Towards a Better Understanding of the Effects of Tiny Strokes on Cognitive Decline

In recent years it has become clear that we all suffer many tiny, unnoticed strokes as we age. These involve the rupture or blockage of small blood vessels in the brain and resulting damage and cell death in a very small area of tissue. Hypertension, the age-related increase in blood pressure, and consequences of other forms of cell and tissue damage on blood vessel integrity speed up this process, and the aggregate effect of these microstrokes explains some of the correlation between cardiovascular aging and neurodegeneration. Here, researchers make a start on understanding the scale of this effect in living brains:

Evidence overwhelmingly supports a link between cognitive decline and cerebrovascular diseases. Not only do individuals with cerebrovascular diseases have a much higher incidence of cortical microinfarcts (mini-strokes), but post-mortem histological and in vivo radiological studies also find that the burden of microinfarcts is significantly greater among people with vascular cognitive impairment and dementia (VCID) than in age-matched, non-demented individuals. 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. Findings from a recent study provide crucial information for better understanding the impact of microinfarcts, showing that the functional deficits caused by a single microinfarct can affect a larger area of brain tissue and last longer than was previously thought to be the case.

The functional effects of microinfarcts are extremely difficult to study. Not only are most microinfarcts difficult to detect with standard neuroimaging techniques, mismatches between in vivo functional data and post-mortem histological evidence make it nearly impossible to connect microinfarcts to the timeline of cognitive decline. "These infarcts are so small and unpredictable, we just haven't had good tools to detect them while the person was still alive. So, until now, we basically just had post-mortem snapshots of these infarcts at the end of the dementia battle as well as measures of the person's cognitive decline, which might have been taken years before the brain became available for study. 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. It's been estimated that, overall, microinfarcts affect less than 2% 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 over several weeks post-event. The team used photothrombosis to occlude a single arteriole in the barrel cortex of mice fitted with cranial windows. They then compared functional readouts of sensory-evoked brain activity, indicated by activity-dependent c-Fos expression or in vivo two-photon imaging of single vessel hemodynamic responses, to the location of the microinfarct core. 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. Together, these data indicate that functional deficits caused by a single microinfarct occur across a much larger area of viable peri-lesional tissue than was previously understood and that the resulting deficits are much longer-lasting.



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