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.
Fig: Study design and number of patients in each phase. Discovery and replication phases were conducted within the ISSYS cohort (patients with hypertension, aged 50–70, and without dementia and stroke at the baseline visit). In both phases of the study, progression of WMH was defined as a total RPS score greater than or equal to 3. In the discovery phase, cases and controls were matched by age, sex, and baseline WMH burden, while in the replication phase, cases and controls were matched by age and sex. Parts of this figure were supported by Servier Medical Art with permission under the Creative Commons Attribution 3.0 Unported License. The figure was constructed using Microsoft Office Powerpoint 365, GNU image manipulation software and ‘ggplot’ library included in R software. ASAH2, neutral ceramidase; ISSYS, Investigating Silent Strokes in hYpertensives Study; MET, hepatocyte growth factor receptor; MMP9, matrix metalloproteinase-9; RPS, Rotterdam progression scale; WMH, white matter hyperintensities.
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.
Jiménez-Balado, J., Pizarro, J., Riba-Llena, I. et al. New candidate blood biomarkers potentially associated with white matter hyperintensities progression. Sci Rep 11, 14324 (2021). https://doi.org/10.1038/s41598-021-93498-w