Yan Wang, M.D., MSCI

ABSTRACT

Cerebral small vessel disease (CSVD) contributes to roughly 45% of dementia cases worldwide and is a leading cause of disability and cognitive decline in older adults, yet the biology driving its progression remains poorly understood. Structural imaging endpoints such as white matter hyperintensities describe the damage but not its cause. This project pairs blood proteomics with advanced mechanistic MRI in an existing prospective cohort of 143 adults spanning low to high risk of vascular cognitive impairment, with serial imaging and cognitive testing over a mean 28-month follow-up (240 MRIs and 364 cognitive assessments completed; baseline plasma banked for all participants). Using a targeted 220-protein panel enriched for neurodegeneration, synaptic injury, oxidative stress, inflammation, and endothelial dysfunction pathways, Aim 1 will identify proteomic signatures associated with MRI measures of tissue hypoxia, blood-brain barrier permeability, and glymphatic clearance. Aim 2 will test whether baseline proteins predict the rate of white matter disease progression and, as an exploratory sub-aim, cognitive decline at 30 months. Because CSVD is chronic and progressive, identifying mechanism-specific biomarkers before irreversible injury accrues could refine risk stratification, guide targeted therapeutic development, and open the door to prevention. The PI is supported by an NIH K23 through 2030 and plans an R01 application in 2028–2029.
Lay Summary:
Memory problems and dementia are a growing concern in aging populations worldwide, and injury to the small blood vessels of the brain is one of their major causes. The difficulty is that doctors typically recognize this brain injury only after symptoms like memory loss have already appeared — by which point damage is often irreversible. What causes the blood vessel injury in the first place, how to detect it early, and who will decline fastest all remain open questions.
Dr. Wang’s team follows 143 adults with early signs of small vessel disease, collecting advanced brain scans, memory testing, and blood samples over time. The brain scans are unusual in that they measure not just visible damage but underlying processes — whether brain tissue is getting enough oxygen, whether the barrier protecting the brain is leaking, and how well the brain clears metabolic waste. This project will test whether proteins measured in a blood sample taken at the start of the study can predict who goes on to develop worsening brain injury and memory decline. Identifying those at highest risk early, and understanding which biological pathways are driving their decline, is the first step toward treatments that could prevent vascular memory loss rather than simply document it.