Looking Deeply into the Causes of Dementia
by Caitlin Hayes
Constantino Iadecola, director of the Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, has always liked to take things apart and to understand how things work. Even as a child, growing up in a village of around 3,000 people between Naples and Rome, he liked to tinker with electronics. Once in medical school, he was attracted to neuroscience partly because of the complex instrumentation that researchers used.
As a music-lover, Iadecola still tinkers with amplifiers and modifies guitars in his off-hours, but the ultimate complex system that he seeks to understand is the brain. In the course of this quest, he has uncovered the role blood vessels play in the health of the brain, shifting paradigms in how researchers think about some of the brain’s most devastating diseases: Alzheimer’s, stroke, and other dementia.
The Interplay of Blocked Blood Vessels and Alzheimer’s Disease
Twenty-five years ago, the science around Alzheimer’s disease was primarily focused on neurons. Researchers had identified plaques, made up of a peptide called amyloid-beta, that interfere with neuron function. Iadecola discovered that amyloid-beta peptides were also causing blockages in the blood vessels, restricting blood flow to the brain, and perpetuating disease.
“This idea was not initially well accepted by the Alzheimer’s community,” Iadecola says. “But later, neuropathological data and imaging in patients confirmed what we proposed, based on our research in animal models. Now it’s become mainstream, and everybody agrees that vessels have an important role in all kinds of dementias.”
Iadecola continues to investigate the mechanisms with support from multiple grants from the National Institutes of Health. “What are the cells that are involved?” he asks. “Why and how does this blood flow insufficiency interact with the pathology of the disease to make it worse?”
In collaboration with Chris B. Schaffer, Meinig School of Biomedical Engineering, Iadecola is investigating the role white blood cells play in blocking the vessels. In a previous study, Schaffer and Iadecola found that amyloid-beta causes white blood cells to stick to the walls of capillaries, plugging them up — a case of bad plumbing. Now they are trying to identify the molecular signaling that causes white blood cells to initially stick to capillary walls. These findings could aid in directing the development of new therapies for the disease, with new targets.
How Hypertension, Stroke, and Dementia Are Connected
Stroke is the second most common cause of death in the world, and hypertension is the major risk factor for both stroke and vascular cognitive impairment, a dementia caused by faulty or damaged blood vessels. One might assume that high blood pressure would stretch the vessels, or alter them mechanically, but Iadecola has found that the mechanisms of hypertension are more subtle and the effects, uniquely severe.
“It’s biochemical,” he says. “Some of the factors that drive up blood pressure, peptides like angiotensin-2, act on the blood vessels and prevent them from working normally. As a result, the brain is always on the brink of not getting enough oxygen.”
In a healthy brain, functional hyperemia, an excess of blood summoned by working neurons, provides enough blood to flow to active areas of the brain, without depriving other areas. Hypertension blunts this blood flow increase. “In patients with hypertension, every time they use their brain, they risk going into ischemia, because there is not enough blood flow to go around,” Iadecola says. “This prevents their ability to use the brain correctly and increases their likelihood of developing dementia or strokes.”
Iadecola has also found a significant overlap between the kinds of damage done to blood vessels by hypertension and stroke, and the damage seen in Alzheimer’s patients — conditions that were once thought distinct. Therefore, Iadecola says that finding ways to improve the performance of blood vessels — and more advocacy for staying mentally active, and maintaining a healthy diet and exercise regimen — could decrease the likelihood and the severity of strokes and dementia, as well as Alzheimer’s.
Why Does the Brain Die After Ischemic Stroke?
“During an ischemic stroke, a blood vessel to the brain suddenly gets blocked, stopping the flow of blood, and within seconds, the brain stops working, and within minutes, it’s going to die,” Iadecola says. “Why is that?”
Initially, he explains, researchers thought this was a point of no return — it was like throwing a switch that could not be turned back on. Over the years, Iadecola and others have discovered that the lack of blood triggers many processes that take hours and days to complete. “Within the blood-starved brain, there are several different processes that take on a life of their own, and they keep killing the brain by different mechanisms for hours or even days after the onset of symptoms,” Iadecola says.
“You see these patients who can walk and talk one second, and the next they’re totally paralyzed. It made me ask why and how it happens, and what can we do about it.”
Understanding these processes could hugely impact the degree and speed of recovery in patients who suffer strokes and could even lead to strategies for prevention. Iadecola is particularly interested in the role of immune cells, which he discovered are directed to the brain when ischemia occurs. These cells both contribute to the damage and aid in recovery. “We’re asking now if we can develop treatments to control the entry of immune cells to the brain and only let them do good things and prevent them from doing bad things,” Iadecola says.
Josef Anrather, Brain and Mind Research Institute, Weill Cornell Medicine, in collaboration with Iadecola and others, recently discovered that changing the bacterial composition in the gut can have an effect on these immune cells, triggering them to protect the brain rather than harm it. “There are millions of people every year who undergo medical procedures that result in strokes,” Iadecola says. “So if we could make the brain more resistant to ischemia just by changing the composition of the gut flora, it would be a tremendous advantage.”
This prevention could even be achieved without the use of drugs, by changing the gut microbes of at-risk patients with certain diets and other interventions. Iadecola and Anrather continue to investigate which species of microbiota are beneficial and which deleterious.
Pulling It All Together through Basic and Translational Research, Clinical Practice and Teaching
As a young student, Iadecola was most interested in basic research, locking himself in the lab through medical school in Rome and as a postdoctoral fellow at Weill Cornell Medicine (then named Cornell University Medical College), working under the late Donald J. Reis, Neurology. At the end of his fellowship, Reis advised Iadecola to get out of the lab and pursue neurology training. “It cost me four years of my life and lots of sleep,” Iadecola says of the clinical residency he took, “but it allowed me to train with some of the greatest neurologists in the world — Fred Plum and Jerome Posner.”
“That’s when it all came together,” Iadecola continues. “You see these patients who can walk and talk one second, and the next they’re totally paralyzed. It made me ask why and how it happens, and what can we do about it.”
While clinical experience reinforced his desire to do work with translational value, Iadecola remains modest about his contributions to medicine. “These diseases have the most devastating effects on patients and their families and caregivers, and my dream is to one day contribute in a minimal way,” he says. “But taking research to the clinical setting often takes a long time, with people passing the torch to the next generation.”
It follows that Iadecola greatly values teaching and training his students and junior colleagues, knowing they will carry that torch. “Now I’m in a dream position, which is to do my research and train the next generation,” says Iadecola. “Our medical school is in a great period of expansion and success, with collaboration between the campuses — it’s a great time to be at Cornell and be in a leadership position here at Weill.”
While Iadecola still occasionally needs to bring electronics to an expert when he can’t figure out a problem, it is not so easy for the brain, he says. “But I do have fantastic colleagues and collaborators,” he adds. “We have a lot of fun working together and have great respect for each other. And we create a very nurturing environment for the younger generation to get their feet wet, branch out, and move forward toward independence.”
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