Projects Funded 2023

Table of Contents

2023 ALS Canada-Brain Canada Discovery Grant Program

Can this new way of analyzing brain imaging data help researchers predict and monitor the progression of ALS?

Developing machine learning models of disease progression and survival outcomes in ALS patients: evaluating the utility of structural brain MRI as an ALS biomarker

$125,000 awarded to Dr. Mahsa Dadar, McGill University, in collaboration with Dr. Sanjay Kalra, University of Alberta 

Previous imaging studies have revealed changes in specific brain regions among people living with ALS. However, the extent and location of these changes can differ significantly from person to person. This has led researchers to question whether the variability in brain atrophy patterns is linked to the diversity in symptoms often observed in people with ALS, such as age of onset, disease duration, cognitive changes, and more. If such a link exists, measuring these brain changes could provide a non-invasive way for health care professionals to monitor disease progression more accurately and possibly even predict future clinical symptoms and survival outcomes.  

Deformation-based morphometry (DBM) is a sensitive method for quantifying changes in various brain regions using magnetic resonance imaging (MRI). The team previously demonstrated the potential of DBM as a biomarker for ALS in a small group of individuals with the disease. With this award, they will leverage a more comprehensive data set collected through national initiatives such as the Canadian ALS Neuroimaging Consortium (CALSNIC) and the Comprehensive Analysis Platform To Understand, Remedy, and Eliminate ALS (CAPTURE ALS) to explore the relationship between DBM measurements and clinical symptoms. 

Using artificial intelligence, Dr. Dadar aims to uncover complex patterns in the data that otherwise may have remained undetectable with individual methods alone. This multidimensional approach may reveal insights into the mechanisms behind disease progression, survival, and clinical symptoms. The goal of this study is to develop non-invasive MRI-based biomarkers for ALS and predictive models that could change how healthcare professionals monitor and track the disease. Ultimately, these findings will contribute to a deeper understanding of ALS and advance our ability to effectively manage the disease. 

Can boosting a vital protein in the brain help to slow the progression of ALS?

Role of neurofilament NfL depletion in TDP-43-mediated pathogenesis

$125,000 awarded to Dr. Jean-Pierre Julien, Université Laval, in collaboration with Dr. Angela Genge, McGill University 

Neurofilament light (NfL) is an essential building block of nerve cells, and elevated levels of NfL in bodily fluids (such as blood or cerebrospinal fluid) can indicate damage or death of these cells. NfL is now recognized as one of the most important and useful biomarkers for ALS. Abnormal accumulations of an ALS-linked protein called TDP-43, which are present in approximately 97 per cent of ALS cases, can hinder the production of NfL within cells.  

These findings, based on studies conducted in mouse models of ALS, suggest that reduced NfL levels could negatively affect the health of motor neurons. This discovery adds a new layer to our understanding of the intricate processes involved in ALS, highlighting the role of TDP-43 in regulating NfL production and the potential impact of this on motor neuron well-being. 

With this award, Dr. Julien will explore the extent to which lower NfL levels associated with TDP-43 dysfunction contribute to ALS. Using a novel viral delivery system, researchers will boost NfL levels in mice with TDP-43 dysfunction. Researchers hope that restoring NfL synthesis will alleviate, in part, the symptoms and cellular defects associated with ALS. The outcomes of this study will advance our understanding of disease mechanisms associated with TDP-43 dysfunction and, if successful, may lay the foundation for future ALS treatment options. 

Is this newly discovered tag on TDP-43 key to understanding and treating ALS?

Dynamic palmitoylation regulates TDP-43 nucleocytoplasmic transport in ALS 

$125,000 awarded to Dr. Dale Martin, University of Waterloo, in collaboration with Dr. Max Rousseaux, University of Ottawa, and Dr. Christine Vande Velde, Université de Montréal 

In over 97 per cent of all ALS cases, a protein called TDP-43, typically found within the nucleus of a cell, becomes trapped outside in the cytoplasm, forming clumps or aggregates. While mutations in the TDP-43 gene are responsible for this dysfunction in a small subset of cases, the cause for the majority of people living with ALS is still unknown. Therefore, identifying cellular mechanisms that regulate TDP-43 biology is key to uncovering disease processes in most cases. 

