What the white spots show

They show up as bright white spots when you get a brain MRI: lesions called white matter hyperintensities, or WMH. And their presence suggests something may be wrong with your brain’s white matter: there could be structural abnormalities.

The lesions are pretty common in people over 60 years old, and they become progressively more common with age. About 20 per cent of people over 60, and more than 90 per cent of people over 80, have them.

Studies have hinted that these small lesions in white matter might have something to do with thinning of the cerebral cortex.

Now, in new research published in Nature Communications, there’s proof that they do.

Working with colleagues in the U.S. and Europe involved in the Cohorts of Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, researchers at Université de Montréal point to clear genetic reasons why WMH appear so routinely in older adults.

“We set out to study WMH and their potential link to cortical atrophy, a core feature in dementia,” explained co-lead researcher, Zdenka Pausova, an UdeM pediatrics professor and scientist at the UdeM-affiliated CHU Sainte-Justine hospital research centre.

“We were motivated by a critical question: could genetic factors underlie the association between WMH and cortical thinning, and might they also explain part of the observed risk for dementia? What we found was that yes, they can.”

In their large-scale investigation into the genetics of WMH-associated cortical thinning, Pausova and her co-researchers gathered and analyzed data from 51,065 participants across 10 cohorts;  all were of European ancestry, the youngest 19 years old and the oldest 100.

“The findings confirmed that, across all cohorts, higher WMH volume was consistently associated with lower cortical thickness,” said Pausova’s husband and co-lead author Tomas Paus, an UdeM psychiatry and neuroscience professor who’s also a scientist at Sainte-Justine.

“That was true even when we adjusted for typical vascular risk factors like hypertension and diabetes,” Pausova added. “Particularly notable was the insula, a key brain region for integrating sensory, emotional, and cognitive functions, where we observed the strongest correlation.”

A genome-wide association study (meta-GWAS) was performed to explore genetic loci associated with this WMH-related cortical atrophy. The researchers identified 20 significant loci, of which 15 have an influence on genes within the cortex, particularly those involved in axonal transport and cytoskeletal organization, essential for maintaining neuronal health.

Moreover, these genetic signals were enriched in vascular cell types and cells supporting neuronal health, such as astrocytes and oligodendrocytes. This pattern aligns well with the hypothesis that disruptions in small blood vessels and axonal health may contribute to cortical thinning, connecting vascular risk to cortical atrophy, the scientists say.

“One particularly important aspect of our study was constructing a polygenic risk score based on our meta-GWAS,” said Pausova. “Applied to an independent dataset of 500,000 individuals in Finland, it showed that higher genetic vulnerability to WMH-related cortical atrophy predicts increased risk for both vascular and all-cause dementia.”

This finding underscores the need to consider vascular health in understanding dementia risk, as well as the genetic susceptibility to it that some individuals may carry, the scientists conclude in their study.