Brain microbleeds, often encountered in people with dementia and particularly Alzheimer’s disease, could well play a role in the onset of these conditions. Thanks to a new animal model, a research team in Lille has been making headway in exploring this potential link.
Could brain microbleeds play a role in the onset of cognitive impairment? This is what the findings of researchers in Lille* would suggest.
These episodes of bleeding in the brain are so tiny that only recent advances in imaging have made it possible to detect them. Little is known about them for the moment: unlike major brain hemorrhages, whose consequences are harmful for the brain, their effect on health is unknown. However, their presence is strongly associated with dementia and its severity. Whereas these microbleeds are observed in around 5% of the general population, this figure shoots up to between 35 and 85% of people with vascular dementia and to between 16 and 32% of those with Alzheimer’s disease. Such consistency suggests a causal link… but this needs to be proven! "It is entirely possible that the presence of these microbleeds is coincidental", summarizes research leader Sophie Gautier*.
A marked cognitive deficit
To elucidate this point, the researchers developed a reliable and reproducible animal model. They used healthy mice in which they made intracerebral (frontoparietal) microinjections of collagenase, a protein that degrades the vascular components and causes bleeding. As such, they were able to create cortical microbleeds detectable by MRI. Six weeks later, the researchers then evaluated the animals’ motor and cognitive functions using various tests.
The researchers found that the mice with the microbleeds moved around just as well as the control mice (those without microbleeds). They also appeared less anxious. However, their visual and spatial memory was defective. And it is this memory which primarily relies on the hippocampus, a brain region particularly affected in Alzheimer’s disease. The animals had a lot of difficulty finding their bearings in a circuit with visual markers which are meant to be memorized, as well as in retaining visual signals that were presented repetitively. "These disorders are systematic and pronounced in the event of a microbleed. Furthermore, PETscan analysis shows that the hippocampal metabolism is also diminished, suggesting a loss of function", explains Sophie Gautier.
Another interesting finding is that the animals' response to the microbleed can be modulated by a pharmacological agent. A statin, in this case atorvastatin, makes it possible to limit cognitive losses in the event of induced microbleeds, and to obtain test results that are virtually equivalent to those of healthy mice. It was an obvious choice to test this particular drug because "nearly 90% of patients who have had a stroke or who have Alzheimer’s disease are prescribed a statin for high cholesterol or in the event of cardiovascular risk. The links between statins and cognition are debated and must be clarified", emphasizes Sophie Gautier. The animals concerned received the statin starting from the collagenase injection and throughout the monitoring period.
This research has therefore narrowed the link between microbleeds and cognitive deficit. Next on the list for the team is to clarify the mechanistic aspects: is inflammation involved? edema? oxidation reactions? "The fact that a statin partially offsets the effects of the microbleed on cognitive functions and that it modulates the inflammatory pathway is an initial avenue to explore", explains Sophie Gautier. In parallel, the team continues to observe the specific aspects of this link according to sex and also according to a potential predisposition to dementia.
*unit 1171 Inserm/Université Lille 2/Lille regional university hospital, Degenerative and vascular cognitive disorders, Lille
S. Bergeron et al. Role of cortical microbleeds in cognitive impairment: In vivo behavioral and imaging characterization of a novel murine model. J Cereb Blood Flow Metab, online edition of January 1, 2018