Recent research has uncovered a specific cellular process called palmitoylation, which appears to play a significant role in TDP-43 biology. Palmitoylation involves the addition of a small tag to a protein that can influence how it functions and where it is located within a cell. Preliminary results indicate that TDP-43 undergoes palmitoylation in cells, and that this may contribute to the cytoplasmic buildup and aggregation often observed in ALS.  

With this award, Dr. Martin seeks to better understand how palmitoylation regulates TDP-43 localization, function and aggregation using both cellular and animal models of ALS. By identifying the proteins that regulate this process, the team hopes to uncover new therapeutic targets for ALS. Ultimately, their goal is to design new therapeutic interventions that can correct TDP-43 dysfunction, which is of great interest as the outcomes from this study could advance our understating of almost all cases of ALS.  

Can these worm models help researchers better understand and even block the spread of ALS pathology?

Investigating inhibition of TDP-43 propagation as a therapeutic strategy for ALS

$125,000 awarded to Dr. Alex Parker, Université de Montréal, in collaboration with Dr. Guy Rouleau, McGill University 

Abnormalities in a protein called TDP-43 are present in approximately 97 per cent of all ALS cases. Typically residing in the nucleus of a cell (a central compartment housing our DNA) TDP-43 is often found in the cytoplasm (the region outside the nucleus) in individuals with ALS. In this cytoplasmic location, it tends to form clumps or aggregates, impairing its normal function. It has been hypothesized that TDP-43 may contribute to disease progression through the spread of its toxic aggregated form from cell to cell within the central nervous system. 

Recognizing the potential significance of TDP-43 propagation in ALS pathology, Dr. Parker and his team will use this award to develop animal models for studying the transfer of TDP-43 proteins between motor neurons. In Dr. Parker’s lab, they specialize in using small worms called C. elegans, measuring only a millimeter in length. Due to their short lifespans and a genetic makeup sharing 60 percent similarity with humans, these worms are well-suited for research purposes. 

Using the C. elegans model, researchers will have a unique opportunity to observe and manipulate potentialTDP-43 propagation in a living environment, providing insights that have been challenging to obtain in other model systems. Furthermore, the team plans to screen for molecules that can halt the possible spread of TDP-43in this system. Lead candidates will be tested in a human model system, which if successful, the team hopes would eventually progress to clinical studies. Ultimately, the proposed research aims to identify molecules that could block the spread of TDP-43 and potentially pave the way for developing new therapeutics.  

How does fatty acid metabolism influence motor neuron health? 

Investigating mechanisms of altered lipid droplet dynamics in ALS

$125,000 awarded to Dr. Chantelle Sephton, Université Laval, in collaboration with Dr. Liang Li, University of Alberta 

Lipids encompass a diverse group of molecules, including fatty acids, oils, and specific components of cell membranes. They play crucial roles in the body, serving as a source of energy, contributing to the construction of cell membranes, and participating in signaling pathways. The cellular processes responsible for managing these lipids are collectively referred to as lipid metabolism. Recent studies suggest that dysregulation of these processes may occur in ALS, leading to the accumulation of lipid droplets in brain cells. 

With this award, Dr. Sephton will investigate how lipid metabolism is affected in ALS, utilizing a mouse model carrying a mutation in the ALS-associated gene fused in sarcoma (FUS). These ALS-FUS mice, validated in the Sephton lab, display both motor function and cognition defects, similar to those commonly observed in ALS. Additionally, they exhibit the accumulation of lipid droplets and toxic lipid byproducts in specific brain regions, making them an ideal model for studying how lipid metabolism is affected in ALS. These investigations will also extend to other ALS mouse models, including SOD1 and TDP-43. Furthermore, researchers will explore whether the drug arimoclomol can influence lipid dysregulation in these diverse models. 

By examining the broader role of lipid metabolism in ALS, this study will help to deepen our understanding of its significance to the disease. The ultimate goal is to identify potential new targets for intervention, providing valuable insights that could pave the way for effective therapeutic strategies, not only in ALS but also in other neurodegenerative diseases. 

Can investigating protein shapes reveal important puzzle pieces for future treatment strategies?

Correlating quaternary structure of pathological protein aggregates with phenotypic presentation of ALS

$125,000 awarded to Dr. Valerie Sim, University of Alberta, in collaboration with Dr. Sumit Das, University of Alberta, and Dr. Sanjay Kalra, University of Alberta.

