Extracellular vesicle protein levels are related to brain atrophy and cerebral white matter lesions in patients with manifest vascular disease: the SMART-MR study

Abstract

ObjectivesExtracellular vesicles (EVs) and their protein levels have been identified as a potential risk marker for the development of vascular disease. In the present study, we assessed whether levels of four previously identified EV proteins (cystatin C, serpin G1, serpin F2 and CD14) are associated with cerebral white matter lesions (WMLs) and brain atrophy.DesignCohort study; cross-sectional and prospective.SettingSingle centre, secondary and tertiary setting.Participants1309 patients with manifest vascular disease from the Second Manifestations of ARTerial disease-MR (SMART-MR) study, of which 994 had successful brain MRI and EV protein level measurements.OutcomesWML and brain parenchymal fraction (BPF), as parameter for brain atrophy, at baseline and follow-up.Statistical methodsThe relationship between EV protein levels and WML volume (expressed as log transformed percentage of intracranial volume) and BPF (expressed percentage of intracranial volume) on 1.5 T brain MRI was assessed with multivariable linear regression modelling. Subsequently, the relationship between baseline EV protein levels and progression of atrophy and WML was analysed in 534 patients, in whom a follow-up MRI was obtained after 4 years.ResultsHigher EV-cystatin C and EV-CD14 were significantly associated with larger WML volume (linear regression coefficient (95% CI) 0.10 log %/SD (0.04 to 0.17) and 0.14 log %/SD (0.07 to 0.20), respectively. Higher EV-CD14 was associated with more brain atrophy (–0.14%/SD; –0.27 to –0.01). Baseline EV-CD14 was significantly associated with increase of WMLs (0.11 log %/SD (0.04 to 0.18)). No relationship with EV-serpins was observed at baseline or at follow-up.ConclusionsEV proteins cystatin C and CD14 are related to cerebral WMLs and the progression of brain atrophy in patients with manifest vascular disease, potentially identifying EVs in the aetiology of structural brain changes.

Candidate biomarkers of multiple system atrophy in cerebrospinal fluid

“…Evidence has revealed that cystatin C binds to β-amyloid, resulting in the inhibition of β-amyloid deposition in senile plaques of AD (Sastre et al, 2004;Kaeser et al, 2007;Kanhai et al, 2014).…”

Part Two: Extracellular Vesicles as a Risk Factor in Neurodegenerative Diseases

“…Following translocation to ECs through exosome internalization, miR-132 regulates the expression of vascular ECs cadherin (VE-cadherin), an important adherens junction protein, by directly targeting eukaryotic elongation factor 2 kinase [31]. In addition, two proteins found in peripherally circulating plasma EVs, cystatin C and CD14, have been linked to the development of brain atrophy and to cerebral white matter lesions, a small vessel disease within the brain [32]. Because exosomes contain transferrin and insulin receptor [25,28], which mediate macromolecular passing through the blood-brain barrier (BBB), peripherally infused modified exosomes containing specific RNA were used to knockdown a specific gene in mouse brain [32][33][34].…”

“…In addition, two proteins found in peripherally circulating plasma EVs, cystatin C and CD14, have been linked to the development of brain atrophy and to cerebral white matter lesions, a small vessel disease within the brain [32]. Because exosomes contain transferrin and insulin receptor [25,28], which mediate macromolecular passing through the blood-brain barrier (BBB), peripherally infused modified exosomes containing specific RNA were used to knockdown a specific gene in mouse brain [32][33][34]. Considering the extraordinary intricate cytoarchitecture of the brain, the presence of EVs in the adult brain is hard to be documented.…”

“…Different neuronal cell types and molecules concur to regulate the improvement of brain vasculature [31,[80][81][82]. Each cell, including neurons and astrocytes [32,83], is able to produce EVs enriched in specific proteins, lipids, and RNAs. EVs can stimulate targeted neural cells and surrounding neural tissues, which are important elements of vascular integrity preservation.…”

“…A number of studies have shown that EVs regulate arterial stiffness [32,85] which is linked to small vessel [32,[86][87][88], and platelet-derived EVs seem to be important players in the formation of cerebral microthrombi which lead to brain atrophy and consequent cognitive degeneration. It is believed that the prothrombotic nature of an elevated number of platelet-derived EVs reported in the acute phase of cerebral infarction may conduct to infarct progression [32,84,89,90]. EV proteins cystatin C and CD14 have been shown to be related to cerebral white matter lesions and the progression of brain atrophy in patients with manifest vascular disease, suggesting a role for EVs in the etiology of structural brain changes [32].…”