Why the brain is more reluctant to function as we age

New findings, led by neuroscientists at the University of Bristol and published this week in the journal Neurobiology of Aging, reveal a novel mechanism through which the brain may become more reluctant to function as we grow older. 

It is not fully understood why the brain's cognitive functions such as memory and speech decline as we age. Although work published this year suggests cognitive decline can be detectable before 50 years of age. The research, led by Professor Andy Randall and Dr Jon Brown from the University's School of Physiology and Pharmacology, identified a novel cellular mechanism underpinning changes to the activity of neurones which may underlie cognitive decline during normal healthy aging. 

The brain largely uses electrical signals to encode and convey information. Modifications to this electrical activity are likely to underpin age-dependent changes to cognitive abilities. 

The researchers examined the brain's electrical activity by making recordings of electrical signals in single cells of the hippocampus, a structure with a crucial role in cognitive function. In this way they characterised what is known as "neuronal excitability" — this is a descriptor of how easy it is to produce brief, but very large, electrical signals called action potentials; these occur in practically all nerve cells and are absolutely essential for communication within all the circuits of the nervous system. 

Action potentials are triggered near the neurone's cell body and once produced travel rapidly through the massively branching structure of the nerve cell, along the way activating the synapses the nerve cell makes with the numerous other nerve cells to which it is connected. 

The Bristol group identified that in the aged brain it is more difficult to make hippocampal neurones generate action potentials. Furthermore they demonstrated that this relative reluctance to produce action potential arises from changes to the activation properties of membrane proteins called sodium channels, which mediate the rapid upstroke of the action potential by allowing a flow of sodium ions into neurones. 

Professor Randall, Professor in Applied Neurophysiology said: "Much of our work is about understanding dysfunctional electrical signalling in the diseased brain, in particular Alzheimer's disease. We began to question, however, why even the healthy brain can slow down once you reach my age. Previous investigations elsewhere have described age-related changes in processes that are triggered by action potentials, but our findings are significant because they show that generating the action potential in the first place is harder work in aged brain cells. 

"Also by identifying sodium channels as the likely culprit for this reluctance to produce action potentials, our work even points to ways in which we might be able modify age-related changes to neuronal excitability, and by inference cognitive ability." 

Source: University of Bristol [February 01, 2012]

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Diet, nutrient levels linked to cognitive ability, brain shrinkage

New research has found that elderly people with higher levels of several vitamins and omega 3 fatty acids in their blood had better performance on mental acuity tests and less of the brain shrinkage typical of Alzheimer's disease – while "junk food" diets produced just the opposite result. 

The study was among the first of its type to specifically measure a wide range of blood nutrient levels instead of basing findings on less precise data such as food questionnaires, and found positive effects of high levels of vitamins B, C, D, E and the healthy oils most commonly found in fish. 

The research was done by scientists from the Oregon Health and Science University in Portland, Ore., and the Linus Pauling Institute at Oregon State University. It was published today in Neurology, the medical journal of the American Academy of Neurology. 

"This approach clearly shows the biological and neurological activity that's associated with actual nutrient levels, both good and bad," said Maret Traber, a principal investigator with the Linus Pauling Institute and co-author on the study. 

"The vitamins and nutrients you get from eating a wide range of fruits, vegetables and fish can be measured in blood biomarkers," Traber said. "I'm a firm believer these nutrients have strong potential to protect your brain and make it work better." 

The study was done with 104 people, at an average age of 87, with no special risk factors for memory or mental acuity. It tested 30 different nutrient biomarkers in their blood, and 42 participants also had MRI scans to measure their brain volume. 

"These findings are based on average people eating average American diets," Traber said. "If anyone right now is considering a New Year's resolution to improve their diet, this would certainly give them another reason to eat more fruits and vegetables." 

Among the findings and observations: 

• The most favorable cognitive outcomes and brain size measurements were associated with two dietary patterns – high levels of marine fatty acids, and high levels of vitamins B, C, D and E. 

• Consistently worse cognitive performance was associated with a higher intake of the type of trans-fats found in baked and fried foods, margarine, fast food and other less-healthy dietary choices. 

