Blood Vessels in the Eye Linked With IQ, Cognitive Function

The width of blood vessels in the retina, located at the back of the eye, may indicate brain health years before the onset of dementia and other deficits, according to a new study published in Psychological Science, a journal of the Association for Psychological Science.

Research shows that younger people who score low on intelligence tests, such as IQ, tend to be at higher risk for poorer health and shorter lifespan, but factors like socioeconomic status and health behaviors don’t fully account for the relationship. Psychological scientist Idan Shalev of Duke University and colleagues wondered whether intelligence might serve as a marker indicating the health of the brain, and specifically the health of the system of blood vessels that provides oxygen and nutrients to the brain.

To investigate the potential link between intelligence and brain health, the researchers borrowed a technology from a somewhat unexpected domain: ophthalmology.

Shalev and colleagues used digital retinal imaging, a relatively new and noninvasive method, to gain a window onto vascular conditions in the brain by looking at the small blood vessels of the retina, located at the back of the eye. Retinal blood vessels share similar size, structure, and function with blood vessels in the brain and can provide a way of examining brain health in living humans.

The researchers examined data from participants taking part in the Dunedin Multidisciplinary Health and Development Study, a longitudinal investigation of health and behavior in over 1000 people born between April 1972 and March 1973 in Dunedin, New Zealand.

The results were intriguing.

Having wider retinal venules was linked with lower IQ scores at age 38, even after the researchers accounted for various health, lifestyle, and environmental risk factors that might have played a role.

Individuals who had wider retinal venules showed evidence of general cognitive deficits, with lower scores on numerous measures of neurospsychological functioning, including verbal comprehension, perceptual reasoning, working memory, and executive function.

Surprisingly, the data revealed that people who had wider venules at age 38 also had lower IQ in childhood, a full 25 years earlier.

It’s “remarkable that venular caliber in the eye is related, however modestly, to mental test scores of individuals in their 30s, and even to IQ scores in childhood,” the researchers observe.

The findings suggest that the processes linking vascular health and cognitive functioning begin much earlier than previously assumed, years before the onset of dementia and other age-related declines in brain functioning.

“Digital retinal imaging is a tool that is being used today mainly by eye doctors to study diseases of the eye,” Shalev notes. “But our initial findings indicate that it may be a useful investigative tool for psychological scientists who want to study the link between intelligence and health across the lifespan.”

The current study doesn’t address the specific mechanisms that drive the relationship between retinal vessels and cognitive functioning, but the researchers surmise that it may have to do with oxygen supply to the brain.

“Increasing knowledge about retinal vessels may enable scientists to develop better diagnosis and treatments to increase the levels of oxygen into the brain and by that, to prevent age-related worsening of cognitive abilities,” they conclude.

Microbleeding in Brain May Be Behind Senior Moments

People may grow wiser with age, but they don’t grow smarter. Many of our mental abilities decline after midlife, and now researchers say that they’ve fingered a culprit. A study presented here last week at the annual meeting of the Association for Psychological Science points to microbleeding in the brain caused by stiffening arteries. The finding may lead to new therapies to combat senior moments.

This isn’t the first time that microbleeds have been suspected as a cause of cognitive decline. “We have known [about them] for some time thanks to neuroimaging studies,” says Matthew Pase, a psychology Ph.D. student at Swinburne University of Technology in Melbourne, Australia. The brains of older people are sometimes peppered with dark splotches where blood vessels have burst and created tiny dead zones of tissue. How important these microbleeds are to cognitive decline, and what causes them, have remained open questions, however.

Pase wondered if high blood pressure might be behind the microbleeds. The brain is a very blood-hungry organ, he notes. “It accounts for only 2% of the body weight yet receives 15% of the cardiac output and consumes 20% of the body’s oxygen expenditure.” Rather than getting the oxygen in pulses, the brain needs a smooth, continuous supply. So the aorta, the largest blood vessel branching off the heart, smooths out blood pressure before it reaches the brain by absorbing the pressure with its flexible walls. But as people age, the aorta stiffens. That translates to higher pressure on the brain, especially during stress. The pulse of blood can be strong enough to burst vessels in the brain, resulting in microbleeds.

