University of Alberta researchers have discovered a new method to identify the severity of Lou Gehrig’s disease in patients and track its progression.
The U of A team, led by Sanjay Kalra, a professor in the Division of Neurology, has made progress toward an imaging biomarker for white-matter degeneration in the brains of ALS patients, which they hope will lead to earlier diagnosis and potential new therapeutics.
Examining how the brain is wired
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a debilitating neurological disease that affects one in 50,000 Canadians. Diagnosing the disease is not straightforward because there is no definitive test and it can mimic other neurological disorders early on.
The research, conducted at four sites in Canada in collaboration with a group in Germany, involved using diffusion tensor imaging (DTI), a type of magnetic resonance imaging (MRI) scan. Kalra explained that most MRI scans examine the gross or “macro” structure of the brain, and a radiologist looks for any signs of abnormalities. DTI examines the “micro” structure of the brain by measuring the diffusion (movement) of water. Diffusion of water with a preferential direction occurs within specific brain structures, including white matter.
Kalra, who is also a member of the Neuroscience and Mental Health Institute, likened DTI measuring to water flowing through a pipe. In most cases, it will move along the length of the pipe. Likewise, in the brain water diffuses along the length of the nerves, but when a neuron is damaged, water begins to spread in all directions. The movement is measured through a value called fractional anisotropy (FA).
The FA value allows researchers to assess the wiring of the brain without having to open it up. Kalra and his team identified the most significant degeneration in the corticospinal tract, a major area of the brain affected by ALS, as it controls movement in the body. Researchers were also able to monitor the corticospinal tract degeneration over a relatively short time period to track the progression of the disease.
Building a structure for future clinical trials
Kalra noted that clinical trials don’t operate out of a single centre, so any potential test to evaluate new drugs must be able to function in multiple locations at once.
“That’s a huge strength of CALSNIC, and it’s actually the only prospective harmonized ALS-specific neuroimaging study that’s ongoing right now.”
“They have to be standardized, they have to be validated, they have to eventually be affordable, but the first steps are to make sure you can actually do the same test with confidence and good reliability and accuracy at every centre,” he said.
For that purpose, Kalra founded the Canadian ALS Neuroimaging Consortium (CALSNIC) to develop and evaluate MRI-based biomarkers in ALS across multiple centres. There are currently seven active centres, with two in the United States.
“That’s a huge strength of CALSNIC, and it’s actually the only prospective harmonized ALS-specific neuroimaging study that’s ongoing right now,” he said.
Within CALSNIC, Kalra’s lab is focused on identifying biomarkers that could have a major impact for ALS patients. According to Kalra, a primary issue with ALS is that there currently isn’t a way to measure the severity of the disease or monitor its progression.
“My lab is trying to develop MRI-based measures that can do just that—measure the amount of disease in the brain. Then you could use that for several things including speeding up the diagnostic process, better learning the biology of ALS, seeing how some patients are different and why, and then ultimately using that information in clinical trials to assess novel therapies. All of this work is directed at finding treatments faster.”
The significance of biomarkers
Biomarkers can work in several ways to help patients with ALS. Earlier diagnosis through the aid of biomarkers would allow patients to enter a drug study at an earlier stage in their disease, when a new treatment would likely be more effective. Some biomarkers could also identify which patients would be better suited to certain drugs. The use of biomarkers also means fewer patients needed for drug studies and a faster drug-discovery process, said Kalra.
The next steps for Kalra’s lab and CALSNIC involve looking at other imaging methods beyond DTI, as well as examining blood and spinal fluid, to try to find other biomarkers. He also has a new consortium in the works, the Comprehensive Analysis Platform to Understand Remedy and Eliminate ALS (CAPTURE ALS), which will combine all the biomarker-centric data from ALS patients in multiple centres and form a biorepository under an umbrella of open science.
The study, “A prospective harmonized multicenter DTI study of cerebral white matter degeneration in ALS,” was published in Neurology. CALSNIC is funded by an operational grant from the Canadian Institutes of Health Research and an Arthur J. Hudson Translational Team Grant from the ALS Society of Canada and Brain Canada.