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Blood-Brain Barrier Breakdown Precedes Protein Build-Up and Correlates with Cognitive Decline

Article In Brief

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“The results from this study and others suggest that the BBB may be a target for therapy. Whether sealing the vessel wall in these regions of interest can potentially arrest or reverse cognitive dysfunction remains to be determined by future studies.”—DR. BERISLAV ZLOKOVIC

Researchers reported that a biomarker for a breach in the blood-brain barrier integrity, called soluble platelet-derived growth factor receptor-beta, could prove useful in predicting impending clinical cognitive impairment.

The breakdown of the blood-brain barrier (BBB) occurs earlier than, and is independent of, an accumulation of either amyloid or tau in people with early cognitive decline, even in the absence of recognized vascular risk factors, according to a study published in the January 14 online edition of Nature Medicine.

The finding adds to the growing recognition that BBB breakdown may be a seminal process that drives the pathogenesis of dementia.

The study demonstrated the potential of a new biomarker for BBB integrity, called soluble platelet-derived growth factor receptor-beta (sPDGFR-beta). Measuring sPDGFR-beta in the cerebrospinal fluid (CSF) may prove useful in predicting impending clinical cognitive impairment, said the study's lead author Berislav Zlokovic, MD, PhD, chair and professor of physiology and neuroscience at the Keck School of Medicine at the University of Southern California. But, he added, more work will be needed to understand its potential in this regard.

sPDGFR-beta is shed by capillary pericytes, a principal component of the BBB, and its presence in CSF is an indication of barrier damage, Dr. Zlokovic explained. Vascular contributions to dementia have long been recognized, he noted, including in Alzheimer's disease (AD). But it has been hypothesized that vascular changes seen in AD were due to the toxic effects of amyloid-beta (Abeta) or tau accumulation.

Study Design, Findings

To explore the alternative hypothesis, that BBB defects contributed to cognitive dysfunction independent of protein accumulation, Dr. Zlokovic and colleagues compared levels of sPDGFR-beta in CSF of individuals with a Clinical Dementia Rating (CDR) score of 0 (n=82), 0.5 (n=65), or 1.0 (n=17), indicating no, very mild, or mild dementia, respectively.

Dr. Zlokovic found that the level of sPDGFR-beta increased with the CDR score, an effect that was not found for Abeta or tau. In a subset of patients who underwent amyloid PET imaging, the relationship of sPDGFR-beta to CDR score remained significant after controlling for brain amyloid levels.

The correlation of sPDGFR-beta levels and CDR score was independent of vascular risk factors, including a history of cardiovascular disease, hypertension, diabetes, and stroke. Neither were there any differences between CDR groups in 20 inflammatory or neurodegeneration markers.

Taken together, Dr. Zlokovic said, these findings indicate that sPDGFR-beta, and the damage to the BBB that it signifies, increases early in older individuals at the beginning stages of dementia, is not secondary to tau or amyloid, is independent of vascular risk factors, and is not associated with inflammatory or neurodegenerative processes.

Next, Dr. Zlokovic imaged 73 subjects, using dynamic contrast-enhanced MRI, a technique he and his colleagues have recently developed as a way to assess BBB permeability throughout the brain. Compared with those with a CDR score of 0, permeability was increased in those with a score of 0.5, specifically in the hippocampus and several of its subregions, as well as the parahippocampal gyrus, but not in the frontal or temporal cortices, subcortical white matter, or other regions.

“Surprisingly, this increased breakdown was truly independent of CSF Abeta or tau status, or hippocampal volume,” Dr. Zlokovic said, but it did correlate with sPDGFR-beta levels.

Given that BBB breakdown is detectable earlier than the accumulation of amyloid or tau, what is their pathogenic relationship? “Our analysis indicates that BBB breakdown is independent of Abeta or tau biomarkers,” Dr. Zlokovic said, meaning it is not caused by those proteins. And there is some evidence that barrier breakdown may in fact drive their accumulation.