• The range of demographic and lifestyle habits examined included age, gender, education, smoking, drinking, blood pressure, body mass index and many others. 

• The use of blood analysis helped to eliminate issues such as people's flawed recollection of what they ate, and personal variability in nutrients absorbed. 

• Much of the variation in mental performance depended on factors such as age or education, but nutrient status accounted for 17 percent of thinking and memory scores and 37 percent of the variation in brain size. 

• Cognitive changes related to different diets may be due both to impacts on brain size and cardiovascular function. 

The epidemiology of Alzheimer's disease has suggested a role for nutrition, the researchers said in their study, but previous research using conventional analysis, and looking in isolation at single nutrients or small groups, have been disappointing. The study of 30 different blood nutrient levels done in this research reflects a wider range of nutrients and adds specificity to the findings. 

The study needs to be confirmed with further research and other variables tested, the scientists said. 

Source: Oregon State University [December 28, 2011]

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Sea snails help scientists explore a possible way to enhance memory

Efforts to help people with learning impairments are being aided by a species of sea snail known as Aplysia californica. The mollusk, which is used by researchers to study the brain, has much in common with other species including humans. Research involving the snail has contributed to the understanding of learning and memory. 

At The University of Texas Health Science Center at Houston (UTHealth), neuroscientists used this animal model to test an innovative learning strategy designed to help improve the brain's memory and the results were encouraging. It could ultimately benefit people who have impairments resulting from aging, stroke, traumatic brain injury or congenital cognitive impairments. 

The proof-of-principle study was published on the Nature Neuroscience website on Dec. 25. The next steps in the research may involve tests in other animal models and eventually humans. 

The strategy was used to identify times when the brain was primed for learning, which in turn facilitated the scheduling of learning sessions during these peak periods. The result was a significant increase in memory. 

"We found that memory could be enhanced appreciably," said John H. "Jack" Byrne, Ph.D., senior author and chair of the Department of Neurobiology and Anatomy at the UTHealth Medical School. 

Building on earlier research that identified proteins linked to memory, the investigators created a mathematical model that tells researchers when the timing of the activity of these proteins is aligned for the best learning experience. 

Right now, the scheduling of learning sessions is based on trial and error and is somewhat arbitrary. If the model proves effective in follow-up studies, it could be used to identify those periods when learning potential is highest. 

"When you give a training session, you are starting several different chemical reactions. If you give another session, you get additional effects. The idea is to get the sessions in sync," Byrne said. "We have developed a way to adjust the training sessions so they are tuned to the dynamics of the biochemical processes." 

Two groups of snails received five learning sessions. One group received learning sessions at irregular intervals as predicted by a mathematical model. Another group received training sessions in regular 20-minute intervals. 

Five days after the learning sessions were completed, a significant increase in memory was detected in the group that was trained with a schedule predicted by a computer. But, no increase was detected in the group with the regular 20-minute intervals. 

The computer sorted through 10,000 different permutations in order to determine a schedule that would enhance memory. 

To confirm their findings, researchers analyzed nerve cells in the brain of snails and found greater activity in the ones receiving the enhanced training schedule, said Byrne, the June and Virgil Waggoner Chair of Neurobiology and Anatomy at UTHealth. 

"This study shows the feasibility of using computational methods to assist in the design of training schedules that enhance memory," Byrne said.  

Source: University of Texas Health Science Center at Houston [December 25, 2011]

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A new way of approaching the early detection of Alzheimer's disease

One of our genes is apolipoprotein E (APOE), which often appears with a variation which nobody would want to have: APOEε4, the main genetic risk factor for sporadic Alzheimer's disease (the most common form in which this disorder manifests itself and which is caused by a combination of hereditary and environmental factors). 

It is estimated that at least 40% of the sporadic patients affected by this disease are carriers of APOEε4, but this also means that much more still remains to be studied. The researcher at the University of the Basque Country (UPV/EHU) Xabier Elcoroaristizabal has opened up a channel for making a start by analysing candidate genes which, always in combination with APOEε4, could help to explain more cases. 

