{"id":32339,"date":"2016-04-28T10:31:30","date_gmt":"2016-04-28T14:31:30","guid":{"rendered":"http:\/\/www.bumc.bu.edu\/busm\/?p=32339"},"modified":"2016-04-28T10:31:30","modified_gmt":"2016-04-28T14:31:30","slug":"unraveling-alzheimers-disease-part-3-work-it-out","status":"publish","type":"post","link":"https:\/\/www.bumc.bu.edu\/camed\/2016\/04\/28\/unraveling-alzheimers-disease-part-3-work-it-out\/","title":{"rendered":"Unraveling Alzheimer\u2019s Disease \/\/ Part 3 Work It Out"},"content":{"rendered":"
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\"Karin
Karin Schon, PhD, assistant professor of anatomy and neurobiology, and a BU Alzheimer\u2019s Disease Center faculty member. Photo by Cydney Scott.<\/figcaption><\/figure>\n

Can exercise\u00a0help delay or prevent the disease?<\/h4>\n

Alzheimer\u2019s disease is an epidemic. It attacks the brain\u2019s nerve cells, causing memory loss, behavioral changes, confusion, and deterioration of language skills. It affects more than 5 million Americans 65 and older, and that is expected to increase to 13.8 million by 2050 unless science finds a treatment. Alzheimer\u2019s and other forms of dementia are projected to cost the nation $236 billion this year and the figure could reach $1 trillion by 2050, according to the Alzheimer\u2019s Association<\/a>.<\/p>\n

At Boston University, dozens of researchers are looking for tests that could lead to early diagnosis and interventions to prevent or delay the disease, running clinical trials that may result in treatments and an eventual cure, working to understand genetic risk factors, and studying Alzheimer\u2019s impact on caregivers.<\/p>\n

The Boston University Alzheimer\u2019s Disease Center<\/a>, established in 1996, is one of 31 such centers nationwide funded by the National Institutes of Health<\/a> and dedicated to conducting research into the disease, enhancing clinical care, and providing education.<\/p>\n

In this special report, BU Today<\/em> examines the work of five BU researchers.<\/p>\n

W<\/span>hen Karin Schon enrolled in a 12-week fitness training program during her doctoral studies in cognitive neuroscience at BU, she expected it to improve her health. But she had no idea that it would also shape her research.<\/strong><\/p>\n

Before she took a single step, her trainers gave her a fitness test that measured body fat, weight, and cardiovascular fitness. That first test provided a baseline; another test three months later would determine if the program had made a difference. \u201cI liked it from a scientific perspective,\u201d says Schon<\/a> (GRS\u201905), a School of Medicine assistant professor of anatomy and neurobiology, and a BU Alzheimer\u2019s Disease Center<\/a> faculty member, who studies the effects of physical activity on the aging brain. \u201cIt felt like I was participating in a study.\u201d<\/p>\n

The program worked. She lost about 20 pounds, her cardiovascular fitness improved, and she was able to hold plank (the upper position of a push-up and a test of core strength and endurance) for nearly seven minutes.<\/p>\n

\u201cThis program had such an impact on me physically,\u201d says Schon, who later became an accomplished half-marathon runner. \u201cI was also curious. I thought that it must have an effect on the brain if it has an effect on the body.\u201d<\/p>\n

Schon\u2019s fitness program coincided with her graduate work and prompted a new research question: What effect does exercise have on the brain, particularly on memory?<\/p>\n

Studies in animals showed that increased levels of exercise, such as running on a wheel, improved the function of the hippocampus. But Schon found almost no studies of the effects of exercise on the human brain. \u201cI started to connect the dots,\u201d she says. \u201cAnd I found a gap.\u201d<\/p>\n

She decided to study the effects of exercise on memory, and in 2010 won a Pathway to Independence Award from the National Institute on Aging<\/a>, which provided five years of funding to pursue her idea. \u201cExercise should be great for healthy aging,\u201d she says. \u201cIf exercise improves memory in healthy adults as it does in animals, maybe it can be a way to ameliorate cognitive decline.\u201d<\/p>\n

