What if a simple blood test could determine if your own metabolism is hurting your brain? And if by having this knowledge, doctors could treat a disease you didn’t know you had before it could cause damage as you age?
This is the promise of a potential new biomarker validated through ONDRI research.
This recently published1 research was led by Di Yu, a PhD candidate in the laboratory of Dr. Walter Swardfager at the University of Toronto and Sunnybrook Research Institute. Yu et al propose a potential disease mechanism in which changes in the metabolism of a type of dietary fat – linoleic acid – are related to cerebral small vessel disease (SVD).
This important finding builds on previous research, including Ms. Yu’s own master’s studies.2
Defining cerebral small vessel disease
The large veins and arteries that carry blood to and from the brain branch into hundreds of miles of smaller vessels; these transport oxygen, other nutrients and immune cells through every local brain area and clear out waste from every brain cell.
Small vessels have big jobs. Wear and tear over many years can lead them to become blocked, inflamed, and leaky, symptoms of cerebral SVD. Most people over the age of 65 have at least some amounts of SVD that can be seen on an MRI.3 The symptoms can range from a barely noticeable slowing of thinking speed, to impairments to day-to-day function such as problems with memory, walking or balance.
Older adults with cerebral SVD are at a significantly higher risk of developing stroke, Alzheimer’s disease and other dementia-related diseases. While scientists and physicians have made great strides in understanding and treating pathology affecting the larger vessels, our knowledge of how the smaller vessels function – and sometimes become damaged – remains surprisingly limited.
For this study, researchers accessed blood samples from ONDRI’s foundational study, specifically the cerebrovascular disease group, which was segmented into people with small vessel vs. large vessel strokes. Researchers then quantified the concentrations of linoleic acid4 metabolites in the samples. They found that participants with small vessel stroke had a distinct pattern of lipid metabolism compared to those who had large vessel stroke.
The researchers also examined MRI scans from these same participant groups. The distinct pattern of lipid metabolism observed was higher in people who had larger amounts of their brains affected by SVD. As well, this same group showed blood brain barrier leakage, with shrinking of the brain in key regions that are firstly affected when dementia processes begin.
These same patterns were not evident in the large vessel stroke group, making this an exciting potential differentiator between how small and large vessel disease might be contributing to degeneration of the brain.
“This biochemical process doesn’t appear to be signalling a traffic jam on a highway or large thoroughfare. It seems to be saying there are thousands of tiny roadblocks on the small streets and back lanes of the brain, all at once,” said Dr. Swardfager, assistant professor of Pharmacology & Toxicology and principal investigator of the study.
“The city still runs at first, but the garbage doesn’t get collected, and over time the lights start to go out neighbourhood by neighborhood. That’s small vessel disease,” he continued.
Understanding the pathway that turns good fats turn into bad
Lipids are the many fats that we consume in our day-to-day diets, including omega-6, omega-3, saturated and trans fats, to name a few. Many of these fats are broken down by the body to provide energy, to make up our cell membranes, and to perform a great number of other functions.
Lipids can become harmful when we eat too many of them, or when our body’s conversion of them into different metabolites becomes skewed towards a particular pathway. This can generate amounts of certain metabolites that promote harmful processes or damage cells directly. The effects of these metabolites need to be better understood by scientists.
A growing number of researchers see potential for drugs that target specific parts of lipid pathways such as soluble epoxide hydrolase. The current study lends new evidence to Dr. Swardfager’s theory that conversion of dietary fats into toxins by soluble epoxide hydrolase can impair and damage the small vessels of the brain, making it vulnerable to depression, stroke and dementia.
The correlations seen here do not prove the pathway is a cause of small vessel disease, but they do call for a better understanding of the role of this pathway in the brain’s blood vessels.
“The value of our study is to highlight new potential to prevent or treat vascular disease, specifically disease of the small vessels.” Says Ms. Yu. “With multiple new lipid-targeting drugs coming down the pipeline, identifying a feature of cerebrovascular disease that is specific to the small vessels may help identify people who would most benefit from advances in therapeutics,” she continued.
- “Soluble epoxide hydrolase derived linoleic acid oxylipins, small vessel disease markers and neurodegeneration”, published in the Journal of the American Heart Association, December, 2022, http://doi.org/10.1161/JAHA.122.026901
- Linoleic acid is commonly found in plant oils. The body converts dietary linoleic acid into epoxides first, and then into diols via the “soluble epoxide hydrolase” enzyme when there is inflammation.