To identify and follow blood vessel-related changes in the brain that contribute to cognitive impairment and dementia, researchers and clinicians typically rely on MRI to evaluate “downstream” biological markers – those at the end of a cascade of events. But a multicenter led by UCLA researchers could lead to a cost-effective blood test to identify changes occurring near the top of the chain, potentially identifying at-risk patients at an earlier stage.
“We studied a protein in the blood that is critical in the formation of blood vessels but that also appears to play a role in vascular permeability associated with cognitive decline. Evaluating data from a large group of patients with a range of vascular risk profiles and cognition ranging from unimpaired to mild dementia, we found that plasma levels of this protein, placental growth factor (PlGF), could potentially be used as a biomarker to screen for and monitor cognitive impairment and dementia,” said Jason Hinman, MD, PhD, a vascular neurologist at UCLA Health, Interim Co-Director of the for Alzheimer’s Research and Care at and senior author of an article in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.
Dysfunctional cells lining blood vessels in the brain are increasingly recognized as a key driver of processes leading to cerebral small vessel disease (CSVD), a major contributor to cognitive decline and dementia. The leaky vessels are believed to allow fluid and inflammatory molecules to seep into brain tissue. CSVD is typically diagnosed through costly brain MRI, where areas of vascular-mediated brain injury appear as bright spots on clinical MRI sequences – called white matter hyperintensities, or WMH. WMH and other structural changes are late markers of vascular brain injury.
The researchers studied possible associations involving several factors: plasma levels of PlGF, a highly sensitive research MRI measure of fluid accumulation in the brain called white matter free water (FW), white matter hyperintensities, and patients’ scores on cognitive assessments. Results were consistent with models suggesting that elevated PlGF increases vascular permeability, leading to accumulation of fluid in the brain’s white matter, development of white matter hyperintensities and subsequent cognitive impairment.
“As a biomarker for cerebral small vessel disease and the vascular contributions to cognitive impairment and dementia (VCID), PlGF could be used as a cost-effective screening tool for identifying patients at risk for vascular brain injury before the insidious onset of cognitive decline,” said first author Kyle Kern, MD, a vascular neurologist at UCLA Health and researcher at David Geffen School of Medicine at UCLA. “As a simple blood test, such a tool would be valuable not only for patients and clinicians, but also for researchers identifying patients for clinical trials,” he said.
The study was conducted by researchers involved in MarkVCID, a multisite consortium established to validate candidate biomarkers for CSVD through recruitment of participants from diverse racial and ethnic backgrounds, with a range of vascular risk factors, and across the spectrum of cognitive impairment. Participants were 55 or older and had undergone brain MRI and blood tests for PlGF levels.
The authors said that while the study’s multicenter design and large, diverse sample support the use of PlGF as a biomarker, additional longitudinal studies are needed to reach conclusions about causation and timing in the relationships among PlGF, FW, WMH, and cognition. Ideally, PlGF could be used to screen younger populations for whom currently available treatments and lifestyle modifications may prevent or reverse the deleterious effects of vascular injury before the onset of cognitive dysfunction. The research group is recruiting patients for future studies.
Authors A full list of authors is included with the article.
Funding National Institutes of Health, Grant/Award Numbers: U24NS100591, UH2NS100599, UH2/UH3NS100605, UH2NS100588, UH2NS100608, UH2NS100606, UH2NS100598, UH2NS100614, UF1NS125513, the BrightFocus Foundation.
Disclosures The authors report no conflicts.
Article Alzheimer's & Dementia: The Journal of the Alzheimer's Association. “White Matter Free Water Mediates the Associations Between Placental Growth Factor, White Matter Hyperintensities, and Cognitive Status.”
Article Title: White Matter Free Water Mediates the Associations Between Placental Growth Factor,
White Matter Hyperintensities, and Cognitive Status
DOI 10.1002/alz.14408