A protein exhibits toxic behaviour described as “prion-like” when it meets two essential criteria: firstly, it induces normally-folded proteins to change shape, adopting a toxic form; and secondly, it initiates a chain reaction, spreading throughout the nervous system. Prion diseases, including scrapie in sheep, mad cow disease in cattle, and Creutzfeldt-Jakob disease in humans, are well-known examples of this phenomenon.

There is a growing belief among researchers that a prion-like mechanism may contribute to the progression of ALS, and that the size and shape of the protein aggregates could influence their toxicity and spreading ability. Some even hypothesize that the shapes of the different aggregate may correlate with clinical symptoms, potentially explaining the varied symptoms observed in individuals with ALS.

With this award, Dr. Sim and her team will utilize sophisticated techniques, such as asymmetric flow field-flow fractionation, conformational stability assays, and real-time quaking conversion, to explore these hypotheses. These techniques will enable them to identify the specific shapes and sizes of misfolded proteins associated with ALS. More specifically, they will analyze brain tissue samples generously donated by eight individuals who had ALS, studying the complete size range of two common ALS-linked proteins, TDP-43 and SOD1. Their aim is to correlate the biophysical features of these proteins with clinical symptoms, ultimately hoping to pinpoint the most relevant protein structures that drive disease progression. This deeper understanding of the underlying mechanisms of ALS not only adds another crucial piece to the intricate ALS puzzle but also has the potential to open avenues for developing more targeted therapies. 

Can a deeper understanding of nerve-muscle connections uncover new ways to treat ALS?

Spatial-temporal determinants of NMJs: from genes to function

$300,000 awarded to Dr. Richard Robitaille, Université de Montréal, in collaboration with Dr. Sandrine Da Cruz, KU Leuven (Belgium), and Dr. Danielle Arbour, Université de Montréal

The neuromuscular junction (NMJ) acts as the connection point between motor neurons and muscle fibers, allowing signals from the brain to reach muscles. In ALS, researchers believe that the early disconnection of motor neurons from muscles at the NMJ is a crucial event. Despite the significance of NMJs, our understanding of the changes occurring in ALS remains limited.

To address this gap in understanding, Dr. Robitaille and team will use advanced functional and molecular techniques to unravel the intricacies of NMJ changes during the disease. First, they plan to identify the molecular signatures of vulnerability and resistance across various NMJ states – whether intact or damaged. Second, they will explore changes in the different types of fat, or lipid, molecules present to investigate whether NMJs could serve as a potential source of biomarkers for ALS. Finally, they will use ALS models developed from human cells to study mechanisms underlying NMJ maintenance and loss in ALS.

Overall, this project aims to better understand the complex organization of NMJs in ALS by investigating the link between their state of innervation and their functional, molecular, and chemical properties. Through a comprehensive study of NMJs, Dr. Robitaille and team hope to illuminate the complexities of ALS progression and, in turn, pave the way for innovative strategies to diagnose and treat the disease. 

Can targeting the stress response within cells lead to more effective therapies for ALS?

Relevance of stress granule dynamics to ALS pathogenesis in vivo

$300,000, in partnership with Dr. Jean-Pierre Canuel Fund – SLA Québec and Brain Canada, awarded to Dr. Christine Vande Velde, Université de Montréal, in collaboration with Dr. Jonathan Watts, UMass Chan Medical School (USA)

ALS places constant stress on motor neurons, the nerve cells responsible for voluntary muscle movement, causing them to deteriorate and die. G3BP1 is a crucial protein in the formation of stress granules, protective structures that healthy cells produce when exposed to stress. These stress granules safeguard vulnerable RNA molecules, which play a vital role in translating genetic instructions and overseeing protein production, protecting them from damage. Recent evidence suggests that the disruption of proper stress granule dynamics may play a central role in the processes underlying ALS.

Traditionally, most lines of research exploring the role of stress granules in ALS have sought to inhibit their formation as a potential therapeutic approach. However, recent evidence from Dr. Vande Velde’s lab raises questions about the validity of this approach. They hypothesize that impaired stress granule dynamics may make motor neurons more vulnerable, suggesting that strategies to boost stress granule formation could be more valuable in treating the disease. Additionally, the team has found that TDP-43 dysfunction, a feature present in 97 per cent of all ALS cases, negatively impacts stress granule dynamics.