A stumbling block has been accurately measuring the blood pressure that the brain experiences. The hand-pumped armband devices commonly used in doctor’s offices measure only the local pressure of blood in the arm, known as the brachial pressure. To calculate aorta stiffness, the “central blood pressure” in the aorta is needed. A technique for measuring central blood pressure was developed in the late 1990s, called applanation tonometry (AT). It works by comparing the pressure wave of blood from the heart with the reflected pressure wave from the vessels farthest from the heart—the aorta stiffness is calculated from the difference in pressure from the two. Devices for measuring AT have appeared on the market that are fast and painless.

To see if central blood pressure and aorta stiffening are related to cognitive abilities, Pase and colleagues recruited 493 people in Melbourne, 20 to 82 years old. They made traditional blood pressure measurements and also used AT to measure central blood pressure and estimate aorta stiffness. They also measured their subjects’ cognitive abilities with a standard battery of computer tests.

Central blood pressure and aorta stiffness alone were sensitive predictors of cognitive abilities, Pase reported at the meeting. The higher the central pressure and aorta stiffness, the worse people tended to perform on tests of visual processing and memory. The traditional measures of blood pressure in the arm were correlated with only scores on one test of visual processing.

To prove that aorta stiffening causes microbleeds, the researchers will need to repeat the experiment on the same people over the course of several years, using neuroimaging as well to establish that aorta stiffening leads to both microbleeding and cognitive decline. Pase notes that other causes of microbleeding have been proposed, such as weakening of blood vessels in the brain.

"This work is so important because the problem is so pervasive," says Earl Hunt, a veteran intelligence researcher at the University of Washington, Seattle, who was not involved in the work. The individual effects of these microbleeds are probably too small to measure. "But even a trifling difference multiplied a million times is big," he says. Pase’s collaborator at Swinburne, Con Stough, is now leading a study of how to prevent microbleeding through dietary supplements. He proposes that the elasticity of the aorta could be preserved by providing fatty acids or antioxidants that help maintain its structure. The results are expected in 2015.

Averting the Devastating Effects of Stroke

Researchers at the University of Connecticut Health Center are studying ways to prevent the devastating injuries to the body caused by stroke, a leading cause of serious long-term disability.

One American dies from stroke, sometimes called a “brain attack,” every four minutes. More than five times that many people survive a stroke, and for them, the physical damage it causes can be enormous.

“Stroke often doesn’t kill you, but some patients say they would have rather died than be left with severe disability and not be able to care for themselves,” says Dr. Louise D. McCullough, professor of neurology and neuroscience and director of stroke research. “People can often be disabled from their stroke. They need assistance with feeding and sometimes can’t get out of bed. Many can’t speak or communicate, and this is very isolating. And now we’re seeing an increasing number of stroke survivors as our population ages.”

There are two types of stroke. Ischemic strokes, which account for the vast majority, happen when clots block the blood vessels to the brain and cut off blood flow. Hemorrhagic strokes happen when the wall of a blood vessel breaks and blood leaks into the surrounding brain. Signs of either type of stroke include sudden numbness or weakness of the face or arm or leg, especially on one side of the body, as well as sudden confusion, difficulty speaking or understanding, trouble seeing or walking, dizziness or loss of balance, and/or a sudden severe headache.

McCullough’s research focuses on ischemic stroke. This type of stroke can be treated in an emergency room with “clot-busting” medication called tissue plasminogen activator (tPA), which helps reduce damage to the brain. But tPA can be effective only if given within a few hours of a stroke, and many people don’t immediately realize they are having a stroke and don’t seek help right away. In addition, some people can’t receive tPA because of other health issues.

“Nationwide, only 5 to 8 percent of people who have a stroke get tPA effectively,” she says. “So we’ve been limited in treatment. We’ve never been able to find a drug to protect the brain after stroke. Reperfusion (restoring the blood flow using tPA) is less useful because the brain is already damaged.”

So McCullough’s research involves studying factors such as what contributes to brain injury after a stroke and how it might be reversed. Because women tend to do worse than men in terms of survival and disability, she also is studying the role that hormones play in stroke risk and recovery.

Much of the understanding about stroke and its treatment has stemmed from research in men, but not all of those findings can benefit women, she points out. “Stroke is different in women – how we present, how we respond to drugs, how we recover. Women have a higher risk of stroke, a slower recovery and more cognitive problems. We need to understand the sex differences on a cellular level. For example, cell death occurs by different pathways in the two sexes. We’re trying to figure out why the biology is different and whether that’s important to therapy.”

