping fuel the brain by transporting glucose, lipids, amino acids, and neurotransmitters.

I'm sure this study will be greeted by many as great news, but remember it was done with MICE, and not humans, so one should be cautious in generalizing the results. But the researchers think that it does apply to humans, and may explain why some studies find some health benefits to low levels of daily alcohol intake, even better than no alcohol, and many negative effects to higher levels of alcohol intake - thus the J-shaped curve of effects seen in studies. [NOTE: Studies also find that alcohol consumption can cause cancer, and this is dose related. Studies find the Mediterranean diet (which includes low to moderate levels of alcohol) beneficial for brain health.]

By the way - no, the mice didn't receive wine as the press release from the Univ. of Rochester says. The mice actually received "intraperitoneal injections of low, intermediate, and high doses of ethanol" or just plain saline (the control group). From Science Daily:

In wine, there's health: Low levels of alcohol good for the brain

While a couple of glasses of wine can help clear the mind after a busy day, new research shows that it may actually help clean the mind as well. The new study, which appears in the journal Scientific Reports, shows that low levels of alcohol consumption tamp down inflammation and helps the brain clear away toxins, including those associated with Alzheimer's disease.

"Prolonged intake of excessive amounts of ethanol is known to have adverse effects on the central nervous system," said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center (URMC) and lead author of the study. "However, in this study we have shown for the first time that low doses of alcohol are potentially beneficial to brain health, namely it improves the brain's ability to remove waste." The finding adds to a growing body of research that point to the health benefits of low doses of alcohol. While excessive consumption of alcohol is a well-documented health hazard, many studies have linked lower levels of drinking with a reduced risk of cardiovascular diseases as well as a number of cancers.

Nedergaard's research focuses on the glymphatic system, the brain's unique cleaning process that was first described by Nedergaard and her colleagues in 2012. They showed how cerebral spinal fluid (CSF) is pumped into brain tissue and flushes away waste, including the proteins beta amyloid and tau that are associated with Alzheimer's disease and other forms of dementia. Subsequent research has shown that the glymphatic system is more active while we sleep, can be damaged by stroke and trauma, and improves with exercise.

The new study, which was conducted in mice, looked at the impact of both acute and chronic alcohol exposure. When they studied the brains of animals exposed to high levels of alcohol over a long period of time, the researchers observed high levels of a molecular marker for inflammation, particularly in cells called astrocytes which are key regulators of the glymphatic system. They also noted impairment of the animal's cognitive abilities and motor skills.

Animals that were exposed to low levels of alcohol consumption, analogous to approximately 2 ½ drinks per day, actually showed less inflammation in the brain and their glymphatic system was more efficient in moving CSF through the brain and removing waste, compared to control mice who were not exposed to alcohol. The low dose animals' performance in the cognitive and motor tests was identical to the controls.

"The data on the effects of alcohol on the glymphatic system seemingly matches the J-shaped model relating to the dose effects of alcohol on general health and mortality, whereby low doses of alcohol are beneficial, while excessive consumption is detrimental to overall health" said Nedergaard. "Studies have shown that low-to-moderate alcohol intake is associated with a lesser risk of dementia, while heavy drinking for many years confers an increased risk of cognitive decline. This study may help explain why this occurs. Specifically, low doses of alcohol appear to improve overall brain health." [Original study. Especially interesting is the Introduction & Discussion sections.]

Published on Leave a comment on A Curcumin Supplement That Actually Has Health Benefits?

The spice turmeric is a very popular supplement nowadays, believed to have all sorts of health benefits due to the curcumin in it (e.g. that it is anticancer, anti-Alzheimer's, anti inflammatory). And yes, studies in the lab (in vitro and in vivo) look very promising. However, a large 2017 review of existing studies also found evidence that "curcumin is unstable under physiological conditions and not readily absorbed by the body, properties that make it a poor therapeutic candidate". In other words, the hype for curcumin supplements is not matching the reality, especially or probably because it is so poorly absorbed by humans. But researchers keep trying. And keep in mind that turmeric has other compounds in it also - it is not just curcumin and nothing else.

A "double-blind, placebo-controlled clinical trial" is the best evidence for something being effective. That means a study where people are randomly assigned to groups, no one actually knows who is getting what, and there is a placebo group that is getting a "sham" treatment. A recent study did exactly that in testing a new formulation of curcumin (Theracurmin) that was easily absorbed (bioavailable) by the persons participating in the study.

