Blood-Brain Barrier Dysfunction in Neurological Diseases
Danny JJ Wang1
1University of Southern California (USC), United States

Synopsis

Keywords: Neuro: Brain function, Contrast mechanisms: Perfusion, Image acquisition: Quantification

Blood-brain barrier (BBB) plays a critical role in the delivery of oxygen and nutrients to the brain, clearance of toxic metabolites, and protection of the central nervous system (CNS) from infection. Impaired BBB function is implicated in a number of serious CNS diseases, such as multiple sclerosis, stroke, brain tumors, Alzheimer's disease and small vessel disease. Assessment of BBB permeability commonly relies on dynamic contrast enhanced MRI using Gd-based contrast agents. Recently, contrast and non-contrast MRI methods have emerged to assess BBB water exchange. The combination of these MRI methods has revealed the mechanism of BBB dysfunction in neurological disorders.

Introduction

Blood-brain barrier (BBB) plays a critical role in the delivery of oxygen and nutrients to the brain, clearance of toxic metabolites, and protection of the central nervous system (CNS) from infection. Compromised or impaired BBB function is implicated in a number of serious CNS diseases, such as multiple sclerosis (MS), stroke, brain tumors, CNS infection, Alzheimer's disease (AD) and cerebral small vessel disease (cSVD). As shown in Fig. 1, the BBB consists of several functional elements (1): endothelial cells (EC) lining the capillaries with tight junctions (TJs) between ECs. The endothelial monolayer is surrounded by a discontinuous layer of pericytes separated by the basement membrane. Adjacent to the pericytes are the astrocyte feet on which aquarporin-4 (AQP4) water channels are distributed. Damage to the BBB can increase the permeability of the walls of the blood vessels within the brain, leading to the influx of neurotoxic and pro-inflammatory molecules, and invoking local inflammatory responses. This, in turn, further disrupts the integrity of the BBB and may lead to hemorrhagic transformation in stroke, metastatic initiation in tumors, or neurodegeneration in AD.

Methods

Currently, assessment of BBB permeability relies on CSF sampling of albumin through lumbar puncture to measure CSF/plasma albumin ratio and/or dynamic contrast enhanced (DCE) MRI using Gd-based contrast agents (GBCAs). Since albumin (66 kDa) and GBCAs (~550 Da) have relatively large molecular weights, BBB permeability has to reach a critical level before extravasation occurs. In addition, GBCAs have potential renal complications, and have been linked to Gd deposition in the brain especially in persons undergoing repeated DCE scans. Recently, both contrast and non-contrast MRI methods have emerged to assess BBB water exchange (1). In contrast agent based approaches, an intravascular contrast agent is introduced into the blood pool to increase intravascular-extravascular T1 differences. Because T1 interactions are short range, any changes in the T1 of the extravascular compartment can be attributed to trans-BBB water exchange. In contrast agent free approaches, a number of ASL methods have been introduced for assessment of BBB function, including diffusion-weighted (DW) ASL and multi-echo (ME) ASL techniques for measuring the rate of water exchange (kw) across the BBB (2-5).

Results

While DCE MRI measures of Ktrans are sensitive to BBB disruption in tumor, stroke and MS, it remains challenging to measure subtle changes of BBB permeability in aging, AD and cSVD, which requires long scan time and there are considerable heterogeneities in imaging parameters and protocols (6). Community efforts for harmonizing DCE MRI protocols have emerged such as HARNESS consortium (7). Existing evidence showed Ktrans in hippocampus increases in APOE4 carriers and subjects with mild cognitive impairment (MCI)(8,9) (Fig. 2). However, Ktrans was not associated with Abeta or tau protein. There is also converging evidence supporting increased BBB permeability in cSVD (10). However, recent studies using DW ASL reported reduced BBB water exchange rate kw in aging, cognitive decline and cSVD (11-14), and decreased kw was associated with Abeta in CSF or PET (Fig. 3). These seemingly contradictive findings between BBB permeability to GBCA and water exchange rate can be explained in the context of multiple components of the BBB and their different functions. In fact, contrast-based MRI studies have reported increased Ktrans and reduced kw in aging, MS and brain tumor (15,16), which has been attributed to active co-transport of water across the BBB through Na,K-ATPase pump.

Summary and Discussion

Accumulating evidence suggests that BBB dysfunction is a core mechanism in a number of neurological disorders. Emerging contrast and noncontrast MRI methods have been developed to assess BBB function and helped unveil the underlying biological mechanisms of BBB dysfunction and failure in a range of neurologic disorders.

Acknowledgements

NIH grants UF1-NS100614, R01-EB014922 and RF1-NS122028

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Figures

Fig 1a) Schematic plot of BBB structure; b) enlarged view BBB structure and trans-membrane water exchange and transport of glucose and nutrients (Dickie et al Prog in Nuclear Magn Reson Sepctro 2020)

Fig 2. DCE MRI showed increasing Ktrans in hippocampus in APOE4 carriers and CDR0.5 subjects (Montagne, Nation, et al., Nature2020)

Fig. 3. Kw decreases in APOE4 carriers and correlated with brain iron levels, β-amyloid loads (Uchita et al JNNP (2022);Kw correlated with CSF Abeta-42 (Gold, Shao et al Alzheimer & Dementia (2021)

Proc. Intl. Soc. Mag. Reson. Med. 31 (2023)