Imaging blood–brain barrier dysfunction in animal disease models

Abstract

SUMMARYThe blood-brain barrier (BBB) is a highly complex structure, which separates the extracellular fluid of the central nervous system (CNS) from the blood of CNS vessels. A wide range of neurologic conditions, including stroke, epilepsy, Alzheimer's disease, and brain tumors, are associated with perturbations of the BBB that contribute to their pathology. The common consequence of a BBB dysfunction is increased permeability, leading to extravasation of plasma constituents and vasogenic brain edema. The BBB impairment can persist for long periods, being involved in secondary inflammation and neuronal dysfunction, thus contributing to disease pathogenesis. Therefore, reliable imaging of the BBB impairment is of major importance in both clinical management of brain diseases and in experimental research. From landmark studies by Ehrlich and Goldman, the use of dyes (probes) has played a critical role in understanding BBB functions. In recent years methodologic advances in morphologic and functional brain imaging have provided insight into cellular and molecular interactions underlying BBB dysfunction in animal disease models. These imaging techniques, which range from in situ staining to noninvasive in vivo imaging, have different spatial resolution, sensitivity, and capacity for quantitative and kinetic measures of the BBB impairment. Despite significant advances, the translation of these techniques into clinical applications remains slow. This review outlines key recent advances in imaging techniques that have contributed to the understanding of BBB dysfunction in disease and discusses major obstacles and opportunities to advance these techniques into the clinical realm.

A Dual-Labeled Annexin A5 is not Suited for SPECT Imaging of Brain Cell Death in Experimental Murine Stroke

“…It cannot be foreseen for a particular compound and therefore needs to be evaluated. 25 In the case of Annexin, however, the difference in molecular weight between the different AnxA5 compounds seems to be negligible, with B36,500 Da for Cy5.5-AnxA5 and 38,650 Da for HIS-cys-AnxA5-AF568.…”

Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood − brain barrier using MRI-guided focused ultrasound

“…Unfortunately, the BBB also limits systemically administered drugs from reaching the brain in therapeutically relevant concentrations [3,4]; thus, drug dose and efficacy are often limited by systemic side effects [5]. In the case of some CNS disorders, such as glioblastoma, Alzheimer’s, Parkinson’s, cerebral palsy, epilepsy and stroke, the BBB can be impaired and “leaky” [6-8]; however, this impairment is often heterogeneous and diseased cells are often found in normal brain parenchyma in regions supplied by healthy blood vessels with normal BBB function [9]. Other CNS disorders, including lysosomal storage diseases[10], depression [11], and recurrent migraines [12] present even higher obstacles to effective drug delivery into the brain.…”

The blood–brain barrier—Gatekeeper to neuronal homeostasis: Clinical implications in the setting of stroke

“…However, recent animal experiments and preliminary human data give new hope that targeting the immune response might turn into a realistic approach to prevent epilepsy [15,[139][140][141][142][143][144]. The correct selection of patients for such treatments may turn to be a critical step toward implementing specific, mechanism-based treatments, hence supporting efforts to develop reliable methods for measuring vascular permeability and local cerebral inflammation [14,[145][146][147].…”