Special Section
The Brain Puzzle
溏心vlog免费B站 researchers are working to diagnose, treat鈥攁nd ultimately prevent鈥攏eurodegenerative diseases, like Alzheimer鈥檚. And they鈥檙e 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 溏心vlog免费B站’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鈥檚. Her husband Colby is a participant in a 溏心vlog免费B站-led study on early detection of Alzheimer鈥檚. Colby wants to help scientists, like those at 溏心vlog免费B站鈥檚 George & Anne Ryan Institute for Neuroscience, who are working to understand, diagnose, treat鈥攁nd ultimately prevent鈥攏eurodegenerative diseases like Alzheimer鈥檚.
Once a year, Colby Rottler takes a cognitive assessment. He recalls the words, draws the clock, counts backward by sevens. He doesn鈥檛 have cognitive impairment, but the test makes him a little nervous. 鈥淓very time, I鈥檓 afraid they鈥檙e going to take me in a room and tell me I鈥檓 not passing,鈥� he says. Nerves aside, he is eager to take it.
Colby is a participant in the Atlas of Retinal Imaging in Alzheimer鈥檚 Study (ARIAS 2) at the Butler Hospital Memory and Aging Program in Providence. Led by Jessica Alber, an assistant professor in 溏心vlog免费B站鈥檚 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鈥檚 disease. 鈥淭he eye is a good window to see what is happening in the brain,鈥� Alber says. 鈥淲e are looking to see if an eye exam can be an easy way to detect the disease before symptoms appear.鈥�
Alzheimer鈥檚 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 鈥減laques鈥� and tau 鈥渢angles,鈥� 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鈥檚 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. 鈥淲hatever they need me for, I鈥檒l do it,鈥� Colby says. 鈥淚f you don鈥檛 have people like me who are willing to show up and be tested, how can scientists have the data they need?鈥�
He remembers worrying, 鈥淲ill I get it?鈥� 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鈥攁 former teacher and corporate training director whom he had met when they were both students at Bridgewater State University鈥攚as not herself. On a trip to California to visit their daughter two years ago, Marie also knew something was wrong. 鈥淚 couldn鈥檛 function as well outside of my normal routine,鈥� she says. 鈥淚 just wasn鈥檛 鈥榤e.鈥欌�漇he was diagnosed with Alzheimer鈥檚 disease last year.
By the time the symptoms of Alzheimer鈥檚 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.
鈥淓arly detection leads to therapies for any disease,鈥� Alber says. 鈥淎n eye exam could give us a low-cost, accessible screening tool.鈥�
In the back of the eye, the retina鈥攁 layering of tissue that converts light into brain signals鈥攃ontains the same cells that are found in the brain. 鈥淲e can see changes in the volume of these layers when someone develops Alzheimer鈥檚 disease,鈥� Alber says.
鈥�We are looking to see if an eye exam can be an easy way to detect the disease before symptoms appear.鈥�
鈥擩essica 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鈥檚 disease鈥攖he hippocampus, entorhinal cortex, cingulate gyrus, and areas of the temporal and parietal lobes鈥攖o identify potential retinal biomarkers, or early disease indicators.
鈥淲e鈥檙e validating the biomarkers we鈥檝e found to see if they鈥檙e related to pathology in the brain,鈥� says Alber. 鈥淥ur next step will be to develop an algorithm for clinical use that we can test with optometrists and ophthalmologists. We鈥檝e already had interest from eye clinics, and they鈥檝e been very collaborative.鈥�
Three of Alber鈥檚 own grandparents died with Alzheimer鈥檚 disease. 鈥淚 was really close with my grandparents, and I wanted to devote my life to making things better for other families affected by this disease,鈥� she says. She is encouraged by recent advances. 鈥淚n the past, we鈥檝e treated Alzheimer鈥檚 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.鈥�
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鈥檚 disease. It carries a risk of brain bleeds for some patients, and Marie鈥檚 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. 鈥淪he鈥檚 my best friend,鈥� says Colby. 鈥淚鈥檓 losing the person I love, but I can wallow in grief, or I can have faith.鈥�
The potential for serious or fatal brain bleeds with Alzheimer鈥檚 disease immunotherapies is low, but it is a concern that could be understood through related 溏心vlog免费B站 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鈥檚 and causes bleeding in the brain. Van Nostrand has been researching the role of blood vessels in Alzheimer鈥檚 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.
