Special Section
The Brain Puzzle
URI researchers are working to diagnose, treat—and ultimately prevent—neurodegenerative diseases, like Alzheimer’s. And they’re investigating the factors that can help keep our brains healthy as we age.
Stories by Nicole Maranhas
Illustrations by Jean-Francois Podevin
Colby and Marie Rottler walk together at Butler Hospital in Providence, where Colby participates in a study, led by Jessica Alber of URI’s Ryan Institute for Neuroscience, on using eye exams to screen for early-stage Alzheimer’s disease.
In This Together
An Alzheimer’s Story
Marie Rottler has Alzheimer’s. Her husband Colby is a participant in a URI-led study on early detection of Alzheimer’s. Colby wants to help scientists, like those at URI’s George & Anne Ryan Institute for Neuroscience, who are working to understand, diagnose, treat—and ultimately prevent—neurodegenerative diseases like Alzheimer’s.
Once a year, Colby Rottler takes a cognitive assessment. He recalls the words, draws the clock, counts backward by sevens. He doesn’t have cognitive impairment, but the test makes him a little nervous. “Every time, I’m afraid they’re going to take me in a room and tell me I’m not passing,” he says. Nerves aside, he is eager to take it.
Colby is a participant in the Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS 2) at the Butler Hospital Memory and Aging Program in Providence. Led by Jessica Alber, an assistant professor in URI’s George & Anne Ryan Institute for Neuroscience, the $10.3 million, National Institutes of Health-funded project is the second phase of a study on using standard eye exams to screen for early-stage Alzheimer’s disease. “The eye is a good window to see what is happening in the brain,” Alber says. “We are looking to see if an eye exam can be an easy way to detect the disease before symptoms appear.”
Alzheimer’s disease is the most common form of dementia. It affects one in nine adults over the age of 65, with 82 million Americans projected to be living with the disease by 2050. While genetic risk plays a role for some, its cause largely remains a mystery. Much research has focused on two puzzling hallmarks of the disease: amyloid-beta “plaques” and tau “tangles,” two proteins that overaccumulate in the brain to form sticky buildup between brain cells or tangled clumps inside them.
Colby was inspired to join an Alzheimer’s disease registry six years ago after a longtime friend was diagnosed. Since then, he has participated in both phases of ARIAS, including cognitive and functional assessments, brain and eye scans, and blood tests. “Whatever they need me for, I’ll do it,” Colby says. “If you don’t have people like me who are willing to show up and be tested, how can scientists have the data they need?”
He remembers worrying, “Will I get it?” At the time, it seemed like his worst fear.
There were signs that became hard to ignore: asking the same questions over and over again, forgetting appointments, making uncharacteristic mistakes paying bills. Colby saw that his wife of 53 years, Marie—a former teacher and corporate training director whom he had met when they were both students at Bridgewater State University—was not herself. On a trip to California to visit their daughter two years ago, Marie also knew something was wrong. “I couldn’t function as well outside of my normal routine,” she says. “I just wasn’t ‘me.’”She was diagnosed with Alzheimer’s disease last year.
By the time the symptoms of Alzheimer’s disease appear, the disease has likely been developing for decades. It is currently diagnosed by positron emission tomography (PET) scan or lumbar puncture, procedures that are expensive, invasive, and not widely available. Testing is done after people experience symptoms, once the disease has reached its late stages.
“Early detection leads to therapies for any disease,” Alber says. “An eye exam could give us a low-cost, accessible screening tool.”
In the back of the eye, the retina—a layering of tissue that converts light into brain signals—contains the same cells that are found in the brain. “We can see changes in the volume of these layers when someone develops Alzheimer’s disease,” Alber says.
“We are looking to see if an eye exam can be an easy way to detect the disease before symptoms appear.”
—Jessica Alber, Assistant Professor of Biomedical and Pharmaceutical Sciences
The ARIAS 2 study uses imaging to track changes to the optic tract and shrinkage to specific brain regions associated with Alzheimer’s disease—the hippocampus, entorhinal cortex, cingulate gyrus, and areas of the temporal and parietal lobes—to identify potential retinal biomarkers, or early disease indicators.