And yes - they found health benefits, specifically improvements in memory and attention in those persons taking the curcumin supplements over a 18 month period (as compared to those taking a placebo and whose memory and attention deteriorated over that time). The subjects (who were between 50 and 90 years of age) did not have dementia at the start of the study, but were showing signs of "normal aging" or had mild neurocognitive disorder. Brain scans (before and after treatment) suggested that the behavioral and cognitive benefits from curcumin were associated with "decreases in plaque and tangle accumulation in brain regions moduating mood and memory" - so it had anti-inflammatory and/or anti-amyloid brain effects.

So...  Stay tuned. Meanwhile, perhaps frequent eating of foods containing turmeric may also have beneficial effects, as some studies suggest. From Science Daily:

Curcumin improves memory and mood

Lovers of Indian food, give yourselves a second helping: Daily consumption of a certain form of curcumin -- the substance that gives Indian curry its bright color -- improved memory and mood in people with mild, age-related memory loss, according to the results of a study conducted by UCLA researchers. .... Found in turmeric, curcumin has previously been shown to have anti-inflammatory and antioxidant properties in lab studies. It also has been suggested as a possible reason that senior citizens in India, where curcumin is a dietary staple, have a lower prevalence of Alzheimer's disease and better cognitive performance.

The double-blind, placebo-controlled study involved 40 adults between the ages of 50 and 90 years who had mild memory complaints. Participants were randomly assigned to receive either a placebo or 90 milligrams of curcumin twice daily for 18 months. All 40 subjects received standardized cognitive assessments at the start of the study and at six-month intervals, and monitoring of curcumin levels in their blood at the start of the study and after 18 months. Thirty of the volunteers underwent positron emission tomography, or PET scans, to determine the levels of amyloid and tau in their brains at the start of the study and after 18 months.

The people who took curcumin experienced significant improvements in their memory and attention abilities, while the subjects who received placebo did not, Small said. In memory tests, the people taking curcumin improved by 28 percent over the 18 months. Those taking curcumin also had mild improvements in mood, and their brain PET scans showed significantly less amyloid and tau signals in the amygdala and hypothalamus than those who took placebos. The amygdala and hypothalamus are regions of the brain that control several memory and emotional functions. [Original study.]

Published on Leave a comment on Can There Be Negative Effects From Retirement?

Many people look forward to retirement, thinking of all the wonderful things they will finally be able to do.  However, what no one expects is that retirement can have a negative effect on their cognitive functioning. This is what a long-term study carried out by researchers Baowen Xue etal at the University of London in the United Kingdom found. The study tracked 3,433 civil servants for the 14 years before retirement, and then another 14 years afterward. The participants were given periodic examinations to assess their cognitive functioning (verbal memory, abstract reasoning, etc.).

The researchers found that when people did eventually retire, they experienced decline in their verbal memory 38 percent faster than before they stopped working. They concluded that the act of retirement significantly accelerates verbal memory decline. They also found that a higher employment grade was protective against verbal memory decline while people were still working, but this ‘protective effect’ was lost when individuals retired, resulting in a similar rate of decline after retirement across the different employment grades.

The researchers pointed out that the adverse effect of retirement on verbal memory is consistent with the results of other studies. That's why they stress how important it is to continue undertaking mentally stimulating activities after retirement in order to prevent this decline. The researchers felt that the study results supported the ‘use it or lose it’ hypothesis regarding verbal memory function. But the good news was that retirement seemed to have little impact on other domains of cognitive functions, such as abstract reasoning and verbal fluency. They just showed normal age-related declines over time.

From European Journal of Epidemiology: Effect of retirement on cognitive function: the Whitehall II cohort study

According to the ‘use it or lose it’ hypothesis, a lack of mentally challenging activities might exacerbate the loss of cognitive function. On this basis, retirement has been suggested to increase the risk of cognitive decline, but evidence from studies with long follow-up is lacking. We tested this hypothesis in a cohort of 3433 civil servants who participated in the Whitehall II Study, including repeated measurements of cognitive functioning up to 14 years before and 14 years after retirement. Piecewise models, centred at the year of retirement, were used to compare trajectories of verbal memory, abstract reasoning, phonemic verbal fluency, and semantic verbal fluency before and after retirement.