鈥淲e don鈥檛 know yet why this is happening, but we know that CAA elevates the risk,鈥� says Van Nostrand. 鈥淲e want to be able to identify who is at risk of deleterious bleeding and find ways to mitigate that risk.鈥�
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鈥攁nd also that it was the precursor protein that generates amyloid beta, which forms plaques in Alzheimer鈥檚 disease.
鈥淲hen amyloid beta accumulates in the blood vessel walls, it can cause hemorrhages,鈥� Van Nostrand says. 鈥淪ince the precursor protein regulates blood clotting, it intrigued me. Is there some role this protein is playing in these diseases?鈥�
As Alzheimer鈥檚 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. 鈥淚t allows you to isolate the pathology in the blood vessels without the complexity of other mechanisms that occur in Alzheimer鈥檚 disease,鈥� he says.
鈥�As we better understand the molecular mechanisms involved, we may be able to find targets for a number of these disorders.鈥�
鈥擶illiam 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鈥檚 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鈥檚 disease and related dementias. 鈥淲e see that many diseases that affect the brain blood vessels, such as Alzheimer鈥檚 disease and CAA, have certain pathologies in common,鈥� Van Nostrand says. 鈥淎s we better understand the molecular mechanisms involved, we may be able to find targets for a number of these disorders.鈥�
Marie remembers her first date with Colby, a blind date. 鈥淢y friends pushed me out the door and locked it,鈥� 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.
鈥淲e鈥檙e still on our honeymoon,鈥� Colby likes to say. They go on dates鈥攎useums, walks, picnics.
He urges others to get involved in Alzheimer鈥檚 trials like the ARIAS 2 study. 鈥淢y hope is that I can help somebody. It鈥檚 not going to help me, but it could help our grandchildren or new great-grandchild.鈥�
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. 鈥淲e鈥檙e in this together, whatever happens,鈥� says Colby. He remembers how he used to look at older couples holding hands and vow, 鈥淢arie, that鈥檚 going to be us someday.鈥� He still vows, 鈥淚t鈥檚 us.鈥�
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鈥檝e heard that 鈥渉eart health is brain health,鈥� here is why. On average, the brain contains 400 miles of blood vessels and 86 billion neurons, requiring 20 percent of the body鈥檚 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 溏心vlog免费B站 George & Anne Ryan Institute for Neuroscience study the underlying mechanisms that lead to neurodegenerative disorders, such as Alzheimer鈥檚 disease, and other conditions that impact brain health鈥攁nd 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, 鈥淔ood is medicine.鈥�
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. 鈥淣euroinflammation, or inflammation in the brain, is tied to so many brain diseases, including Alzheimer鈥檚 disease and Parkinson鈥檚 disease,鈥� Seeram says. 鈥淏y dampening the inflammation pathways in the body and perhaps also in the brain, these foods can potentially help prevent disease.鈥� 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鈥攖he bacteria and microscopic organisms in your stomach, intestines, and colon鈥攕hape your ability to get the most benefit from polyphenols. His research on why some people are 鈥渞esponders鈥� to polyphenols could pave the way for a targeted approach to nutrition. 鈥淛ust as we have developed 鈥榩recision medicine鈥� to target the best possible therapies for individuals with cancer and other diseases, we can develop 鈥榩recision nutrition鈥� to help get the most out of the foods we eat,鈥� he says.