His thesis is entitled "Molecular markers in mild amnestic cognitive impairment and Alzheimer's disease" (Marcadores moleculares en deterioro cognitivo leve tipo amnesico y enfermedad de Alzheimer). An initial article on this can be read in the journal BMC Neuroscience. 

The long-term aim is to contribute towards the early detection of Alzheimer's disease by identifying signs that could be detectable in the very early phases. And, as Elcoroaristizabal explains, while there is no cure for this disorder, the alternative is to get ahead of it and delay its development: 

"Certain preventive measures involving cognitive stimulation delay its appearance. There are even new drugs that could start to be used earlier. Today there is no solution, but the more we maintain a person's correct cognitive state, the better." 

Mild amnestic, cognitive impairment 

The individuals who develop Alzheimer's go through a transition period first of all, and this could be the key moment for the effective application of preventive measures. This is mild cognitive impairment (MCI), in which slight cognitive alterations take place but do not affect everyday activities. 

Among the different types of MCI, one affects memory almost exclusively (amnestic MCI), and those people who suffer from it have a high probability of developing the disorder. The difficult and interesting part is knowing which genetic components are linked to this impairment and also in determining by what percentage the risk of developing the disease increases, a task which Elcoroaristizabal has set himself. 

"If we can identify which genes are involved and what susceptibility factors there are, preventive measures could be taken," he explains. 

So a contrast study has been carried out among a sample of patients with MCI, ones with Alzheimer's and healthy people. This can be used to observe the changes and narrow down the field for the zones to be studied, so that candidate genes can be sought there. 

Elcoroaristizabal himself notes one example among the many others identified: "It has been observed that the brain's capacity to control cholesterol levels seems to play a key role throughout the illness. So, protein encoding genes linked to this control have been analysed." 

In this quest for candidate genes, Elcoroaristizabal has confirmed that the APOEε4 genetic variation is, in fact, the main risk factor for developing Alzheimer's disease. But it does not end there; he has identified several genes which, as long as they are manifested in combination with APOEε4, could take us one step further towards the early detection of this disorder. 

"Genes that in some way are connected with neurotransmission channels, oxidative stress or the effectiveness of oestrogens seem to be linked to a greater risk for APOEε4 carriers," he explains. Specifically, the candidate genes are as follows: COMT (neurotransmission), SOD2 (oxidative stress elimination) and ESR1 and ESR2 (oestrogen action facilitators).  

Source: Basque Research [December 23, 2011]

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Brain size may predict risk for early Alzheimer's disease

New research suggests that, in people who don't currently have memory problems, those with smaller regions of the brain's cortex may be more likely to develop symptoms consistent with very early Alzheimer's disease. The study is published in the December 21, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology. 

"The ability to identify people who are not showing memory problems and other symptoms but may be at a higher risk for cognitive decline is a very important step toward developing new ways for doctors to detect Alzheimer's disease," said Susan Resnick, PhD, with the National Institute on Aging in Baltimore, who wrote an accompanying editorial. 

For the study, researchers used brain scans to measure the thickness of regions of the brain's cortex in 159 people free of dementia with an average age of 76. The brain regions were chosen based on prior studies showing that they shrink in patients with Alzheimer's dementia. Of the 159 people, 19 were classified as at high risk for having early Alzheimer's disease due to smaller size of particular regions known to be vulnerable to Alzheimer's in the brain's cortex, 116 were classified as average risk and 24 as low risk. At the beginning of the study and over the next three years, participants were also given tests that measured memory, problem solving and ability to plan and pay attention. 

The study found that 21 percent of those at high risk experienced cognitive decline during three years of follow-up after the MRI scan, compared to seven percent of those at average risk and none of those at low risk. 

"Further research is needed on how using MRI scans to measure the size of different brain regions in combination with other tests may help identify people at the greatest risk of developing early Alzheimer's as early as possible," said study author Bradford Dickerson, MD, of Massachusetts General Hospital in Boston and a member of the American Academy of Neurology. 

The study also found 60 percent of the group considered most at risk for early Alzheimer's disease had abnormal levels of proteins associated with the disease in cerebrospinal fluid, which is another marker for the disease, compared to 36 percent of those at average risk and 19 percent of those at low risk. 