We found that all domains of cognition declined over time. Declines in verbal memory were 38% faster after retirement compared to before, after taking account of age-related decline. In analyses stratified by employment grade, higher employment grade was protective against verbal memory decline while people were still working, but this ‘protective effect’ was lost when individuals retired, resulting in a similar rate of decline post-retirement across employment grades. We did not find a significant impact of retirement on the other cognitive domains. In conclusion, these findings are consistent with the hypothesis that retirement accelerates the decline in verbal memory function. This study points to the benefits of cognitively stimulating activities associated with employment that could benefit older people’s memory.

Published on Leave a comment on Being Overweight In Midlife and Higher Risk of Dementia

Interesting study results - being overweight (a higher body mass index or BMI) is linked to dementia more than 20 years later, but in the few years before dementia onset body mass index (BMI) is lower in those who develop dementia than in those who don't develop dementia. The researchers hypothesize that 2 processes are going on:  A higher BMI (overweight or obese) in mid-life is harmful (a direct effect), and then there is weight loss during the preclinical dementia phase. Bottom line: best is a normal weight in mid-life to try to prevent dementia later on in life. From Science Daily:

Obesity increases dementia risk

People who have a high body mass index (BMI) are more likely to develop dementia than those with a normal weight, according to a new UCL-led study. The study, published in the Alzheimer's & Dementia journal, analysed data from 1.3 million adults living in the United States and Europe. The researchers also found that people near dementia onset, who then go on to develop dementia, tend to have lower body weight than their dementia-free counterparts.

"The BMI-dementia association observed in longitudinal population studies, such as ours, is actually attributable to two processes," said lead author of the study, Professor Mika Kivimäki (UCL Institute of Epidemiology & Health). "One is an adverse effect of excess body fat on dementia risk. The other is weight loss due to pre-clinical dementia. For this reason, people who develop dementia may have a higher-than-average body mass index some 20 years before dementia onset, but close to overt dementia have a lower BMI than those who remain healthy."

In this study, researchers from across Europe pooled individual-level data from 39 longitudinal population studies from the United States, the United Kingdom, France, Sweden, and Finland. A total of 1,349,857 dementia-free adults participated in these studies and their weight and height were assessed. Dementia was ascertained using linkage to electronic health records obtained from hospitalisation, prescribed medication and death registries.

A total of 6,894 participants developed dementia during up to 38 years of follow-up. Two decades before symptomatic dementia, higher BMI predicted dementia occurrence: each 5-unit increase in BMI was associated with a 16-33% higher risk of this condition (5 BMI units is 14.5 kg for a person 5'7" (170 cm) tall, approximately the difference in weight between the overweight and normal weight categories or between the obese and overweight categories). In contrast, the mean level of BMI during pre-clinical stage close to dementia onset was lower compared to that in participants who remained healthy. [Original study.]

Published on Leave a comment on Exercise Is a Maintenance Program For the Brain?

It's reassuring to see that there are positive things one can do to maintain brain health as one ages. With normal aging, the brain typically shrinks a little with each passing decade  - starting from about the age of 40. But one recent Australian study, which reviewed the results of many other studies, found that exercise slows down this shrinkage in humans, specifically in the left hippocampus. That is, that aerobic exercise had a significant positive effect on the volume of the left hippocampus. This matches the result of animal studies.

The researchers pointed out that some studies found increases also in other parts of the human brain from exercise (e.g. in the white matter), but that they did not look at and review those studies. [See posts on research.] The good news is that positive effects were from exercise programs generally lasting less than 12 months. But it is unknown which type of exercise is best, or whether it is general "activity level and movement" that is most important. Bottom line: Get out there and move, move, move for brain health. And for cardiorespiratory fitness. It's all linked and it's all good. From Medical Xpress:

Exercise maintains brain size, new research finds

Aerobic exercise can improve memory function and maintain brain health as we age, a new Australian-led study has found. In a first of its kind international collaboration, researchers from Australia's National Institute of Complementary Medicine at Western Sydney University and the Division of Psychology and Mental Health at the University of Manchester in the UK examined the effects of aerobic exercise on a region of the brain called the hippocampus, which is critical for memory and other brain functions.

Brain health decreases with age, with the average brain shrinking by approximately five per cent per decade after the age of 40. Studies in mice and rats have consistently shown that physical exercise increases the size of the hippocampus but until now evidence in humans has been inconsistent.

