Blood Protein PlGF May Offer Cheaper Early Screen for Vascular Cognitive Decline

For now, the standard way to see blood vessel damage in the brain is an MRI. It is expensive, and by the time it shows anything, the injury is usually well along. A multicenter study led by researchers at UCLA suggests there may be a way to catch the problem earlier, using a blood draw instead.

The protein at the center of the work is placental growth factor, or PlGF. It is known for its role in forming blood vessels, but the team believes it also contributes to vascular permeability, the leakiness tied to cognitive decline. The findings appear in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. Jason Hinman, MD, PhD, a vascular neurologist at UCLA Health and interim co-director of the Mary S. Easton Center for Alzheimer's Research and Care at the David Geffen School of Medicine at UCLA, is the senior author. Kyle Kern, MD, also a vascular neurologist at UCLA Health, is the first author.

The condition in question is cerebral small vessel disease, a major contributor to cognitive decline and dementia. Researchers increasingly see dysfunctional cells lining the brain's blood vessels as a key driver. The leading view is that leaky vessels let fluid and inflammatory molecules seep into brain tissue. Clinicians typically diagnose the disease with brain MRI, where areas of vascular injury show up as bright spots called white matter hyperintensities. Those spots, like other structural changes, are late markers of damage, at the far end of a cascade of events. The hope is that a blood test could read a signal nearer the top of that chain.

The data came from MarkVCID, a multisite consortium set up to validate candidate biomarkers for small vessel disease. It recruits participants from diverse racial and ethnic backgrounds, with a range of vascular risk factors, and across the spectrum of cognitive impairment, from unimpaired to mild dementia. Everyone in this analysis was 55 or older and had both a brain MRI and a blood test for PlGF.

The researchers looked at how four things related to one another: PlGF in blood plasma, white matter free water (a highly sensitive research MRI measure of fluid accumulation in the brain), white matter hyperintensities, and scores on cognitive assessments. The results fit a proposed sequence. Elevated PlGF increases vascular permeability, fluid builds up in the white matter, hyperintensities develop, and cognitive impairment follows.

Hinman said the results suggest PlGF could be used to screen for and monitor cognitive impairment and dementia. Kern framed it as a cost-effective way to identify people at risk of vascular brain injury before cognitive decline sets in. A simple blood test, he said, would serve patients and clinicians, and would also help researchers find participants for clinical trials.

The authors are careful about the limits. They say the multicenter design and the large, diverse sample support PlGF as a biomarker. But conclusions about causation and timing among PlGF, free water, hyperintensities and cognition will require longitudinal studies that follow people over time. This study shows the measures move together, and the sequence is consistent with the model, but it does not settle the order of events.

The longer-term aim is to screen younger people, for whom existing treatments and lifestyle changes may prevent or reverse vascular injury before cognitive problems begin. The research group is recruiting patients for future studies.