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Cerebral Microbleeds in Murine Amyloid Angiopathy: Natural Course and Anticoagulant Effects
Marilena Marinescu1, Li Sun1, Marc Fatar1
1From the Division of Brain Sciences, Imperial College London, United Kingdom (M.M., R.V.); Departments of Neurology (M.M., L.S., R.V.) and Cardiology (L.L.), University of Heidelberg, Germany; Department of Neurology, Medical Faculty Mannheim (M.F.), Computer Assisted Clinical Medicine (A.N., L.S.), University Heidelberg, Mannheim, Germany; and Department of Cardiometabolic Research, Boehringer Ingelheim, Biberach, Germany (J.v.R.).
Background And Purpose:
Cerebral microbleeds (CMBs) predispose patients to intracerebral hemorrhage. Preclinical models to examine the effects of antithrombotic treatments on the development of clinically overt intracerebral hemorrhage are needed. We examined the natural course of CMB development and the effects of long-term anticoagulation with warfarin or dabigatran on cerebral micro- and macrohemorrhage in mice overexpressing the APP23 (amyloid precursor protein).
Methods:
Repeated susceptibility-weighted magnetic resonance imaging was performed in APP23 mice at the age of 18 and 21 months, respectively. After establishing stable long-term anticoagulation effects of warfarin and dabigatran on number and total volume of CMBs, the outcome parameters were compared with nonanticoagulated control.
Results:
CMBs were equally located in lobar and deep brain regions, and number and total volume of CMBs increased over time. Anticoagulation with either warfarin or dabigatran did not increase CMBs in APP23 significantly. Mice treated with warfarin numerically had a higher mortality (nonanticoagulated: 31%; dabigatran: 35% versus warfarin: 55%; P=0.21). In postmortem brains of prematurely dying animals warfarin caused significantly more frequently large intracerebral hemorrhage than control and dabigatran.
Conclusions:
Anticoagulation with warfarin or dabigatran for 3 to 4 months does not promote the formation of CMBs in aged APP23 mice. Nevertheless, warfarin but not dabigatran is associated with a higher risk of extensive intracerebral hemorrhage, suggesting that this model may allow preclinical safety evaluation of antithrombotic therapies.
Insights
Long-term anticoagulation with warfarin or dabigatran did not increase cerebral microbleeds (CMBs) in aged mice. However, warfarin increased the risk of severe intracerebral hemorrhage, suggesting its use in preclinical safety evaluations.
Area of Science:
- Neuroscience
- Pharmacology
- Biomedical Research
Background:
- Cerebral microbleeds (CMBs) are indicators of increased risk for intracerebral hemorrhage.
- Preclinical models are essential for evaluating antithrombotic treatments' effects on hemorrhage development.
Purpose of the Study:
- To investigate the natural progression of CMBs in aged mice overexpressing amyloid precursor protein (APP23).
- To assess the impact of long-term anticoagulation with warfarin and dabigatran on CMBs and macrohemorrhage in this model.
Main Methods:
- APP23 mice underwent repeated susceptibility-weighted magnetic resonance imaging at 18 and 21 months.
- Established anticoagulation with warfarin or dabigatran, then compared CMBs and hemorrhage outcomes with non-anticoagulated controls.
Main Results:
- CMB number and volume increased over time in APP23 mice, appearing in both lobar and deep regions.
- Neither warfarin nor dabigatran significantly increased CMBs.
- Warfarin treatment was associated with numerically higher mortality and significantly more frequent large intracerebral hemorrhages postmortem compared to controls and dabigatran.
Conclusions:
- Three to four months of anticoagulation with warfarin or dabigatran did not promote CMB formation in aged APP23 mice.
- Warfarin, but not dabigatran, was linked to an elevated risk of extensive intracerebral hemorrhage.
- This APP23 mouse model shows potential for preclinical safety assessments of antithrombotic therapies.