The researchers systematically reviewed 14 clinical trials which examined the brain scans of 737 people before and after aerobic exercise programs or in control conditions. The participants included a mix of healthy adults, people with mild cognitive impairment such as Alzheimer's and people with a clinical diagnosis of mental illness including depression and schizophrenia. Ages ranged from 24 to 76 years with an average age of 66. The researchers examined effects of aerobic exercise, including stationary cycling, walking, and treadmill running. The length of the interventions ranged from three to 24 months with a range of 2-5 sessions per week.

Overall, the results – published in the journal NeuroImage– showed that, while exercise had no effect on total hippocampal volume, it did significantly increase the size of the left region of the hippocampus in humans.

"When you exercise you produce a chemical called brain-derived neurotrophic factor (BDNF), which may help to prevent age-related decline by reducing the deterioration of the brain," Mr Firth said. "Our data showed that, rather than actually increasing the size of the hippocampus per se, the main 'brain benefits' are due to aerobic exercise slowing down the deterioration in brain size. In other words, exercise can be seen as a maintenance program for the brain.".... Interestingly, physical exercise is one of the very few 'proven' methods for maintaining brain size and functioning into older age.

Published on Leave a comment on System of Lymph Vessels Discovered In the Brain

I can't resist posting excerpts from a recent article announcing that researchers just found an entirely new lymph system ("lymphatic vessels") in the brain that transports fluid in the brain, and is probably "crucial to metabolic and inflammatory processes".  The image in this post shows the system in the brain. Amazing that it is only now "discovered" - apparently it was noticed by an anatomist 2 centuries ago, but this was pooh-poohed by modern day physicians. Until now. Excerpts from the Atlantic:

Scientists Somehow Just Discovered a New System of Vessels in Our Brains

You are now among the first people to see the brain’s lymphatic system. The vessels in the photo above transport fluid that is likely crucial to metabolic and inflammatory processes. Until now, no one knew for sure that they existed. Doctors practicing today have been taught that there are no lymphatic vessels inside the skull. Those deep-purple vessels were seen for the first time in images published this week by researchers at the U.S. National Institute of Neurological Disorders and Stroke.

In the rest of the body, the lymphatic system collects and drains the fluid that bathes our cells, in the process exporting their waste. It also serves as a conduit for immune cells, which go out into the body looking for adversaries and learning how to distinguish self from other, and then travel back to lymph nodes and organs through lymphatic vessels.

Senior investigator Daniel Reich trained as both a neurologist and radiologist, and his expertise is in inflammatory brain disease. The connection between the immune system and the brain is at the core of what he says he spends most of his time thinking about: multiple sclerosis. The immune system appears to modulate or even underlie many neurologic diseases, and the cells of the central nervous system produce waste that needs to be washed away just like other metabolically active cells. This discovery should make it possible to study how the brain does that, how it circulates white blood cells, and how these processes may go awry in diseases or play a role in aging.

Around the same time, researchers discovered fluid in the brains of mice and humans that would become known as the “glymphatic system.” It was described by a team at the University of Rochester in 2015 as not just the brain’s “waste-clearance system,” but as potentially helping fuel thebrain by transporting glucose, lipids, amino acids, and neurotransmitters.

Wouldn’t neurosurgeons, at some point in their meticulous down-to-the-millimeter dissecting of brains, have stopped and said, “Hey ... what’s this thing?”The lymph vessels probably escaped detection because they’re inside a thick membrane, the dura mater, which is the consistency of leather. They run alongside blood vessels that are much larger, and on MRI the signal that creates the images is dominated by the blood vessels.  

But this pathway appears crucial to life and health. A 2013 study in Science found that glymphatic flow seems to increase by almost double during sleep (in mice). Sleep disturbances are a common feature in Alzheimer’s and other neurologic disorders, and it’s possible that inadequate clearing of the brain’s waste products is related to exacerbating or even causing the disease.... 

The flow of glymphatic fluid can change based on a person’s intake of omega-3 fatty acids, a study showed earlier this year. Preliminary findings like these together suggest a pathway through which nutrition and sleep can be related to neurologic disorders. Optimizing this glymphatic flow could become a central theme for the future of neurologic health. “If all of this is true, there probably is a connection between these two systems, glymphatic and lymphatic,” Reich said. “And that would be one of the major functions of cerebrospinal fluid.”

From The Atlantic. Credit: Daniel Reich/ National Institute of Neurological Disorders and Stroke

Published on Leave a comment on Blueberries and Children’s Mental Processes

For years studies have suggested that eating blueberries and other berries is good for our health (here, here, and here). Now another study suggests that eating wild blueberries benefits children's thinking, specifically attention and "executive function" (mental processes which lets people plan, organize, and complete tasks). What was nice in this study was that it was "double-blind"- which meant that biases couldn't influence the results. 

