Genetic Discovery Will Revolutionize Understanding Of Gene Expression

Over the past decade, research in the field of epigenetics has revealed that chemically modified bases are abundant components of the human genome and has forced us to abandon the notion we've had since high school genetics that DNA consists of only four bases.

Over the past decade, research in the field of epigenetics has revealed that chemically modified bases are abundant components of the human genome and has forced us to abandon the notion we've had since high school genetics that DNA consists of only four bases. Now, researchers have made a discovery that once again forces us to rewrite our textbooks. This time, however, the findings pertain to RNA, which like DNA carries information about our genes and how they are expressed. The researchers have identified a novel base modification in RNA which they say will revolutionize our understanding of gene expression [Credit: © Attila Németh / Fotolia]

Now, researchers at Weill Cornell Medical College have made a discovery that once again forces us to rewrite our textbooks. This time, however, the findings pertain to RNA, which like DNA carries information about our genes and how they are expressed. The researchers have identified a novel base modification in RNA which they say will revolutionize our understanding of gene expression.

Their report, published in the journal Cell, shows that messenger RNA (mRNA), long thought to be a simple blueprint for protein production, is often chemically modified by addition of a methyl group to one of its bases, adenine. Although mRNA was thought to contain only four nucleobases, their discovery shows that a fifth base, N6-methyladenosine (m6A), pervades the transcriptome. The researchers found that up to 20 percent of human mRNA is routinely methylated. Over 5,000 different mRNA molecules contain m6A, which means that this modification is likely to have widespread effects on how genes are expressed.

"This finding rewrites fundamental concepts of the composition of mRNA because, for 50 years, no one thought mRNA contained internal modifications that control function," says the study's senior investigator, Dr. Samie R. Jaffrey, an associate professor of pharmacology at Weill Cornell Medical College.

"We know that DNA and proteins are routinely modified by chemical switches that have profound effects on their function in both health and disease. But biologists believed mRNA was simply an intermediate between DNA and protein," he says. "Now we know mRNA is much more complex, and defects in RNA methylation can lead to disease."

Indeed, as part of the study, the researchers demonstrated that the obesity risk gene, FTO (fat mass and obesity-associated), encodes an enzyme capable of reversing this modification, converting m6A residues in mRNA back to regular adenosine. Humans with FTO mutations have an overactive FTO enzyme, which results in low levels of m6A and causes abnormalities in food intake and metabolism that lead to obesity.

The researchers uncovered links between m6A and other diseases as well.

"We found that m6A is present in many mRNAs encoded by genes linked to human diseases, including cancer as well as several brain disorders, such as autism, Alzheimer's disease, and schizophrenia," says the study's lead investigator, Dr. Kate Meyer, a postdoctoral researcher in Dr. Jaffrey's laboratory. 

"Methylation in RNA is a reversible modification that appears to be a central step in a wide variety of biological pathways and physiological processes," she says.

The first time that m6A was detected in mRNA was in 1975, but at the time scientists were unsure whether this finding was a result of contamination by other RNA molecules, Dr. Jaffrey says. Over 90 percent of RNA is either transfer RNA (tRNA) or ribosomal RNA (rRNA), cellular workhorses that are routinely modified.

But Dr. Jaffrey says he has always been interested in the idea that mRNA may be modified - "DNA, proteins, other forms of RNA are modified, so why not mRNA?" he says - so he and investigators in his laboratory developed a technique to help them uncover methylation in mRNA taken from both mouse and human samples.

They used two different antibodies that recognize and bind to m6A in mRNA in order to selectively isolate the mRNAs that contain m6A. By subjecting these mRNAs to next-generation sequencing, they were able to identify the sequence of each individual mRNA they had isolated. Co-authors Dr. Christopher Mason and Dr. Olivier Elemento, assistant professors from the Department of Physiology and Biophysics and Computational Genomics in Computational Biomedicine at Weill Cornell Medical College, then developed computational algorithms to reveal the identity of each of these methylated mRNAs.

The Weill Cornell researchers don't know how the thousands of m6As they detected in humans work to control the function of mRNAs, but they do note that the m6As are located near "stop codons" in mRNA sequences. These areas signal the end of translation of the mRNA, suggesting that m6A might influence ribosomal function. "But we really don't know yet," says Dr. Mason, a co-lead investigator on the study. "It may allow other proteins to bind to mRNA, or subject these mRNAs to a whole new regulatory pathway. Our bioinformatics analyses are providing several hints about the possible impact of methylation on RNA function."

Indeed, in their study, the investigators have already found that m6A sites frequently occur in regions of mRNA that are highly conserved across several species of vertebrates. "This shows that m6A sites are not just important for humans, but rather are maintained under selection across hundreds of millions of years of evolution, and thus are likely of critical importance for all animals," Dr. Mason says.

"This is the first demonstration of an epitranscriptomic modification - alterations in RNA function that are not due to changes in the underlying sequence," he adds.

"These findings are very, very exciting, and amazing, really, when you consider that mRNA has been around for so long and that nobody realized, in all this time, that they were being regulated in this way," Dr. Jaffrey says. "It was right under our noses."

In addition to investigating how m6A regulates mRNAs within cells, the researchers are now focused on identifying the enzymes and pathways that control mRNA methylation.

Their study already demonstrates that FTO is capable of reversing adenosine methylation and suggests that it acts on a large proportion of cellular mRNA. "FTO mutations are estimated to occur in one billion people worldwide and are a leading cause of obesity and type 2 diabetes. Our studies link m6A levels in mRNA to these major health problems and identify for the first time the mRNAs which are potentially targeted by FTO," Dr. Meyer says.

