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A new microinfarcts model produces widespread bilateral infarcts and persistent cognitive deficits in middle-aged
Zhongwu Liu1, Mikkala Mccann1, Brianna Powell1
1Department of Neurology, Henry Ford Hospital, Detroit, MI, United States of America.
Background:
Multi-infarct dementia (MID), a severe form of vascular cognitive impairment, results from cumulative impact of multiple cerebral microinfarcts (MMIs). Current preclinical models primarily rely on unilateral induction of MMIs, which fails to reproduce bilateral lesion distribution and persistent cognitive decline characteristic of human disease.
Objective:
To develop and characterize a modified bilateral MMI model that more accurately reflects the clinical and pathological features of MID.
Methods:
Twelve-month-old male C57BL/6J mice underwent either unilateral or bilateral MMI induction by microsphere embolization via the internal carotid artery. Bilateral induction was achieved by transiently occluding the contralateral common carotid artery during microsphere infusion. Behavioral assessments using novel object recognition (NOR) and elevated plus maze (EPM) were conducted on days 7, 14, and 28 post-surgery. Histological Hematoxylin and Eosin staining and immunohistochemical analyses using antibodies against Iba1 and GFAP were performed to evaluate lesion distribution and neuroinflammation.
Results:
The modified bilateral procedure successfully induced widespread infarcts across both hemispheres. Bilateral MMI mice exhibited significantly greater and persistent cognitive impairment, demonstrated by a reduced NOR discrimination index and decreased open-arm exploration in the EPM persisting through day 28, than did unilateral MMI mice. Histological analysis confirmed bilateral microinfarcts and significant increase in Iba1- and GFAP-positive staining, indicating robust and sustained bilateral neuroinflammation.
Conclusion:
This modified bilateral MMI procedure reproduces key pathological and functional features of human MID, overcoming the limitations of traditional unilateral models. The new model provides a clinically relevant platform for investigating mechanisms underlying vascular cognitive impairment and evaluating potential disease-modifying therapies.
Insights
This study developed a new bilateral model for multi-infarct dementia (MID) in mice. The improved model shows persistent cognitive decline and neuroinflammation, offering a better preclinical platform for MID research.
Area of Science:
- Neuroscience
- Vascular Biology
- Cognitive Impairment Research
Background:
- Multi-infarct dementia (MID) stems from cumulative microinfarcts (MMIs), but current models fail to replicate human disease pathology.
- Unilateral MMI models do not accurately represent bilateral lesion distribution or persistent cognitive deficits seen in patients.
Purpose of the Study:
- To create and validate a modified bilateral MMI model in mice.
- This model aims to better mimic the clinical and pathological characteristics of human MID.
Main Methods:
- C57BL/6J mice underwent unilateral or bilateral MMI induction via microsphere embolization.
- Behavioral tests (NOR, EPM) and histological analyses (H&E, Iba1, GFAP) assessed cognitive function and neuroinflammation.
- Bilateral induction involved transient occlusion of the contralateral carotid artery.
Main Results:
- The bilateral MMI model induced widespread infarcts and persistent cognitive impairment, outperforming unilateral models.
- Bilateral MMI mice showed significantly reduced novel object recognition and open-arm exploration.
- Histology confirmed bilateral lesions and sustained neuroinflammation (increased Iba1 and GFAP).
Conclusions:
- The modified bilateral MMI model accurately replicates key features of human MID.
- This clinically relevant model overcomes limitations of unilateral approaches.
- It serves as a valuable platform for studying MID mechanisms and testing therapies.
