Biomarkers in vascular dementia: A recent update

Vascular dementia (VaD) affects a broad spectrum of patients with various manifestations of cognitive decline, which could be attributed to cerebrovascular or cardiovascular disease. Diagnosis of VaD depends on the identification of environmental and genetic risk factors including; cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Mitochondrial oxidative stress, hypoxic ischemia, inflammation, accumulation of advanced glycation products, and proinflammatory cytokines have been implicated in the pathogenesis of VaD. Hence it is exceedingly important to determine the risk factors and molecular pathology by identifying specific biomarkers that can be broadly classified as: biochemical, molecular, genetic, endocrinological, anatomical, imaging, and neuropathological; for the early differential diagnosis, prognosis, and effective treatment of VaD. The biomarkers of VaD in the serum and cerebrospinal fluid samples include; phosphorylated tau, amyloid-β, matrix metalloproteases, sulfatids, albumin, and proinflammatory C-reactive proteins. In addition, Charnoly body (CB) formation and microRNAs can be detected as preapoptotic biomarkers of compromised mitochondrial bioenergetics to further confirm VaD. CB formation occurs in response to nutritional stress and/or neurotoxic insult in the most vulnerable hippocampal neurons due to cerebrovascular insufficiency, and can be attenuated by dietary interventions, physiological zinc supplementation, and metallothioneins (MTs). MTs provide ubiquinone-mediated neuroprotection by serving as free radical scavengers, by maintaining the mitochondrial redox balance, by inhibiting CB formation, and by inhibiting progressive neurodegenerative α-synucleinopathies. MTs also regulate zinc-mediated transcriptional activation of genes involved in cell growth, proliferation, and differentiation, and hence may be used as novel biomarkers of VaD. In addition to genetic analysis of MTs, Notch3, apolipoprotein E4, nitric oxide synthase, and cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy; omics and microRNA analyses may provide novel biomarkers of VaD. This review provides recent update on in-vitro biomarkers from the serum and cerebrospinal fluid samples and in-vivo neuroimaging biomarkers for the differential diagnosis and effective clinical management of VaD.