The investigators are currently working to understand how defective regulation of m6A in patients with FTO mutations causes obesity and metabolic disorders, and they are also developing tests to rapidly identify compounds that inhibit FTO activity. These compounds are expected to inhibit the overactive FTO found in humans, potentially leading to novel therapeutics for diabetes and obesity.

Source: Medical News Today {May 19, 2012]

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Powerful Function of Single Protein That Controls Neurotransmission Discovered

Scientists at Weill Cornell Medical College have discovered that the single protein -- alpha 2 delta -- exerts a spigot-like function, controlling the volume of neurotransmitters and other chemicals that flow between the synapses of brain neurons. The study, published online in Nature, shows how brain cells talk to each other through these signals, relaying thoughts, feelings and action, and this powerful molecule plays a crucial role in regulating effective communication.

In the study, the investigators also suggest how the widely used pain drug Lyrica might work. The alpha 2 delta protein is the target of this drug and the new work suggests an approach to how other drugs could be developed that effectively twist particular neurotransmitter spigots on and off to treat neurological disorders. The research findings surprised the research team, which includes scientists from University College London.

"We are amazed that any single protein has such power," says the study's lead investigator Dr. Timothy A. Ryan, professor of Biochemistry and associate professor of Biochemistry in Anesthesiology at Weill Cornell Medical College. "It is indeed rare to identify a biological molecule's function that is so potent, that seems to be controlling the effectiveness of neurotransmission."

The researchers found that alpha 2 delta determines how many calcium channels will be present at the synaptic junction between neurons. The transmission of chemical signals is triggered at the synapse by the entry of calcium into these channels, so the volume and speed of neurotransmission depends on the availability of these channels.

Researchers discovered that taking away alpha 2 delta from brain cells prevented calcium channels from getting to the synapse. "But if you add more alpha 2 delta, you can triple the number of channels at synapses," Dr. Ryan says. "This change in abundance was tightly linked to how well synapses carry out their function, which is to release neurotransmitters."

Before this study, it was known that Lyrica, which is used for neuropathic pain, seizures and fibromyalgia, binds to alpha 2 delta, but little was understood about how this protein works to control synapses.

Lifting up the Hood

Dr. Ryan is building what he calls a "shop manual" of neurological function, much of which centers on synaptic neurotransmission. In 2007 and 2008, he discovered crucial clues to how neurons repackage the chemicals used to signal across synapses. In 2011, Dr. Ryan discovered that distinct neurons differently tune the speed by which they package these chemicals. And in a recent study published April 29 in Nature Neuroscience, he described, for the first time, the molecular mechanisms at the synapse that control the release of dopamine, a crucial neurotransmitter.

"We are looking under the hood of these machines for the first time," he says. "Many neurological diseases are considered to arise from pathologies of synaptic function. The synapse is so complex; at least a few thousand genes control how they work. Repairing them through treatment requires that we understand how they work."

Dr. Ryan and his team often use two tools to conduct these studies -- they pin fluorescent tags on to molecules involved in synaptic function, and use ultra sensitive microscopy technology to watch these molecules up close and in real-time.

The researchers used the same toolkit to examine the function of calcium channels, which triggers neurotransmission. "At all synapses, the secretion of a neurotransmitter is driven by the arrival of an electric impulse, initiated by another neuron," Dr. Ryan says. When this impulse arrives at the nerve terminal it triggers the opening of calcium channels. The calcium that rushes in is the key trigger that drives a synapse to secrete its neurotransmitter.

"We have known for the past half century that calcium is a key controller of neurotransmission," he says. "Any small change in calcium influx has a big impact on neurotransmission."

Protein Acts like a Shipping Label

But the number of calcium channels at the synapse is not static. Neurons constantly replace worn out channels, and to do this, they build the channels in the neuron's cell body and then package them up and ship them to the nerve terminal. In some cases, that is a very long journey -- as much as a few feet, such as the distance between the brain and the base of the spinal cord or the length of a leg.

In the study, researchers tagged fluorescent proteins onto a gene that encodes protein that makes a calcium channel and delivered it to neurons. They then watched the progress of the newly formed channels as they made their way, from day four to day seven, from the bodies of neurons to the synapse.

They also manipulated the levels of alpha 2 delta, a suspected calcium channel partner, and discovered that when the protein was increased, more calcium channels were moved to the synapse. Less alpha 2 delta reduced the flow. "We discovered that alpha 2 delta made the decision of how many calcium channels should be shipped the length of the neuron to the synapse," Dr. Ryan says. "It's like the channels couldn't be transported without an alpha 2 delta shipping label."

The research team found however that alpha 2 delta must work in at least two steps. When they impaired a piece of alpha 2 delta that resembles proteins that are involved in how cells bind to each other, they found that this broken alpha 2 delta could still help get calcium channels shipped down to synapses. But once there, they no longer helped drive neurotransmitter release. "This means that not only does alpha 2 delta help to get calcium channels shipped out, but it also implies that something at the synapse has to sign-off on receiving the calcium channels, putting them in the right place for them to do their job," Dr. Ryan says.

The researchers suggest that Lyrica might work by interfering with this final step since the piece of alpha 2 delta they "broke" that prevents the signing-off resembles parts of proteins that allows them to stick to each other in a kind of handshake.

These findings suggest that future therapies designed to manipulate neurotransmission could try to target this handshaking process, Dr. Ryan says. To do this will require that researchers identify the missing partner in the handshake.