Flavonoids are a diverse group of phytonutrients (plant chemicals) found in almost all fruits and vegetables. They are powerful antioxidants with anti-inflammatory and immune system benefits. And yes, other studies have also found various benefits to mental processes with an increase of flavonoids in the diet - in both children and adults.

What foods contain flavonoids? There are 6 main classes of flavonoids, and each is found in different foods: - Anthocyanidins – found in red, purple,and blue berries, red wine, and red and purple grapes. - Flavonols - found in onions, leeks, broccoli, Brussels sprouts, kale, tea, berries, beans, and apples. - Flavones - found in parsley, celery, and hot peppers. - Isoflavones - found in soybeans, soy products, and legumes. - Flavanones - found in citrus fruit and tomatoes. - Flavanols - found in tea, red wine, grapes, apples, fava beans, and cocoa. From Medical Xpress:

Blueberries may improve attention in children following double-blind trial

Primary school children could show better attention by consuming flavonoid-rich blueberries, following a study conducted by the University of Reading. In a paper published in Food & Function, a group of 7-10 year olds who consumed a drink containing wild blueberries or a matched placebo and were tested on their speed and accuracy in completing an executive task function on a computer.The double blind trial found that the children who consumed the flavonoid-rich blueberry drink had 9% quicker reaction times on the test without any sacrifice of accuracy. In particular, the effect was more noticeable as the tests got harder.

Previous [Univ. of] Reading research has shown that consuming wild blueberries can improve mood in children and young people, simple memory recall in primary school children, and that other flavonoid rich drinks such as orange juice, can also improve memory and concentration.

Wild blueberries are grown and harvested in North America, and are smaller than regular blueberries, and are higher in flavonoids compared to regular varieties. The double-blind trial used a flavonoid-rich wild blueberry drink, with a matched placebo contained 8.9 g of fructose, 7.99 g of glucose and 4 mg of vitamin C matching the levels of nutrients found in the blueberry drink. [Original study.] 

Published on Leave a comment on Magnesium and Dementia Link?

Interesting study finding - that both high and low levels of magnesium is associated with a higher risk of dementia. Magnesium is an essential mineral needed for more than 300 biochemical reactions in the body. According to a large study done in the Netherlands of people who were followed for about 8 years - there was a U-shaped incidence of dementia based on their levels of magnesium. The lowest incidence was in those with "in the middle" normal levels of magnesium in the blood. All the study participants were mentally healthy when the study started.

The researchers stated that magnesium levels are considered "relatively stable over time", but a limitation of the study is that they only looked at magnesium levels once - at the beginning of the study, so they could have changed over time. Of course further studies are needed. [Other posts on magnesium and health - here, here, and here.]

Magnesium is widely available in foods. Foods that are good sources of magnesium include: spinach and other dark green leafy vegetables, almonds, cashews, peanuts, bananas, soybeans, kidney and black beans (legumes), whole grains, lentils, seeds, yogurt, brown rice, potatoes, and avocados. It is recommended that magnesium is obtained from the diet, and not from supplements (due to health risks from high doses). From Science Daily:

Both high, low levels of magnesium in blood linked to risk of dementia

People with both high and low levels of magnesium in their blood may have a greater risk of developing dementia, according to a study published in the September 20, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The study involved 9,569 people with an average age of 65 who did not have dementia whose blood was tested for magnesium levels. The participants were followed for an average of eight years. During that time, 823 people were diagnosed with dementia. Of those, 662 people had Alzheimer's disease. The participants were divided into five groups based on their magnesium levels. Both those with the highest and the lowest levels of magnesium had an increased risk of dementia, compared to those in the middle group.

Both the low and high groups were about 30 percent more likely to develop dementia than those in the middle group. Of the 1,771 people in the low magnesium group, 160 people developed dementia, which is a rate of 10.2 per 1,000 person-years. For the high magnesium group, 179 of the 1,748 people developed dementia, for a rate of 11.4 per 1,000 person-years. For the middle group, 102 of the 1,387 people developed dementia, for a rate of 7.8. Kieboom noted that almost all of the participants had magnesium levels in the normal range, with only 108 people with levels below normal and two people with levels above normal. [Original study.]