ALS is difficult to diagnose because no single test or procedure can firmly identify the disease. Current diagnostic tests for ALS focus on ruling out other diseases that share similar initial symptoms. For example, magnetic resonance imaging (MRI) is a test typically used to eliminate a diagnosis of cancer, multiple sclerosis or pressure on the spinal cord due to arthritis. A standard MRI analysis of a person with ALS, however, usually shows normal results.

The lack of a reliable diagnostic test for ALS means that it takes on average about a year for a diagnosis to be confirmed. “The delay means we can’t help people sooner, nor identify them early enough to enter a clinical trial,” said Dr. Sanjay Kalra in an interview with ALS Canada. “This issue is actually hindering the clinical investigation of drug therapies. If we could identify people with different types and progressions of ALS more quickly, we could find a breakthrough therapy faster. A test is desperately needed that can determine if a drug is working in clinical trial.” Dr. Kalra is a professor in the department of medicine (neurology) and member of the Neuroscience and Mental Health Institute at the University of Alberta.

 

Looking for ALS in Brain Images

Dr. Kalra has been intrigued with finding a way to harness the power of imaging to uncover the early signs of ALS since his medical residency when he met neurologist Dr. Douglas Arnold, an MRI specialist at the Montréal Neurological Institute and Hospital. “My residency research rotation was only supposed to last six months, but after realizing the potential power of this technology in research and really enjoying working with people with ALS, I decided to continue and eventually stayed as a postdoctoral fellow specializing in MRI for ALS,” said Dr. Kalra.

Dr. Kalra has secured funding for his imaging research program from a number of sponsors including the Canadian Institutes of Health Research (CIHR), the major agency of the Canadian government responsible for funding health research in Canada. His focus has been to develop and validate advanced MRI methods that can be used as a biomarker, a biological marker that allows physicians to detect disease earlier, monitor disease progression and evaluate new therapies.

In 2013 he founded the Canadian ALS Neuroimaging Consortium (CALSNIC), a multidisciplinary team of experts from across Canada that includes neurologists, MRI scientists, computing scientists, neuropathologists and a biostatistician. Since then, the CALSNIC team has been working together on a national scale to develop advanced MRI methods to find biomarkers in people with ALS and related conditions.

Dr. Kalra and three colleagues at the University of Alberta in Edmonton conducted a preliminary study in 2014-2015 to look for biomarkers in brain images using MRI scans of 19 people with ALS and 20 healthy participants for comparison. They analyzed the images with 3D texture analysis, an advanced method that allowed them to look for statistically significant patterns of brain degeneration not normally visible to the naked eye. They examined voxels, tiny 3D spaces in the brain about a cubic millimetre in size.

The researchers found different texture features in regions of the brain affected by ALS and frontotemporal dementia in people with ALS compared to people without ALS. They also discovered that some features were associated with clinical observations, such as disease duration and differences in finger tapping speed. The study was funded in part by an ALS Canada Discovery Grant.

 

Going Big: The First Large Imaging Study in the World

Based on encouraging research results in this preliminary study and other work, Dr. Kalra wants to confirm the findings in a larger group of people with ALS. “The ALS field has seen an explosion of imaging studies in the last five years, but for the most part, they have been single-centre studies that used different methods in small groups of patients, so it has been difficult to draw conclusions on the best method to use,” he said. “To develop and validate the use of MRI biomarkers , especially for their potential use in clinical trials, we need to confirm that our these methods will work well on a large scale, in every clinic.”

In 2015, Dr. Kalra and a team of 13 other investigators applied for a grant from ALS Canada and were successful. The resulting ALS Canada – Brain Canada Arthur J. Hudson Translational Team Grant of $2.94 million – the largest grant awarded in ALS Canada’s history – is funding the first large multicentre imaging study focused on ALS in the world, according to Dr. Kalra. The study seeks to enroll over 700 volunteers split between people with ALS and people without ALS for comparison in seven locations: Calgary, Edmonton, Vancouver, London, Toronto, Montreal and Quebec City. Some sites are currently recruiting and others will be up and running soon. Participants receive a baseline MRI and clinical evaluation followed by two follow-up visits.

Always thinking ahead, Dr. Kalra is already considering how to expand CALSNIC further to increase the value of the network. “Another purpose of setting up the CALSNIC infrastructure is that it allows us to probe other questions. I’m excited that it has spurred other ALS research and collaborations,” said Dr. Kalra, “such as at the University of Toronto where Dr. Yana Yunusova is studying speech changes in patients across the CALSNIC network and will be able to compare the findings with our imaging data. In the future, I would like to see CALSNIC build a comprehensive resource of tissue, imaging and clinical descriptions that all scientists can access to understand the disease better.”

