New candidate blood biomarkers potentially associated with white matter hyperintensities progression

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.

Correlations of Plasma Biomarkers and Imaging Characteristics of Cerebral Small Vessel Disease

“…Joan Jiménez-Balado has used a proteomic approach to find 41 proteins significantly expressed in participants with WMH progression compared to matched controls. Furthermore, neutral ceramidase (ASAH2) is negatively associated with the progression of WMH in the follow-up ( p = 0.01) [ 40 ], which was not reported in the past. ASAH2 prevents the accumulation of ceramides through the sphingolipid metabolism hydrolyzing ceramides pathway [ 85 ], which has been shown to be associated with AD neurological pathologies, and consequently affects cognitive function [ 86 ].…”

“…Elkind [13] 1244 lacunar stroke CRP RSSI Jiyang Jiang [14] 327 elderly participants aged 70 to 90 years MIC-1/GDF15 WMH Charlotte Andersson [15] 3374 Framingham Offspring GDF15, ST2 WMH, brain atrophy Arnab Datta [16] 45 lacunar stroke proteomic RSSI Andrea Vilar-Bergua [17] 972 hypertension N-glycome Profile WMH [19] 324 CIND; AD GDF15 WMH, RSSI, lacune Amelia K. Boehme [20] 1244 lacunar stroke IL-6, amyloid A, TNFR1, CD40L, MCP1 RSSI Li Yang [21] 56 lacunar stroke Lipidomic RSSI Yanan Zhu [22] 315 CIND; AD t IL-6, IL-8, TNF-α WMH, RSSI, lacune Thomas Gattringer [23] 579 RSSI NfL WMH, RSSI Ki-Woong Nam [24] 2875 people with a health check-up NLR WMH Huimin Fan [25] 389 lacunar stroke Homocysteine RSSI Huang Guoxiang [26] 408 noncritically ill hospitalized patients Cystatin C WMH Jacek Staszewski [27] 123 CSVD vascular and systemic inflammation biomarkers WMH, lacune Daniela Pinter [28] 78 RSSI NfL RSSI Simon R. Cox [29] 593 elderly participants aged 73 to 76 years S100β WMH Esther M.C. van Leijsen [30] 487 CSVD Aβ WMH, CMB, lacune Weimin Wei [31] 346 hypertension BNP WMH, CMB, RSSI Yanan Zhu [32] 310 CIND; AD HGF WMH, CMB, RSSI, lacune Emer R. McGrath [33] 1603 Framingham Offspring GDF-15, NT-proBNP WMH, brain atrophy Yan Sun [34] 1029 CIND NfL WMH Peng Xu [35] 12 lacunar stroke miR-133, IL-6, IL-8, CRP, TNF-α RSSI Larisa A. Dobrynina [36] 70 CSVD NR2ab WMH, lacune Yi Qu [37] 496 CIND NfL WMH, CMB, RSSI, CSVD burden Alison E Fohner [38] 1362 elderly participants aged 65 years or older NfL, total Tau, GFAP, UCH-L1 WMH Bibek Gyanwali [39] 434 CIND NT-proBNP, hs-cTnT, GDF-15 WMH, CMB, RSSI, lacune Joan Jiménez-Balado [40] 24 hypertension proteomic WMH Yuek Ling Chai [41] 384 CIND; AD OPN WMH, brain atrophy Andres da Silva-Candal [42] 624 hypertension or diabetes w TWEAK WMH Sanne Kuipers [43] 494…”

Genetic Predisposition for White Matter Hyperintensities and Risk of Mild Cognitive Impairment and Alzheimer’s Disease: Results from the HELIAD Study

“…Therefore, a more sophisticated strategy that integrates PRS with plasma biomarkers and considerations of lifestyle as well as environmental factors might be necessary to establish more precise proxies for pathology. Moreover, the genetic predisposition for WMH burden was determined based on the effects of common variants identified in GWASs, while other rare variants, haplotypes, epigenetic components, and biomarkers known to affect WMH volume were not examined [61][62][63][64]. The modifying effect of CR could not be assessed for other brain pathologies such as tau and amyloid deposition [31,65].…”

Epigenetic Clock Explains White Matter Hyperintensity Burden Irrespective of Chronological Age

“…Clinical studies have shed light on which clinical variables relate to increased WMH burden, being age and high blood pressure; factors that have been consistently associated with WMH [5]. Furthermore, several studies have explored whether blood biomarkers that were altered in stroke patients also correlated with the WMH burden [6,7]. However, most groups have focused on proteomic studies [7], while epigenetics of WMH have received less attention.…”

“…Furthermore, several studies have explored whether blood biomarkers that were altered in stroke patients also correlated with the WMH burden [6,7]. However, most groups have focused on proteomic studies [7], while epigenetics of WMH have received less attention. Epigenetics (the regulation of gene expression without altering the DNA sequence) might provide insight on which pathological mechanisms trigger WMH accumulation.…”