In the July 17 JAMA Neurology, scientists led by Lenore Launer, National Institute on Aging, Bethesda, Maryland, report that enlarged spaces around the brain’s blood vessels are associated not only with cerebrovascular trouble but also with cognitive decline and vascular dementia. Visible in magnetic resonance imaging (MRI), these gaps are called large perivascular spaces (L-PVSs). They could represent a new marker that heralds cerebrovascular disease and vascular dementia.
“This prospective study demonstrates that L-PVSs are associated with small vessel disease and development of vascular dementia,” said Roxana Carare, University of Southampton, England, in the U.K.
“This is a relatively new marker,” Launer told Alzforum. “We would like to see it incorporated into a risk score, where several markers of small vessel disease would be a robust predictor of whether someone is at increased risk for dementia.”
Holes Herald Trouble. Large perivascular spaces (white arrowheads) appear around blood vessels in the basal ganglia (left) and white matter (right). [© 2017, American Medical Association. All rights reserved.]
The areas surrounding blood vessels are normally microscopic. They help drain fluid and metabolic waste from the brain. However, these spaces expand with age and some become visible by MRI, appearing as round or tubular hyperintensities on scans.
Epidemiologic data suggest that PVSs go hand in hand with small vessel disease and cognitive impairment (Ramirez et al., 2015; Zhu et al., 2010). However, longitudinal data examining the association is scarce (Zhu et al., 2010). What’s more, most studies focus on small PVSs under 3 mm in diameter. Launer’s team wanted to test the link prospectively, and focus on PVSs bigger than 3 mm, considered a more severe form of the lesion.
To do this, first author Jie Ding and colleagues used data from the prospective Age, Gene/Environment Susceptibility–Reykjavik (AGES-Reykjavik) Study. Sampling from the population, 5,764 people had a baseline MRI and cognitive testing between 2002 and 2006. The tests measured verbal memory, processing speed, and executive function. Of the original sample, 2,612 returned for both follow-up MRI and cognitive tests between 2007 and 2011. The researchers measured white-matter hyperintensities, microbleeds, and subcortical infarcts—all signs of small vessel disease.
At the five-year mark, 424 people had L-PVSs. At baseline, people with L-PVSs had more subcortical infarcts, microbleeds, and white-matter hyperintensity progression than people without L-PVSs. The more a person had, the more advanced their small vessel disease.
The cognitive function measurably associated with L-PVSs over the five-year follow-up was processing speed. It slowed in people with L-PVSs, most dramatically in those who had two or more of the markers at baseline. They were also four times more likely to develop clinical vascular dementia, diagnosed according to the criteria of the State of California Alzheimer Disease Diagnostic and Treatment Centers (Chui et al., 1992). However, their risk for all-cause dementia or Alzheimer’s disease stayed the same as that of the general population, meaning L-PVSs constitute a biomarker for vascular, but not other types of dementia.
The researchers remain unsure whether L-PVSs or small vessel disease comes first. Baseline L-PVSs were often seen at the same time as markers of small vessel disease, so it’s not clear. It’s also unclear how strong the association truly is. The scientists cautioned that people who stayed on for follow-up tended to be younger, more educated, and healthier at baseline than those who dropped out. In addition, those who had more severe vascular disease died or were lost to follow-up. That means the association may have gone underestimated.
“This interesting observation adds one more potential biomarker for vascular dementia,” said Costantino Iadecola, Weill Cornell Medical College, New York. “It will probably contribute to a constellation of imaging findings that will speak to an increased incidence of cognitive impairment or vascular disease of the brain.” L-PVSs could help explain why two people with otherwise equal cerebrovascular loads could be cognitively affected to different degrees, he said.
At L-PVSs, clearance slows down and solutes can build up. “Targeting the failure of clearance of fluid along these drainage pathways could be an efficient early therapeutic strategy for aging brains in the prevention of vascular cognitive impairment,” Carare said. However, this will be hard to pull off until researchers clarify the exact mechanism behind the L-PVSs (and its impact on the clearance process), Iadecola added. —Gwyneth Dickey Zakaib
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