Early brain capillary damage was associated with cognitive dysfunction, a study of older adults found.
As cognitive impairment advanced, cerebrospinal fluid (CSF) levels of soluble platelet-derived growth factor receptor-beta — a novel marker of pericyte damage — increased, reported Berislav Zlokovic, MD, PhD, of the Keck School of Medicine of the University of Southern California (USC) in Los Angeles, and colleagues.
This finding suggests that injury to pericytes, which maintain blood-brain barrier integrity, may be an early biomarker of cognitive dysfunction, they wrote in Nature Medicine.
“Individuals with early cognitive dysfunction developed early brain capillary damage, regardless of standard Alzheimer’s biomarker changes in amyloid-beta or tau,” Zlokovic told MedPage Today.
How breakdown in the blood-brain barrier relates to changes in amyloid-beta and tau is unknown, but “vascular dysfunction may represent a previously underappreciated factor contributing to cognitive and functional decline,” Zlokovic added.
The study adds to the overall picture of aging and cognition, noted Ron Petersen, MD, PhD, director of the Mayo Clinic Alzheimer’s Disease Research Center in Rochester, Minnesota, who was not involved with the research.
“When you look at cognition and aging, you have a whole host of players that contribute — amyloid and tau are big players, but there’s also vascular disease, there’s alpha synuclein, there’s TDP-43, and other things we probably haven’t discovered yet,” Petersen told MedPage Today. “It’s really a collection of all these different pathologic elements that contribute to a person’s clinical state and cognitive function as they age. Vascular disease is a prominent one. And small vessel disease is a prominent one, and it goes up rather dramatically with age.”
Brain vasculature is emerging as an important biomarker and therapeutic target for dementia, Zlokovic said. In previous studies, he and other researchers demonstrated that human pericytes shed soluble platelet-derived growth factor receptor-beta when exposed to hypoxia or injury. Last year, he led research that showed pericyte loss compromised white matter structure in mice.
In this study, Zlokovic and co-authors assessed brain capillary damage in older adults using CSF samples of soluble platelet-derived growth factor receptor-beta and measured regional blood-brain barrier permeability using dynamic contrast-enhanced MRI.
The research team studied 161 people at USC (n=74) and Washington University in St. Louis (n=87) who were cognitively normal or had early cognitive dysfunction assessed by the Clinical Dementia Rating (CDR). CDR scores were 0 (normal; n=82), 0.5 (very mild dementia; n=63), or 1 (mild dementia; n=16). Mean age of the sample was about 72, 51.6% were male, and 44.5% carried the APOE ε4 allele.
The researchers stratified participants as positive or negative for 42-residue amyloid-beta, or positive or negative for phosphorylated tau, and excluded people diagnosed with vascular dementia, vascular cognitive impairment, Parkinson’s disease, Lewy body dementia, frontotemporal dementia, or other disorders that might account for cognitive impairment.
They found that CSF soluble platelet-derived growth factor receptor-beta increased with higher CDR scores, suggesting progressive pericyte damage with cognitive dysfunction. Higher soluble platelet-derived growth factor receptor-beta remained a significant predictor of cognitive impairment even after controlling for amyloid-beta or tau.
In a subset of 73 patients who had gadolinium-based contrast MRI, soluble platelet-derived growth factor receptor-beta was positively correlated with blood-brain barrier breakdown, limited to the hippocampus and medial temporal lobe structures.
“These brain regions show the earliest pathology in Alzheimer’s disease and are associated with memory deficits,” observed Gwenn Smith, PhD, of Johns Hopkins School of Medicine, who was not part of the research. “These promising results support further investigation of CSF and MRI measures of blood-brain barrier breakdown as an early pathological event associated with the development of Alzheimer’s disease,” she told MedPage Today.
The findings represent only one point in time, the researchers cautioned. Future studies will look at how soon cognitive decline occurs after blood vessel damage starts.
Researchers were supported by the National Institutes of Health, the Alzheimer’s Association, Cure Alzheimer’s Fund, the Foundation Leducq, and the L.K. Whittier Foundation. The researchers reported no competing interests.