Mini-strokes may have mightier effect than previously thought

 By Katharine Hendrix

When we hear the word "stroke," most of us think of a major, catastrophic health event. But some people, especially those with atherosclerosis or dementia, may have hundreds of tiny "mini-strokes" that are so small they go virtually unnoticed. Because they are so subtle, most researchers thought mini-strokes were of little consequence — until now. 

New research shows that mini-strokes pack a more powerful punch in people suffering from dementia than previously believed, and this information could lead to more effective treatments. Mini-strokes, also known as microinfarcts, were the focus of a study at the Medical University of South Carolina that suggests these very small lesions can do damage that lasts long after the initial impact.

Andy Shih, Ph.D., assistant professor of neurosciences, is senior author on an article about the research in the journal of Cerebral Blood Flow & Metabolism. 

"Although evidence of the link between cognitive decline and microinfarcts has grown over the last decade, microinfarcts just seemed so insignificant compared to the many other, much bigger events that take place in the brains of people with dementia,” Shih said. “Then, in 2012, a meta-analysis by Dr. Steven M. Greenberg and colleagues caught my attention because it showed a very striking, consistent, relationship between microinfarcts and cognitive decline."

The functional effects of mini-strokes are extremely difficult to study, Shih said. Not only are most difficult to detect with standard imaging techniques, but there are also mismatches between functional data collected while a person is alive and histological evidence collected after death. Because many years can separate these data collections, it is nearly impossible to connect microinfarcts observed in the post-mortem brain to the timeline of cognitive decline during the person's life. 

"These infarcts are so small and unpredictable, we just haven't had good tools to detect them while the person was still alive,” said Shih. “So until now, we basically just had post-mortem snapshots of these infarcts at the end of the dementia battle, and measures of the person's cognitive decline that might have been taken years before the brain became available for study." 

Intrigued by the mounting evidence linking cognitive decline with mini-strokes, Shih's group hypothesized that microinfarcts might disrupt brain function beyond what was visible by histology or magnetic resonance imaging. 

"Even though a person may experience hundreds of thousands of microinfarcts in their lifetime, each event is extremely small and thought to resolve in a matter of days," said Shih. "It's been estimated that, overall, microinfarcts affect less than 2 percent of the entire human brain. But those estimates of tissue loss are based only on the 'core' of the microinfarct, the area of dead or dying tissue that we can see in routine, post-mortem, histological stains." 

To investigate their theory of broader impacts, the team developed a mouse model so that they could examine the effects of individual cortical microinfarcts on surrounding tissue function in living subjects over several weeks after a mini-stroke. "We needed a preclinical model to create very predictable lesions that we could follow over time,” said Shih. "Also, we needed to be able to obtain readouts of brain activity that were consistent over time." 

The team fitted mice with cranial windows and then used photothrombosis to create a ministroke and  compared brain activity in the affected area to the ministroke location. Combined with histology data collected after death, the team found that the mini-stroke had affected an area 12 times larger than they had expected. In addition, the mini-stroke depressed brain activity across this area for several weeks after the event, which was much longer than they would have predicted. 

Together, these data indicate that functional deficits caused by a single mini-stroke occur across a much larger area of brain tissue than previously understood and the resulting deficits are much longer lasting. 

"I knew larger strokes could have distant effects, but I was surprised that something of this scale could have such a large effect," said Shih. 

"The MRI signal increased and then went away as we'd expected, but we were surprised on autopsy to see that there was still lots going on — tissue damage and neuro-inflammation. That made us wonder if this tissue could be functioning normally," Shih explained. 

"Even after three weeks, the blood flow responses had only partially recovered. So that means a microinfarct can come and go and you can see it briefly with MRI but it leaves a lasting impression on brain function — possibly for months." 

Importantly, a person with vascular cognitive impairment and dementia is likely to experience other mini-strokes during this recovery time. Furthermore, these tiny infarcts occur not only in the brain's grey matter, where this study was conducted, but also in the white matter, which sends messages from one part of the brain to another. 

"Over time, after you have a lot of microinfarcts, there may be enough accumulated damage in the brain's circuitry to equal the impact of a larger event," said Shih.

According to Shih, one of the most important messages from this study is that conventional methods used in clinical trials do not reveal the entire impact of mini-strokes on brain function. He hopes that his team's contribution to illuminating how they work will help doctors better interpret brain imaging results and help researchers explain some of the relationships they see in clinical studies. The findings might also lead to new strategies to prevent mini-strokes and protect brain function.

"On a clinical level, maybe it's a situation where therapeutics can play a bigger role. Maybe drugs that we already have can mitigate the cumulative damage of microinfarcts,” said Shih. 

"The neuro-protective idea hasn't flown very far for acute stroke, in part, because the window of time for protecting the brain from stroke damage is very narrow. But, for microinfarcts, you don't have to know exactly when they occur. If an MRI shows a person is at high risk for microinfarcts, maybe we can put them on drug for a while to reduce the impacts of these lesions."