Source: American Academy of Neurology [December 21, 2011]

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Cannabis harms the brain - but that's not the full story

For the first time, scientists have proven that cannabis harms the brain. But the same study challenges previously-held assumptions about use of the drug, showing that some brain irregularities predate drug use. 

Professor Dan Lubman, from Turning Point Alcohol and Drug Centre and Monash University, along with a team of researchers from Melbourne University have conducted a world-first study examining whether these brain abnormalities represent markers of vulnerability to cannabis use. 

“Previous evidence has shown that long-term heavy cannabis use is associated with alterations in regional brain volumes,” Professor Lubman said. 

“Although these changes are frequently attributed to the neurotoxic effects of cannabis, no studies have examined whether structural brain abnormalities are present before the onset of cannabis use until now.” 

To fill this void in present studies, Professor Lubman and his team recruited participants from primary schools in Melbourne, Australia, as part of a larger study examining adolescent emotional development. 

Of the 155 original participants who underwent structural magnetic resonance imaging at age 12, 121 completed a follow-up survey measuring substance use four years later. It was found that by age 16, 28 participants had commenced using cannabis. 

“This is an important developmental period to examine, because although not all individuals who initiate cannabis use during this time will go on to use heavily, early cannabis use has been associated with a range of negative outcomes later in life,” Professor Lubman said. 

Their findings revealed that youth with smaller orbitofrontal cortex (OFC) volumes, part of the frontal lobe of the brain, at age 12 were more likely to have initiated cannabis use by age 16. The volumes of other regions of the brain did not predict later cannabis use. 

“Given the lack of research in this area, we hypothesised that pre-drug use differences would be consistent with the structural abnormalities that have been found in studies of heavy users,” Professor Lubman said. 

“What we found is that only the OFC predicted later cannabis use, suggesting that this particular part of the frontal lobe increases an adolescent’s vulnerability to cannabis use. However, we also found no differences in brain volume in other parts of the brain that we have shown to be abnormal in long-term heavy cannabis users, confirming for the first time, that cannabis use is neurotoxic to these brain areas in humans.” 

The OFC plays a primary role in inhibitory control and reward-based decision making; previous studies of adolescent cannabis users have demonstrated subtle deficits in problem-solving, attention, memory and executive functions. 

“In adult cannabis users, decreased activation of the OFC has been associated with faulty decision-making, suggesting that a reduced ability to weigh the pros and costs of one’s actions might render certain individuals more prone to drug problems,” Professor Lubman said. 

“These results have important implications for understanding neurobiological predictors of cannabis use, but further research is still needed to understand their relationships with heavier patterns of use in adulthood as well as later abuse of other substances.” 

This research has been published online in Biological Psychiatry, the official journal of the Society of Biological Psychiatry. 

Source: Monash University [December 13, 2011]

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What do animals 'know'? More than you may think

Rats use their knowledge to make decisions when faced with ambiguous situations, UCLA psychologists report.

A rat finds a reward in an ambiguous situation [Credit: Aaron Blaisdell/UCLA Psychology]

"Rats often make judgments and behave as if they're rational creatures," said UCLA associate professor of psychology Aaron Blaisdell, a member of UCLA's Brain Research Institute and senior author of a new study published in the December issue of the journal Psychonomic Bulletin and Review.

"To make a decision in the face of uncertainty, rats call on prior history and reasoning," Blaisdell said. "They apply what they know to a situation where they are uncertain. The rats are not necessarily thinking like little humans, but they have learned through experience. A lot of animal behavior seems to be rational. Their behavior follows logical inferences."


Blaisdell, an expert in animal cognition (he avoids the phrase "animal intelligence"), and Cynthia Fast, the study's lead author and a UCLA graduate student in psychology, report on a series of experiments in which 74 female rats were rewarded with a sugar solution — which rats like about as much as teenagers like soda, Blaisdell said — for pressing a lever under certain conditions but not under others, which they learned to differentiate. 

