Spatial Connections between Brain Waste Clearance Dysfunction and White Matter Tissue Injury May Serve as Early Structural Biomarkers in Alzheimer's Disease

Magnetic Resonance Imaging (MRI) of the brain is a powerful tool for studying aging and neurodegenerative diseases. This non-invasive scan provides superb anatomical detail, distinguishing tissue such as gray and white matter, and cerebrospinal fluid. With age, there is a visible reduction in global brain volume along with white matter (WM) and hippocampal volumes; patchy hyperintensities or lesions in the WM (WML) also become more prominent and numerous. In addition to tissue loss and injury, there are prominent vascular changes that occur, including cerebral microbleeds, perivascular, and small vessel changes. Vascular integrity supports the brain's demand for oxygen and glucose, prevents entry of unwanted molecules, and clears metabolic waste products - all of which become less effective with age. Some changes observed with normal aging overlap and are more conspicuous in Alzheimer's Disease (AD). As the disease advances, certain regions of the brain reveal specific, temporal atrophy patterns which can be tracked with structural MRI to observe pathological progression after amyloid plaques begin to accumulate. 

Serena Tang is a graduate student in Dr. Tosun's lab who recently leveraged deep learning-based MRI segmentation maps to analyze the spatial associations between enlarged perivascular spaces (EPVS) and WML across the AD continuum. PVS are fluid-filled compartments surrounding the brain's microvasculature that serve as the structural conduit for glymphatic flow, a waste clearance mechanism in the brain. Enlargement of PVS may be a compensatory response to dysfunctional or blocked clearance. EPVS and WML are both consequences of microvascular injury. Interestingly, the number and size of EPVS have been correlated with AD pathology and cognitive decline. Serena thus hypothesized that EPVS and WML may be spatially coupled through interstitial fluid stagnation, where impaired clearance is associated with WM injury.

To assess spatial relationships, Serena looked at EPVS distribution, volume, and count at certain distances away from WML in cognitively unimpaired (CU) individuals, those with mild cognitive impairment (MCI), and individuals with AD dementia. A higher density of EPVS were found within 5-15 mm of WML in individuals with early AD (those who had evidence of amyloid burden), primarily the MCI individuals. This spatial relationship seemed to de-couple as the disease became more advanced. 

The spatial coupling between EPVS and WML in early stages of AD may be an attempt to compensate for reduced clearance in an area of high vascular vulnerability, where fluid is stagnant and the region contains microstructural damage that precedes WML growth. 

This study shows that MRI-visible EPVS and WML can be used as surrogate biomarkers for AD pathology. The spatial connection between waste clearance (EPVS) and WM tissue injury (WML) highlights a critical window where neurovascular dysfunction ultimately drives cognitive decline.

This research study is published in Frontiers in Neuroscience:

Tang S, Thropp P, Hausle I, Younes K and Tosun D (2026) Spatial coupling of enlarged perivascular spaces and white matter lesions across the Alzheimer’s disease continuum.  Front. Neurosci. 20:1772024.  doi: 10.3389/fnins.2026.1772024