"We hope these exciting findings are providing a new direction in how to make better drugs to control communication between brain cells," Dr. Ryan says.

The study was funded by the National Institutes of Mental Health and the Welcome Trust. Co-authors of the study include Dr. Michael B. Hoppa from Weill Cornell Medical College, and Dr. Beatrice Lana, Dr. Wojciech Margas, and Dr. Annette C. Dolphin from University College London.

Source: NewYork-Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College [May 13, 2012]

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Genes and Vascular Risk Modify Effects of Aging On Brain and Cognition

Efforts to understand how the aging process affects the brain and cognition have expanded beyond simply comparing younger and older adults.

"Everybody ages differently. By looking at genetic variations and individual differences in markers of vascular health, we begin to understand that preventable factors may affect our chances for successful aging," said Wayne State University psychology doctoral student Andrew Bender, lead author of a study supported by the National Institute on Aging of the National Institutes of Health and now in press in the journal Neuropsychologia.

The report, "Age-related Differences in Memory and Executive Functions in Healthy APOE ε4 Carriers: The Contribution of Individual Differences in Prefrontal Volumes and Systolic Blood Pressure," focuses on carriers of the ε4 variant of the apolipoprotein (APOE) gene, present in roughly 25 percent of the population. Compared to those who possess other forms of the APOE gene, carriers of the ε4 allele are at significantly greater risk for Alzheimer's, dementia and cardiovascular disease.

Many studies also have shown that nondemented carriers of the APOE ε4 variant have smaller brain volumes and perform less well on cognitive tests than carriers of other gene variants. Those findings, however, are not consistent, and a possible explanation may come from examining interactions between the risky genes and other factors, such as markers of cardiovascular health. Prior research in typical samples of older adults has shown that indeed other vascular risk factors -- such as elevated cholesterol, hypertension or diabetes -- can exacerbate the impact of the APOE ε4 variant on brain and cognition, but it is unclear if such synergy of risks is present in healthy adults.

Thus, Wayne State researchers evaluated a group of volunteers from 19 to 77 years of age who self-reported as exceptionally healthy on a questionnaire that screened for a number of conditions, representing a "best case scenario" of healthy aging. The research project, led by Naftali Raz, Ph.D., professor of psychology and director of the Lifespan Cognitive Neuroscience Research Program at WSU's Institute of Gerontology, tested different cognitive abilities known for their sensitivity to aging and the effects of the APOE ε4 variant. Those abilities include speed of information processing, working memory (holding and manipulating information in one's mind) and episodic memory (memory for events).

Researchers also measured participants' blood pressure, performed genetic testing to determine which APOE variant participants carried, and measured the volumes of several critical brain regions using a high-resolution structural magnetic resonance imaging brain scan. Bender and Raz showed that for older APOE ε4 carriers, even minor increases in systolic blood pressure (the higher of the two numbers that are reported in blood pressure measures) were linked with smaller volumes of the prefrontal cortex and prefrontal white matter, slower speed of information processing, reduced working memory capacity and worse verbal memory. Notably, they said, that pattern was not evident in those who lacked the ε4 gene variant.

The study concludes that the APOE ε4 gene may make its carriers sensitive to negative effects of relatively subtle elevations in systolic blood pressure, and that the interplay between two risk factors, genetic and physiological, is detrimental to the key brain structures and associated cognitive functions.

"Although genes play a significant role in shaping the effects of age and vascular risk on the brain and cognition, the impact of single genetic variants is relatively small, and there are quite a few of them. Thus, one's aging should not be seen through the lens of one's genetic profile," cautioned the study's authors. They continued, "The negative impact of many genetic variations needs help from other risk factors, and while there isn't much one can do about genes, a lot can be done about vascular risk factors such as blood pressure or cholesterol."

"Everybody should try to keep those in check, although people with certain genetic variants more so than others." Raz said. "Practically speaking, even with the best deck of genetic cards dealt to you, it still makes sense to reduce risk through whatever works: exercise, diet or, if those fail, medication."

Because the study is part of a longitudinal project, he and Bender said the immediate future task now is to determine how the interaction between risky genes and vascular risk factors affect the trajectory of age-related changes -- not differences, as in this cross-sectional study -- in brain and cognition.

Source: Wayne State University - Office of the Vice President for Research [May 09, 2012]

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Keep aging brains sharp

Exercising, eating a healthy diet and playing brain games may help you keep your wits about you well into your 80s and even 90s, advises a new book by researchers at George Mason University. 

"These are all cheap, easy things to do," says Pamela Greenwood, an associate professor in the Department of Psychology on Mason's Fairfax, Va. campus. "We should all be doing them anyway. You should do them for your heart and health, so why not do them for your brain as well?" 

For the past 20 years, Greenwood and Raja Parasuraman, University Professor of Psychology, have studied how the mind and brain age, focusing on Alzheimer's disease. Their book, "Nurturing the Older Brain and Mind" published by MIT Press, came out in March. The cognitive neuroscientists geared the book to middle-aged readers who want to keep their mental snap. 

"We know that if we can put off dementing illnesses even by a year or two through lifestyle changes, that will reduce the number of people with Alzheimer's disease, which is reaching epidemic proportions," Parasuraman says. 

Not everyone's brain declines when retirement age hits. "You can look at a group of 65-year-olds — some are in nursing homes, and some are running the world," Greenwood says. 

Now that more workers are staying on the job longer for economic reasons and because countries are upping the retirement age, keeping the mind agile becomes paramount, Parasuraman says. 

