A new study from the Keck School of Medicine of USC tested a biomarker linked to vascular dementia in four separate groups and proposed an explanation for how cognitive impairment arises. The findings have just been published in Alzheimer’s and dementia®: The Journal of the Alzheimer’s Association.
Vascular dementia is the most common form of dementia after Alzheimer’s disease. It has similar symptoms, including problems with memory, decision-making and language, and poses a significant public health problem as the world’s population continues to age.
The condition is most commonly caused by cerebral small vessel disease (cSVD), which damages the small blood vessels in the brain, but researchers don’t yet know the exact mechanism that links cSVD to dementia. One theory involves problems with the glymphatic system, which helps remove 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 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 3,750 people. The researchers then used a technique called 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 cause cognitive decline.
The key finding is that we found a clear association between DTI-ALPS and cognitive function in all four cohorts, with ages ranging from middle age to older adulthood.”
Danny JJ Wang, PhD, senior author of the study and professor of neurology and radiology and director of imaging technology innovation at Stevens INI of the Keck School of Medicine
Wang and his team also analyzed the progression of symptoms in the study participants, and found a possible pathway to explain how glymphatic problems lead to cognitive impairment. Their results provide a target for clinical researchers looking to develop treatments for vascular dementia, Wang said, and may also prove useful for treating symptoms of Alzheimer’s disease.
Validation of the biomarker
The DTI-ALPS biomarker relies on magnetic resonance imaging (MRI) to measure water movement along perivascular spaces, fluid-filled areas surrounding the brain’s blood vessels that are an important part of the glymphatic system. If researchers detect changes in the DTI-ALPS score, it may indicate damage and indicate that the waste disposal system is not functioning properly.
In the current 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 skills 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 poorer executive function. That link was independently verified 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 role of the glymphatic system in cSVD and vascular dementia, Wang said. The racial and ethnic diversity of the participant groups, as well as the age range (averaged between 56 and 76 years 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 that links 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 possible way, “the initial waste processing is hindered, causing accumulation of free water in the white matter of the brain. This leads to tissue damage and ultimately cognitive impairment,” said the paper’s first author, Xiaodan Liu, MD, PhD, a former postdoctoral fellow at USC Stevens INI, now an assistant professor of radiology at the University of California, San Francisco.
More research, including longitudinal 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.
These studies could explore improving 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 could help. The findings may also provide clues for treating Alzheimer’s disease, which has been linked to low DTI-ALPS scores in other studies.
About this research
In addition to Wang, the study’s other authors are Xiaodan Liu, Xingfeng Shao and Kay Jann of the Laboratory for fMRI Technology, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California; Steven Cen and John M. Ringman of the Department of Neurology, Keck School of Medicine of USC, University of Southern California; Pauline Maillard and Charles S. DeCarli of the University of California, Davis; Giuseppe Barisano from Stanford University; Arvind Caprihan from the Mind Research Network, Albuquerque, New Mexico; Hanzhang Lu of Johns Hopkins University School of Medicine; Konstantinos Arfanakis of the Illinois Institute of Technology and Rush University Medical Center, Chicago, Illinois; Brian T. Gold of the University of Kentucky; Sudha Seshadri, Claudia L. Satizabal and Mohamad Habes of the University of Texas Health Science Center at San Antonio, San Antonio, Texas; Alexa S. Beiser of Boston University; Joel H. Kramer and Lara Stables from the University of California, San Francisco; Herpreet Singh, Kristin Schwab, and Steven M. Greenberg of Massachusetts General Hospital, Boston, Massachusetts; and Karl G. Helmer of Harvard Medical School, Massachusetts General Hospital, and Massachusetts Institute of Technology.
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]
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Magazine reference:
Liu, et al. (2024). MRI-free water mediates the association between diffusion tensor image analysis along the perivascular space and executive function in four independent middle-aged cohorts. Alzheimer’s and dementia. doi.org/10.1002/alz.14453.