Shih AY, Blinder P, Tsai PS, Friedman B, Stanley G, Lyden PD, Kleinfeld D.
The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit.
Nat Neurosci. 2013 Jan;16(1):55-63.
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This article by Shih et al. is an elegant study that addresses the pathological and cognitive consequences of cerebral microinfarcts. Using rats, the authors created microinfarcts targeting individual penetrating arterioles and venules, and showed that a column of pathological changes associated with infarcts radiated from the occluded vessels. There are several notable and novel findings in this study.
First, the authors demonstrate that infarcted penetrating venules exhibit very similar consequences as observed with infarcted penetrating arterioles, including loss of neuronal function, oxidative damage, activation of neuroinflammatory cells, and blood-brain barrier compromise. On the other hand, infarction of deep microvessels appeared rather innocuous, producing little tissue damage.
Second, administration of the NMDA receptor antagonists MK-801 and memantine markedly reduced the infarct size, whether in penetrating arterioles or venules.
Third, a rather interesting part of the study were the experiments to address cognitive deficits of microinfarcts. In this case, the authors targeted penetrating vessels that lie within a single cortical column associated with the vibrissa primary sensory cortex. Infarction of a specific penetrating vessel within this specific cortical column impaired the sensory response to allow the rat to make a decision. Of note, these experiments indicate that this type of microinfarct can indeed have deleterious cognitive consequences. However, reducing the infarct-associated damage with NMDA receptor antagonists can prevent this type of cognitive deficit.
Finally, one of the more significant findings in this report is that the damage associated with numerous microinfarcts, within proximity to one another, can actually combine to form a larger infarct lesion. The NMDA receptor antagonists MK-801 and memantine were shown to restrict this coalescing of numerous microinfarcts.
Even though these studies were performed in a rat model, they may have potential implications for microinfarcts in humans. For example, the findings suggest that micro-/silent infarcts may not be so silent. Although there may not be overt signs of impairment, subtle deficits could occur, accumulate, and, over time, manifest as vascular cognitive impairment. Under conditions where multiple microinfarcts might occur, they could possibly cause synergistic damage resulting in consequences reflecting that of a more serious infarct that results in palpable clinical symptoms. Although NMDA receptor antagonists were not successful in human clinical trials for larger ischemic strokes, perhaps they may prove more efficacious for limiting microinfarct damage. However, a significant hurdle to overcome would be an effective and timely way to detect micro-/silent infarcts, since there would likely be a limited window for therapeutic intervention.
In this paper from the group of David Kleinfeld, the authors address whether microinfarcts in the elderly brain have significant consequences for neurological and cognitive function. Using a rat model, individual blood vessels were occluded on the cortical surface of the brain by activation of the circulating photosensitizer, rose bengal. Deep microvessels were occluded using a pulsed laser. Occlusion of individual cortical penetrating arterioles and venules resulted in microinfarcts that led to cognitive dysfunction in a behavioral task. One of the most interesting observations in this paper is that damage caused by both single and coalesced microinfarcts could be ameliorated by post-occlusion application of memantine, a drug that is used for the treatment of Alzheimer's disease and vascular dementia. There was also a significant improvement in cognitive function following the administration of memantine.
The main significance of this paper is firstly, that targeted vascular occlusion leading to microinfarcts in specific areas can be used to produce measurable neurological deficits; secondly, that even small infarcts can produce neurological and behavioral defects; and thirdly, that the reduction in size of the infarcts by the administration of memantine also results in amelioration of neurological and behavioral function.
As the authors of this paper point out, the anatomical arrangement of vessels penetrating the cerebral cortex is very similar in rodents and humans. This emphasizes the importance of this study for human stroke medicine, particularly in the prevention of microinfarcts and their prompt treatment.