Fluid biomarkers of vascular cognitive Impairment: From vascular pathophysiology to potential clinical applications

Vascular cognitive impairment (VCI) refers to cognitive decline resulting from cerebrovascular pathology, affecting one or more cognitive domains. Chronic vascular risk factors and acute cerebrovascular events contribute significantly to this condition. Identifying fluid biomarkers indicative of vascular injury is crucial for early prevention, accurate diagnosis, and assessing treatment efficacy in VCI. Chronic vascular injury leads to arterial lesions, blood-brain barrier disruption, venous tortuosity and obstructed drainage, enlarged perivascular spaces, and impaired glymphatic drainage. This review explores biomarkers involved in VCI pathogenesis, including neurodegenerative proteins, inflammatory mediators, oxidative stress markers, metabolic byproducts, acute phase reactants, vasoactive neuropeptides, the cerebrospinal fluid/plasma albumin quotient, neurofilament light chain, circulating CD34 + cells, and miRNAs. Most biomarkers are derived from blood and cerebrospinal fluid, with the exception of 8-hydroxydeoxyguanosine, excreted in urine. Combining biomarkers from various fluid sources can enhance diagnostic accuracy for VCI. Given the interplay between blood buffering and renal excretion in biomarker production, we advocate for further research into urine-derived biomarkers. These may offer valuable insights for early detection of vascular changes and ultra-early prediction of VCI.