For the book, Parasuraman and Greenwood examined only scientific studies, theirs and others, ranging from neurological to physiological. A few surprises leaped out of the data. 

"Several old dogmas were overturned," Parasuraman says. "There's the tired old joke that we're losing brain cells as we age — maybe starting as young as 20 or 30 — and it's all downhill after that." 

Not so, new research reveals. Not only are some 60-year-olds as sharp as 20-year-olds, but their brains still create new cells. Brain cells may not grow as fast as bone or skin cells, but grow they do, particularly in the hippocampus. "It's the area of the brain that's very important to memory and is affected by Alzheimer's disease," Parasuraman says. 

Novel experiences and new learning help new brain cells become part of the circuitry. Parasuraman points to a study of terminally ill cancer patients whose brains were still forming new neurons. "If a person who's in a terminally ill state can generate new neurons, then surely healthy people can," Parasuraman says. 

Brain games and new experiences may build up "white matter," which insulates neurons as they carry signals, Greenwood says. In older brains, this white matter insulation develops holes and signals go awry. 

Older adult gamers are winning skills to help them move through life, Parasuraman says. "We are looking at everyday problem solving," he says. "Are you better at balancing a checkbook? Are you better at making decisions in a grocery store? We're finding you get better at those tasks (after playing the video games in the study)." 

Moving large muscle groups also builds brain matter. In one study detailed in the book, older, sedentary people began walking or did stretching exercises for 45 minutes, three times a week. "Those people actually became smarter over time," Greenwood says. "You don't have to be running Ironman marathons. You can just walk briskly three or four times a week." 

Another best bet for an active mind is a nutritious diet that limits calories to the minimum amount needed to keep a body healthy. No starvation diets, though. "The strongest evidence we have is not very pleasant, which is dietary restriction, reducing calories," Parasuraman says. "That clearly improves longevity and cognition. The evidence in animals is very strong. Such dietary restriction may never be popular. But perhaps every-other-day fasting as an approximation to it is something people would tolerate: You eat normally one day, and the next day you don't." 

Popping supplements won't fill a nutritionally deficient diet, Parasuraman says. "A lot of people think, 'I can eat junk food and then take a pill.' No. You have to eat fruits and vegetables, leafy vegetables. It has to be part of the regular diet because otherwise it's not absorbed." 

Fat cells help make up cell membranes. The unsaturated fats found in fish and olive oils may boost flexibility in these membranes. The more flexible membranes are, the better they may work, scientists theorize. Saturated fats such as butter have to go because these fats vie with healthy fats for a place in the cell membrane, Greenwood explains. 

Greenwood and Parasuraman want people to know that getting old doesn't mean getting senile. "The bottom line message of the book is really a hopeful one," Greenwood says. "There are lots of things that you can do (to keep your brain healthy)." 

Source: George Mason University [April 04, 2012]

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Lifelong brain-stimulating habits linked to lower Alzheimer’s protein levels

A new study led by researchers at the University of California, Berkeley, provides even more reason for people to read a book or do a puzzle, and to make such activities a lifetime habit. 

PET scans reveal amyloid plaques, which appear as warm colors such as red and orange. The middle scan is from a person with no symptoms of cognitive problems, but with evident levels of amyloid plaque in the brain [Credit: Susan Landau and William Jagust]

Brain scans revealed that people with no symptoms of Alzheimer’s who engaged in cognitively stimulating activities throughout their lives had fewer deposits of beta-amyloid, a destructive protein that is the hallmark of the disease. 

While previous research has suggested that engaging in mentally stimulating activities – such as reading, writing and playing games – may help stave off Alzheimer’s later in life, this new study identifies the biological target at play. This discovery could  guide future research into effective prevention strategies. 

“These findings point to a new way of thinking about how cognitive engagement throughout life affects the brain,” said study principal investigator Dr. William Jagust,  a professor with joint appointments at UC Berkeley’s Helen Wills Neuroscience Institute, the School of Public Health and Lawrence Berkeley National Laboratory. “Rather than simply providing resistance to Alzheimer’s, brain-stimulating activities may affect a primary pathological process in the disease. This suggests that cognitive therapies could have significant disease-modifying treatment benefits if applied early enough, before symptoms appear.” 

An estimated 5.4 million Americans live with Alzheimer’s disease, but the numbers are growing as baby boomers age. Between 2000 and 2008, deaths from Alzheimer’s increased 66 percent, making it the sixth-leading killer in the country. There is currently no cure, but a draft of the first-ever National Alzheimer’s Plan, released this week, revealed that the U.S. government is aiming for effective Alzheimer’s treatments by 2025. 

The new study, to be published Monday, Jan. 23, in the Archives of Neurology, puts the spotlight on amyloid – protein fibers folded into tangled plaques that accumulate in the brain. Beta-amyloid is considered the top suspect in the pathology of Alzheimer’s disease, so finding a way to reduce its development has become a major new direction of research. 

A molecular model of amyloid protein fibrils. Formed when mis-folded proteins self-assemble into fibrous sheet structures, they are found in the brains of sufferers of Alzheimer's disease [Credit: Susan Landau and William Jagust]

The researchers note that the buildup of amyloid can also be influenced by genes and aging – one-third of people age 60 and over have some amyloid deposits in their brain – but how much reading and writing one does is under each individual’s control. 

