Emerging Biomarkers in Vascular Cognitive Impairment and Dementia: From Pathophysiological Pathways to Clinical Application

Abstract

Vascular pathology is the second most common neuropathology of dementia after Alzheimer's disease (AD), with small vessels disease (SVD) being considered the major cause of vascular cognitive impairment and dementia (VCID). This review aims to evaluate pathophysiological pathways underlying a diagnosis of VCID. Firstly, we will discuss the role of endothelial dysfunction, blood-brain barrier disruption and neuroinflammation in its pathogenesis. Then, we will analyse different biomarkers including the ones of inflammatory responses to central nervous system tissue injuries, of coagulation and thrombosis and of circulating microRNA. Evidences on peripheral biomarkers for VCID are still poor and large-scale, prospectively designed studies are needed to translate these findings into clinical practice, in order to set different combinations of biomarkers to use for differential diagnosis among types of dementia.

Keywords: CSF biomarkers; blood biomarkers; peripheral biomarkers; vascular cognitive impairment; vascular dementia; vascular disease.

Figure 1

Endothelial dysfunction and cerebral inflammatory response in VCID. Endothelial dysfunction, observed in VCID, could lead to an increase in BBB permeability, a subsequent exposure of neural cells to harmful substances and a rise of inflammatory environment. The result is an activation of glial cells in the CNS, which finally lead to neuron damage. During inflammatory response, leukocytes are recruited from the circulation into the extravascular space. The activation of endothelial cells lead to the expression of adhesion molecules on their surfaces, allowing the binding to reciprocal molecules on the surfaces of circulating leukocytes. Indeed, activated endothelial cells up-regulate the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and selectins (P-selectin, E-selectin). L-selectin is mainly expressed on leukocytes. The increased BBB permeability lead to infiltration of inflammatory factors like interleukins, chemokines, cytochines, MMPs, TNFα, TLR4, CRP. Upon entry into the brain, these inflammatory factors can exacerbate white matter damage (demyelination, axonal loss, oligodendrocyte degeneration), cause neurodegeneration and cell death as well as enhance neuroglial inflammation. (VCID: vascular cognitive impairment and dementia; BBB: blood–brain barrier; CNS: central nervous system; MMPs: TNFα: Tumor necrosis factor; CRP: C-reactive protein).