“We’re validating the biomarkers we’ve found to see if they’re related to pathology in the brain,” says Alber. “Our next step will be to develop an algorithm for clinical use that we can test with optometrists and ophthalmologists. We’ve already had interest from eye clinics, and they’ve been very collaborative.”
Three of Alber’s own grandparents died with Alzheimer’s disease. “I was really close with my grandparents, and I wanted to devote my life to making things better for other families affected by this disease,” she says. She is encouraged by recent advances. “In the past, we’ve treated Alzheimer’s as if it were a single disease. We know now that it will probably require a menu of treatments, with targeted biomarker testing to tailor the treatments to each patient.”
Marie became one of the first patients at Butler to receive one such treatment, an immunotherapy that targets amyloid plaques. The treatment, which was approved by the Food and Drug Administration last summer, is not a cure, but it is the first therapy to show signs of slowing the rate of cognitive decline, by about 27 percent, in people with Alzheimer’s disease. It carries a risk of brain bleeds for some patients, and Marie’s treatment was put on pause for this reason late last year. Her infusions resumed in the spring.
Colby is hopeful that the immunotherapy will help slow further decline. “She’s my best friend,” says Colby. “I’m losing the person I love, but I can wallow in grief, or I can have faith.”
The potential for serious or fatal brain bleeds with Alzheimer’s disease immunotherapies is low, but it is a concern that could be understood through related URI research.
William Van Nostrand, co-executive director of the Ryan Institute, is a foremost expert in cerebral amyloid angiopathy (CAA), a disease that often occurs alongside Alzheimer’s and causes bleeding in the brain. Van Nostrand has been researching the role of blood vessels in Alzheimer’s disease and related disorders, including CAA, for 30 years. In January, he began a collaboration with pharmaceutical giant Eli Lilly to investigate the brain bleed risk in immunotherapy treatments.
“We don’t know yet why this is happening, but we know that CAA elevates the risk,” says Van Nostrand. “We want to be able to identify who is at risk of deleterious bleeding and find ways to mitigate that risk.”
A biochemist by training, Van Nostrand was a graduate student at the University of California, Irvine when he became interested in a protein of then-unknown function. Few thought it was worth studying, but he sensed it was important. He persisted and found that the protein played a role in blood clotting—and also that it was the precursor protein that generates amyloid beta, which forms plaques in Alzheimer’s disease.
“When amyloid beta accumulates in the blood vessel walls, it can cause hemorrhages,” Van Nostrand says. “Since the precursor protein regulates blood clotting, it intrigued me. Is there some role this protein is playing in these diseases?”
As Alzheimer’s disease and CAA both involve abnormal aggregation and deposition of amyloid beta in the brain blood vessels, Van Nostrand explains that modeling CAA provides a unique opportunity to study what might be happening to cause bleeding in immunotherapy treatments. “It allows you to isolate the pathology in the blood vessels without the complexity of other mechanisms that occur in Alzheimer’s disease,” he says.
“As we better understand the molecular mechanisms involved, we may be able to find targets for a number of these disorders.”
—William Van Nostrand, Co-Executive Director of the Ryan Institute for Neuroscience; Herrmann Professor of Neuroscience
The collaboration with Eli Lilly could be an important step in widening access to immunotherapy treatments, such as the one Marie is receiving, for Alzheimer’s disease patients who are not good candidates for the treatment because of CAA or other risk factors. His work could also shed light on other small vessel disorders, including hypertension, that can lead to Alzheimer’s disease and related dementias. “We see that many diseases that affect the brain blood vessels, such as Alzheimer’s disease and CAA, have certain pathologies in common,” Van Nostrand says. “As we better understand the molecular mechanisms involved, we may be able to find targets for a number of these disorders.”
Marie remembers her first date with Colby, a blind date. “My friends pushed me out the door and locked it,” she says. She saw two young men standing in the hallway and instantly hoped the one with the nice smile was Colby. It was.
