Van Eldik discusses research to reduce Alzheimer’s and other neurodegenerative diseases
By Ed Lane
‘Dementia increasing in prevalence… It’s going to bankrupt our country’
Linda J. Van Eldik is director of the University of Kentucky’s Sanders-Brown Center on Aging and the Alzheimer’s Disease Center. Van Eldik holds a bachelor’s degree in biology from Calvin College and completed her doctorate in microbiology and immunology at Duke University, which is where she became interested in neuroscience. Her research primarily focuses on inflammation, which normally fights off infection and injury to protect the body, but in the case of acute injuries or chronic diseases like Alzheimer’s, can produce detrimental effects.
After a postdoctoral fellowship at Rockefeller University in New York, Van Eldik served on the faculty of Vanderbilt University and Northwestern University before joining UK in 2010. In addition to her research and administrative work, she has also been a mentor to students and has worked with more than 27 postdoctoral scientists and seven predoctoral trainees.
Ed Lane: How long have you been affiliated with the University of Kentucky and when did you become director of the Sanders-Brown Center on Aging?
Linda Van Eldik: On Feb. 1, 2010, I was hired to be the director of the Sanders-Brown Center on Aging (SBCoA). I had been associate director of the Alzheimer’s Disease Center at Northwestern University for about 16 years before I moved to UK.
EL: What inspired you to enter this particular field – studying aging and neurodegenerative diseases?
LVE: I started to become really interested in biology when I was in college. I was a biology major, but I wasn’t studying anything related to the brain. My Ph.D. was actually in immunology and virology – studying viruses and how they affect the immune system. When I became a faculty member, I became interested in the brain because a protein I was studying that affected the immune system was also found in high levels in the brain. I was wondering what it was doing there, so I went to California to learn neuroscience. I did a six-month sabbatical and fell in love with neuroscience, and I have been studying the brain ever since.
EL: How long has Sanders-Brown been researching Alzheimer’s disease and other neurodegenerative disorders?
LVE: The center was established in 1978. In 1985, it became one of the first 10 National Institutes of Health-funded Alzheimer’s disease centers in the country. Our team has been working on neurodegenerative disorders for more than 30 years.
EL: What is the center’s major source of research funding at this time?
LVE: It’s primarily from NIH, as all biomedical science is, which makes research funding more difficult in these challenging economic times. NIH funds only a very small percentage of the grant proposals it receives, so SBCoA has to rely a lot more on other funding sources.
EL: How important are private gifts to the center in continuing its research initiatives? What percentage of the center’s funding is through gifting versus the NIH?
LVE: Gift funding is very important. SBCoA currently receives about 70 percent of its funding from NIH or other granting agencies, with the other funding coming from the university, state government, private donations, endowments and philanthropic gifts. Because NIH funding is declining and it is much more difficult to get research grants, gift funding will become significantly more important in the future. Also, high-risk ideas almost never receive funding from the government, although cures and treatments almost always come from creative and novel ideas and discoveries. Gift funding helps continue the center’s cutting-edge research.
EL: Dr. William Markesbery served as Sanders-Brown’s director for more than 30 years until his death in 2010. Research conducted under Markesbery’s leadership included the Nun Study, PREADVISE study and the brain study. Which of those studies are ongoing at this time, and which have been concluded?
LVE: The PREADVISE study of antioxidants was one of the first clinical trials in which Bill Markesbery was involved. The trial began in 2002 as an addition to an existing trial that was examining the use of vitamin E and selenium for preventing prostate cancer. The purpose of the study is to determine if reducing oxidative stress by taking antioxidants can prevent Alzheimer’s disease and related dementias. Oxidative stress is kind of like rust in the brain, like the rust you get on metal from too much oxygen. That occurs as people age, and it’s thought to be an early (disease) event that happens in the brain. Bill Markesbery had shown that oxidative stress could contribute to Alzheimer’s pathology in the brain. This study is in its last year right now, and so we’ll soon be analyzing the data. PREADVISE has been a huge bonus because its findings have also generated additional grants.
The brain study is also still ongoing; it involves following a cohort of normal volunteers who agree to come in every year for memory tests and donate their brains upon death. This study has been a tremendous resource for research because SBCoA can follow what happens to people before they have memory problems. We can then determine what changes are occurring in the brain decades before symptoms begin. That’s really important now, because it’s become clear that disease-relevant changes in the brain are occurring 10 to 15 years before memory problems are evident. Early intervention is essential.