With this award, Dr. Vande Velde will assess the impact of age and environmental stress on stress granule biology and the development of ALS-related symptoms in a mouse model mimicking TDP-43 abnormalities. Furthermore, the team will investigate whether modifying key regulators of stress granules, such as G3BP1 or eIFA1, can rescue their formation in mice. Overall, the project seeks to deepen our understanding of the molecular mechanisms underlying ALS and explore new therapeutic possibilities. If successful, the outcomes of this study could lay the foundation for future therapeutic strategies aimed at restoring stress granule dynamics in ALS.

2023 ALS Canada-Brain Canada Career Transition Award

Can these gene-based strategies help restore a normal balance in the brain?

Therapeutic validation of gene-based strategies aimed at restoring neuronal KCC2 in ALS

$250,000 awarded to Dr. Sahara Khademullah at the Cervo Brain Research Centre, Université Laval

Within the brain and spinal cord, neurons pass electrical signals to each other through specialized chemicals called neurotransmitters, capable of either exciting or inhibiting them. Maintaining a proper balance between the excitatory and inhibitory signals is crucial for normal brain function and allows for complex movements like walking.

In ALS, there is an early imbalance between excitation and inhibition in the nervous system. This imbalance may be linked to changes in the inhibitory system, and modifying this system has shown promise as a treatment strategy for ALS. With this award, Dr. Khademullah will investigate the effectiveness of using gene-based therapies to restore a normal balance in mouse models of ALS.

The study will focus on a protein called KCC2, which acts like a gatekeeper controlling the entry and exit of chloride ions from cells as part of the inhibition process. Dr. Khademullah has previously shown that KCC2 levels are decreased in ALS mice prior to the onset of symptoms, leading her to believe that restoring normal levels of KCC2 may help to correct the excitation imbalance and slow or even stop disease progression. The findings from this study will provide early preclinical evidence for gene-based strategies that, if successful, could pave the way for further development of innovative treatments for people living with ALS.

Dr. Khademullah is committed to applying her training and expertise to ALS research, aiming to validate KCC2 as a therapeutic target for ALS. Ultimately, her goal is to establish a research group investigating the role of inhibition and excitation in ALS, contributing to advancements in understanding and treating the disease.

2023 ALS Canada Acceleration Grants

Epidemiological study of ALS in Colombia and Ethiopia

Our current understanding of ALS comes almost exclusively from studying a very small proportion of the world. Some of the largest leaps forward in our learnings to date have come from studying the genetics of individuals with ALS, yet most of the world’s genetically diverse populations are nowhere to be found in the databases being used. Unfortunately, many underrepresented global populations lack the infrastructure to support quality care, let alone research. Starting research in many of these regions is also complex. Usually, it requires a local doctor or advocate to champion building a foundation within the area that addresses the value of research in the appropriate way for the regional culture.

History shows that critical, timely investments in the work of key clinical leaders in areas on the cusp of starting research on ALS can go a very long way toward stimulating larger follow-up investments that pave the way for exponential growth and impact. This initial work often requires collaboration between experts from well-supported regions of the world and local clinician experts to develop the appropriate mechanisms within the local systems and culture.

South America and Africa are massive, heavily populated continents where even using the term underrepresented in ALS research is an understatement. However, the work of some key individuals over the past few years has helped position both continents toward a path of contribution to our global understanding of ALS that could be significant.

One of these individuals is Professor Mónica Povedano of Hospital Universitari de Bellvitge in Barcelona, Spain, who, in collaboration with Professor Orla Hardiman of Trinity College Dublin, has been working with colleagues in Colombia and Ethiopia to make inroads on building clinical and research infrastructure in South America and Northern Africa.

To support this work, an ALS Canada Acceleration Grant was awarded to Professor Povedano to collaborate with Dr. Martha Peña of the Roosevelt Institute in Bogotá, Colombia and Dr. Dereje Melka at Addis Ababa University in Ethiopia to enhance their blossoming research capacities by doing the first ever comparative study in ALS across these diverse ethnic backgrounds alongside data from European individuals. The study will first focus on differences in the distribution and characteristics between the groups but also use validated measures of disease and genetics for these comparisons. In South America, some of the foundational work was started by Prof. Hardiman in collaboration with a Latin-American Epidemiologic Network for ALS (LAENALS). Prof. Povedano will work closely with LAENALS as well.