In addition, women and men respond differently to different types of drugs. McCullough points to basic aspirin as an example of this. In women, a daily dose of aspirin can help prevent stroke but seems to have no impact in preventing heart disease. In men, the opposite is true.

Interestingly, McCullough also has found a correlation between social factors and stroke. In a study funded by the National Institutes of Health (NIH), McCullough is using mouse models to understand the role that social isolation might play in ischemic stroke.

“We’ve found that isolation is as big a risk factor for having a stroke as hypertension (high blood pressure),” she explains. “We also found that if we induce a stroke in a mouse that is isolated from others, the stroke is 40 percent bigger. And three days after a stroke, a mouse that is placed with others does better than a mouse that is alone. So now we’re saying that with hospitalized patients, maybe we should put someone who has had a stroke in a room with, say, someone who has had a hip replacement.”

McCullough earned her medical degree and Ph.D. from UConn’s School of Medicine. She completed an internship, residency and fellowship at Johns Hopkins University in Baltimore before returning to Connecticut after her father, a physicist, suffered a disabling stroke. She hopes her research will help people like her father as well as future generations, including her four children ranging in age from 7 to 13, whose framed artwork covers larger portions of the walls in her office than do the smaller certificates honoring her with Best Doctor awards and Outstanding Teacher recognition.

In a nearby office, Dr. Lauren Hachmann Sansing, assistant professor of neurology, is looking at stroke in another way. Her research focuses on hemorrhagic stroke, the type that results from a ruptured blood vessel in the brain. “This type of stroke is devastating,” she explains. “It affects two million patients a year, and only 50 percent survive it. People may become paralyzed, unable to speak and unconscious due to the mass of blood within the brain.”

This intracerebral bleeding induces an immune reaction in the body in which white blood cells (leukocytes) travel to the brain in response to the injury. Unfortunately, this does further harm by causing brain swelling and actually worsens the cell death caused by the stroke. Sansing has obtained an NIH K08 grant – funds awarded to support the research of new physician-scientists – to study how this immune reaction can be prevented.

“Using a mouse model, we are measuring and quantifying how many leukocytes travel to the brain and how we could block them using certain anti-inflammatory drugs, such as arthritis drugs that target this cell population,” Sansing says. “We are working to determine which pathways are active in patients after a stroke, and we think we are onto something. We’re using drugs already tested in humans, with good safety data, and so we already know the dosing. If we find efficacy in animal models, we can go right to safety in human studies.”

Working to understand and treat this secondary wave of injury after a stroke is an interesting mix of the neurology and immunology courses that Sansing enjoyed as a student. She completed undergraduate studies at Cornell University, her medical degree at SUNY Stony Brook School of Medicine, and a master’s in translational research (which involves converting scientific discovery into health improvement) at the University of Pennsylvania, where she also completed an internship, residency and fellowships in vascular neurology and translational medicine.

“We’re hopeful about our work,” Sansing says. “But there have been many, many treatments for stroke that have worked in animal models but failed to improve outcomes in patients. With the evolution of biomarkers studies and the ability to study proteins and activation in patients, we have a lot of insights into what we should go after as potential targets. Dr. McCullough and I have a large biobank of samples from stroke patients who have donated blood samples to help us study the disease. These samples help ensure that what we study in our animal models is important in our patients.”

Both McCullough and Sansing are involved in active research while also seeing patients, and they say their studies are greatly benefitted by doing both. “It’s like a big puzzle,” Sansing explains. “We create a model, study it, go back to patients, then go back to research. Our overall goal is to someday say we have a new treatment that can make a difference in people’s lives.”

Drugs targeting blood vessels may be candidates for treating Alzheimer’s

University of British Columbia researchers have successfully normalized the production of blood vessels in the brain of mice with Alzheimer’s disease (AD) by immunizing them with amyloid beta, a protein widely associated with the disease.

While AD is typically characterized by a build-up of plaques in the brain, recent research by the UBC team showed a near doubling of blood vessels in the brain of mice and humans with AD.

The new study, published online last week in Scientific Reports, a Nature journal, shows a reduction of brain capillaries in mice immunized with amyloid beta – a phenomenon subsequently corroborated by human clinical data – as well as a reduction of plaque build-up.

