Imaging blood-brain barrier dysfunction: A state-of-the-art review from a clinical perspective

Abstract

The blood-brain barrier (BBB) consists of specialized cells that tightly regulate the in- and outflow of molecules from the blood to brain parenchyma, protecting the brain's microenvironment. If one of the BBB components starts to fail, its dysfunction can lead to a cascade of neuroinflammatory events leading to neuronal dysfunction and degeneration. Preliminary imaging findings suggest that BBB dysfunction could serve as an early diagnostic and prognostic biomarker for a number of neurological diseases. This review aims to provide clinicians with an overview of the emerging field of BBB imaging in humans by answering three key questions: (1. Disease) In which diseases could BBB imaging be useful? (2. Device) What are currently available imaging methods for evaluating BBB integrity? And (3. Distribution) what is the potential of BBB imaging in different environments, particularly in resource limited settings? We conclude that further advances are needed, such as the validation, standardization and implementation of readily available, low-cost and non-contrast BBB imaging techniques, for BBB imaging to be a useful clinical biomarker in both resource-limited and well-resourced settings.

Keywords: blood-brain barrier dysfunction; diagnostic imaging; magnetic resonance imaging; neurodegeneration; positron emission tomography.

FIGURE 1

Schematic overview of components of the blood-brain barrier. (A) Cross-section through the neurovascular unit, consisting of endothelial cells, pericytes, astrocytes, the basement membrane, neurons, and immune cells. (B) Illustration of the unique properties of the blood-brain barrier endothelial cells: (1) The presence of intercellular tight junctions and the absence of fenestration limiting paracellular diffusion, and (2) the presence of specific transporters to regulate in- and efflux of substrates (transcellular transport). EC, endothelial cell.

FIGURE 2

Schematic representation of the main processes driving BBB disruption, the key factors involved and the role of BBB imaging in stroke, cancer, AD, epilepsy, TBI, and MS. (A) BBB breakdown is initiated by ischemia and deteriorates with sustained hypoperfusion and inflammation. BBB breakdown is a precursor of more serious clinical consequences of ischemic stroke such as hemorrhagic transformation. (B) Brain tumors may disrupt the integrity of the BBB by the secretion of VEGF and is characterized by neurovascular decoupling, altered pericyte populations, reduction in the expression of tight junctions and changes in transcytosis mechanisms. (C) The initial insult leading to BBB breakdown is unknown. The resulting influx of pro-inflammatory molecules and the disturbed clearance of tau and Aβ triggers vascular-mediated secondary neuronal injury, degeneration and cognitive impairment in AD. (D) Epilepsy may induce BBB dysfunction, and conversely, BBB disruption may also cause (further) epileptic episodes. (E) Repetitive subconcussive forces and subsequent BBB dysfunction is known to be a risk factor for epilepsy and for late-life dementia (especially AD). (F) In MS, focal inflammation secondary to BBB disruption may trigger an inflammatory cascade leading to demyelination and axonal loss. Some features of the BBB have been omitted for simplicity (see Figure 1 for a detailed overview of the components of the BBB). AD, Alzheimer’s Disease; TBI, traumatic brain injury; MS, multiple sclerosis; BBB, blood-brain barrier; VEGF, vascular endothelial growth factor; TJ, tight junctions; Aβ, β-amyloid; K⁺, potassium.

FIGURE 3

General principle of the imaging techniques used to measure BBB integrity. PET, Positron emission tomography; SPECT, Single-photon emission computerized tomography; DCE MRI, Dynamic contrast-enhanced magnetic resonance imaging; ASL MRI, arterial spin labeling MRI; pCT, perfusion computed tomography; CA, contrast agent; HU, hounsfield units; P-gp, P-glycoprotein; MRP1, multidrug resistance-associated protein 1; T1w, T1-weighted; T2w, T2-weighted.

FIGURE 4

Different ways of BBB impairment, PET radiopharmaceuticals and their specific target on the blood-brain barrier. BBB, Blood-brain barrier; MRP1, Multidrug Resistance Protein 1; P-gp, P-glycoprotein; GLUT, glucose transporter; AQP, aquaporin; DTPA, diethylenetriaminepentaacetic; FDG, fluorodeoxyglucose.

FIGURE 5

PET tracers [¹¹C]Butanol and [¹⁵O]H₂O. 1. Difference in extraction fraction of both tracers. 2. Use of 2 tracers to yield an index of BBB permeability. (A) Flow of freely diffusible tracer across an intact BBB. (B) Flow of [¹⁵O]H₂O across an intact BBB. Water transport is modulated by AQP-4 channels. The extraction fraction of water will be lower than that of a freely diffusible tracer, [11C]Butanol. 3. Flow of [¹⁵O]H₂O across a disrupted BBB. (C) The extraction fraction of water will increase because of water extravasation into the brain through the BBB. AQP4, aquaporin-4; E_w, extraction fraction of water; E_diff, extraction fraction of diffusible tracer.

FIGURE 6

Examples of ME-ASL perfusion-weighted MRI images in a cognitively normal, 70-year-old man (Manson et al., 2020).