Amyloid Aggregation in the Brain as a Driver of White Matter Hyperintensities
A white matter hyperintensity is a small areas of tissue damage in the brain, such as results from rupture of a small blood vessel and consequent bleeding. These areas of damage are readily visible in MRI scans, and their prevalence is known to correlate with loss of cognitive function and rising dementia risk. Here, researchers provide evidence to suggest that this process is primarily the result of amyloid-β aggregation in the brain rather than vascular aging processes.
Bright spots called white-matter hyperintensities (WMHs) often appear on MRI scans of people with familial or sporadic Alzheimer's disease (AD), and they tend to intensify as the disease progresses. Some scientists think they reflect cerebrovascular disease. However, researchers now offer a different explanation. They reported that WMHs worsened most in people with extensive neurodegeneration, amyloid plaques, or cerebral microbleeds, a sign of cerebral amyloid angiopathy (CAA), while WMH severity did not correlate with vascular risk. They concluded that WMHs are driven by AD pathology.
Researchers compared the total volume of WMHs to cardiovascular risk, as measured by the Framingham Heart Study cardiovascular disease risk score, and to the amount of amyloid, be it plaques or CAA. Researchers drew data from clinical records and almost 4,000 brain scans of 1,141 people from three longitudinal cohorts: the Harvard Aging Brain Study, the Alzheimer's Disease Neuroimaging Initiative, and the Dominantly Inherited Alzheimer Network. At baseline, WMH volume was greatest among those who were oldest, had the least gray matter, the highest amyloid burden, or who had two or more cerebral microbleeds, a commonly used indicator of CAA that can only be diagnosed at autopsy. Over time, WMHs worsened more among these people than among their respective controls.
This fits with the idea that amyloid constricts blood vessels. Researchers have found that soluble amyloid-β slowed cerebral blood flow in wild-type and amyloidosis mice and that vascular injury can be prevented if reactive oxygen species (ROS) scavengers are administered before the peptide settles into vessels as CAA. ROS are a major cause of vessel damage by amyloid-β. Did vascular health factor into WMH severity? Surprisingly, the amount of WMHs had no correlation with cardiovascular risk score after accounting for age, gray-matter volume, amyloid burden, and cerebral microbleeds. The authors concluded that amyloid and gray-matter atrophy, i.e., neurodegeneration, drives the brain lesions rather than small-vessel disease.