The Nun Study used to be here. SBCoA has the data from the study, and those data are being used in new studies. It followed a group of sisters over the age of 75 years from the School Sisters of Notre Dame and looked at the autobiographical essays they wrote when they entered their order in their late teens and early 20s. Researchers examined whether the nuns’ early literary skills, such as including many ideas and thoughts into their sentences, correlated with whether they developed dementia in their 70s and 80s. In general these nuns were very healthy, but there were interesting correlations. Researchers found that the sisters who had strong language and writing skills early in life were less likely to develop dementia many decades later. And that created a lot of publicity many years ago. The Nun Study also showed that nuns who expressed more positive emotions in their autobiographies lived significantly longer than those nuns who expressed fewer positive emotions, suggesting that a positive emotional outlook early in life can help people live longer. All these longitudinal studies are providing important new knowledge about dementia risk factors and the complex relationship between pathological changes in the brain and cognitive impairment.
EL: Was there ever a study of professors, scientists, mathematicians, people who use their brains extensively during their daily lives?
LVE: It is known that a higher educational level correlates with a lower risk of developing dementia, but I don’t believe there’s been a specific study just on, for example, professors. There have been a variety of studies suggesting that regular use of your brain and activities that require complex mental activity, such as playing a musical instrument, doing crossword puzzles, learning something new, reading or other ways to stay mentally active, can reduce a person’s risk for AD.
EL: As the study and research of AD continues to expand and progress, how has the scope of research changed at SBCoA?
LVE: SBCoA was an early pioneer in studying normal individuals, which is where the field of research is now going, so we are ahead of the curve. Our center has about 500 people in what used to be called the Brains Cohort, a group of volunteers that the center follows every year. We also have about 200 additional people who have transitioned into some kind of impairment. Our researchers are trying to develop biomarkers – ways to determine if a person has an enhanced risk of developing or is on the way to developing AD or if the person will remain normal.
How do you determine if a normal individual who has no memory problems is going to develop AD? There’s imaging, actually taking pictures of the brain in a living person, to detect changes that are consistent with AD. There are biomarkers in cerebrospinal fluid that researchers are interested in defining and determining if they correlate with transitions into dementia or not. We’re also conducting risk-factor research.
EL: With regard to the brain study, SBCoA follows individuals for years before their death, and then immediately upon death researchers autopsy the brain. Can you explain the value of the autopsy?
LVE: The autopsy is the gold standard for diagnosing the cause of death. Did this person really have AD or did they have something else that was causing their dementia? Alzheimer’s is just one type of dementia, and an individual can have very similar memory problems but actually have a different disease. So it’s very important to know what disease the person had, especially once effective medications for different neurodegenerative diseases are developed. A medication for Alzheimer’s may not be effective in a person with vascular dementia or hippocampal sclerosis, which is very prevalent in people who are very elderly, age 90 or above. In the very elderly, hippocampal sclerosis is almost as prevalent as Alzheimer’s disease, but clinical symptoms look the same. So you need an autopsy to determine what caused that person to have their clinical symptoms.
Also, researchers may think a particular protein or gene is a factor in the disease process, and autopsy allows them to use human brain samples to directly test their ideas. A very short postmortem interval, from the time of death until the brain is removed, is needed because high-quality samples of the brain are very important for the research. SBCoA has one of the shortest postmortem intervals, averaging two to four hours, of all 27 Alzheimer’s centers in the country. Other research centers sometimes have up to 24-hour intervals. Our rapid autopsies are possible because SBCoA has very highly dedicated volunteers who call immediately when their family member dies. Also, because the Lexington area is relatively small, there is not a long delay in arriving here for autopsy. And we have a 24/7 on-call autopsy service that’s run by two of our faculty. They’re available to perform autopsies 365 days a year.
EL: How do you archive the autopsy information so researchers can refer to it in the future?
LVE: We take part of the brain and fix it, section it and then actually look at final details under the microscope. A portion of the brain is immediately frozen at minus-80 degrees, for use by researchers who may want to analyze samples of tissue. The samples, databases and a biostatistical core are managed by Dr. Richard Kryscio. We have wonderful statisticians, and all data are uploaded to a national coordinating center. Because the network of Alzheimer’s centers throughout the country can share information, they are able to make better statements about whether something is cause-and-effect and whether something looks like it is part of the disease.
EL: How many professionals and staff members are employed by the center?