Update

In the first several months of their ALS Canada Acceleration Grant funding, things have evolved in South America. In September 2023, Dr. Peña, Prof. Povedano, and Prof. Hardiman, held the inaugural meeting of a new South American ALS clinician network called ELATAM. In Africa, a network of clinics is also developing through Prof. Jeannine Heckmann in Cape Town, South Africa. Providing seed funding to support Ethiopian research can hopefully add to the momentum on the continent.

Dr. David Taylor, Vice-President of Research and Strategic Partnerships at ALS Canada, feels the timing is perfect for this Acceleration Grant. “Incorporating the contributions of underrepresented areas will be critical to our understanding and ability to treat ALS, and this can’t happen without initial investments to build the foundation. It’s important that we grab this present opportunity of having strong leaders in these areas and support them to expand and evolve research capacity so that the world can benefit as soon as possible.”

Contributing globally helps Canadians

Beyond learning from disease statistics, genetics, and environmental impacts in these regions, developing the infrastructure to support clinical trials is a win-win scenario for people affected by ALS in these areas and for affected individuals around the world (including Canada). Running trials in underrepresented regions will bring potentially beneficial experimental therapeutic access to these countries and accelerate opportunities to discover treatments available to Canadians if they work.

One current example of this mutual benefit lies in treatments for individuals with SOD1 ALS, a form caused by a variant in the superoxide dismutase 1 gene. An effective treatment called tofersen is approved as Qalsody in the United States but is also available in many countries through expanded access programs provided by Biogen. Despite the benefit of tofersen, multiple companies are trying to improve on its success by targeting SOD1 ALS with potentially more robust and less burdensome or invasive delivery. For the world to learn if these new options can provide greater value, studies would need to recruit individuals and doing so in areas where tofersen is available will be difficult. However, in African and South American clinics where there is a significant number of people with SOD1 ALS, these exciting new experimental treatments could be accessed by local individuals while the rest of the world can learn from their involvement in these studies.

The progressive nature of ALS necessitates urgency in our scientific attempts to understand the disease, but the complexity of the disease suggests longer-term strategies that could yield a significant impact, which are also important complementary pieces. We need to tackle ALS from all angles, and the learnings from regions of the world that we have yet to begin to look at will undoubtedly provide crucial information toward our vision of a world free of ALS. Through this Acceleration Grant, we are strategically investing in work that will eventually bring entire continents into the global effort, ultimately speeding up impact back to future Canadians diagnosed with the disease.

Unravelling early ALS: An EEG-MRI investigation of presymptomatic C9ORF72

One of the core mysteries of ALS that we still need to solve is why the disease differs from person to person, what we call heterogeneity. A better understanding of different forms of ALS will allow for more effective and efficient clinical trials of experimental treatments and will pave the way towards a day when we can offer a more personalized medicine approach, where an individual’s treatment regimen would be specific to them. A great example would be cancer, where present-day treatments differ greatly depending on the location and type someone has.

Dr. Stefan Dukic, a postdoctoral researcher at University Medical Centre Utrecht (UMC Utrecht) in The Netherlands, has been developing a non-invasive way to subgroup people with ALS far better than current methods using clinical observation and amazingly, it may be possible for individuals before symptom onset. A method called resting-state electroencephalogram (EEG) uses simple brain electrodes placed on the scalp to measure the brain’s electrical activity. Dr. Dukic, along with colleagues at world-leading clinical centres in Dublin, Ireland, and Utrecht, and under the co-supervision of Profs. Orla Hardiman and Leonard van den Berg, at respective institutions, demonstrated for the first time that EEG can capture abnormal patterns of motor and cognitive brain activity in ALS and that these patterns revealed four distinct clusters across the people studied. Surprisingly, these clusters also correlated with distinct clinical profiles and disease trajectories, indicating that EEG-detected brain patterns may be able to predict how someone’s ALS will progress. This exciting initial work was published in the journal Brain in 2022.

Dr. Dukic is now poised to evolve his EEG work closer toward potential use in practice and to see how it might have additional, perhaps even better, application in ALS. The next steps involve strengthening the power of EEG by combining it with another non-invasive technique, magnetic resonance imaging (MRI), to form a combination measurement. He also aims to use this combination measurement to look for pre-symptomatic markers of ALS by studying asymptomatic family members of individuals with ALS who carry known hereditary genetic variants and comparing them to data from controls and people already diagnosed.

