Mini-Literature Review

I had the opportunity to work in a lab which studies rodent models of stroke recovery.

More specifically, the project I was involved in looked at the impact of cerebral microinfarctions

on the behaviour of mice. The first article in this review describes the mouse model of diffuse

microinfarction used in this project and the second article examines a clinical study looking at

the relationship between microvascular brain pathology and late-life motor impairment.

Cerebral microinfarcts are defined as microscopic regions of cellular death or tissue

necrosis; they can be considered like a microscopic stroke. These lesions are not visible on

standard pathological examinations or conventional structural MRI. Microinfarcts are common

in the aging brain, present in 30% of people aged over 65 years old. Furthermore, current data

suggests that microinfarcts can cause clinical symptoms, notably cognitive impairment. [1]

At the moment, studying microinfarcts is quite difficult in human patients and is

predominantly done post-mortem. Gergely Silasi et al. conducted a study to find a reliable

animal model for small-vessel disease described in the article “A mouse model of small-vessel

disease that produces brain-wide-identified microocclusions and regionally selective neuronal

injury”. [2] Although rodent models already exist for the purpose of looking at the impact of

microocclusions, they have their flaws. For example, laser light can be used to induce thrombosis

or microhemorrhage in the neocortex of mice or rats to disrupt blood flow in single vessels.

Another existing model consists of injecting cholesterol-derived microcrystals through the

carotid artery producing many clots, mimicking microinfarcts in humans. However, it can be

very challenging to locate these crystals histologically thus making it difficult to know how

many crystals actually become lodged in arterioles.

 In the mouse model by Silasi et al., fluorescent microspheres with a diameter of ~20μM

were injected unilaterally into the common carotid artery (CCA) to produce microocclusions.

The experiment was performed on thymocyte-differentiation antigen 1-GFP-m mice, eliminating

the need to perform additional labeling to visualize neurons afterwards. In order to see the

obstruction in the blood flow of mice, Texas red-conjugated dextran was injected an hour before

the perfusion fixation. The dextran is mostly retained in arterioles that are blocked by lodged

microspheres while the rest of the vessels are cleared, making it possible to locate the

microocclusions. Following the sacrifice of the mice, structural damage was assessed by

confocal imaging in GFP-labeled cells in thin histologic sections for sequential neuronal

analysis.

After quantification of the distribution of the microspheres, it can be seen that 423±218

microspheres lodged in each brain. Majority of the microspheres were lodged in the cortex or the

thalamus. In addition, the average diameter of the blocked vessels corresponds to the

measurement of penetrating arteriole diameter in vivo of 10-20μM. The researchers also found

that 16.4% of the lodged microspheres produced noticeable damage to neuronal structure, mostly

in the hippocampus and white matter compared to the neocortex. Additionally, neuronal damage

in the hippocampus was more severe than the cortex, striatum or thalamus. Lastly, microglial

activation was only present in 21% of occlusion sites, indicating that only a subset of occlusions

lead to ischemic injury.

These findings demonstrate that this mouse model produces structural damage similar to

the disruption seen in patients with small-vessel disease. The model also partially reflects the

distribution of lesions in patients. This study is of great significance as it shows that injection of
microspheres in mice can be used as an effective animal model to study the effects of

microocclusions in the brain.

In the aging population, impaired motor function is common, however the root of these

impairments is uncertain. In the clinical study “Microvascular brain pathology and late-life

motor impairment” Buchman et al. aim to see if microvascular brain pathology is associated with

late-life motor impairment. Although multiple studies have linked microvascular brain

pathologies to cognitive decline, this angle focusing on motor function had not been looked at

before. [3]

This study was completed on a large scale with more than 2500 elderly people

undergoing motor assessment tasks, with the brain of 850 deceased participants evaluated for

microvascular pathologies. Motor performance tests included finger strength, pinch and grip

strength, gait and balance. The results of these examinations were then converted into a global

motor score (GMS). Certain regions of the brains were assessed post-mortem after being fixed

and examined for microscopic cerebral infarcts, CAA and cerebral arteriolosclerosis as well as

other cerebrovascular pathologies. The data collected was analyzed using Spearman correlations.

Focusing on the findings related to microinfarcts, evidence of one or more microinfarcts

was present in 60% of the cases. These microinfarcts were discreetly associated with

arteriolosclerosis and showed a trend with CAA. The total number of microinfarcts could be

related to reduced GMS proximate to death, more specifically subcortical microinfarcts had an

impact on the GMS, whereas cortical microinfarcts did not. Further breakdown of the results

show that multiple microinfarcts are associated to lower GMS as a oppose to single

microinfarcts. The analysis was repeated to see if any of the pathologies were more strongly
associated with an individual motor task. It was found that microinfarcts caused a subtle, yet

significant decrease specifically in manual dexterity and gait.

These findings suggest that there is indeed motor impairments due to microvascular brain

pathology, notably post-microinfarction, although the effects are discreet. Moreover, this gives

us a better clue of the severity of the motor impairments and their impact on people.

Microvascular brain pathology could possibly explain the weakening in strength seen in older

people as it has been shown that loss of muscle mass does not account for this decline. This

study is important as it brings to light an independent cause of late-life motor impairment that is

currently under-studied. Ultimately, this article provides an important basis for other studies of

this kind, crucial to expanding our knowledge on cerebral disease and its consequences.
References

[1] Buchman, A. S., Yu, L., Boyle, P. A., Levine, S. R., Nag, S., Schneider, J. A., & Bennett, D.
A. (2013). Microvascular brain pathology and late-life motor impairment. Neurology, 80(8),
712–718. https://doi.org/10.1212/WNL.0b013e3182825116

[2] Silasi, G., She, J., Boyd, J. D., Xue, S., & Murphy, T. H. (2015). A mouse model of small-
vessel disease that produces brain-wide-identified microocclusions and regionally selective
neuronal injury. Journal of cerebral blood flow and metabolism : official journal of the
International Society of Cerebral Blood Flow and Metabolism, 35(5), 734–738.
https://doi.org/10.1038/jcbfm.2015.8

[3] Buchman, A. S., Yu, L., Boyle, P. A., Levine, S. R., Nag, S., Schneider, J. A., & Bennett, D.
A. (2013). Microvascular brain pathology and late-life motor impairment. Neurology, 80(8),
712–718. https://doi.org/10.1212/WNL.0b013e3182825116