The rats, none of which were harmed, first learned to expect the sugar reward if they pressed a lever when they saw one of two lights illuminated in their enclosure but not when they saw both lights on. After learning this pattern in 90 days, the rats were shown only one illuminated light while the other light was covered. In this case, the rats searched less for the sugar solution, as if both lights were on. This indicated, Blaisdell said, that the rats imagined the other light to be on, even though they could not see it. 

"Their behavior is consistent with their having an image of the light being on," Blaisdell said. "When we didn't cover the light, they knew what decision to make. They have the ability to hold an image of something that is not there and make a decision based on that." 

"Their prior learning influenced how they perceived this ambiguity," Fast said. "The rats responded less in this condition than they would if there was just a single light but more than they would if both lights were on. It would be like your driving on your commute and approaching an intersection where you know there is a traffic light but you can't see it because a tree branch or a bus in front of you is blocking your view. You approach slowly until you're able to see if the light is red or green. The rats seem to be doing the same thing. It's as if they reason, 'Hmm, I can't see the light on the right; maybe it's on,' and they press the lever less than they would if there were just a single light on."

The research was federally funded by the National Science Foundation.

In another experiment, rats were given the reward only if they pressed a lever when both lights were on, but not when either light was on alone — a pattern they learned much more quickly (in only 30 days). Then the psychologists covered one of the lights to study how the rats would respond. 

What was surprising, they said, was that covering the light in this case did not seem to have any impact on the rats' decision to respond. They continued to behave as if they were certain that the covered light was not on.

 To find out why, the researchers conducted a follow-up experiment in which the rats were again given the reward for pressing the lever when both lights were on (but not when only one was on), and they were also given the reward if they pressed the lever when they heard a tone or a clicking sound — but not the tone and clicking sound simultaneously. Other rats were given the reward only if the tone and clicking sound occurred together, not separately.

"The rats are capable of learning that too," Fast said. "They learn to differentiate among these different lights and different auditory cues and can tell them all apart." 

"It takes them a long time," Blaisdell said.

The rats were more sensitive to ambiguity when the uncertainty followed the more challenging training involving both the lights and the auditory cues, even in the condition that failed to make a difference previously, Fast and Blaisdell report.

"The difficulty of the task the rats are engaged in affects how they deal with uncertainty," Blaisdell said. "When the task is more difficult, they address it in a more sophisticated fashion. As far as I know, that has not been shown with any animal before."

 Little is known about how human imagination works, but an understanding of how widespread imagination is across the animal kingdom can shed light on the origins of imagination,
Blaisdell said. 

The aging brain 

The ability to make decisions in ambiguous situations declines with age, Blaisdell and Fast noted.

"With aging, decision-making becomes more fragile, especially in the face of lack of information," Blaisdell said. 

Blaisdell is interested in learning the brain mechanisms involved in decision-making and perhaps applying this research to human cognition and neural changes that occur with aging or with degenerative diseases. He also hopes to gain new insights into how we learn.

"There is still so much we don't know about learning," he said. "The more we can understand about how the brain supports cognition, the more we will be able to look for where cognition is going wrong when the brain malfunctions." 

Author: Stuart Wolpert | Source: University of California Los Angeles [December 08, 2011]

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Tapping the brain orchestra

Researchers at the Norwegian University of Life Sciences (UMB) and Forschungszentrum Jülich in Germany have developed a new method for detailed analyses of electrical activity in the brain. The method, recently published in Neuron, can help doctors and researchers to better interpret brain cell signals. In turn, this may lead to considerable steps forward in terms of interpreting for example EEG measurements, making diagnoses and treatment of various brain illnesses. 

A forest of neurons [Credit: Hermann Cuntz]

Researchers and doctors have been measuring and interpreting electrical activity generated by brain cells since 1875. Doctors have over the years acquired considerable practical skills in relating signal shapes to different brain illnesses such as epilepsy. However, doctors have so far had little knowledge on how these signals are formed in the network of nerve cells. 

"Based on methods from physics, mathematics and informatics, as well as computational power from the Stallo supercomputer in Tromsø, we have developed detailed mathematical models revealing the connection between nerve cell activity and the electrical signal recorded by an electrode," says Professor Gaute Einevoll at the Department of Mathematical Sciences and Technology (IMT) at UMB. 