She remembers their wedding, held on a Thursday night at a local restaurant, when Colby was called early to Navy flight training. She remembers being stationed in Italy as newlyweds. She remembers the telegram she sent to Colby at the base when she found out she was pregnant with their first child.
“We’re still on our honeymoon,” Colby likes to say. They go on dates—museums, walks, picnics.
He urges others to get involved in Alzheimer’s trials like the ARIAS 2 study. “My hope is that I can help somebody. It’s not going to help me, but it could help our grandchildren or new great-grandchild.”
Colby remembers the brown sweater he wore on their blind date. He remembers that Marie turned out to be the beautiful girl he had seen around campus.
They look for ways to make life easier. They plan ahead. “We’re in this together, whatever happens,” says Colby. He remembers how he used to look at older couples holding hands and vow, “Marie, that’s going to be us someday.” He still vows, “It’s us.”
For information about the ARIAS 2 study, contact arias@butler.org.
PHOTOS: NORA LEWIS; MICHAEL SALERNO
Smart Food, Smart Moves
Researchers in the colleges of pharmacy and health sciences are investigating lifestyle factors, such as diet and exercise, that can influence brain health.
If you’ve heard that “heart health is brain health,” here is why. On average, the brain contains 400 miles of blood vessels and 86 billion neurons, requiring 20 percent of the body’s blood supply to function. Genetic risk can play a role in age-related disorders, but physical activity, diet, sleep, and environment are factors that influence the aging brain.
Researchers affiliated with the URI George & Anne Ryan Institute for Neuroscience study the underlying mechanisms that lead to neurodegenerative disorders, such as Alzheimer’s disease, and other conditions that impact brain health—and find that, just as you can take steps to support a healthy heart, strong bones, or overall well-being, you can help your brain stay healthy as you age.
Brain Food
Hippocrates is thought to have said, “Food is medicine.”
Navindra Seeram, professor and chair of biomedical and pharmaceutical sciences, says that food is also prevention. His bioactive botanical research lab is focused on plant compounds, such as polyphenols (found in fruits and vegetables, spices, coffees, teas, and dark chocolate), that are beneficial to brain and overall health. He is particularly interested in ellagitannins, a powerful group of polyphenols found in pomegranates, berries and other fruits, and nuts.
One of the major benefits of polyphenols is their anti-inflammatory properties. “Neuroinflammation, or inflammation in the brain, is tied to so many brain diseases, including Alzheimer’s disease and Parkinson’s disease,” Seeram says. “By dampening the inflammation pathways in the body and perhaps also in the brain, these foods can potentially help prevent disease.” His research has shown that some beneficial plant compounds may even be able to cross the blood-brain barrier for greater positive impact.
Seeram also studies how gut microbiota—the bacteria and microscopic organisms in your stomach, intestines, and colon—shape your ability to get the most benefit from polyphenols. His research on why some people are “responders” to polyphenols could pave the way for a targeted approach to nutrition. “Just as we have developed ‘precision medicine’ to target the best possible therapies for individuals with cancer and other diseases, we can develop ‘precision nutrition’ to help get the most out of the foods we eat,” he says.
Seeram emphasizes that colorful plant-based foods will have important benefits for most people. “For the majority of us,” he says, “it’s within our control to choose what we eat and give ourselves the best advantage.”
Power Moves
It isn’t a magic pill (or a guarantee), but wide-ranging research shows that exercise is a potent contributor to long-term brain health. While the Centers for Disease Control and Prevention recommends 150 minutes per week of moderate-intensity aerobic movement (such as brisk walking), plus muscle-strengthening activities (working out with weights or exercise bands, for example) twice a week, almost any physical activity counts.
Here are some key takeaways from URI researchers who study the connection between exercise and brain health:
Physical Activity of Any Kind
Fitness-focused exercise reduces disease risk more effectively, but physical activity of any kind—a neighborhood stroll, weeding the garden, playing with the grandkids—increases blood flow to the brain and can help decrease inflammation or increase cognitive reserve. “Any time you engage in physical activity, you do something positive for your health,” says Christie Ward-Ritacco, associate professor of kinesiology. “The best exercise is the one you will do.”