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An artists rendering depicting leaks in capillaries that supply the brain, which a study suggests could be an early biomarker of cognitive dysfunction.

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“At this point we know sPDGFR-beta is sensitive to changes in the medial temporal lobe, possibly at an early stage, but for this to be clinically applicable, there needs to be more validation, with patients with different degrees of pathology, and most importantly, we need pathological confirmation of the findings.”—DR. KEJAL KANTARCI

“Our work and the research by some other groups indicate that the blood-brain barrier plays a critical role in regulating Abeta brain levels, clearing it from the brain into the bloodstream, and regulating its return,” Dr. Zlokovic added. Both processes are affected by aging, with lower expression of specific transporters over time, favoring accumulation of Abeta in the brain.

In addition, breakdown of the BBB “lets into the brain many toxic blood-derived proteins that are typically found in amyloid-beta plaques, for example fibrinogen, which also activates inflammation,” he noted. A small body of work in AD animal models supports the idea that barrier breakdown precedes the inflammatory response, amyloid pathology, or behavioral deficits, “but more work is needed to prove this definitively,” he said.

More work will also be needed to determine whether sPDGFR-beta can predict cognitive decline over time; longitudinal studies are underway in APOE4 carriers, who are at increased risk for developing AD, Dr. Zlokovic said, with results expected in the coming year, if all goes well.

“The results from this study and others suggest that the BBB may be a target for therapy,” Dr. Zlokovic said. “Whether sealing the vessel wall in these regions of interest can potentially arrest or reverse cognitive dysfunction remains to be determined by future studies,” he said.

Expert Commentary

“This is a very interesting study, with potentially very important findings,” commented Kejal Kantarci, MD, professor of radiology at the Mayo Clinic in Rochester, MN. “One of the original findings in this paper is that changes in the blood-brain barrier were localized to the mediotemporal lobe, which hasn't been reported before.”

It was surprising, she said, that the breakdown was independent of vascular risk factors, “given the premise that breakdown of the barrier is related to vascular pathology.” It would be interesting to repeat the study in people with diagnosed vascular dementia, to determine if they have similar, or perhaps more severe, BBB pathology, Dr. Kantarci added.

It may be too early to judge the clinical utility of sPDGFR-beta as an early biomarker for cognitive decline, she cautioned. “At this point we know sPDGFR-beta is sensitive to changes in the medial temporal lobe, possibly at an early stage, but for this to be clinically applicable, there needs to be more validation, with patients with different degrees of pathology, and most importantly, we need pathological confirmation of the findings.”

Katerina Akassoglou, PhD, senior investigator at the Gladstone Institute of Neurological Disease and professor of neurology at the University of California, San Francisco, studies the effects of leakage of fibrinogen into the brain, which she has shown triggers neuroinflammation.

Dr. Akassoglou noted that shedding of sPDGFR-beta into the CSF is a potentially very useful biomarker for early barrier breakdown but is not itself likely to be the pathogenic trigger for cognitive decline. “This indicates that there is significant dysfunction of the neurovascular unit that allows the leakage of blood protein into the brain in Alzheimer's disease, and that appears to be a very early event.”

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“We still dont know how cognitive decline arises from breaching of the blood-brain barrier, which will be important for developing therapies to mitigate the damage from this very early insult in the pathway to dementia. That could be a game-changer for Alzheimers disease and other neurodegenerative diseases.”—DR. KATERINA AKASSOGLOU

“We still don't know how cognitive decline arises from breaching of the blood-brain barrier,” she said, “which will be important for developing therapies to mitigate the damage from this very early insult in the pathway to dementia. That could be a game-changer for Alzheimer's disease and other neurodegenerative diseases.”

Disclosures

Dr. Zlokovic and the commentators disclosed no conflicts.

Link Up for More Information

• Nation DA, Sweeney MD, Montagne A, et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction https://www.nature.com/articles/s41591-018-0297-y. Nat Med 2019; Epub 2019 Jan 14.