Microphone in a crowd 

The problem of interpreting electrical signals measured by electrodes in the brain is similar to that of interpreting sound signals measures by a microphone in a crowd of people. Just like people sometimes all talk at once, nerve cells are also sending signals "on top of each other". 

The electrode records the sounds from the whole orchestra of nerve cells surrounding it and there are numerous contributors. One cubic millimetre can contain as many as 100,000 nerve cells. 

Treble and bass 

Similar to bass and treble in a soundtrack, high and low frequency electrical signals are distinguished in the brain. 

"This project has focused on the bass - the low frequency signals called "local field potential" or simply LFP. We have found that if nerve cells are babbling randomly on top of each other and out of sync, the electrode's reach is narrow so that it can only receive signals from nerve cells less than about 0.3 millimetres away. However, when nerve cells are speaking simultaneously and in sync, the range can be much wider," Einevoll says. 

Large treatment potential 

Better understanding of the electrical brain signals may directly influence diagnosing and treatment of illnesses such as epilepsy. 

"Electrodes are already being used to measure brain cell activity related to seizures in epilepsy patients, as well as planning surgical procedures. In the future, LFP signals measured by implanted electrodes could detect an impending epilepsy seizure and stop it by injecting a suitable electrical current," Einevoll says. 

"A similar technique is being used on many Parkinson's patients, who have had electrodes surgically implanted to prevent trembling," Researcher Klas Pettersen at UMB adds. 

Einevoll and Pettersen also outline treatment of patients paralysed by spinal cord fracture as another potential area where the method can be used. 

"When a patient is paralysed, nerve cells in the cerebral cortex continue to send out signals, but the signals do not reach the muscles, and the patient is thus unable to move arms or legs. By monitoring the right nerve cells and forwarding these signals to for example a robot arm, the patient may be able to steer by his or her thoughts alone," Einevoll says. 

The Computational Neuroscience Group at UMB has already established contacts with clinical research groups in the USA and Europe for further research on using the approach in patient treatment.  

Author: Torunn Moe | Source: Norwegian University of Life Sciences [December 08, 2011]

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Drug reverses aging-associated changes in brain cells

Drugs that affect the levels of an important brain protein involved in learning and memory reverse cellular changes in the brain seen during aging, according to an animal study in the December 7 issue of The Journal of Neuroscience. The findings could one day aid in the development of new drugs that enhance cognitive function in older adults. 

Aging-related memory loss is associated with the gradual deterioration of the structure and function of synapses (the connections between brain cells) in brain regions critical to learning and memory, such as the hippocampus. Recent studies suggested that histone acetylation, a chemical process that controls whether genes are turned on, affects this process. Specifically, it affects brain cells' ability to alter the strength and structure of their connections for information storage, a process known as synaptic plasticity, which is a cellular signature of memory. 

In the current study, Cui-Wei Xie, PhD, of the University of California, Los Angeles, and colleagues found that compared with younger rats, hippocampi from older rats have less brain-derived neurotrophic factor (BDNF) -- a protein that promotes synaptic plasticity -- and less histone acetylation of the Bdnf gene. By treating the hippocampal tissue from older animals with a drug that increased histone acetylation, they were able to restore BDNF production and synaptic plasticity to levels found in younger animals. 

"These findings shed light on why synapses become less efficient and more vulnerable to impairment during aging," said Xie, who led the study. "Such knowledge could help develop new drugs for cognitive aging and aging-related neurodegenerative diseases, such as Alzheimer's disease," she added. 

The researchers also found that treating the hippocampal tissue from older animals with a different drug that activates a BDNF receptor also reversed the synaptic plasticity deficit in the older rats. Because histone acetylation is important in many functions throughout the body, these findings offer a potential pathway to treat aging-related synaptic plasticity deficits without interfering with histone acetylation. 

"It appears that lifelong shifts in gene regulation steadily deprive the brain of a key growth factor and cause a collapse of the 'machinery' supporting memory, cognition, and the viability of neurons," said Gary Lynch, PhD, a synaptic plasticity expert at the University of California, Irvine. "The very good news suggested by this study is that it may be possible to reverse these effects." 