A Stevie Fever Foundation-ALS Canada Acceleration Grant was awarded to provide personnel support to drive this work forward faster by recruiting participants, collecting data, and analyzing results at more than twice the speed Dr. Dukic can currently maintain. He also aims to greatly increase the size of the study compared to his originally published work in 2022. This would enhance the reliability of results, particularly when discovering sensitive patterns in individuals with underlying disease processes beginning but not yet experiencing any symptoms.

“Finding innovative ways to detect the earliest signs of disease, long before symptoms begin, could be the key to someday preventing ALS as we know it today. Providing support to accelerate discovering if this non-invasive strategy can detect underlying pathology and potentially lead to earlier diagnosis and treatment is exactly the type of exciting opportunity this program was created for,” says Dr. David Taylor, Vice-President, Research and Strategic Partnerships, ALS Canada.

Contributing to the global ALS landscape

Dr. Dukic aims for EEG to be used in ALS far beyond The Netherlands and Ireland. His results from 2022 will undoubtedly spark confirmatory work in other countries and may stimulate others to study its potential in asymptomatic genetic variant carriers. EEG is widely available and relatively inexpensive to perform, and with that comes collaboration, something Trinity College and UMC Utrecht already do very well across Europe. Colleagues in Ireland, Prof. Roisin McMackin, Prof. Bahman Nasseroleslami and others are also exploring the utility of EEG in other ways.

Uniquely, Canada has the most detailed MRI data on ALS in the world, thanks to the Canadian ALS Neuroimaging Consortium (CALSNIC) and CAPTURE (Comprehensive Analysis Platform To Understand, Remedy, and Eliminate) ALS initiatives led by Dr. Sanjay Kalra at the University of Alberta. EEG has not been incorporated into any of the Canadian ALS studies, but establishing a joint EEG-MRI measure through the Acceleration Grant could yield strong future collaborations here and a potential to embrace its value earlier than in other regions.

It’s still early to know the full value of EEG and EEG-MRI in ALS and whether it will ultimately provide human impact. This funding will help Dr. Dukic find that out faster, which is no small thing for ALS.

2023 ALS Canada-Brain Canada Clinical Research Fellowship

Can we better understand the experience of younger middle-aged adults with ALS to help guide age-appropriate management of the disease?

Younger middle-aged adults with amyotrophic lateral sclerosis and their family caregivers: an exploration of their experiences and perspectives

$200,000 awarded to Dr. Andrea Parks at Sunnybrook Health Sciences Centre

Approximately 10% of people living with ALS will receive their diagnosis before turning 50. Younger middle-aged adults with ALS often face unique challenges regarding their family, employment, and financial responsibilities. Yet, there is limited research to better understand the complex physical, psychological, and social challenges faced by younger middle-aged adults with ALS and their families.

Dr. Andrea Parks aims to better understand these unexplored age-specific complexities. With this award, Dr. Parks will conduct a thorough review of existing knowledge about how age and life stage impact the experience of ALS, including physical, psychological, social, and spiritual aspects, as well as care needs and access to support services. Additionally, 25 younger middle-aged adults diagnosed with ALS at 55 or younger, along with 25 family caregivers, will participate in interviews to delve into their experiences.

Ultimately, Dr. Parks aims to provide a comprehensive understanding of the experiences and challenges faced by both younger middle-aged adults with ALS and their family caregivers. Her research will provide foundational knowledge that can be used to help guide the development of innovative, age-group appropriate interventions and support services for this specific population.

Dr. Parks’ career goal is to become an academic clinician-scientist, integrating clinical practice with a research program that addresses issues that significantly impact people affected by ALS and their families. This work builds upon a previous award where Dr. Parks set out to characterize the different types of psychological distress observed in ALS patients, with the long-term goal of developing a routine screening tool to enhance early identification of psychological distress and guide appropriate management strategies. Dr. Parks brings a unique expertise to the field that will help provide Canadians living with ALS the highest quality of care. While completing this fellowship, she will also be working towards a PhD in Clinical Epidemiology and Health Care Research.

2023 ALS Canada-Brain Canada Trainee Awards

Can a combination of advanced brain imaging and artificial intelligence uncover a biomarker to better track disease progression?