“The discovery provides further evidence of the role that an overabundance of brain blood vessels plays in AD, as well as the potential efficacy of amyloid beta as basis for an AD vaccine,” says lead investigator Wilfred Jefferies, a professor in UBC’s Michael Smith Laboratories.

“Now that we know blood vessel growth is a factor in AD, if follows that drugs targeting blood vessels may be good candidates as an AD treatment.”

AD accounts for two-thirds of all cases of dementia. The number of Canadians living with dementia is expected to reach 1.4 million by 2013, according to the Alzheimer’s Society of Canada.

Some Autism Behaviors Linked to Altered Gene

Scientists at Washington University School of Medicine in St. Louis have identified a genetic mutation that may underlie common behaviors seen in some people with autism, such as difficulty communicating and resistance to change.

An error in the gene, CELF6, leads to disturbances in serotonin, a chemical that relays messages in the brain and has long been suspected to be involved in autism.

The researchers identified the error in a child with autism and then, working in mice, showed that the same genetic alteration results in autism-related behaviors and a sharp drop in the level of serotonin circulating in the brain.

While the newly discovered mutation appears to be rare, it provides some of the first clues to the biological basis of the disease, the scientists report Feb. 13 in the Journal of Neuroscience.

“Genetically, autism looks very complicated, with many different genetic routes that lead to the disease,” says lead author Joseph D. Dougherty, PhD, an assistant professor of genetics at Washington University. “But it’s not possible to design a different drug for every child. The real key is to find the common biological pathways that link these different genetic routes and target those pathways for treatment.”

Autism is known to have a strong genetic component, but the handful of genes implicated in the condition so far explain only a small number of cases or make a small contribution to symptoms.

This led Dougherty and senior author Nathaniel Heintz, PhD, a Howard Hughes Medical Institute investigator at Rockefeller University, to speculate that some of the most common behavioral symptoms of autism may be caused by disruptions in a common biological pathway, like the one involved in serotonin signaling.

‘Robot’ cells answer call to arms

By thinking of cells as programmable robots, researchers at Rice University hope to someday direct how they grow into the tiny blood vessels that feed the brain and help people regain functions lost to stroke and disease.

Rice bioengineer Amina Qutub and her colleagues simulate patterns of microvasculature cell growth and compare the results with real networks grown in their lab. Eventually, they want to develop the ability to control the way these networks develop.

The results of a long study are the focus of a new paper in the Journal of Theoretical Biology.

“We want to be able to design particular capillary structures,” said Qutub, an assistant professor of bioengineering based at Rice’s BioScience Research Collaborative. “In our computer model, the cells are miniature adaptive robots that respond to each other, respond to their environment and pattern into unique structures that parallel what we see in the lab.”

When brain cells are deprived of oxygen – a condition called hypoxia that can lead to strokes – they pump out growth factor proteins that signal endothelial cells. Those cells, which line the interior of blood vessels, are prompted to branch off as capillaries in a process called angiogenesis to bring oxygen to starved neurons.

How these new vessels form networks and the shapes they take are of great interest to bioengineers who want to improve blood flow to parts of the brain by regenerating the microvasculature.

“The problem, especially as we age, is that we become less able to grow these blood vessels,” Qutub said. “At the same time, we’re at higher risk for strokes and neurodegenerative diseases. If we can understand how to guide the vessel structures and help them self-repair, we are a step closer to aiding treatment.”

Damaged Blood Vessels Loaded with Amyloid Worsen Cognitive Impairment in Alzheimer’s Disease

A team of researchers at Weill Cornell Medical College has discovered that amyloid peptides are harmful to the blood vessels that supply the brain with blood in Alzheimer’s disease — thus accelerating cognitive decline by limiting oxygen-rich blood and nutrients. In their animal studies, the investigators reveal how amyloid-ß accumulates in blood vessels and how such accumulation and damage might be ultimately prevented.

Their study, published in the Feb. 4 online edition of the Proceedings of the National Academy of Sciences (PNAS), is the first to identify the role that the innate immunity receptor CD36 plays in damaging cerebral blood vessels and promoting the accumulation of amyloid deposits in these vessels, a condition known as cerebral amyloid angiopathy (CAA).