“This is the first time cognitive activity level has been related to amyloid buildup in the brain,” said study lead author Susan Landau, research scientist at the Helen Wills Neuroscience Institute and the Berkeley Lab. “Amyloid probably starts accumulating many years before symptoms appear. So it’s possible that by the time you have symptoms of Alzheimer’s, like memory problems, there is little that can be done to stop disease progression. The time for intervention may be much sooner, which is why we’re trying to identify whether lifestyle factors might be related to the earliest possible changes.” 

The researchers asked 65 healthy, cognitively normal adults aged 60 and over (average age was 76) to rate how frequently they participated in such mentally engaging activities as going to the library, reading books or newspapers, and writing letters or email. The questions focused on various points in life from age 6 to the present. 

The participants took part in extensive neuropsychological testing to assess memory and other cognitive functions, and received positron emission tomography (PET) scans at the Berkeley Lab using a new tracer called Pittsburgh Compound B that was developed to visualize amyloid. The results of the brain scans of healthy older individuals with various levels of lifetime cognitive activity were compared with those of 10 patients diagnosed with Alzheimer’s disease and 11 healthy people in their 20s. 

The researchers found a significant association between higher levels of cognitive activity over a lifetime and lower levels of beta-amyloid in the PET scans. They analyzed the impact of other factors such as memory function, physical activity, self-rated memory ability, level of education and gender, and found that lifelong cognitive engagement was independently linked to amyloid deposition. 

Notably, the researchers did not find a strong connection between amyloid deposition and levels of current cognitive activity alone. 

“What our data suggests is that a whole lifetime of engaging in these activities has a bigger effect than being cognitively active just in older age,” said Landau. 

The researchers are careful to point out that the study does not negate the benefits of kicking up brain activity in later years. 

“There is no downside to cognitive activity. It can only be beneficial, even if for reasons other than reducing amyloid in the brain, including social stimulation and empowerment,” said Jagust. “And actually, cognitive activity late in life may well turn out to be beneficial for reducing amyloid. We just haven’t found that connection yet.” 

Other study authors include researchers from UC San Francisco’s Memory and Aging Center and Department of Neurology, and Rush University Medical Center’s Alzheimer’s Disease Center in Chicago. 

The National Institutes of Health and the Alzheimer’s Association helped support this research. 

Author: Sarah Yang | Source: UC Berkeley [January 23, 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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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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Alzheimer's vaccine cures memory... of mice

A vaccine that slows the progression of Alzheimer's disease and other types of dementia has been developed by researchers at the University of Sydney's Brain and Mind Research Institute (BMRI). 

The vaccine, which targets a protein known as tau, prevents the ongoing formation of neurofibrillary tangles in the brain of a mouse with Alzheimer's disease. 

This progressive neurodegenerative disease affects more than 35 million people worldwide. The tau protein is also involved in front temporal dementia, the second most common form of dementia in people younger than 65 years. 

The results of the study which led to the production of the vaccine have been published today in the scientific journal PLoS ONE. 

Lead author on the study, Associate Professor Lars Ittner, from the Alzheimer's and Parkinson's Disease Laboratory says: 

"Our study is the first to show that a vaccine targeting the tau protein can be effective once the disease has already set in. 

"The vaccine appears to have a preventative effect: slowing the development of further tangles, rather than clearing existing ones, but the exact mechanism involved is not yet understood," he said. 

According to Associate Professor Ittner, scientists have been working on vaccines targeting the amyloid plaques seen in Alzheimer's for many years with a few currently in clinical trials. 

"Most of the other vaccines targeting tau were tested only before or around the onset of the disease in animal models, but the vast majority of people with Alzheimer's disease are only diagnosed after the symptoms have appeared. 

"We are already collaborating with the US pharmaceutical industry to develop this new vaccine for humans. 

"Although we have a long way to go before the vaccine might be available for human use, these early results are very promising and a great reward for the countless hours spent in the lab by me and my team!" 

Source: The University of Sydney [December 09, 2011]

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Antioxidant has potential in the Alzheimer's fight

When you cut an apple and leave it out, it turns brown. Squeeze the apple with lemon juice, an antioxidant, and the process slows down. 

Simply put, that same "browning" process—known as oxidative stress—happens in the brain as Alzheimer's disease sets in. The underlying cause is believed to be improper processing of a protein associated with the creation of free radicals that cause oxidative stress. 

Now, a study by researchers in the University of Georgia College of Pharmacy has shown that an antioxidant can delay the onset of all the indicators of Alzheimer's disease, including cognitive decline. The researchers administered an antioxidant compound called MitoQ to mice genetically engineered to develop Alzheimer's. The results of their study were published in the Nov. 2 issue of the Journal of Neuroscience. 

According to the Alzheimer's Society, more than 5 million Americans currently suffer from the neurodegenerative disease. Without successful prevention, almost 14 million Americans will have Alzheimer's by 2050, accounting for healthcare costs of more than $1 trillion a year. 

Oxidative stress is believed to cause neurons in the brain to die, resulting in Alzheimer's. Study author James Franklin, an associate professor of pharmaceutical and biomedical sciences, has studied neuronal cell death and oxidative stress at UGA since 2004. 

"The brain consumes 20 percent of the oxygen in the body even though it only makes up 5 percent of the volume, so it's particularly susceptible to oxidative stress," said Franklin, coauthor of the study along with Meagan McManus, who received her Ph.D. in neuroscience from UGA in 2010. 

The UGA researchers hypothesized that antioxidants administered unsuccessfully by other researchers to treat Alzheimer's were not concentrated enough in the mitochondria of cells. Mitochondria are structures within cells that have many functions, including producing oxidative molecules that damage the brain and cause cell death. 