\"Researcher
Researcher Karin Schon with a functional magnetic resonance imaging (fMRI) machine. Schon uses fMRI to study the connection between physical fitness and memory performance. Her work may eventually lead to interventions for Alzheimer\u2019s disease. Photo by Cydney Scott<\/figcaption><\/figure>\n

In the United States today, cognitive decline is a serious concern. One in three senior citizens dies with Alzheimer\u2019s disease or another form of dementia and the number of cases is rising, according to the Alzheimer\u2019s Association<\/a>. The costs of caring for people with Alzheimer\u2019s is expected to be approximately $1 trillion by 2050. These numbers are staggering, and given that the US health care system is already straining to meet health care demands, rather frightening.<\/p>\n

Schon\u2019s idea, however, could change the equation. What if something as simple as a brisk daily walk delayed the onset of Alzheimer\u2019s disease? Since she started looking into this in 2008, the number of studies suggesting a connection between exercise and the human brain has increased dramatically. \u201cThis is about lifestyle changes,\u201d says Rhoda Au<\/a> (Questrom\u201995), a MED professor of neuropsychology and a School of Public Health professor of epidemiology, who is one of Schon\u2019s mentors and collaborators. \u201cIf you can make healthy lifestyle changes early on, maybe you can prevent disease later on. There\u2019s nothing that\u2019s going to reduce health care costs faster than removing the need for it.\u201d<\/p>\n

Schon studied psychology as an undergraduate at the University of Hamburg in Germany, and afterwards the aging brain during a stint at the National Institutes of Health<\/a>. As a graduate student at BU, she joined the lab of neuroscientist Chantal Stern, a College of Arts & Sciences professor of psychological and brain sciences, and learned to use functional magnetic resonance imaging (fMRI) to study the hippocampus, a seat of memory in the brain.<\/p>\n

To measure memory capabilities, Schon showed study participants pictures in a series. She presented one image, then another, then a test picture, with delays between each presentation. The participants determined if they had seen the test picture before, as in the game Concentration.<\/p>\n

She\u2019s found that the fMRI patterns during the delays predict whether or not someone remembers the picture 15 minutes later. \u201cIt makes sense,\u201d she says. \u201cIf I just saw this picture, maybe I\u2019m thinking about it for awhile.\u201d<\/p>\n

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Strolling for Fitness<\/h3>\n<\/div>\n

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How does one assess someone\u2019s fitness level? It takes time, science, and a little sweat.<\/p>\n

Read more<\/a><\/p>\n<\/div>\n<\/div>\n

She used this method to study the relationship between fitness and memory. She recruited a group of students from BU to take a fitness test and then look at pictures in the fMRI scanner. She discovered an indirect connection between fitness and memory performance. A growth hormone called BDNF appears to connect the two. \u201cThere\u2019s greater memory accuracy with greater levels of BDNF in more fit individuals,\u201d explains Rachel Nauer (GRS\u201915,\u201920), a graduate student, and a marathon runner, in Schon\u2019s Brain Plasticity and Neuroimaging Laboratory<\/a>.<\/p>\n

BDNF is also known to play a role in the growth of new neurons in the brain. This discovery provided Schon with the first of several connections between her research and Alzheimer\u2019s disease.<\/p>\n

Making a connection to Alzheimer\u2019s disease in any research program is difficult. The disease, even with all that\u2019s known about it, is still mysterious. It occurs when a protein called amyloid forms plaques in the brain. Tangles, caused by tau, a different protein, follow, as does neurodegeneration, the loss of brain cells.<\/p>\n

It isn\u2019t clear yet what causes plaques to form in the first place, or if those plaques directly cause tangles to appear. Also, plaques may begin forming in the brain 20 years before a person begins to misplace car keys or forget names. This long lead time makes it extremely difficult to study the progression of the disease and especially difficult to show that an intervention slows progression.<\/p>\n

