Increase in blood\u2013brain barrier leakage in healthy, older adults

Inge C M Verheggen,Frans R J Verhey,Walter M Palm,Walter H Backes,Martin P J van Boxtel,Ed H B M Gronenschild,Jacobus F A Jansen,Joost J A de Jong,Alida A Postma

doi:10.1007/s11357-020-00211-2

Inge C M Verheggen, Frans R J Verhey + Show 7 more

Open Access

https://doi.org/10.1007/s11357-020-00211-2

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Abstract

Blood–brain barrier (BBB) breakdown can disrupt nutrient supply and waste removal, which affects neuronal functioning. Currently, dynamic contrast-enhanced (DCE) MRI is the preferred in-vivo method to quantify BBB leakage. Dedicated DCE MRI studies in normal aging individuals are lacking, which could hamper value estimation and interpretation of leakage rate in pathological conditions. Therefore, we applied DCE MRI to investigate the association between BBB disruption and age in a healthy sample. Fifty-seven cognitively and neurologically healthy, middle-aged to older participants (mean age: 66 years, range: 47–91 years) underwent MRI, including DCE MRI with intravenous injection of a gadolinium-based contrast agent. Pharmacokinetic modeling was applied to contrast concentration time-curves to estimate BBB leakage rate in each voxel. Subsequently, leakage rate was calculated in the white and gray matter, and primary (basic sensory and motor functions), secondary (association areas), and tertiary (higher-order cognition) brain regions. A difference in vulnerability to deterioration was expected between these regions, with especially tertiary regions being affected by age. Higher BBB leakage rate was significantly associated with older age in the white and gray matter, and also in tertiary, but not in primary or secondary brain regions. Even in healthy individuals, BBB disruption was stronger in older persons, which suggests BBB disruption is a normal physiologically aging phenomenon. Age-related increase in BBB disruption occurred especially in brain regions most vulnerable to age-related deterioration, which may indicate that BBB disruption is an underlying mechanism of normal age-related decline.Netherlands Trial Register number: NL6358, date of registration: 2017-03-24.

Highlights

An increasing number of people are reaching older ages (Lutz et al 2008), and studies into the causes and prevention of age-related disorders are becoming increasingly important
Cerebral microvascular alterations, occurring over time and contributing to blood–brain barrier (BBB) breakdown, could be a promising topic to study in relation to normal age-related decline (Farkas and Luiten 2001; Norton et al 2019)
Experienced neuroradiologists visually rated white matter lesion load according to the Fazekas scale (Fazekas et al 1993) (W.P.) and brain atrophy using the global cortical atrophy (GCA) scale (Pasquier et al 1996) (A.P.), to confirm our sample could be considered neurologically healthy

Summary

Introduction

An increasing number of people are reaching older ages (Lutz et al 2008), and studies into the causes and prevention of age-related disorders are becoming increasingly important. People who age without any overt pathological condition may still experience some degree of age-related decline (Woodruff-Pak 1997). This decline shows large interindividual differences (Rapp and Amaral 1992), while it remains unclear what factors determine whether someone will be strongly affected by age or hardly experience any age-related setback. The endothelium contains specialized transport systems that allow nutrients to move from the blood to the brain, while waste products are removed in the opposite direction (Montagne et al 2017; Zhao et al 2015). The BBB thereby protects the brain from concentration fluctuations that occur in the blood stream, which is essential for neuronal and synaptic functioning (Zlokovic 2008)

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