"MitoQ selectively accumulates in the mitochondria," said McManus, who is now studying mitochondrial genetics and dysfunction as a postdoctoral researcher at Children's Hospital of Philadelphia. 

"It is more effective for the treatment to go straight to the mitochondria, rather than being present in the cell in general," she said. 

Although he had not previously conducted research on Alzheimer's disease, Franklin was moved to approve McManus' research proposal to take his laboratory research in a more clinical direction in part because of her family's history with the disease. 

"Two of my grandparents had Alzheimer's disease, but they presented with it very differently. While my granddad often couldn't remember who we were, he was still the same soulful funnyman I'd always loved. But the disease changed my grandmother's mind in a different way, and turned her into someone we'd never known," said McManus. 

"So the complexity of the disease was most intriguing to me. I wanted to know how and why it was happening, and more importantly, how to stop it from happening to other people," she said. 

In their study, mice engineered to carry three genes associated with familial Alzheimer's were tested for cognitive impairment using the Morris Water Maze, a common test for memory retention. The mice that had received MitoQ in their drinking water performed significantly better than those that didn't. Additionally, the treated mice tested negative for the oxidative stress, amyloid burden, neural death and synaptic loss associated with Alzheimer's. 

Source: University of Georgia [December 14, 2011]

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Scientists provide potential explanation for mechanisms of associative memory

Researchers from the University of Bristol have discovered that a chemical compound in the brain can weaken the synaptic connections between neurons in a region of the brain important for the formation of long-term memories. The findings, published in the Journal of Neuroscience, may also provide a potential explanation for the loss of memory associated with Alzheimer's. 

Acetylcholine, a neurotransmitter, is released in the brain and is known to play an important role in normal brain functions such as sleep, attention, and learning and memory. Until now the mechanisms by which this transmitter controls such processes were not well understood. 

The findings, led by researchers from the University's MRC Centre for Synaptic Plasticity in the School of Physiology and Pharmacology, highlight the mechanisms by which acetylcholine controls communication between neurons located in the prefrontal cortex and may help in understanding how higher cognitive processing is controlled in this important brain area. 

Professor of Cellular Neuroscience, Zafar Bashir and his team have demonstrated how electrical stimulation of the prefrontal cortex leads to the release of acetylcholine from synaptic terminals and the subsequent weakening of synaptic connections between neurons. 

When acetylcholine is released it binds to specific receptors and starts a molecular cascade which triggers physiological alterations in how prefrontal cortical neurons are 'wired' together. The findings suggest that the persistent weakening of synaptic connections between neurons induced by the endogenous release of acetylcholine in the prefrontal cortex may underlie the formation of new associative memories. 

The authors speculate that the memory impairments associated with Alzheimer's dementia may result, in part, from a loss of synaptic plasticity in the prefrontal cortex related to the depletion of brain acetylcholine that occurs in the disease. 

Dr Douglas Caruana, who carried out the experiments, said: "Disruptions in cholinergic signaling in the prefrontal cortex are known to affect how the brain encodes lasting associations between objects and places, and a depletion of brain acetylcholine levels in the cortex is a classic hallmark of Alzheimer's dementia'." 

Professor Bashir added: "Acetylcholinesterase inhibitors are the most widely used medication to treat individuals with Alzheimer's dementia and the enhancement of synaptic plasticity by acetylcholinesterase inhibition that we now demonstrate may be a way in which these drugs provide clinical efficacy." 

Source: University of Bristol [December 13, 2011]

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Neuroscientists Boost Memory in Mice Using Genetics and a New Memory-Enhancing Drug

When the activity of a molecule that is normally elevated during viral infections is inhibited in the brain, mice learn and remember better, researchers at Baylor College of Medicine reported in a recent article in the journal Cell. 

Laboratory mouse [Credit: impactlab]

"The molecule PKR (the double-stranded RNA-activated protein kinase) was originally described as a sensor of viral infections, but its function in the brain was totally unknown," said Dr. Mauro Costa-Mattioli, assistant professor of neuroscience at BCM and senior author of the paper. Since the activity of PKR is altered in a variety of cognitive disorders, Costa-Mattioli and colleagues decided to take a closer look at its role in the mammalian brain. 

Super memory 

The authors discovered that mice lacking PKR in the brain have a kind of "super" memory. "We found that when we genetically inhibit PKR, we increased the excitability of brain cells and enhanced learning and memory, in a variety of behavioral tests," he said. For instance, when the authors assessed spatial memory (the memory for people, places and events) through a test in which mice use visual cues for finding a hidden platform in a circular pool, they found that normal mice had to repeat the task multiple times over many days in order to remember the platform's location. By contrast, mice lacking PKR learned the task after only one training session. 

Costa-Mattioli and colleagues wanted to know how this molecular process actually works. They found that when PKR is inhibited, the increased synaptic activity (that is, the enhanced communication between neurons) is caused by gamma interferon, another molecule involved in immunity. 

"These data are totally unexpected, and show that two molecules classically known to play a role in viral infection and the immune response regulate the kind of brain activity that leads to the formation of long-term memory in the adult brain," said Costa-Mattioli. 

Drug targets PKR 

Another key finding made by Costa-Mattioli and his team of researchers was the fact that this process could be mimicked by a PKR inhibitor -- a small molecule that blocks PKR activity and thus acts as a "memory-enhancing drug." 

"It is indeed quite amazing that we can also enhance both memory and brain activity with a drug that specifically targets PKR." Definitely then, the next step is to use what we have learned in mice and to try to improve brain function in people suffering from memory loss, said Costa-Mattioli. 