Enter Jake Gyllenhaal<\/h4>\n

So instead of focusing on Alzheimer\u2019s disease directly, Schon is focusing on links to it in the brain. One link is BDNF, which helps the brain grow new neurons. In the hippocampus, that neurogenesis occurs in a subregion called the dentate gyrus. The dentate gyrus is of particular interest to Schon because exercise enlarges it in animal studies.<\/p>\n

\"An
An analysis technique called voxel-based morphometry reveals the anatomy of specific brain regions, such as the hippocampus (gold) and entorhinal cortex (blue), from functional magnetic imaging data. Schon\u2019s lab found that higher levels of fitness correlated with increased entorhinal cortex volume on the right side (red). An ongoing exercise intervention study will help determine whether the brain region grows as fitness improves. Image courtesy of Schon<\/figcaption><\/figure>\n

A second link to Alzheimer\u2019s disease is right nearby, in the entorhinal cortex, which is connected to the dentate gyrus. Schon\u2019s team recently found that the entorhinal cortex is bigger in people with higher fitness levels. Animal studies suggest that these two regions of the brain\u2014the dentate gyrus and the entorhinal cortex\u2014malfunction first in Alzheimer\u2019s disease. \u201cWe started thinking it would be really interesting to look at these brain regions in the context of an exercise intervention in humans,\u201d Schon says.<\/p>\n

She plans to study the effects of exercise on the entorhinal cortex, pending NIH funding. She is also studying an exercise intervention focusing on the dentate gyrus. To do this, she and Nauer needed to develop a method to specifically stimulate the dentate gyrus. What they needed was an extremely sensitive test to detect changes in this tiny brain region, and potentially, to connect them to subtle behavior changes that other cognitive tests miss.<\/p>\n

The new test Schon\u2019s group developed builds on Schon\u2019s earlier fMRI methods for stimulating the hippocampus. The team presents images in a series, but they use special images that trigger the brain to perform a process called pattern separation. Pattern separation deciphers subtle differences in images and\u2014critically\u2014it occurs in the dentate gyrus. So they believe the method triggers activity in a seat of neurogenesis in the brain, and a place of earliest vulnerability in Alzheimer\u2019s.<\/p>\n

Nauer illustrates the types of images they show using familiar faces, such as actors Jake Gyllenhaal, Joseph Gordon Levitt, and John Travolta, although in the actual experiments, the images are of unfamiliar scenes. In her example, she shows faces that have been morphed using computer software so that they have specific degrees of similarity. One face might be 90 percent Gyllenhaal and 10 percent Levitt, for example, and another might be 90 percent Levitt and 10 percent Gyllenhaal. As the degree of similarity increases, the images become harder to decipher.<\/p>\n

They are still recruiting young people age 18 to 35 and older people age 55 to 85 who are currently sedentary for the study. Participants enroll in a fitness program similar to the one Schon took years ago. Nauer and Matt Dunne, a research study technician in the Schon lab, give each participant aerobic and muscle function tests and a series of memory tests, including the pattern separation test in the fMRI. They also sample BDNF levels.<\/p>\n

\"To
To stimulate subregions of the hippocampus, Schon lab members developed a pattern separation test that challenges participants to differentiate images with overlapping features. Computer software has morphed these images of famous faces (from left, Joseph Gordon Levitt, Jake Gyllenhaal, and John Travolta) to be 50-50 Levitt and Gyllenhall (bottom left) and 50-50 Gyllenhaal and Travolta. With so much overlap, the similarities and differences between these photos are hard to decipher. Image courtesy of Schon<\/figcaption><\/figure>\n

