New candidate blood biomarkers potentially associated with white matter hyperintensities progression

Joan Jiménez-Balado,Elena Palà,Mar Hernández-Guillamon,Jesús Pizarro,Iolanda Riba-Llena,Júlia Faura,Joan Montaner,Pilar Delgado,Anna Penalba

doi:10.1038/s41598-021-93498-w

Abstract

We aimed to discover blood biomarkers associated with longitudinal changes in white matter hyperintensities (WMH). This study was divided into a discovery phase and a replication phase. Subjects in both studies were patients with hypertension, aged 50–70, who underwent two magnetic resonance imaging (MRI) sessions and blood extractions over a 4-year follow-up period. In the discovery phase, we screened 1305 proteins in 12 subjects with WMH progression and in 12 matched control subjects. We found that 41 proteins were differentially expressed: 13 were upregulated and 28 were downregulated. We subsequently selected three biomarkers for replication in baseline and follow-up samples in 80 subjects with WMH progression and in 80 control subjects. The selected protein candidates for the replication were MMP9 (matrix metalloproteinase-9), which was higher in cases, MET (hepatocyte growth factor receptor) and ASAH2 (neutral ceramidase), which were both lower in cases of WMH progression. Baseline biomarker concentrations did not predict WMH progression. In contrast, patients with WMH progression presented a steeper decline in MET over time. Furthermore, cases showed higher MMP9 and lower ASAH2 levels than controls at the follow-up. These results indicate that MMP9, MET, and ASAH2 are potentially associated with the progression of WMH, and could therefore be interesting candidates to validate in future studies.

Highlights

We aimed to discover blood biomarkers associated with longitudinal changes in white matter hyperintensities (WMH)
We found that MMP9 and MET significantly decreased within visits, while ASAH2 increased
One possible explanation might be that the decrease in MET within visits reflects the downregulated activity of neuroprotective processes and angiogenesis, which might be explained by a lower hepatocyte growth factor (HGF)/MET binding

Summary

Introduction

We aimed to discover blood biomarkers associated with longitudinal changes in white matter hyperintensities (WMH). Cases showed higher MMP9 and lower ASAH2 levels than controls at the follow-up These results indicate that MMP9, MET, and ASAH2 are potentially associated with the progression of WMH, and could be interesting candidates to validate in future studies. There is a long therapeutic window in which preventive strategies could attempt to slow or halt this evolution For this purpose, it is crucial to understand the pathophysiology of WMH, especially if we aim to develop adequate clinical interventions[2]. It is crucial to understand the pathophysiology of WMH, especially if we aim to develop adequate clinical interventions[2] Nowadays these changes in WMH can only be detected with the use of serial magnetic resonance imaging (MRI), which complicates the diagnosis of WMH in most settings due to the elevated cost of neuroimaging techniques. Most of these studies had cross-sectional designs, so it was not Scientific Reports | (2021) 11:14324

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