Aerobic Exercise
Nicole Logan, assistant professor of kinesiology, finds that aerobic exercise is particularly impactful on two areas of the brain, the hippocampus and frontal-parietal areas, related to memory, learning, and executive function (cognitive skills such as planning, time management, and decision-making.) “We see that aerobic exercise promotes neuroplasticity, blood flow, and biomarkers of stress,” says Logan, “and this helps deliver more oxygen and nutrients to the brain.”
Staying Active for People with Dementia
“Although studies have shown that exercise is effective for improving physical and cognitive function, staying active can be challenging for anyone, especially people with chronic health conditions, such as dementia,” says Ellen McGough, professor and chair of physical therapy. As part of her research, she works with senior health centers to implement exercise programs that are feasible and fun for people with Alzheimer’s disease and other neurodegenerative conditions. “We use procedural activities, such as ‘row the boat’ or ‘pick the apple’ that people can do without excessive effort or becoming frustrated,” McGough says. “Music, social support, and a positive environment also help make exercise enjoyable for most people.”
Walking and Positive Self-Talk
“Even a brief interruption from sedentary time has a measurable impact on mental and physical health,” says Mark Hartman, an assistant professor of kinesiology. He recommends walking as one of the best forms of exercise, both for its ease and long-term benefits, especially for nonathletes who may not enjoy high-intensity workouts. He also advises that the brain can positively or negatively impact exercise behavior: “When you think, ‘I can’t do this,’ the frontal cortex upregulates unpleasant feeling states in the amygdala, leading to an avoidance response.” Conversely, positive self-talk helps to generate good feelings that can make exercise more appealing.
John Robinson Talks
Practical Brain Science
How does lifestyle contribute to long-term brain health? Ryan Institute co-executive directors and longtime collaborators John Robinson and William Van Nostrand study this question, with a particular focus on the relationship between cardiovascular exercise and Alzheimer’s disease and brain aging. Robinson, a behavioral neuroscientist, often gives talks to community groups, including URI’s Osher Lifelong Learning Institute, to share the latest research.
Here are some of the questions he’s asked most often:
What can I do to help keep my brain healthy as I age?
Exercise is one of the most powerful beneficial factors. It protects the cardiovascular system, which is a critical component of brain health. It is also shown to be cognitively enhancing and neuroprotective, while offsetting risk factors such as hypertension, insulin resistance, obesity, and high triglycerides that can lead to conditions that impact brain health.
Do I need to be a lifelong exerciser to get the benefits?
While it would be best to be active throughout life, it’s never too late to start. It appears that some benefits can happen quickly. Someone who is prediabetic, for example, could see normal blood sugar levels within 30 days. We also see that brain-derived neurotrophic factor, which is essential for memory and learning, may respond to a single bout of exercise, although this doesn’t mean that you only need to exercise once. It’s a behavioral change.
What other lifestyle factors are important?
While exercise is one of the most important factors, when combined with other modifiable lifestyle factors such as dietary modification, good sleep, and a rich cognitive and social environment, the benefits add up in enhancing brain health.
Why do I know people who exercise and still develop Alzheimer’s disease?
There are never guarantees. This is about probabilities and providing the most accurate information possible so that people are empowered to make informed choices. This is not about trying to make people feel guilty or feel that it’s their fault if they develop dementia. It’s also important to note that these lifestyle changes are also about enhancing your overall health. Exercise can help connect you with others or provide goals that are rewarding to achieve—both of which, as it turns out, are also good for your brain.
Should I be eating a Mediterranean diet?
The Mediterranean diet gets a lot of attention, but there are other diets that also have great properties and are extremely healthy. We do know that highly processed foods are not the best choices, although even that is complicated. People have cultural and emotional connections to food, and not everyone can readily obtain healthy foods. Across the board, plant-based foods like leafy greens, berries, and fiber feed the gut microbiome (the colony of bacteria in your gut), which is important to brain health. Recommendations to eat a variety of foods in moderate amounts for general health make sense for brain health, as well.
Are there brain benefits to alcohol?
