Identifying patients at risk for vascular brain injury before the onset of cognitive decline
21 December 2024: To identify and track blood vessel-related changes in the brain that contribute to cognitive impairment and dementia, researchers and clinicians typically rely on MRI to assess “downstream” biological markers – those at the end of a cascade of events. However, a multicentre study led by UCLA researchers could lead to a cost-effective blood test to detect changes occurring earlier in the process, potentially identifying at-risk patients at an earlier stage.
“We studied a protein in the blood that is crucial for blood vessel formation but also appears to play a role in vascular permeability linked to cognitive decline. By evaluating data from a large group of patients with varying 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 Mary S. Easton Center for Alzheimer’s Research and Care at the David Geffen School of Medicine at UCLA, 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 recognised 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 fluid accumulation 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 of vascular brain injury before the subtle onset of cognitive decline,” said first author Kyle Kern, MD, a vascular neurologist at UCLA Health and researcher at the 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 added.
The study was conducted by researchers involved in MarkVCID, a multisite consortium established to validate candidate biomarkers for CSVD through the 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 aged 55 or older and had undergone brain MRI and blood tests for PlGF levels.
The authors stated that while the study’s multicentre 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 harmful effects of vascular injury before the onset of cognitive dysfunction. The research group is recruiting patients for future studies.