Investigating disease progression and survival outcomes in ALS patients using deep learning and deformation based morphometry

$78,000 awarded to Dr. Isabelle Lajoie, a postdoctoral fellow in Dr. Mahsa Dadar’s lab at the Douglas Hospital Research Centre, McGill University

Previous imaging studies have uncovered changes in certain brain regions of people living with ALS. The extent and location of these changes, however, can differ significantly from person to person. This has led researchers to question whether the variability in brain atrophy patterns is linked to the diversity in symptoms often observed in people with ALS, such as age of onset, disease duration, cognitive changes, and more. If such a link exists, measuring these brain changes could provide a non-invasive way for health care professionals to monitor disease progression more accurately and possibly even predict future clinical symptoms and survival outcomes.

Deformation-based morphometry (DBM) is a sensitive method for quantifying changes in various brain regions using magnetic resonance imaging (MRI). With this award, Dr. Lajoie will take advantage of comprehensive data sets already collected through national initiatives such as the Canadian ALS Neuroimaging Consortium (CALSNIC) and the Comprehensive Analysis Platform To Understand, Remedy, and Eliminate ALS (CAPTURE ALS) to investigate the relationship between DMB measurements and clinical symptoms. With the help of artificial intelligence, she hopes to uncover complex patterns in the data that otherwise may have remained undetectable and explore whether DBM has potential in predicting the course of the disease.

Through this work, Dr. Lajoie seeks to identify a much-needed non-invasive biomarker for ALS, which could change how healthcare professionals monitor and track the disease. The information gained will deepen our understanding of the mechanisms underlying disease progression, clinical symptoms, and survival, ultimately advancing our ability to effectively manage the disease.

Can this sophisticated method to measure brain activity help researchers better understand the role of hyperexcitability in ALS and its connection to symptoms?

Profiling cortical excitability in ALS using threshold tracking transcranial magnetic stimulation and multimodal biomarkers

$75,000 awarded to Liane Phung, a PhD student co-supervised by Dr. Agessandro Abrahao and Dr. Lorne Zinman at Sunnybrook Research Institute

In the intricate network of the brain and spinal cord, neurons communicate with one another via specialized chemicals known as neurotransmitters. When this signaling network functions properly, a delicate balance is maintained between excitatory and inhibitory chemicals. A hallmark feature of ALS, thought to occur even before symptoms appear, is that motor neurons in the brain become overexcited (or hyperexcitable). This change occurs at the cellular level and can’t be noticed by people who experience it, but researchers have found evidence of hyperexcitability in both electrical recordings from the brain and markers in the cerebrospinal fluid of people with ALS. The relationship between hyperexcitability and clinical symptoms, however, remains unclear.

With this award, Liane will explore the link between hyperexcitability in ALS and various clinical and neuroimaging parameters, in addition to a fluid-based biomarker. Excitability circuits of the brain will be assessed using threshold-tracking transcranial magnetic stimulation (TT-TMS), a non-invasive technique that uses a magnetic field to stimulate nerve cells. In the first aim, Liane will analyze data from a group of 100 healthy controls to establish “normal” values for various TT-TMS parameters. She will then assess the reliability of these different TT-TMS measurements in a smaller group of 20 individuals living with ALS over a three-day period. Finally, she will seek to identify specific clinical profiles associated with hyperexcitability by comparing TT-TMS measurements from 30 individuals with ALS with demographic, neuroimaging, and clinical data (such as ALSFRS-R scores and blood neurofilament light levels – a biomarker for neurodegeneration).

This research could help to validate TT-TMS as a method to detect non-invasive biomarkers for ALS, aiding in diagnosis and potentially leading to more personalized treatment options in the future. Efforts to identify specific disease profiles, or subgroups, based on hyperexcitability may also help to improve clinical trial design, as the ability to enroll participants by specific ALS subtypes would reduce heterogeneity and therefore enhance the likelihood of detecting treatment effects.

Do acute viral infections play a role in triggering onset or accelerating the progression of ALS?

Determining the contribution of acute viral infection on the onset and progression of ALS

$25,000 awarded to Art Marzok, a PhD student in Dr. Matthew Miller’s lab at McMaster University

Both genetic and environmental factors are believed to influence the onset and progression of ALS, accounting for some of the differences we see in people living with the disease. Viral infections represent one potential environmental risk factor. For example, emerging evidence suggests that endogenous retroviruses like HERV-K, remnants of viral DNA passed down from our ancestors’ past infections, may promote inflammation and motor neuron degeneration in a subset of ALS cases. However, very little is known about the role acute viral infections may play in contributing to the onset of ALS, which are sudden and rapid infections, such as those caused by influenza and coronaviruses.

