There’s more to white matter that matters

Dr. SilbertNovember 8, 2016

Story by David Edwards

October's featured paper is titled, "Comparison of cerebral blood flow and structural penumbras in relation to white matter hyperintensities: A multi- modal magnetic resonance imaging study," and is published in The Journal of Cerebral Blood Flow and Metabolism. The paper is published by Nutta-on Promjunyakul, Ph.D., and a team led by Lisa Silbert, M.D., M.C.R., associate professor of neurology, OHSU School of Medicine.

White matter hyperintensities (WMHs) are areas that appear particularly bright and intense on certain MRI brain scans. Also called "bright signals," they're commonly found in elderly people, grow over time and are associated with small vessel ischemic disease. Unfortunately, higher WMH volume is associated with increased cognitive deficiency, motor impairment, stroke and mortality. 

The area of normal appear white matter (NAWM) immediately surrounding WMHs has a high risk of converting to WMHs, and is referred to as the WMH penumbra. Researchers have studied the underlying characteristics of this "WMH expansion" for many years, including what exactly makes the WMH penumbra uniquely prone to WMH conversion.

Nutta-on PromjunyakulBasic brain biology

Previous research has shown that WMH penumbras have two characteristics: They have reduced white matter integrity and reduced cerebral blood flow. While these characteristics provide clues about the consequences of aging in the brains of elderly patients, it doesn't answer how this process occurs from a biological standpoint. One longstanding question is: Which of these processes happens first? Do microstructural changes to the white matter occur before the cerebral blood flow is compromised, or is it the other way around? 

Another longstanding question is the size and depth of the WMH penumbra. Specifically, when measuring the white matter integrity (also called the "structural penumbra"), researchers found that the WMH penumbra was around 3-8 mm thick. In contrast, when measuring the cerebral blood flow (also called the "CBF penumbra"), researchers in Dr. Lisa Silbert's group in OHSU's Department of Neurology estimated the WMH penumbra to be around 12 mm thick. 

This discrepancy would suggest that reduced cerebral blood flow is a greater contributor to WMHs than reduced white matter integrity. However, a head-to-head comparison of these measurements in the same group of people, which would be required to answer this hypothesis, had not been done. 

Answering two questions

This month's featured paper by Dr. Silbert, addresses both of these questions. "What interested me about this paper was the combination of imaging modalities to understand how changes in blood flow relate to apparent structural lesions of the white matter in aging brain," said Mary Heinricher, Ph.D., associate dean for basic research, OHSU School of Medicine.

Researchers in Dr. Silbert's lab selected 82 people who were over 65 years old and who, based on neuropsychological exams, showed no signs of cognitive impairment. They scanned the brains of the participants and used custom algorithms to identify the size of the WMHs, along with the sizes of the structural and CBF penumbras.

Not surprisingly, they found that the WMH penumbra had the previously identified characteristics –lower cerebral blood flow and damaged white matter integrity –compared to surrounding normal brain tissue. Interestingly, they also found that the greater the distance from the WMHs, the lower the presence of these characteristics. These results suggest that reduced cerebral blood flow and white matter integrity may precede the development of new WMHs, and therefore could provide important imaging markers for brain tissue that is "at risk" for developing WMHs.

A clearer way

When quantifying the WMH penumbra, Dr. Silbert and colleagues found that while the structural penumbra measurements were similar to previous reports (2-9 mm), the CBF penumbra measurements were estimated at 13–14 mm. That means that there is significantly more brain tissue surrounding WMHs that show impaired CBF but do not show damaged white matter integrity. This suggests that the impaired CBF may precede the damaged white matter integrity. However, longitudinal studies are being conducted by Dr. Silbert to confirm this finding.

The study provides key information into the brain development of elderly people, and specifically the measurement and growth of damaging WMHs. Understanding the extent of WMH expansion –both how to quantify this expansion and identify the mechanism behind expansion –is critically important for this population. For example, it provides a clearer way to monitor treatment of WMHs or preventing the growth of WMH penumbras. Additionally, it strengthens the idea of using treatment strategies in this population that improve cerebral blood flow, including exercise and medication.



Comparison of cerebral blood flow and structural penumbras in relation to white matter hyperintensities: A multi- modal magnetic resonance imaging study. J Cereb Blood Flow Metab 2016 Sep;36(9):1528-36. Nutta-on Promjunyakul, David L Lahna, Jeffrey A Kaye, Hiroko H Dodge, Deniz Erten-Lyons, William D Rooney, and Lisa C Silbert.

Top photo, from left: David Lahna, Lisa Silbert, Erin Boespflug; bottom photo: Nutta-on Promjunyakul

About the OHSU School of Medicine Paper of the Month

The OHSU School of Medicine spotlights a recently published faculty research paper each month. The goals are to describe to the public the exceptional research happening at OHSU as well as inform our faculty of the innovative work underway across the school’s departments, institutes and disciplines. The monthly paper is selected by Associate Dean for Basic Research Mary Heinricher, Ph.D. Learn more