LVE: SBCoA has over 100 people, including faculty, staff and students, all working together. That includes basic scientists and clinical scientists. It’s a very interactive and collaborative group.
EL: How well coordinated is research produced by NIH-funded AD centers? Are the centers generally collaborative or competitive?
LVE: In terms of the 27 centers that NIH funds, they all interact and collaborate, especially through data-sharing initiatives. For example, SBCoA makes all of its tissue, brain and blood samples available to other researchers. Each center has to renew its NIH grant every five years. In 2010, SBCoA was doing that, compiling information, and we realized that our center had sent out over 14,000 specimens all over the world in that previous five-year period. SBCoA is one of the top-performing neuropathology groups, based originally on Bill Markesbery’s expertise. Now Dr. Peter Nelson, an outstanding neuropathologist, is the neuropathology core leader of our Alzheimer Center, and he’s building on Bill’s legacy. SBCoA freely makes its samples available; some other centers charge for samples, but we don’t. SBCoA has an Aperio ScanScope, a wonderful high-quality microscope that automatically scans images. This allows researchers to obtain high-resolution images and get very precise and quantitative information about brain changes.
EL: What are the major areas of research now being conducted by Sanders-Brown?
LVE: The center not only studies AD, it also has programs on Down Syndrome – a risk for later development of dementia; on stroke; on vascular dementia; and on risk factors, what’s important in terms of prevention or what might increase risk. We also have an active clinical trials program that’s testing new potential drugs.
EL: In addition to managing the entire center, you lead one of the research teams. So you’re pulled between research and management duties. How much time do you spend on each?
LVE: I’m supposed to spend about 20 percent of my effort on directing Sanders-Brown. In reality, I can divide my 80 hours of time per week (smiles) any way I want. I delegate to people and let them take care of areas they need to manage. For example, I have an outstanding research laboratory manager who supervises the day-to-day activities of the lab. If I didn’t have him doing that, I would have to spend a lot more time on the nitty-gritty there. I have a weekly meeting where the entire lab team reviews the experiments we conducted in the prior week and talks about plans for the next week. Those are short-term goals, but we also keep in mind our mid-term and longer-term agendas.
In terms of managing the whole center, we have a wonderful group of scientists at Sanders-Brown, and I don’t try to micromanage them. We have a monthly faculty meeting where we serve lunch and talk about issues of importance to the center, and then we also have project-specific meetings. For instance, we’re preparing a new grant proposal on vascular dementia; so, we’re meeting every other week as a group to plan. We also have an executive committee meeting of the Alzheimer’s center every two weeks. That’s a complex endeavor, so we meet regularly to discuss issues and make decisions.
In terms of the frequency and the composition of meetings, it depends on what the issues are. We try to make meetings productive by developing an agenda ahead of time, making decisions and establishing action items at the meeting.
EL: What are the missions of the Alzheimer’s center?
LVE: Our Alzheimer’s center is a research center whose mission is to catalyze innovative research, outreach, education and clinical programs. If a person has a memory problem or wants to be seen medically, we refer them to the memory disorders clinic in neurology. But, of course, the same physicians who work in our Alzheimer’s center also see patients in the memory disorders clinic. Patients evaluated for memory problems will likely see Dr. Greg Jicha or Dr. Charlie Smith, or our newest faculty member, Dr. Ronan Murphy, who started in November. Other doctors in neurology see other kinds of complaints. I should also say that our Alzheimer’s center clinic conducts free memory screens every month. If a person wants to be tested, they can call and find out when the next screening is happening.
EL: What are some new or expanded programs you have initiated since becoming executive director?
LVE: Memory Café has been really successful. It’s a program to bring together people with dementia or other cognitive impairment and their families or caregivers in a social situation. Memory Café does fun things such as engaging in music or art or other activities where participants can interact in a social environment, without stigma.
We also conduct a number of educational events; for example, we initiated an annual Markesbery Symposium, named in honor of Bill, that includes both a scientific session and a community session. We also started a program to educate medical students who often are never exposed to geriatrics. The students are able to talk with elderly people and understand the issues they face.
EL: Certain minority groups have a higher incidence of neurodegenerative diseases, and SBCoA has a special outreach program. How does that work?