Although Costa-Mattioli's memory pill may be years away from approval by the U.S. Food and Drug Administration, its impact on society and medicine could be very profound. There are roughly 6 million Americans and 35 million people world-wide with Alzheimer's disease and more than 70 million Americans over the age of 60 who may suffer from aged-associated impairment of memory. 

Costa-Mattioli said, "More investigation is undoubtedly necessary to translate these findings to effective therapies but we would be delighted if our scientific studies were to contribute in some way to this ultimate goal." 

"Our identity and uniqueness is made up of our memories," Costa-Mattioli said. "This molecule could hold the key to how we can keep our memories longer, but also how we create new ones." 

Others who contributed to the research include: first author Ping Jun Zhu, Wei Huang, Jong W. Yoo, Loredana Stoica, Hongyi Zhou, Jeffrey Noebels, all at BCM; Andon N. Placzek, currently with Mercer University School of Medicine; Michael J. Friedlander and Djanenkhodja Kalikulov currently with Virginia Tech; Kresimir Krnjevic, McGill University; and John C. Bell, Ottawa Health Research Institute. 

The research was supported through funding from the Searle Scholars Program (award to Costa-Mattioli), the Cynthia and George Mitchell Founds (award to Costa-Mattioli), the National Institute of Neurological Diseases and Stroke, the National Institute for Child Health and Development, the BCM Intellectual and Developmental Disabilities Research Center and the National Eye Institute. 

Source: Baylor College of Medicine [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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Eating fish reduces risk of Alzheimer's disease

People who eat baked or broiled fish on a weekly basis may be improving their brain health and reducing their risk of developing mild cognitive impairment (MCI) and Alzheimer's disease, according to a study presented today at the annual meeting of the Radiological Society of North America (RSNA). 

"This is the first study to establish a direct relationship between fish consumption, brain structure and Alzheimer's risk," said Cyrus Raji, M.D., Ph.D., from the University of Pittsburgh Medical Center and the University of Pittsburgh School of Medicine. "The results showed that people who consumed baked or broiled fish at least one time per week had better preservation of gray matter volume on MRI in brain areas at risk for Alzheimer's disease." 

Alzheimer's disease is an incurable, progressive brain disease that slowly destroys memory and cognitive skills. According to the National Institute on Aging, as many as 5.1 million Americans may have Alzheimer's disease. In MCI, memory loss is present but to a lesser extent than in Alzheimer's disease. People with MCI often go on to develop Alzheimer's disease. 

For the study, 260 cognitively normal individuals were selected from the Cardiovascular Health Study. Information on fish consumption was gathered using the National Cancer Institute Food Frequency Questionnaire. There were 163 patients who consumed fish on a weekly basis, and the majority ate fish one to four times per week. Each patient underwent 3-D volumetric MRI of the brain. Voxel-based morphometry, a brain mapping technique that measures gray matter volume, was used to model the relationship between weekly fish consumption at baseline and brain structure 10 years later. The data were then analyzed to determine if gray matter volume preservation associated with fish consumption reduced risk for Alzheimer's disease. The study controlled for age, gender, education, race, obesity, physical activity, and the presence or absence of apolipoprotein E4 (ApoE4), a gene that increases the risk of developing Alzheimer's. 

Gray matter volume is crucial to brain health. When it remains higher, brain health is being maintained. Decreases in gray matter volume indicate that brain cells are shrinking. 

The findings showed that consumption of baked or broiled fish on a weekly basis was positively associated with gray matter volumes in several areas of the brain. Greater hippocampal, posterior cingulate and orbital frontal cortex volumes in relation to fish consumption reduced the risk for five-year decline to MCI or Alzheimer's by almost five-fold. 

"Consuming baked or broiled fish promotes stronger neurons in the brain's gray matter by making them larger and healthier," Dr. Raji said. "This simple lifestyle choice increases the brain's resistance to Alzheimer's disease and lowers risk for the disorder." 

The results also demonstrated increased levels of cognition in people who ate baked or broiled fish. 

"Working memory, which allows people to focus on tasks and commit information to short-term memory, is one of the most important cognitive domains," Dr. Raji said. "Working memory is destroyed by Alzheimer's disease. We found higher levels of working memory in people who ate baked or broiled fish on a weekly basis, even when accounting for other factors, such as education, age, gender and physical activity." 

Eating fried fish, on the other hand, was not shown to increase brain volume or protect against cognitive decline. 

Source: Radiological Society of North America [November 30, 2011]

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The brain's zoom button

Everybody knows how to zoom in and out on an online map, to get the level of resolution you need to get you where you want to go. Now researchers have discovered a key mechanism that can act like a zoom button in the brain, by controlling the resolution of the brain's internal maps. 

In this week's edition of Cell, Lisa Giocomo and colleagues at the Kavli Icondnstitute for Systems Neuroscience at NTNU describe how they "knocked out", or disabled, ion channels in the grid cells of the mouse brain. Grid cells are equivalent to a longitude and latitude coordinate system in the brain, with the grid cell firing at the cross-point where the longitude and latitude lines meet. This network enables the brain to make internal maps. Ion channels mediate signals between the inside and the outside of the cells. When the researchers knocked out the ion channels, they found that the resolution of the maps created by the mouse brain became coarser, in that the area covered by each grid cell was larger. 

