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Collaborative research between the University of Kentucky (UK) and University of Southern California (USC) suggests that a noninvasive neuroimaging technique may index early-stage blood-brain barrier dysfunction associated with small vessel disease. Cerebral small vessel disease is the most common cause of vascular cognitive impairment, with a significant proportion of cases going on to develop dementia. blood-brain barrier dysfunction represents a promising early marker of small vessel disease because the blood-brain barrier regulates a number of important metabolic functions, including clearance of toxic brain substances.
Advanced blood-brain barrier dysfunction can be detected with neuroimaging measures such as positron emission tomography (PET) scanning and dynamic contrast-enhanced (DCE) MRI. However, these methods require exposure to radiation or contrast agents and may only detect moderate to advanced stages of blood-brain barrier tissue disruption. The UK-USC study used a novel, noninvasive MRI method called diffusion-prepared arterial spin labeling (DP-ASL), which was developed by Xingfeng Shao PhD and Danny Wang PhD at USC. The DP-ASL method indexes subtle blood-brain barrier dysfunctions associated with altered water exchange rate across the blood-brain barrier.
In the UK-USC study, healthy older adults (67 to 86 years old) without cognitive impairment were scanned with the DP-ASL sequence at the UK's Magnetic Resonance Imaging and Spectroscopy Center. In addition, study participants volunteered for lumbar cerebrospinal fluid draw as part of their enrollment in the study at UK's Sanders-Brown Center on Aging (SBCoA). The study focused on cerebrospinal fluid levels of amyloid-beta (Aβ), which are abnormally low when this protein is not adequately cleared from the brain into the CSF.
Results indicated that low cerebrospinal fluid levels of Aβ were associated with a low blood-brain barrier water exchange rate assessed with the DP-ASL method. "Our results suggest that DP-ASL may provide a noninvasive index of blood-brain barrier clearance dysfunction prior to any detectable cognitive impairment," said Brian Gold PhD, professor in the UK department of Neuroscience and SBCoA.
Gold is the lead author of the article, which appears in a recent issue of Alzheimer's & Dementia: The Journal of the Alzheimer's Association. Wang, a professor of Neurology and Radiology at USC, the study's senior author, said, "Our data indicate the important role of blood-brain barrier water exchange in the clearance of amyloid-beta, and the potential for using DP-ASL to noninvasively assess blood-brain barrier water exchange in clinical trials of small vessel disease."
In addition to Gold, several others from UK contributed to the research including Dr. Gregory Jicha, professor in the department of Neurology and SBCoA, Donna Wilcock PhD, professor in the department of Physiology and SBCoA, Tiffany Sudduth and Elayna Seago.
Results from the UK-USC study also support growing evidence that blood-brain barrier dysfunction may represent a link between small vessel disease and clinical diagnosis of Alzheimer disease. Excess accumulation of Aβ is a hallmark feature of individuals who receive a clinical diagnosis of Alzheimer disease. However, Aβ pathology is also seen in many cases of small vessel disease. Results from the UK-USC study are consistent with theories suggesting that insufficient clearance of Aβ through the blood-brain barrier may impair blood-brain barrier function which, in turn, may further accelerate accumulation of Aβ in the brain. Gold noted that "an important topic for future research is why some individuals with blood-brain barrier dysfunction and impaired Aβ clearance may develop cognitive declines associated with Alzheimer disease while others develop more vascular-like cognitive declines."
Source: News Release
University of Kentucky
May 5, 2021