LVE: Dr. Deborah Danner is the center’s director of education and outreach. She has spent a lot of time developing relationships with the African-American community in the Lexington area. We started something called AADOP, which is African-American Dementia Outreach Partnership, to increase awareness of AD and the importance of research, and provide support and guidance to families within the African-American community who are affected by memory loss and dementia. We’ve developed trust within the community, and we’ve been very successful at recruiting African-American individuals into our volunteer cohort. It’s important that African-Americans get involved in research, because they’re at a much higher risk of developing dementia than are Caucasians.
EL: Some doctors think that Alzheimer’s tends to onset earlier and that other forms of dementia onset later.
LVE: There’s a genetic form of Alzheimer’s that is a result of gene mutations that will cause the disease, and that’s a very early-onset form but very rare. If you inherit that mutation from your mother or father, you will get Alzheimer’s. Most people who develop AD do so later in life, and it’s not caused by a genetic mutation but by a whole group of genetic risk factors that you inherit, environmental issues and lifestyle. It’s a combination of causes. You can also detect subtle differences between some kinds of dementia using very sensitive psychological tests. For example, frontotemporal dementia tends to affect the front part of the brain, and so it affects executive function, like judgment and decision-making. There’s also vascular dementia; sometimes you can get an idea, at least, of whether a person’s dementia might have a vascular component. Especially here in Kentucky, we’re at a very high risk of vascular complications. Problems with the blood vessels in the brain, such as mini-strokes or changes in blood flow through the brain, can occur as a complication of diabetes or obesity or cardiovascular problems. We have a lot of those medical issues in Kentucky, so when we study the brains of people who have come to autopsy, it’s very common for the brain to show evidence of vascular co-morbidities. It’s actually more common than someone with only Alzheimer’s disease pathology in the brain.
EL: What can individuals do to reduce the chance of being a victim of Alzheimer’s disease or dementia in general?
LVE: What’s good for your heart is also good for your brain. Trying to control your weight, blood pressure and blood sugar, as well as getting regular exercise and eating a healthy diet, are good health goals. There’s a lot of evidence that staying engaged socially and mentally reduces your risk as well.
EL: What about smoking?
LVE: Smoking is bad for you on several levels. It causes an increased risk of dying from cancer and cardiovascular disease. It also appears to contribute to damage of brain blood vessels and increases the risk of Alzheimer’s disease and vascular dementia.
EL: If a benefactor said, “We’d like to fund SBCoA completely for every project you’d like to have,” what would be your top priorities in expanding your research?
LVE: If we had more funding, the center would be able to serve a much larger number of people. We could pursue more clinical trials and try new potential drugs. More people could enter into our biomarker studies, so we could potentially improve our diagnostic ability long before people become clinically impaired. We could integrate more in terms of having all the personnel that we need. Dementia is increasing in prevalence because everybody’s living longer; it’s going to bankrupt our country. It’s already the only disease in the Top 10 without an effective treatment. So we could really focus on our therapeutic efforts as well as trying to earlier identify the people we will need to treat. It’s a two-pronged strategy: We need to develop effective medications and identify the right people to treat.
EL: What percentage of the people upon whom the center conducts a brain autopsy actually had Alzheimer’s disease?
LVE: Our neurologists are very good at diagnosing AD because they are dementia specialists, and so they have quite a high accuracy rate. If they think a person has AD, almost always the brain will show it. They are probably around 90 percent accurate. For doctors who don’t have as much experience looking at dementia, it’s a much lower percentage than that.
EL: When do you think there will be a cure or some successful treatment for Alzheimer’s?
LVE: There’s a lot of hope on the horizon right now. In the past, some researchers have been too exuberant and promised things that didn’t pan out. The national Alzheimer’s plan that has now been accepted by the government is targeting for an effective treatment by 2025. I hope it’s sooner than that, but it’s hard to know unless we get a much bigger infusion of research dollars.
EL: Do you have a closing comment you’d like to make?
LVE: Contribute! Help Sanders-Brown conduct its neurodegenerative research. And it’s not just dollars. It’s also the people who participate in our studies. Talk about Sanders-Brown with your neighbor. One of the big things I’m trying to do is get our name out there more. People all over the nation know the Sanders-Brown Center on Aging; I knew it in Chicago. But when I came here, I’d walk around town and people would say, “What do you do?” and I would say, “I work at the Sanders-Brown Center on Aging,” and they would say, “What’s that?” So talk to your friends; talk us up. All of that helps – Sanders-Brown Center on Aging gets its name out there and more people start to appreciate the world-class, cutting-edge research we’re doing.
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