"If grid cells are similar to a longitude and latitude coordinate system, what determines the distance between the coordinate points of this internal map?" Giocomo asks. "When we knocked out the HCN1 ion channel, the scale of the innate coordinate system increased. It's like losing longitude and latitude lines on a map. Suddenly you can't represent a spatial environment at a very fine scale." 

In a normal brain, the ion channels function as they should, and the brain is able to generate the precise resolution for the map that it needs. But if the ion channels don't work – as was the case in the experimental set up – then the map isn't at the right resolution. 

Future research will aim at determining what effect this might have on spatial memory and navigation. Giocomo says her findings could prove useful for future research on Alzheimer's and related diseases, "particularly because the area that is damaged in Alzheimer's is the area that we are investigating. Also, one of the first things to go wrong with Alzheimer's is that you suddenly start to lose your sense of direction. Of course, we don't know if there is any connection yet, but it might be worth looking into." 

The article in Cell is being published simultaneously with a companion article in Neuron, authored by researchers at the Kavli Institute for Brain Science, at Columbia University in New York. The two Kavli Institutes decided to work cooperatively on the topic, says Edvard Moser, director of the Kavli Institute at NTNU. 

"We believe that this is a great example of collaborative research instead of neck-and-neck competition. We got our knock-out mice from (Eric) Kandel's lab (at Columbia), and they sent a post-doc over here to work with us. We discussed and debated our findings of course, gave each other feedback and input," Moser says. 

The collaborative approach enabled the two institutes to publish linked research data from two interconnected areas of the brain, the entorhinal cortex and the hippocampus. Both sets of data show the effect of removing ion channels in grid cells and place cells. Place cells are thought to base their spatial response based on the calculations of the grid cells, so finding this close correspondence in research results is "very rewarding," Moser says. "It's great that we can find two pieces of evidence that show how scale is represented in our brain, and that we can publish these results at the same time. 

Source: Norwegian University of Science and Technology [November 17, 2011]

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New MRI technique to diagnose or rule out Alzheimer's disease

On the quest for safe, reliable and accessible tools to accurately diagnose Alzheimer's disease, researchers from the Perelman School of Medicine at the University of Pennsylvania found a new way of diagnosing and tracking Alzheimer's disease, using an innovative magnetic resonance imaging (MRI) technique called Arterial spin labeling (ASL) to measure changes in brain function. 

The team determined that the ASL-MRI test is a promising alternative to the current standard, a specific PET scan that requires exposure to small amounts of a radioactive glucose analog and costs approximately four-times more than an ASL-MRI. Two studies now appear in Alzheimer's and Dementia: The Journal of the Alzheimer's Association and Neurology®, the medical journal of the American Academy of Neurology.. 

ASL-MRI can be used to measure neurodegenerative changes in a similar way that fluorodeoxyglucose Positron emission tomography (FDG-PET) scans are currently being used to measure glucose metabolism in the brain. Both tests correlate with cognitive decline in patients with Alzheimer's disease. 

"In brain tissue, regional blood flow is tightly coupled to regional glucose consumption, which is the fuel the brain uses to function. Increases or decreases in brain function are accompanied by changes in both blood flow and glucose metabolism," explained John A. Detre, MD, professor of Neurology and Radiology at Penn, senior author on the papers, who has worked on ASL-MRI for the past 20 years. "We designed ASL-MRI to allow cerebral blood flow to be imaged noninvasively and quantitatively using a routine MRI scanner." 

When Alzheimer's disease is suspected, patients typically receive an MRI initially to look for structural changes that could indicate other medical causes, such as a stroke or brain tumor. Adding about 10-20 minutes to the test time, ASL can be incorporated into the routine MRI and capture functional measures to detect Alzheimer's disease upfront, turning a routine clinical test (structural MRI) into both a structural and functional test. 

"If ASL-MRI were included in the initial diagnostic work-up routinely, it would save the time for obtaining an additional PET scan, which we often will order when there is diagnostic uncertainty, and would potentially speed up diagnosis," said David Wolk, MD, Assistant Professor of Neurology and Assistant Director of the Penn Memory Center, and a collaborator on this research. 

The studies being reported this week show a comparison of ASL-MRI and FDG-PET in a group of Alzhiemer's patients and age-matched controls. Cerebral blood flow and glucose metabolism were measured simultaneously by injecting the PET tracer during the MRI study. The data were then analyzed two different ways. 

In the first study, now online in Alzheimer's and Dementia, ASL-MRI and FDG-PET images from 13 patients diagnosed with Alzheimer's and 18 age-matched controls were analyzed by visual inspection. Independent, blinded review of the two tests by expert nuclear medicine physicians demonstrated similar abilities to rule out (sensitivity) and diagnose (specificity) Alzheimer's. Neither ASL-MRI nor FDG-PET showed a clear advantage from quantitative testing. 

In the second study, published in Neurology, the ASL-MRI and FDG-PET images were compared statistically at each location in the brain by computerized analysis. Data from 15 AD patients were compared to 19 age-matched healthy adults. The patterns of reduction in cerebral blood flow were nearly identical to the patterns of reduced glucose metabolism by FDG-PET, both of which differed from the patterns of reduction in gray matter seen in AD. 

"Given that ASL-MRI is entirely non-invasive, has no radiation exposure, is widely available and easily incorporated into standard MRI routines, it is potentially more suitable for screening and longitudinal disease tracking than FDG-PET," said the Neurology study authors. 

Additional studies will focus on larger sample sizes including patients with mild cognitive impairment and other kinds of neurodegenerative conditions.  

Source: University of Pennsylvania School of Medicine [November 16, 2011]

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