Early identification of vascular cognitive impairment from a multimodal perspective: a combined diagnosis from targeted cognitive assessments, imaging biomarkers, and molecular fluid biomarkers to ecological behavioral characteristics

Abstract

Vascular cognitive impairment (VCI), the second leading cause of dementia, is characterized by heterogeneous pathophysiology and a potentially reversible early phase, underscoring the need for timely identification. This review synthesizes advances across four complementary domains – targeted cognitive assessments, imaging biomarkers, molecular fluid biomarkers, and ecological behavioral characteristics – conceptualized as the TIME framework. Emerging markers, including the peak width of skeletonized mean diffusivity (PSMD), oxygen extraction fraction, brain‐derived extracellular vesicles, and digital gait metrics, enable the detection of microvascular injury before overt cognitive decline. Given the limitations of single modalities, we advocate for multimodal integration via machine learning to capture the disease continuum from vascular insult to clinical impairment. Establishing a standardized, pathophysiologically anchored classification system, analogous to the AT(N) framework in Alzheimer's disease, is essential to advance precision risk stratification and early intervention in VCI.