Big Effects From Tiny Vessels

Improvement in clinical imaging technologies has made it possible to resolve small, previously invisible lesions in the brains of elderly humans. Initially, these lesions were called silent strokes because they do not present with dramatic acute symptoms like major stroke. It was later shown that these small lesions have cognitive consequences and are a contributing factor to age-related mental decline and dementia.1–3 In analogy to large strokes, these microscopic lesions are thought to be caused by disruptions of small blood vessels. The lesions are small simply because the territory covered by a small vessel is limited in size. There are 2 categories of vascular events that could lead to these lesions. First, occlusions of small vessels can prevent blood flow from reaching a region of brain tissue leading to ischemic damage. In addition, microscopic deposits of red blood cell lysis products found in postmortem human studies suggest that microvessels might also hemorrhage.4 Understanding the causes and effects of these small lesions is complicated by the small size of the vessels thought to be involved, resulting in a limited number of animal models that reflect the human pathology. Recent advances in optical tools, both in chronic, high-resolution imaging with multiphoton microscopy and in the innovative use of laser ablation and photothrombosis to generate targeted vascular lesions, have enabled controlled studies of how clotting or hemorrhage of small vessels affect the health and function of brain cells.5,6 Femtosecond laser ablation, in which a high-power laser pulse can be used to selectively ionize a portion of a blood vessel even when it is below the surface of brain tissue, can be used to generate both occlusions and hemorrhages in microvessels (Figure 1).5 Combined with 2-photon imaging in transgenic animals that express fluorescent proteins in …