Blood-brain barrier breakdown in the hippocampus might weaken cognition all on its own. According to a paper in the January 14 Nature Medicine, people with a damaged barrier were more likely to have early signs of cognitive impairment, regardless of any Aβ or tau pathology, or even other signs of vascular disease. Led by Berislav Zlokovic at the University of Southern California in Los Angeles, the study employed both fluid and imaging measures to gauge BBB damage, and cast a weakened barrier as an early biomarker for cognitive dysfunction.
- Researchers used both fluid and imaging measures to gauge integrity of blood-brain barrier.
- BBB damage correlated with cognitive impairment, independently of Aβ, tau, or vascular risk factors.
- Compromised barrier occurred in and around the hippocampus.
“This is an important study that identifies independent indices of BBB disruption as early markers of AD in a carefully studied patient cohort,” commented Costantino Iadecola of Weill Cornell Medical College in New York. “There is an urgent need to identify early biomarkers of disease and novel pathogenic factors, and this study represents a step forward in this direction.”
Vascular dysfunction in the brain is a well-recognized contributor to dementia. Its extent in the brain can range from the widespread vessel damage that underlies vascular dementia to subtler issues such as localized blood brain barrier leaks (Iadecola 2017; Sweeney et al., 2018). Animal studies have indicated that Aβ and tau pathology can inflict damage to the blood-brain barrier. In people, imaging studies have spotted erosion of the barrier in the early stages of AD (Montagne et al., 2017; Bennett et al., 2018; van de Haar et al., 2017; Feb 2015 webinar). However, researchers have yet to understand whether such early barrier breakdown is a cause or consequence of burgeoning AD pathology, or if it exacts a cognitive toll.
First author Daniel Nation and colleagues set out to disentangle the contributions of Aβ, tau, and BBB damage to cognitive decline. They studied two cohorts totaling 164 participants—one from USC and one from Washington University in St. Louis. Based on clinical dementia rating scores, 82 were cognitively normal with a CDR of zero, 65 were mildly impaired with CDR 0.5, and 17 with CDR 1 were deemed impaired. The researchers explicitly excluded participants with vascular dementia or vascular cognitive impairment, but included people who had other vascular risk factors, such as hypertension, diabetes, or cardiovascular disease. All of the volunteers underwent CSF sampling to assess Aβ and phospho-tau, and a subgroup of 35 also had Aβ-PET scans.
The researchers took a two-pronged approach to gauge BBB breakdown. First, they measured the CSF concentration of soluble platelet-derived growth factor receptor-β. This PDGFR-β fragment sheds from the surface of pericytes that line the blood-brain barrier when they respond to cell stress or injury. Zlokovic previously reported that CSF sPDGFR-β correlates with BBB damage (Sagare et al., 2015; Montagne et al., 2015). Second, in a subgroup of 73 volunteers, the researchers used dynamic contrast-enhanced (DCE) MRI to gauge BBB leakiness by tracking levels of an intravenously injected contrast agent.
Nation found sPDGFR-β levels increased with higher CDR scores. Cognitively normal people had significantly lower concentrations of the shed pericyte receptor than did people who were CDR 0.5. People with CDR 1 had higher concentrations still. The same relationship emerged between CDR scores and DCE-MRI: those with CDR 0.5 had higher levels of the contrast agent in the hippocampus and parahippocampal gyrus, but not in cortical or subcortical regions. The participants also took neuropsychological tests to assess cognitive domains including memory, attention/executive function, and language. People who scored poorly on at least one of 10 domains had higher measures of BBB damage than those who scored normally on all domains.
Leaks Strain Cognition. Compared with CDR zero, people with CDR 0.5 had a leakier blood-brain barrier in the hippocampus and parahippocampal gyrus, regardless of Aβ status. [Courtesy of Nation et al., Nature Medicine, 2019.]
Notably, these relationships between BBB damage and cognition held regardless of CSF Aβ or p-tau biomarker status. In fact, BBB damage predicted impairment regardless of hippocampal volume, vascular risk scores, or age as well. Interestingly, neither CSF sPDGFR-β nor DCE-MRI measures of BBB permeability changed with age. In all, the findings suggest that hippocampal BBB damage, and its cognitive toll, occurs outside of the normal trajectory of aging, and is distinct from impairment caused by overall vascular dysfunction, or Aβ and tau pathology, the researchers concluded.
Zlokovic told Alzforum he was surprised that BBB leakiness caused cognitive impairment independently of both AD pathology and vascular risk factors. The findings suggest that the hippocampus and surrounding regions are particularly vulnerable to barrier damage, just as they appear to be prone to tau pathology, he said. The molecular pathways that drive that vulnerability need further study, he added.
Kejal Kantarci of the Mayo Clinic in Rochester, Minnesota, noted the distinct vulnerability of hippocampal regions to barrier dysfunction. “As an independent factor, it is important to know why the breakdown of the BBB influences cognitive function mostly in the medial temporal lobe, but not in other brain regions that were studied,” she wrote. “Confirmation of the findings in cases with vascular cognitive impairment or vascular dementia is needed, which may demonstrate involvement of regions outside of the medial temporal lobe.”
Henrik Zetterberg of the University of Gothenburg in Sweden and Jonathan Schott of the Dementia Research Centre in London commented on the striking independence of hippocampal BBB damage from other vascular problems. This suggests that a predisposition to blood-brain barrier damage may be an independent risk factor for cognitive decline, they added. Zetterberg and Schott will jointly publish an editorial on the paper in an upcoming issue of the journal.
Iadecola wondered whether vascular problems in midlife could set the stage for a compromised barrier years down the line. “Midlife vascular risk factor are linked to late-life dementia, and processes that weaken the barrier could have conceivably started at that time, when the pathogenic processes driving AD also start,” he said.
What underlying syndrome explains the barrier leakage and cognitive impairment in people who tested negative for AD biomarkers? Only time will tell, Zlokovic said. He speculated that many could eventually become AD-biomarker-positive. He said the likelihood that these participants are on a trajectory toward vascular dementia is less likely, because that syndrome is characterized by distinct, and more widespread, vascular abnormalities than observed in this cohort.
Zlokovic proposed that CSF sPDGFR-β could serve as a useful biomarker for cognitive decline and neurodegenerative disease. His group is developing the CSF PDGFR-β assay to increase both sensitivity and standardization, he said.—Jessica Shugart
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