ABSTRACT
Microhemorrhages are common in the aging brain and are thought to contribute to cognitive decline and the development of neurodegenerative diseases, such as Alzheimer's disease. Chronic aspirin therapy is widespread in older individuals and decreases the risk of coronary artery occlusions and stroke. There remains a concern that such aspirin usage may prolong bleeding after a vessel rupture in the brain, leading to larger bleeds that cause more damage to the surrounding tissue. Here, we aimed to understand the influence of aspirin usage on the size of cortical microhemorrhages and explored the impact of age. We used femtosecond laser ablation to rupture arterioles in the cortex of both young (2-5 months old) and aged (18-29 months old) mice dosed on aspirin in their drinking water and measured the extent of penetration of both red blood cells and blood plasma into the surrounding tissue. We found no difference in microhemorrhage size for both young and aged mice dosed on aspirin, as compared to controls (hematoma diameter = 104 +/- 39 (97 +/- 38) µm in controls and 109 +/- 25 (101 +/- 28) µm in aspirin-treated young (aged) mice; mean +/- SD). In contrast, young mice treated with intravenous heparin had an increased hematoma diameter of 136 +/- 44 µm. These data suggest that aspirin does not increase the size of microhemorrhages, supporting the safety of aspirin usage.
Subject(s)
Aspirin/adverse effects , Cerebral Hemorrhage/etiology , Hematoma, Subdural, Intracranial/diagnosis , Platelet Aggregation Inhibitors/adverse effects , Severity of Illness Index , Age Factors , Aging/physiology , Animals , Arterioles/drug effects , Arterioles/pathology , Arterioles/surgery , Aspirin/administration & dosage , Cerebral Cortex/blood supply , Cerebral Cortex/pathology , Cerebral Hemorrhage/pathology , Cerebral Hemorrhage/physiopathology , Disease Models, Animal , Female , Hematoma, Subdural, Intracranial/etiology , Hematoma, Subdural, Intracranial/pathology , Hemostasis/drug effects , Humans , Male , Mice , Mice, Inbred C57BL , Platelet Aggregation Inhibitors/administration & dosageABSTRACT
Microhemorrhages are common in the aging brain, and their incidence is correlated with increased risk of neurodegenerative disease. Past work has shown that occlusion of individual cortical microvessels as well as large-scale hemorrhages can lead to degeneration of neurons and increased inflammation. Using two-photon excited fluorescence microscopy in anesthetized mice, we characterized the acute and chronic dynamics of vessel bleeding, tissue compression, blood flow change, neural degeneration, and inflammation following a microhemorrhage caused by rupturing a single penetrating arteriole with tightly-focused femtosecond laser pulses. We quantified the extravasation of red blood cells (RBCs) and blood plasma into the brain and determined that the bleeding was limited by clotting. The vascular bleeding formed a RBC-filled core that compressed the surrounding parenchymal tissue, but this compression was not sufficient to crush nearby brain capillaries, although blood flow speeds in these vessels was reduced by 20%. Imaging of cortical dendrites revealed no degeneration of the large-scale structure of the dendritic arbor up to 14 days after the microhemorrhage. Dendrites close to the RBC core were displaced by extravasating RBCs but began to relax back one day after the lesion. Finally, we observed a rapid inflammatory response characterized by morphology changes in microglia/macrophages up to 200 µm from the microhemorrhage as well as extension of cellular processes into the RBC core. This inflammation persisted over seven days. Taken together, our data suggest that a cortical microhemorrhage does not directly cause significant neural pathology but does trigger a sustained, local inflammatory response.