Importantly, the study provides the rational bases for targeting CD36 to slow or reverse some of the cognitive deficits in Alzheimer’s disease by preventing CAA.

"Our findings strongly suggest that amyloid, in addition to damaging neurons, also threatens the cerebral blood supply and increases the brain’s susceptibility to damage through oxygen deprivation," says the study’s senior investigator, Dr. Costantino Iadecola, the Anne Parrish Titzell Professor of Neurology at Weill Cornell Medical College and director of the Brain and Mind Research Institute at Weill Cornell Medical College and NewYork-Presbyterian Hospital. "If we can stop accumulation of amyloid in these blood vessels, we might be able to significantly improve cognitive function in Alzheimer’s disease patients. Furthermore, we might be able to improve the effectiveness of amyloid immunotherapy, which is in clinical trials but has been hampered by the accumulation of amyloid in cerebral blood vessels."

Mounting scientific evidence shows that changes in the structure and function of cerebral blood vessels contribute to brain dysfunction underlying Alzheimer’s disease, but no one has truly understood how this happens until now.

Chance finding reveals new control on blood vessels in developing brain

Zhen Huang freely admits he was not interested in blood vessels four years ago when he was studying brain development in a fetal mouse.

Instead, he wanted to see how changing a particular gene in brain cells called glia would affect the growth of neurons.

The result was hemorrhage, caused by deteriorating veins and arteries, and it begged for explanation.

"It was a surprising finding," says Huang, an assistant professor of neuroscience and neurology at the University of Wisconsin-Madison. "I was mainly interested in the neurological aspect, how the brain develops and wires itself to prepare for all the wonderful things it does."

But chance favors the prepared mind, as Louis Pasteur said, and Huang knew he needed to follow up on the suggestion that glia, normally considered “helpers” for the neurons, would affect the growth of blood vessels. For one thing, blood flow is a big deal in the brain, says Huang, whose collaborators included Shang Ma, in the graduate program in cellular and molecular biology at UW-Madison. “We know the brain is very energy-intensive. Per unit of volume, it consumes 10 times as much oxygen as the rest of the body.”

Although it makes intuitive sense that blood vessel development should be guided by neuronal development in some fashion, Huang spent years making sure he wasn’t being mislead by his experiment. Now, he’s satisfied himself, and his scientific reviewers, and the journal PLOS Biology has just published his study.

Research offers new targets for stroke treatments

New research from the University of Georgia identifies the mechanisms responsible for regenerating blood vessels in the brain.

Looking for ways to improve outcomes for stroke patients, researchers led by the UGA College of Pharmacy assistant dean for clinical programs Susan Fagan used candesartan, a commonly prescribed medication for lowering blood pressure, to identify specific growth factors in the brain responsible for recovery after a stroke.

The results were published online Dec. 4 in the Journal of Pharmacology and Experimental Therapeutics

Although candesartan has been shown to protect the brain after a stroke, its use is generally avoided because lowering a person’s blood pressure quickly after a stroke can cause problems-like decreasing much-needed oxygen to the brain-during the critical period of time following a stroke.

"The really unique thing we found is that candesartan can increase the secretion of brain derived neurotrophic factor, and the effect is separate from the blood pressure lowering effect," said study coauthor Ahmed Alhusban, who is a doctoral candidate in the College of Pharmacy. "This will support a new area for treatments of stroke and other brain injury."

Alhusban and Fagan worked with Anna Kozak, a research scientist in the college, and Adviye Ergul, a professor and director of the physiology graduate program at Georgia Health Sciences University. They are the first to show that the positive effects of candesartan on brain blood vessel growth are caused by brain derived neurotrophic factor, or BDNF.

The research shows that when candesartan blocks the angiotensin II type 1 receptor, which lowers blood pressure, it stimulates the AT2 receptor and increases the secretion of BDNF, which encourages brain repair through the growth of new blood vessels.

"BDNF is a key player in learning and memory," said Fagan, the Albert W. Jowdy Professor. "A reduction of BDNF in the brain has been associated with Alzheimer’s disease and depression, so increasing this growth factor with a common medication is exciting."

AT2 is a brain receptor responsible for angiogenesis, or the growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal and vital process in human growth and development-as well as in healing.

(Image: iStock)