Source: Society for Neuroscience [December 07, 2011]

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Researchers identify diabetes link to cognitive impairment in older adults

Many complications of diabetes, including kidney disease, foot problems and vision problems are generally well recognized. But the disease's impact on the brain is often overlooked. 

For the past five years, a team led by Beth Israel Deaconess Medical Center (BIDMC) neurophysiologist Vera Novak, MD, PhD, has been studying the effects of diabetes on cognitive health in older individuals and has determined that memory loss, depression and other types of cognitive impairment are a serious consequence of this widespread disease. 

Now, Novak's team has identified a key mechanism behind this course of events. In a study published in the November 2011 issue of the journal Diabetes Care, they report that in older patients with diabetes, two adhesion molecules – sVCAM and sICAM – cause inflammation in the brain, triggering a series of events that affect blood vessels and, eventually, cause brain tissue to atrophy. Importantly, they found that the gray matter in the brain's frontal and temporal regions -- responsible for such critical functions as decision-making, language, verbal memory and complex tasks – is the area most affected by these events. 

"In our previous work, we had found that patients with diabetes had significantly more brain atrophy than did a control group," explains Novak, Director of the Syncope and Falls in the Elderly (SAFE) Program in the Division of Gerontology at BIDMC and Associate Professor of Medicine at Harvard Medical School. "In fact, at the age of 65, the average person's brain shrinks about one percent a year, but in a diabetic patient, brain volume can be lowered by as much as 15 percent." 

Diabetes develops when glucose builds up in the blood instead of entering the body's cells to be used as energy. Known as hyperglycemia, this condition often goes hand-in-hand with inflammation. Novak wanted to determine if chronic inflammation of the blood vessels was causing altered blood flow to the brain in patients with diabetes. 

To test this hypothesis, Novak's team recruited 147 study subjects, averaging 65 years of age. Seventy one of the subjects had type 2 diabetes and had been taking medication to manage their conditions for at least five years. The other 76 were age and sex-matched non-diabetic controls. 

Study subjects underwent a series of cognitive tests, balance tests and standard blood-pressure and blood-glucose tests. Serum samples were also collected to measure adhesion molecules and several other markers of systemic inflammation. To determine perfusion (blood flow) measures in the brain, patients also underwent functional MRI testing, in which a specialized imaging technique known as arterial spin labeling (developed by BIDMC MR physicist David Alsop, PhD) was used in conjunction with a standard MRI to measure vascular reactivity in several brain regions and to show changes in blood flow. 

As predicted, the scans showed that the diabetic patients not only had greater blood vessel constriction than the control subjects, but they also had more atrophied brain tissue, particularly gray matter. The results also showed that, in the patients with diabetes, the frontal, temporal and parietal regions of the brain were most affected. Similarly, the team's measurements of serum markers confirmed that high glucose levels were strongly correlated with higher levels of inflammatory cytokines. 

"It appears that chronic hyperglycemia and insulin resistance – the hallmarks of diabetes – trigger the release of adhesion molecules [sVCAM and sICAM] and set off a cascade of events leading to the development of chronic inflammation," says Novak. "Once chronic inflammation sets in, blood vessels constrict, blood flow is reduced, and brain tissue is damaged. " 

This discovery now provides two biomarkers of altered vascular reactivity in the brain. "If these markers can be identified before the brain is damaged, we can take steps to try and intervene," says Novak, explaining that some data indicates that medications may improve vascoreactivity. 

But more important, she says, the new findings provide still more reason for doctors and patients to focus greater attention on the management – and prevention – of diabetes. 

"Cognitive decline affects a person's ability to successfully complete even the simplest of everyday tasks, such as walking, talking or writing," says Novak. "There are currently 25.8 million cases of type 2 diabetes in the United States alone, which is more than eight percent of our total population. The effects of diabetes on the brain have been grossly neglected, and, as our findings confirm, are issues that need to be addressed." 

Source: Beth Israel Deaconess Medical Center [November 08, 2011]

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