To stimulate subregions of the hippocampus, Schon lab members developed a pattern separation test that challenges participants to differentiate images with overlapping features. Computer software has morphed these images of famous faces (from left, Joseph Gordon Levitt, Jake Gyllenhaal, and John Travolta) to be 50-50 Levitt and Gyllenhall (bottom left) and 50-50 Gyllenhaal and Travolta. With so much overlap, the similarities and differences between these photos are hard to decipher. Image courtesy of Schon<\/p>\n

The participants are then given an individualized exercise prescription\u2014either an aerobic fitness routine or a resistance training routine\u2014to follow 3 times a week for 12 weeks. Since animal studies indicate that cardiovascular fitness is the key to improved memory, the researchers consider the resistance training group to be a control.<\/p>\n

One of the things that makes Schon\u2019s research so powerful is its interdisciplinary nature. For instance, she\u2019s brought in an exercise physiologist from Brigham and Women\u2019s Hospital<\/a>, Thomas Storer, to evaluate the exercise tests and prescribe the fitness routines. \u201cBoth training programs start out at a level that is doable for the individual and then progress over time with more added challenge,\u201d says Storer. \u201cWe can get a good training effect even with just three days of training per week.\u201d<\/p>\n

Storer\u2019s input adds heft to the program. \u201cStudies like these tend to be done either by neuroscientists who don\u2019t really have the exercise background or people with the exercise background who don\u2019t really know the neuroscience,\u201d says Dunne, a former college soccer player. \u201cWe\u2019re combining the two so we can have a rigorous study from both perspectives.\u201d<\/p>\n

For Nauer, this research isn\u2019t so much about whether exercise will make a difference, but what kind of exercise makes the most difference and how much is needed. \u201cMy focus moving forward is doing research that informs doctors,\u201d she says, \u201cso they may someday prescribe an exercise program rather a drug.\u201d<\/p>\n

Putting a dent in the problem<\/h4>\n

Schon is also working with Au on another exercise intervention, which uses digital cognitive assessments to detect subtle memory changes. These assessments not only record answers to memory questions, but also track the thinking that goes on behind these tasks. The intent of the research, says Au, is to identify changes in behavior that are more subtle than the symptoms a doctor would look for.<\/p>\n

This distinction between disease treatment and disease prevention is a critical one. Exercise may help individuals with cognitive impairments slow the disease, but Au thinks Schon\u2019s work could have much wider implications. The way she sees it, if exercise prevents cognitive decline, it could be a way to shrink the looming specter of Alzheimer\u2019s disease.<\/p>\n

Since 1990, Au has been an investigator for the Framingham Heart Study<\/a>, the nation\u2019s longest running epidemiological study, begun in 1948, supported by the\u00a0National Heart, Lung, and Blood Institute, and run by BU since 1971. According to a study report, delaying Alzheimer\u2019s disease by five years reduces a person\u2019s risk of getting the disease by 50 percent. \u201cEssentially, the disease is competing with mortality,\u201d she explains.<\/p>\n

If fitness delays Alzheimer\u2019s disease enough to reduce the risk by any percentage, that puts a dent in the problem. With the number of Americans with Alzheimer\u2019s possibly reaching 7.1 million in the coming decade, any dent is welcome.<\/p>\n

While Au sees the big picture potential, Schon\u2019s eyes are necessarily on the science. She\u2019s busy writing grant applications, mentoring students, engaging new collaborators, and reading and writing papers. She even took time to take an undergraduate exercise physiology class during her postdoc to round out her skill set.<\/p>\n

She\u2019s also getting back into running. She had knee surgery seven months ago and is just about fully recovered. \u201cI don\u2019t like the status quo right now, not being able to run,\u201d she says. \u201cMy last half marathon was two years ago. I\u2019d love to be able to do that again.\u201d<\/p>\n

This BU Today<\/em> story was written by Elizabeth Dougherty. \u00a0She can be reached at beth@writtenbyelizabethdougherty.com<\/a>.<\/p>\n

Read the other stories in our \u201cUnraveling Alzheimer\u2019s Disease\u201d series here<\/a>.<\/p>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

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