In vivo methods for imaging blood–brain barrier function and dysfunction

Abstract

The blood–brain barrier (BBB) is the interface between the central nervous system and systemic circulation. It tightly regulates what enters and is removed from the brain parenchyma and is fundamental in maintaining brain homeostasis. Increasingly, the BBB is recognised as having a significant role in numerous neurological disorders, ranging from acute disorders (traumatic brain injury, stroke, seizures) to chronic neurodegeneration (Alzheimer’s disease, vascular dementia, small vessel disease). Numerous approaches have been developed to study the BBB in vitro, in vivo, and ex vivo. The complex multicellular structure and effects of disease are difficult to recreate accurately in vitro, and functional aspects of the BBB cannot be easily studied ex vivo. As such, the value of in vivo methods to study the intact BBB cannot be overstated. This review discusses the structure and function of the BBB and how these are affected in diseases. It then discusses in depth several established and novel methods for imaging the BBB in vivo, with a focus on MRI, nuclear imaging, and high-resolution intravital fluorescence microscopy.

Hypergravity Increases Blood–Brain Barrier Permeability to Fluorescent Dextran and Antisense Oligonucleotide in Mice

“…In our previous study [65], the extravasation of IgG (around 150 kDa) was measured, suggesting that the nature of the molecule is also a crucial parameter. Moreover, our data showing the extravasation of antisense oligonucleotide in the cortex and hippocampus confirm that the BBB properties depend on the brain areas and the chemical nature of the markers [82][83][84]. In conclusion, our results showed an increase in the transfer of fluorescent molecules from blood to tissues, suggesting a global modification in effluxes due to hypergravity.…”

Visualization of blood-brain barrier disruption in septic mice with the new method based on in vivo imaging technology

“…24 With characteristics that include not binding to body proteins, complete excretion through urine, and a moderate half-life (about 60 minutes), NaFL is more suitable as a contrast agent for BBB injury than indocyanine green, which requires close binding with plasma proteins and lipids to form a complex to emit uorescence signals, 25 and 5-aminolevulinic acid, which can dissipate uorescence signals for more than 8 hours. 26 Existing BBB dynamic imaging methods include high-resolution in vivo microscopy and imaging examination, 27 which have different applicability; our new method expands and supplements the applicable scenarios of these methods, including facilitating application to drug development for sepsisrelated BBB injury and systemic vascular leakage syndrome. 28,29 In vivo microscopy is more invasive and has a shorter detection ux and time than the new method described in this study.…”

Investigating the structural network underlying brain-immune interactions using combined histopathology and neuroimaging: a critical review for its relevance in acute and long COVID-19

“…The effects of endotheliopathy and BBB leakage can be quite serious, given their contribution in acute and/or chronic neural inflammation and neuronal injury as well as associated neurological clinical manifestations ( 63 ). It should be pointed out that breakdown of the BBB can also be present in clinical conditions other than COVID-19, including acute disorders such as traumatic brain injury, stroke, and seizures or neurodegenerative diseases such as Alzheimer’s disease (AD), vascular dementia, small vessel disease and multiple sclerosis (MS) ( 66 , 69 , 70 ). Importantly, we are able to detect BBB leakage using neuroimaging.…”

“…Importantly, we are able to detect BBB leakage using neuroimaging. The most commonly applied technique is a T 1-weighted dynamic contrast-enhanced (DCE)-MRI, during which a gadolinium-based contrast agent is injected intravenously; leakage of the contrast agent can be detected when it crosses the damaged BBB (e.g., 70 , 71 ). It should be noted that there is substantial comorbidity between COVID-19 and AD ( 72 , 73 ) and the chronic neurological sequelae in Long COVID are also present in AD clinical phenomenology.…”