With this award, Art will investigate whether acute viral infections contribute to the onset or accelerate the progression of ALS symptoms. This work builds upon his previous studies, which showed that mice carrying an ALS-associated mutation (SOD1) and previously exposed to influenza A had an accelerated disease course compared to their uninfected counterparts. Even mice exposed to inactivated virus displayed the same accelerated symptoms, suggesting that the immune response triggered by the infection played a critical role in worsening the disease.

In this study, Art will continue his investigations in mice, seeking to unravel the mechanisms through which viral infections influence ALS. He will also broaden the scope of his research to include SARS-CoV-2, the virus responsible for COVID-19, to explore its impact on ALS progression. This project will provide novel insights into the role of acute viral infections in ALS, which could pave the way for future therapeutic and preventive strategies.

Can a better understanding of how this particular protein influences overall protein production in cells offer insights into treating ALS?

Defective protein translation: a causative pathway in ALS?

$75,000 awarded to Amrita, a PhD student in Dr. Neil Cashman’s lab at the University of British Columbia

In the vast majority of ALS cases, there is an abnormal accumulation of a protein called TDP-43 within neurons. TDP-43 plays a crucial role in processing messenger RNA (mRNA) molecules, which serve as a genetic blueprint for protein synthesis at specific cellular structures called ribosomes. When TDP-43 moves from the nucleus (where it is normally found) to the cytoplasm, a hallmark feature of ALS, it is no longer able to perform its normal function effectively. However, the precise mechanisms underlying how TDP-43 contributes to ALS are not fully understood, making the development of effective therapies challenging.

Previous studies have indicated that a buildup of cytoplasmic TDP-43 leads to a decrease in overall protein production in cells. Research conducted in the Cashman lab highlighted a potential therapeutic role for a specific ribosomal protein called Receptor of Activated C-Kinase 1 (RACK1), as it was shown that lowering RACK1 levels can reduce TDP-43 accumulation in the cytoplasm, partially relocate TDP-43 back to the nucleus, and restore normal protein production within cells. These findings suggest a novel disease mechanism whereby TDP-43 pathology is mediated by RACK1.

With this award, Amrita aims to delve deeper into the relationship between RACK1 and TDP-43 in ALS. Her research will focus on understanding how reduced RACK1 levels promote the restoration of protein production in cells and whether lowering RACK1 expression in fruit fly models of ALS can prevent neurodegeneration. The outcomes of this study could lay the groundwork for exploring RACK1-based therapies for ALS in the future and improve our understanding of mechanisms related to TDP-43 pathology, the specific role of RACK1 in ALS, and more broadly shed light on protein production defects in neurodegenerative diseases.

Will this novel decision aid improve early care planning and symptom management in those experiencing bulbar ALS symptoms?

Development of a shared decision-making aid for bulbar symptom management in ALS

$50,000 awarded to Anna Huynh, a PhD student in Dr. Yana Yunusova’s lab at Sunnybrook Research Institute

Bulbar symptoms, impacting speech and swallowing, are among the most challenging aspects of ALS. Early care planning, especially for bulbar symptoms, is vital to maintain function and quality of life for as long as possible. However, treatment decisions regarding bulbar symptoms heavily rely on personal preference, such as the use of augmentative and alternative communication (AAC) devices and feeding tube placement. These choices are often postponed due to the complexities of the disease and their personal nature, causing individuals with bulbar ALS to delay these decisions until symptoms are fully evident, resulting in multiple competing care priorities.

Decision aids are valuable tools for facilitating preference-sensitive decisions and improving communication between healthcare professionals and patients regarding treatment options. Despite their growing use in the context of ALS, there remains a gap in resources available to support shared decision-making in the management of bulbar symptoms.

With this award, Anna seeks to develop a specialized tool to facilitate decision-making conversations about bulbar symptom management between individuals with ALS, their caregivers, and healthcare professionals. Through interviews, Anna will gain a better understanding of the decision-making process for bulbar symptom management, allowing her to create a tool that considers individual needs and values. She will then develop and refine a prototype decision-making aid to be tested in an ALS clinic, collecting real-world feedback, and assessing user experience.

This work seeks to provide a well-informed and standardized approach to decision-making tailored to the management of bulbar symptoms in ALS. Decision-aids have also been shown to improve professional-patient interactions and ensure decisions align with individual and family values. Thus, this tool has the potential to significantly enhance care for those living with bulbar ALS.