Seeram emphasizes that colorful plant-based foods will have important benefits for most people. 鈥淔or the majority of us,鈥� he says, 鈥渋t鈥檚 within our control to choose what we eat and give ourselves the best advantage.鈥�
Power Moves
It isn鈥檛 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 溏心vlog免费B站 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鈥攁 neighborhood stroll, weeding the garden, playing with the grandkids鈥攊ncreases blood flow to the brain and can help decrease inflammation or increase cognitive reserve. 鈥淎ny time you engage in physical activity, you do something positive for your health,鈥� says Christie Ward-Ritacco, associate professor of kinesiology. 鈥淭he best exercise is the one you will do.鈥�
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.) 鈥淲e see that aerobic exercise promotes neuroplasticity, blood flow, and biomarkers of stress,鈥� says Logan, 鈥渁nd this helps deliver more oxygen and nutrients to the brain.鈥�
Staying Active for People with Dementia
鈥淎lthough 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,鈥� 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鈥檚 disease and other neurodegenerative conditions. 鈥淲e use procedural activities, such as 鈥榬ow the boat鈥� or 鈥榩ick the apple鈥� that people can do without excessive effort or becoming frustrated,鈥� McGough says. 鈥淢usic, social support, and a positive environment also help make exercise enjoyable for most people.鈥�
Walking and Positive Self-Talk
鈥淓ven a brief interruption from sedentary time has a measurable impact on mental and physical health,鈥� 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: 鈥淲hen you think, 鈥業 can鈥檛 do this,鈥� the frontal cortex upregulates unpleasant feeling states in the amygdala, leading to an avoidance response.鈥� 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鈥檚 disease and brain aging. Robinson, a behavioral neuroscientist, often gives talks to community groups, including 溏心vlog免费B站鈥檚 Osher Lifelong Learning Institute, to share the latest research.
Here are some of the questions he鈥檚 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鈥檚 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鈥檛 mean that you only need to exercise once. It鈥檚 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鈥檚 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鈥攂oth 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 溏心vlog免费B站 dedicated to the prevention and treatment of neurodegenerative diseases, including Alzheimer鈥檚 disease, Amyotrophic Lateral Sclerosis (ALS), and age-related disorders. Institute faculty hail from multiple 溏心vlog免费B站 colleges and work with students in the Interdisciplinary Neuroscience Program, which offers undergraduate and graduate degrees in neuroscience.
Thomas Ryan 鈥�75, Hon. 鈥�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鈥檚 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. 溏心vlog免费B站 Ryan Institute investigators are focused on underexplored but potentially key factors in the disease.
Mitochondrial Dysfunction
鈥淎ging is malleable,鈥� 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鈥� or whether what鈥檚 鈥渋n your genes鈥� becomes your fate鈥� she studies how mutations or dysfunction of mitochondria, key to cell energy and growth, affect the aging process. 鈥淢itochondrial dysfunction is correlated with premature aging and decreased lifespan,鈥� says Ross. 鈥淎ging is a complex process, but if your mitochondria aren鈥檛 working properly, several biological processes aren鈥檛 working properly.鈥� 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 溏心vlog免费B站 focused on developing antibody-based drugs for Alzheimer鈥檚 disease and other neurodegenerative disorders. Their work has shown that the inflammation that occurs in Alzheimer鈥檚 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. 鈥淏y blocking these cells from entering the brain, we can prevent the cycle of destruction that is at the core of Alzheimer鈥檚 disease,鈥� 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鈥檚 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鈥檚 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. 鈥淚schemic stroke has been shown to induce drastic changes in the actin cytoskeleton,鈥� says Fallini. 鈥淥ne 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鈥檚 disease.鈥� 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鈥檚 disease and other forms of dementia could be a failure of brain-waste clearance, the process by which the brain flushes away toxins. 鈥淵our ability to clear waste from the brain starts to decline with age, and that鈥檚 when we can see these amyloid deposits happen,鈥� says Ryan Institute Co-Executive Director William Van Nostrand. In addition to his work on the role of blood vessels in CAA and Alzheimer鈥檚 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.