USC Researchers Uncover Hidden “Brain Drain” Responsible for Vascular Dementia

Researchers investigated cerebral small vessel disease, a precursor to dementia, by analyzing data from thousands of participants spanning four distinct groups of middle-aged to older adults. Their study confirmed the validity of a biomarker that could aid in advancing research on potential treatments.

A recent study conducted by the Keck School of Medicine of USC has investigated a biomarker associated with vascular dementia across four distinct groups and offered insights into how cognitive impairment develops. The research findings have been published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Vascular dementia, the second most common form of dementia after Alzheimer’s disease, shares symptoms such as memory loss, difficulties with decision-making, and language impairment. As the global population continues to age, this condition poses a growing public health challenge.

Vascular dementia is typically caused by cerebral small vessel disease (cSVD), which damages the brain’s small blood vessels. However, the precise mechanisms connecting cSVD to dementia remain unclear. One prominent theory involves dysfunction in the glymphatic system, a network responsible for clearing waste from the brain.

A team of researchers from the Mark and Mary Stevens Neuroimaging and Informatics Institute (Stevens INI), part of the Keck School of Medicine, as well as researchers from the Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID) consortium, have found new evidence in support of that theory. With funding from the National Institutes of Health, the group analyzed brain scans and cognitive tests from a total of 3750 people.

The researchers 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 J. J. Wang, PhD, the study’s senior author and a professor of neurology and radiology and director of imaging technology innovation at the Keck School of Medicine’s Stevens INI.

Wang and his team also analyzed the progression of symptoms across study participants, finding a possible pathway to explain how glymphatic problems lead to cognitive impairment. Their 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.

Validating the biomarker

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, Wang and his team analyzed 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—with a total of 3750 participants.

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 racial and ethnic diversity of the participant groups, as well as the range of ages included (averaging between 56 and 76 years of age across cohorts) also suggests that the findings are robust and can be generalized to a broader patient population.

Treatments for vascular dementia

Once the team linked problems with glymphatic function to declines in executive function, they moved on to the next question — why? To find out more, the researchers 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, MD, PhD, a former postdoctoral researcher at the USC Stevens INI, now an assistant researcher in radiology at the University of California, San Francisco.

More research, including longitudinal work, 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.

Reference: “MRI free water mediates the association between diffusion tensor image analysis along the perivascular space and executive function in four independent middle to aged cohorts” by Xiaodan Liu, Pauline Maillard, Giuseppe Barisano, Arvind Caprihan, Steven Cen, Xingfeng Shao, Kay Jann, John M. Ringman, Hanzhang Lu, Konstantinos Arfanakis, Charles S. DeCarli, Brian T. Gold, Sudha Seshadri, Claudia L. Satizabal, Alexa S. Beiser, Mohamad Habes, Joel H. Kramer, Lara Stables, Herpreet Singh, Karl G. Helmer, Steven M. Greenberg, Danny J. J. Wang and the MarkVCID Consortium, 30 December 2024, Alzheimer’s & Dementia.

This work was supported by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging, part of the National Institutes of Health [U24NS100591, UH3NS100599, UH3NS100605, UH3NS100588, UH3NS100608, UH3NS100606, UH3NS100598 and UH3NS100614]