Magnetic Resonance Imaging of Blood-Brain Barrier permeability in Dementia

Abstract

Alzheimer's disease (AD) and cerebral small vessel disease (cSVD) are the two main causes of dementia with blood-brain barrier (BBB) breakdown being a common contributor. Recent advances in neuroimaging techniques offer new possibilities to understand how the brain functions in health and disease. This includes methods such as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) which allows the detection of subtle regional changes in the BBB integrity. The purpose of this work is to provide a review on the recent DCE-MRI findings of subtle BBB leakage focusing on cSVD and AD, including both clinical and pre-clinical studies. Despite being widely used and well-established, we also highlight some of the DCE-MRI challenges and pitfalls faced in the context of dementia inherent to the subtle nature of BBB impairment.

Keywords: Alzheimer's disease; blood-brain barrier; cerebral small vessel disease; dementia; magnetic resonance imaging.

Figure 1.. Blood-brain barrier in health and dementia.

A simplified neurovascular unit (NVU) diagram showing a healthy blood-brain barrier (BBB) with the interactive cellular network at the level of brain capillaries that comprises endothelial cells, pericytes, basal membrane, and astrocyte end-feet (top panel). In dementia, changes to endothelial cells and pericytes lead to loss of function and BBB breakdown with loss of tight junction proteins (bottom panel). Subtle extravasation of Gadolinium (Gd) contrast can be detected using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in both living cerebral small vessel disease (cSVD) and Alzheimer’s disease (AD) participants. Subsequent damage then occurs to the surrounding brain cells such as astrocytes, neurons, and oligodendrocytes contributing to pathology and cognitive decline (Figure created using Biorender.com).

Figure 2.. DCE-MRI and BBB assessment.

DCE-MRI is used to measure BBB integrity by measuring the concentration of gadolinium contrast agent over time in the blood plasma (C_p) and in the brain tissue (C_t). These measured concentrations are then used to calculate the blood-to-brain transfer coefficient (K_trans) and the blood volume (v_p) using the Patlak mathematical model (Figure created using Biorender.com).

Figure 3.. Flow Diagram of literature search.

Recent research articles and reviews (January 1, 2015 - May 7, 2021) focusing on blood-brain barrier (BBB) permeability measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in normal aging, cerebral small vessel disease (cSVD) or Alzheimer’s disease (AD) were recovered from Pubmed search. In addition to the 39 articles retrieved from the systematic search, 11 additional articles highly relevant to our focus were added (green boxes), leading to a total of 50 reviewed papers. Research articles were categorized into three tables: Tables 1 and 2 summarize DCE-MRI studies performed in cSVD participants (11 publications) and in the AD continuum [including normal aging, mild cognitive impairment (MCI), and AD participants] (14 publications), respectively; Table 3 summarizes pre-clinical DCE-MRI studies in animal models relevant to dementia (6 publications). *Some studies have occurrences for several conditions.

Figure 4.. Dynamic contrast-enhanced magnetic resonance imaging and motion correction.

Dynamic contrast-enhanced (DCE) protocol acquisition without contract injection shows percent signal change calculated from a linear fit over time (top images). Left image is the ‘without motion correction’ and shows signal changes up to 25%, particularly at cerebrospinal fluid (CSF)-tissue interface, due to small motions of subjects’ head. Right image is the same dataset after motion correction, which shows almost all signal change is eliminated. Bottom graphs show calculated brain motion relative to the first image along the three principal axis (A-P, anterior-posterior; R-L, right-left; I-S, inferior-superior). Even <0.5 mm of motion can induce significant signal changes (Images courtesy of SRB).