A biomarker linked to vascular dementia has been tested in a new study, and researchers have proposed an explanation for how cognitive impairment arises.
Vascular dementia is usually caused by cerebral small vessel disease (cSVD), which damages the brain’s small blood vessels, but researchers don’t yet know the exact mechanism linking cSVD to dementia. One theory involves problems with the glymphatic system, which helps clear waste from the brain.
A team of researchers have now found new evidence in support of that theory.
The group analysed brain scans and cognitive tests from a total of 3750 people, then used technique known Diffusion Tensor Image Analysis along the Perivascular Space – or DTI-ALPS – to determine how well the glymphatic system was functioning in each person based on their brain scans.
The researchers compared the DTI-ALPS results with the cognitive test results and found that people with lower DTI-ALPS scores also performed lower on cognitive tests. The study confirmed that a low DTI-ALPS score is a biomarker for cSVD and suggests that glymphatic damage may be driving cognitive decline.
“The most significant finding is that we found a clear link between DTI-ALPS and cognitive function in all four cohorts, with ages ranging from middle-age through older adulthood,” said Danny Wang, PhD, the study’s senior author at the Keck School of Medicine’s Stevens INI.
Wang and his team also analysed the progression of symptoms across study participants, finding a possible pathway to explain how glymphatic problems lead to cognitive impairment.
The results provide a target for clinical researchers seeking to develop treatments for vascular dementia, Wang said, and may also prove useful for treating symptoms of Alzheimer’s disease.
The DTI-ALPS biomarker relies on magnetic resonance imaging (MRI) to measure water movement along perivascular spaces, fluid-filled regions around the brain’s blood vessels that are a key part of the glymphatic system. If researchers detect changes in DTI-ALPS score, that can indicate damage and suggest that the waste clearance system is not functioning as it should.
In the present study, the team analysed MRI scans to collect a measure of DTI-ALPS for each participant. They compared those measurements to each person’s level of executive function, a composite score of cognition that includes memory, attention, planning, emotion regulation and other abilities that tend to suffer as dementia progresses.
The researchers found that lower DTI-ALPS scores, which indicated damage to the glymphatic system, were associated with worse executive function. That link was verified independently in four separate participant groups—from the MarkVCID consortium; the University of California, Davis; the University of California, San Francisco; and the Framingham Heart Study.
Independently validating the DTI-ALPS biomarker in each of the four cohorts provides strong evidence for the glymphatic system’s role in cSVD and vascular dementia, Wang said.
The researchers also conducted a mediation analysis, which studies the process or mechanism connecting two or more variables.
In this case, they found that another biomarker – “free water” or excess water in the brain’s white matter – helped explain the link between glymphatic problems and cognitive decline.
In this potential pathway, “first waste clearance is impaired, which causes accumulation of free water in the brain’s white matter. That leads to tissue damage and eventually to cognitive impairment,” said the paper’s first author, Xiaodan Liu, assistant researcher in radiology at the University of California, San Francisco.
More research is needed to confirm whether each step in that pathway is causal. But the team’s findings indicate that the DTI-ALPS score biomarker for vascular dementia is robust and ready to be used in clinical trials, Wang said.
Those studies could explore enhancing glymphatic function as a way to treat vascular dementia. Lifestyle changes such as exercising more and improving sleep quality are one way to do that, Wang said, and future studies may also reveal medications that can help.
The findings could also provide clues for how to treat Alzheimer’s disease, which has been linked to low DTI-ALPS scores in other studies.