From a purely brain health perspective, alcohol has no benefits to brain health. A glass of red wine may contain beneficial compounds, but those benefits are offset by the alcohol. People may choose to enjoy alcohol in moderation, but they should not expect benefits.
Why is there so much conflicting information about diet and exercise?
The World Health Organization synthesizes thousands of studies into simple, easy-to-understand recommendations. When people read about individual studies in the media, it can become confusing. Be patient, as the scientific literature naturally evolves. However, there are principles that are certain: If it sounds too good to be true, it probably is; there are no miracle cures; and stay tuned for more information.
The Ryan Institute for Neuroscience
Founded in 2013, the George & Anne Ryan Institute for Neuroscience is a research center at URI dedicated to the prevention and treatment of neurodegenerative diseases, including Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), and age-related disorders. Institute faculty hail from multiple URI colleges and work with students in the Interdisciplinary Neuroscience Program, which offers undergraduate and graduate degrees in neuroscience.
Thomas Ryan ’75, Hon. ’99, along with his wife, Cathy, established the institute in 2013, naming it after his parents, to support innovation in neurodegenerative disease discovery science and translational medicine.
PHOTO: JAMES P. JONES
Piece by Piece
Although Alzheimer’s disease is not yet fully understood, research over the past 40 years has made important progress. One piece of the puzzle: It is likely to have multiple causes. URI Ryan Institute investigators are focused on underexplored but potentially key factors in the disease.
Mitochondrial Dysfunction
“Aging is malleable,” Jaime Ross, an assistant professor of biomedical and pharmaceutical sciences, likes to emphasize. In addition to looking at how exercise, diet, and other lifestyle factors can influence gene expression— or whether what’s “in your genes” becomes your fate— she studies how mutations or dysfunction of mitochondria, key to cell energy and growth, affect the aging process. “Mitochondrial dysfunction is correlated with premature aging and decreased lifespan,” says Ross. “Aging is a complex process, but if your mitochondria aren’t working properly, several biological processes aren’t working properly.” Her research aims to understand why this dysfunction happens and how exercise might prevent it.
The Brain’s Immune System
MindImmune Therapeutics is a biotech based at URI focused on developing antibody-based drugs for Alzheimer’s disease and other neurodegenerative disorders. Their work has shown that the inflammation that occurs in Alzheimer’s disease is driven by an immune cell, called a dendritic cell, that enters the brain and damages the synaptic connections that allow brain cells to communicate. The team is developing an antibody that targets dendritic cells to keep them out of the brain. “By blocking these cells from entering the brain, we can prevent the cycle of destruction that is at the core of Alzheimer’s disease,” says Bob Nelson, vice president of biology at the company and research professor of neuroscience at the Ryan Institute. MindImmune hopes to begin clinical testing of a novel Alzheimer’s antibody in 18 to 24 months.
Stroke
Studies have found that ischemic stroke, caused by a lack of blood supply to the brain, can raise Alzheimer’s disease risk, but the link is not fully clear. Claudia Fallini, an assistant professor of cell and molecular biology, sees a possible role for the actin cytoskeleton, which plays a critical role in various cellular functions. “Ischemic stroke has been shown to induce drastic changes in the actin cytoskeleton,” says Fallini. “One of our questions is to look at how some of the changes we see in this pathway after a stroke could make surviving brain cells more vulnerable to age-related stressors or other factors linked to Alzheimer’s disease.” She hopes that her work will lead to a better understanding of the mechanisms that lead to cognitive decline as well as improved stroke outcomes.
Brain Waste Clearance
Some research suggests that the abnormal buildup of plaques and tangles in Alzheimer’s disease and other forms of dementia could be a failure of brain-waste clearance, the process by which the brain flushes away toxins. “Your ability to clear waste from the brain starts to decline with age, and that’s when we can see these amyloid deposits happen,” says Ryan Institute Co-Executive Director William Van Nostrand. In addition to his work on the role of blood vessels in CAA and Alzheimer’s disease, his research interests with collaborator and Ryan Institute Co-Executive Director John Robinson include how lifestyle factors, including exercise, may play a role in brainwaste clearance and reduce amyloid accumulation in the blood vessels.