A novel non-invasive neuroimaging technique can detect early-stage dysfunction of the blood–brain barrier (BBB) associated with small vessel disease (SVD), according to new research published in Alzheimer’s & Dementia. Cerebral SVD is the most common cause of vascular cognitive impairment, with many cases leading to dementia.
The BBB is a semipermeable layer of cells that regulates the movement of ions and molecules between the blood and the central nervous system. It transports nutrients and protects the central nervous system from toxins, inflammation and pathogens. The BBB is also involved in clearing excessive amyloid-beta (Aβ) protein from the brain, accumulation of which is associated with the development of Alzheimer’s disease.
Researchers at the University of Kentucky and the University of Southern California used a novel MR imaging technique called diffusion-prepared arterial spin labelling (DP-ASL) to examine water exchange across the BBB and detect subtle BBB dysfunctions associated with altered water exchange rate. They hypothesized that decreased water exchange rate across the BBB may be associated with reduced Aβ clearance, and may represent a biomarker of the early stages of SVD.
The DP-ASL technique uses multiple diffusion weightings to differentiate magnetically tagged water signals from the capillary and brain tissue compartments based on a roughly 100-fold diffusion coefficient difference. The rate of water exchange between these compartments is then derived using a single-pass approximation model of the ASL signal.
The study focused on levels of Aβ in the cerebrospinal fluid, which are abnormally low when this protein is not adequately cleared from the brain. “While Alzheimer’s disease has been linked with BBB dysfunction, few studies have examined the relationship between cerebrospinal fluid and Aβ concentration, and water exchange across the BBB using neuroimaging,” the researchers explain.
The researchers used DP-ASL MRI to scan 39 healthy adults, ranging in age from 67 to 86 years. Most participants also had a lumbar cerebrospinal fluid draw and underwent neuropsychological testing. They report that low water exchange rate across the BBB was associated with low cerebrospinal Aβ concentrations in multiple brain regions of relevance to Alzheimer’s disease (whole brain, frontal lobe, parietal lobe and precuneus, a region involved in complex functions including memory and perception). However, the water exchange rate was only moderately associated with neuropsychological performance.
“Our data indicate the important role of BBB water exchange in the clearance of amyloid-beta, and the potential for using DP-ASL to noninvasively assess BBB water exchange in clinical trials of small vessel disease,” comments senior author Danny Wang, of the USC Stevens Neuroimaging and Informatics Institute, in a press statement.
“The results suggest that DP-ASL may provide a non-invasive index of BBB clearance dysfunction prior to any detectable cognitive impairment,” adds lead author Brian Gold.
The findings also support growing evidence that BBB dysfunction may represent a link between SVD and clinical diagnosis of Alzheimer’s disease. Excess accumulation of Aβ is a hallmark feature of individuals diagnosed with Alzheimer’s disease, but is also seen in many cases of SVD.
The research team recommends that these measurements should be repeated in other cohorts, and in larger numbers of participants, to further evaluate the sensitivity and specificity of this potential marker of BBB-related clearance functions.