This is the first in a series featuring OHSU scientists and the research they conduct using leading-edge imaging at OHSU. From single-cell to whole-body technologies, advanced imaging helps drive new understandings of health and disease.
Cardiovascular disease, stroke are linked to dementia; new research helps explain how with power of MRI
“Heart health is brain health,” is an increasingly common maxim, and that includes an association between high blood pressure, stroke and dementia. The exact nature of that association, however, has remained elusive.
Using rare, specialized imaging equipment, Anusha Mishra, Ph.D., and a team of scientists made two breakthrough discoveries regarding the mechanisms of damage caused by stroke and the association of stroke and eventual onset of dementia. These could lead to new therapeutic interventions.
Mishra’s lab first replicated vascular dysfunction associated with stroke using a rodent model. Working with Zhenzhou Li, Ph.D., and Heather McConnell, Ph.D., two postdoctoral scholars in her group, Mishra discovered that a substance called 20-hydroxyeicosatetraenoic acid, or 20-HETE, is increased after stroke. This substance constricts brain blood vessels after stroke — and is also increased in some forms of hypertension. 20-HETE is made by a class of enzymes that are not active in a healthy brain but that are overly active in a stroke brain. When the team blocked the enzymes, they found that vascular impairment dissipated. But while this basic finding seemed promising, they wanted to see how it worked in the actual brains.
“Our ultimate goal is to learn more about stroke and dementia in humans, so conducting research inside a living being is an important step in our research,” said Mishra. “We needed a different kind of tool to verify the function of the enzyme in vascular impairment, and we found that in magnetic resonance imaging.”
A powerful noninvasive window into the brain
Mishra’s team had discovered the role of 20-HETE by looking at dissected brain tissue. But this method does not include information about blood flow. In order to observe brain vascular function in a living being, the team used ultra-high field magnetic resonance imaging, or MRI. The power of an MRI – and its ability to produce high-resolution images that offer advanced insights — lies in the strength of its magnetic field. MRI uses magnetic field and computer-generated radio waves to produce precise images of organs and tissues—and it’s a common medical tool. What’s special about the system that Mishra used is its strength.
Magnetic field strengths are measured in Teslas. (One Tesla represents a strength 10,000 times that of the earth’s magnetic field.) For instance, an MRI instrument with a 1.5 T magnet can potentially provide a superior image of the body region under study than one with a 1 T magnet. Most MRI machines for patients are at a 3 T resolution.
Mishra used the 12 T MRI housed in the OHSU Advanced Imaging Research Center — it is one of the most powerful MRI systems in the world. The 12 T MRI has a field strength 120,000 times that of the earth’s magnetic field.
The 12 T MRI provides a powerful noninvasive window into the brain and allows investigators to explore unique aspects of disease. In this case, it empowered Mishra’s team, in collaboration with Martin Pike, Ph.D., of the Advanced Imaging Research Center, to verify the function of the enzyme group that makes 20-HETE and show its role in stroke.
Using a technique called arterial spin labeling in the 12 T MRI, researchers observed the decrease in blood flow in a stroke brain and, after blocking the enzyme, saw blood flow was restored. Rodents that had been given a stroke were placed in the MRI machine, where the team imaged blood flow in their brains. Next, the rodents were given a drug to inhibit the 20-HETE-making enzymes. In vivo MRI observations demonstrated that, yes, when these enzymes are inhibited, vascular symptoms of stroke dissolved.
That was the verification the team had hoped to see.
How strokes affect both sides of the brain
In another study, Mishra and postdoctoral scholar Ozama Ismail, Ph.D., used the 12 T MRI to compare the stroke side with the non-stroke side of the brain, many months after the stroke, to investigate how it affects life-long brain health. Surprisingly, they found that, following the stroke to one side of the brain, vascular function in both sides were affected.
A persistent question has been how ischemic strokes, caused by a blockage on one side of the brain, affect the full brain. The power of the 12 T MRI, and its ability to image the whole brain of the living rodent brought new, and unexpected, answers. Had the team only imaged one side of the brain, they would not have discovered that both sides of the brain are impacted during a stroke.
“We were confused at first, because after many months, blood flow dynamics in the two sides of the brain looked the same. We wondered why there was no deficit in the stroke side, no dysfunction,” said Mishra. “But when we compared animals that had never had a stroke, we realized that stroke on one side caused blood flow impairment everywhere.”
Mishra said that is when she realized the stroke’s effect extended far beyond what they had previously thought.
“So this information was something that opened my brain — I realized how big of a problem this was. I was thinking too small. We wouldn’t have discovered this if we weren’t using MRI.”
The lab is interested in what happens over the long course. Improvements in medical treatment for ischemic stroke have increased survival and recovery of stroke patients. But even after recovery, or even in cases of smaller, clinically undetectable strokes, these injuries cause a propensity for dementia and other problems later in life. Upcoming investigations will try to understand how mild stroke causes vascular dysfunction in the whole brain that lasts a long time and contributes to cognitive impairment.
This work was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS110690, the JTMF Foundation and a Pilot Project grant from the Oregon Alzheimer’s disease Research Center. The MRI work was started with a School of Medicine Exploratory Research Seed Grant to use the AIRC.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
All research involving animal subjects at OHSU must be reviewed and approved by the university’s Institutional Animal Care and Use Committee (IACUC). The IACUC’s priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.