ALS Canada has been funding world-class research across Canada for over 30 years to enable discovery of new treatments and therapeutic interventions that have the potential to make an impact on altering the course of the disease or improving the quality of life for people with ALS.

Read more about the ALS Canada Research Program and consider donating today.

 

ALS research is at a significant tipping point, and we can now envision a future where ALS becomes a treatable condition.

This was one of the highlights shared by Dr. David Taylor, Vice President of Research at ALS Canada, during a webinar presentation on June 13, 2017. The webinar was the first in a series of four to provide an update on the latest ALS research, clinical trials and funding programs.

In sharing the advances made in ALS research discovery over the years, Dr. Taylor recalled reading an ALS paper in 2001 that was authored by leading neuroscience researcher Dr. Don Cleveland. The paper outlined four likely contributing causes of ALS, but there was clearly still so much not known about the disease. Since then, however, the major discoveries made possible through research in Canada and around the world have led to significant and exciting progress.

During the webinar, Dr. Taylor shared the milestones of major discoveries since the 1940s and discussed exciting recent advances made possible as the pace of discovery has accelerated significantly. Today, many promising gene targets have been identified, there are several potential therapies in clinical trial, and the drug edaravone (Radicava) was recently approved in the U.S.

Here are key highlights from the webinar:

ALS Discovery Milestones

New Technologies and Big Data

Precision medicine advances mean that it is now possible to study human ALS in a laboratory setting. Using blood samples, scientists can create stem cells, grow them into motor neurons and other important cells relevant to ALS, and then look for differences in biological signatures between people with and without ALS. The technology is expensive, so many organizations are pooling data, resources and findings. In one initiative called Project MinE, ALS Canada is collaborating with organizations in over 17 countries in to map the DNA profiles of more than 15,000 people living with ALS and 7,500 people without ALS. The goal of Project MinE is to identify the “genetic signature” that leads to the development of ALS, in order to be able to target the development of treatments.

Advanced computing platforms that use artificial intelligence and machine learning can process vast amounts of data, such as the data becoming available through Project MinE, and find connections significantly faster than humans can. Researchers in the U.S. recently used IBM Watson Health to sift through information already known up to 2014 about certain aspects of ALS, as a sort of “training test” to see if this form of machine learning could use that knowledge to predict 2015 and 2016 discoveries. When it did, Watson was given all of the information up to 2016 and asked to predict future discoveries. Watson identified five new ALS genes that are currently being validated.

Biomarkers, biological markers in blood or other tissues that indicate the presence of disease or response to treatment, are now known to be critically important for studying ALS: they could help screen people for entry into clinical trials of experimental therapies that are likely to be effective for them, and allow researchers to determine the effectiveness of experimental treatments. While there are currently few biomarkers for ALS, a 2013 Phase 2 trial of the Neuraltus drug NP001 failed to find an effective response across all participants, but on further investigation of the data, a subset of individuals with elevated signs of inflammation showed no disease progression over six months. As a result, a new trial of NP001 is underway where participants are pre-screened for C-reactive protein, a biomarker for inflammation. The identification of biomarkers for ALS will continue to be an important area of exploration.

Clinical Trials

An encouraging number of clinical trials underway are testing new therapies for ALS. In 2016 alone, there were:

Recent FDA Approval of Edaravone (Radicava)

The biggest news in 2017, so far, is the approval of edaravone (Radicava or Radicut) by the United States Food and Drug Administration in May. It’s the second drug to be approved by the FDA for the treatment of ALS: the first drug, riluzole, was approved more than 20 years ago. In clinical trials, edaravone showed a modest but significant slowing of disease progression among participants who were early in their ALS disease progression with mild symptoms and a large vital breathing capacity.

Fueling Future Discoveries

Dr. Taylor is not the only scientist excited about recent progress in ALS research. The same Dr. Cleveland, whose paper Dr. Taylor read back in 2001, recently co-authored a new paper that said, “There is… little doubt that the pace of discovery will continue or even accelerate in several areas of research …most importantly, there will be considerable achievements in the development of therapies for ALS.”

“We now know a wide range of the genetic mutations involved in ALS to study in order to reach the next breakthroughs — but we have more tools than resources or funding to study all of them in a quick and effective way,” said Dr. Taylor. “At ALS Canada, we believe it’s a matter of ‘when’ not ‘if,’ there will be therapies, and that ‘when’ really does depend on funding.”

Future Webinars

Please join us for the next webinars in the series:

All webinars are free, presented online at 12:00 pm Eastern time.

Read about ALS Canada’s Research and consider making a donation today.