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Little Events, Big Difference

The lasting effects of ministrokes may contribute to dementia

by Katharine Hendrix

Dr. Andy Y. Shih

Dr. Andy Y. Shih

Evidence overwhelmingly supports a link between cognitive decline and cerebrovascular diseases. There is a much higher incidence of microinfarcts (mini-strokes) in people with cerebrovascular diseases and, according to post-mortem histological and in vivo radiological studies, a greater burden of microinfarcts among people with vascular cognitive impairment and dementia. Until now, the mechanisms by which these miniscule lesions (~0.05 to 3 millimeters in diameter) contribute to cognitive deficits including dementia have been poorly understood.

“These infarcts are so small and unpredictable, we just haven’t had good tools to detect them while the person was still alive,” says Andy Y. Shih, Ph.D., assistant professor in the Department of Neuroscience at MUSC. “Until now, we 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.”

In an article published ahead of print on January 16, 2017 by the Journal of Cerebral Blood Flow and Metabolism, Shih and colleagues report preclinical findings suggesting that functional deficits caused by a single microinfarct occur across a much larger area of viable perilesional tissue than was previously understood and that the resulting deficits are much longer-lasting.

The team began by hypothesizing that microinfarcts might disrupt brain function beyond what was visible by histology or magnetic resonance imaging (MRI).

“Even though people may experience hundreds of thousands of microinfarcts in their lifetime, each event is extremely small and thought to resolve in a matter of days,” says Shih. “It’s been estimated that, overall, microinfarcts affect less than two 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 vivo for several weeks after the event. Post-mortem, c-Fos immunostaining revealed that an area estimated to be at least 12-times greater in volume than the microinfarct core had been affected by the event. Furthermore, in vivo two-photon imaging of single-vessel, sensory-evoked hemodynamics found that neuronal activity across the affected tissue area remained partially depressed for 14 to 17 days after the microinfarct.

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

Could targeting these microinfarcts help protect against stroke and dementia?

“The neuroprotection 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,” says Shih. “But for microinfarcts, you don’t have to know exactly when they occur. If an MRI shows a person to be at high risk for microinfarcts, maybe we could one day put them on a drug for a while to reduce the impacts of these lesions.”