Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability

Abstract

Vascular dementia is the second most common type of dementia after Alzheimer’s disease (AD). Subcortical ischemic vascular disease refers to a form of vascular cognitive impairment characterized by the presence of diffuse white matter hyperintensities (WMHs) and multiple lacunar infarcts. These neuroimaging findings are mainly caused by cerebral small-vessel disease (cSVD) and relate to aging and cognitive impairment, but they can also be silent and highly prevalent in otherwise healthy individuals. We aimed to review studies on blood and cerebrospinal fluid (CSF) markers related to the presence of WMHs and lacunar infarcts that have been conducted in the past in large population-based studies and in high-risk selected patients (such as those with vascular risk factors, vascular cognitive impairment, or AD). Relevant associations with the presence and progression of cSVD have been described in the blood for markers related to inflammatory processes, endothelial damage and coagulation/fibrinolysis processes, etc. Also, different combinations of CSF markers might help to differentiate between etiologic types of dementia. In the future, to translate these findings into clinical practice and use biomarkers to early diagnosis and monitoring vascular cognitive impairment would require the replication of candidate markers in large-scale, multicenter, and prospectively designed studies.

Figure 1.

Representative examples of imaging markers of cerebral small-vessel disease. From left to right: brain infarct affecting caudate nuclei is shown by a white arrow (fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI)), extensive white matter changes (FLAIR MRI), and enlarged perivascular spaces involving basal ganglia shown by white arrows and moderate tempooccipital brain atrophy (T2 MRI); 1.5 Tesla MR (Signa HDx 1.5, General Electric, Waukesha, WI, USA).

Figure 2.

(a) Main molecular pathways analyzed in subcortical ischemic vascular disease (SIVD). Pie chart of molecular pathways corresponding to those biomarkers reviewed with consistent association with SIVD lesions in more than 1,000 subjects. Portions represent percentage per number of pathways. (b) Functional network of biomarkers reviewed and their predicted partners. Network chart displaying prediction methods (neighborhood, gene fusion, cooccurrence, coexpression, experiments, databases, and textmining) applied to those biomarkers reviewed with consistent association with silent brain infarct (SBI) and white matter hyperintensity (WMH), and their predicted functional partners (underlined in red). Lines represent different link evidences according to different colors, based on databases such as Saccharomyces Genome Database (SGD), Online Mendelian Inheritance in Man (OMIM), FlyBase, and PubMed. Green head arrows: activation; red end lines: inhibition; green lines: coexpression; blue lines: binding; black lines: reaction; gray lines: statistically relevant cooccurrences of genes. Corresponding proteins to gene names of reviewed biomarkers displayed: troponin t (TNNT2), vascular cell adhesion molecule 1 (VCAM1), E-selectin (SELE), interleukin-6 (IL-6), lipoprotein phospholipase A2 (PLA2G7), C- reactive protein (CRP), intercellular adhesion molecule 1 (ICAM1), angiotensin converting enzyme (ACE), von Willebrand factor (vWF), plasminogen activator inhibitor-1 (SERPINE1), and P-selectin (SELP). Corresponding proteins to gene names of predicted partners displayed: urokinase plasminogen activator (PLAU), vitronectin (VTN), tissue plasminogen activator (PLAT), selectin P ligand (SELPLG), integrin beta 2 (ITGB2), integrin alpha L (ITGAL), interleukin-6 signal transducer (IL6ST), interleukin-6 receptor (IL-6R), troponin I type 3 (TNNI3), and troponin C type 1 (TNNC1); STRING database (http://string-db.org/).