Progressive supranuclear palsy (PSP) is a rare brain disorder with no known cure. As it worsens, the disease can cause serious problems with walking, balance, eye movements, swallowing, as well as changes in mood and thinking.
A recent large-scale international study led by Krembil Senior Scientist Dr. Gabor Kovacs identified the underlying stages of disease, which are key to better managing symptoms and developing targets for therapy. “This is the first study that attempts to define stages of PSP,” says Dr. Kovacs. “By knowing where to look, we can better monitor patients and better predict prognoses.”
The research project included international collaborators, including Dr. John Trojanowski from the University of Pennsylvania and Dr. Günter Höglinger from the German Centre for Neurodegenerative Disease. Together, the research team evaluated more than 200 brains affected by PSP and defined six stages of disease progression.
An abnormal protein, known as the pathological tau protein, is seen in the brains of individuals with PSP. The researchers traced how this protein spreads through the brain in distinct paths for each clinical sub-type. The findings showed that irrespective of the disease’s clinical sub-type the first stage of PSP develops in the same brain region.
“Knowing where the pathological accumulation of the tau protein starts in the brain, means that we can now focus on researching this area specifically,” says Dr. Kovacs. “Because this region comprises unique cell populations with different receptors or metabolic activity—we will get a better idea of which brain cells to target with therapy in the early stages of PSP.”
The study was also able to show that the major difference between clinical sub-types of PSP relates not only to the involvement of nerve cells but also to the supporting cells called astroglia and oligodendroglia.
“We’ve provided a conceptual framework for the spread of tau to understand the mechanisms of how pathological tau jumps from one neuron to the next neuron and how the supporting tissue plays a role,” says Dr. Kovacs. “With this understanding, we hope to provide a foundation for basic research to develop blocking agents or therapies to stop the spread of the tau protein.”
Dr. Kovacs is Co-Director of the Rossy Program for PSP research, which is led by Dr. Anthony Lang, Director of the Movement Disorders Clinic at Toronto Western Hospital. Funding for the study was obtained by Dr. Lang. Under the directorship of Dr. Lang and a team of world-leading researchers in movement disorders, it is the only program in Canada dedicated to PSP research and care. The research was also supported by Open Access funding from Projekt DEAL, the National Institutes of Health, the Penn Institute on Aging, Fundació Marató de TV3, the Rossy Foundation, the Edmond J. Safra Foundation, the Bishop Dr. Karl Golser Foundation, the German Research Foundation (DFG), the German Federal Ministry of Education and Research (BMBF), the NOMIS Foundation and the Toronto General & Western Hospital Foundation.
Gabor G. Kovacs, et al. Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol. 2020 Aug;140(2):99-119. doi: 10.1007/s00401-020-02158-2. Epub 2020 May 7.
The genetic material found within a virus is essential for its ability to replicate and spread. Understanding how this genetic material changes as the virus spreads is crucial to developing drug treatments and vaccines.
A research team led by Techna Institute Scientist Dr. Bo Wang has designed an innovative application that can track the changes that occur to the genetics of the SARS-CoV-2 virus as it spreads.
“Mutations in the virus could affect how well a vaccine or treatment works,” says Dr. Wang. “We needed a tool to monitor these changes—similar to how we have other tools for tracking infection cases.”
Developed by Dr. Wang’s doctoral student Hassaan Maan, the new web application, named the COVID-19 Genotyping Tool (CGT), summarizes and analyzes data from around the world. Genetic sequences are pulled from a global repository and compared based on their similarity. Researchers can sort the data by country, continent, collection date and travel history to see if the virus is evolving in time or by geographic region.
The CGT can also be used to directly compare in-house data against globally sourced data. Artificial intelligence algorithms let researchers situate their local data within the global picture in a matter of minutes.
In addition to helping keep a close eye on the virus, analysis from the CGT will help uncover the transmission history of the virus. Patterns in genetic variations will help identify outbreak epicentres and key transmission events. This information can then be used to guide public health policy decisions and efforts toward managing the pandemic.
This work was supported by the Vector Institute for Artificial Intelligence, Sunnybrook Health Sciences Centre, McMaster University, the Public Health Agency of Canada, the University of Manitoba, the CIFAR AI Chairs Program and the generous support of donors.
Maan H, Mbareche H, Raphenya AR, Banerjee A, Nasir JA, Kozak RA, Knox N, Mubareka S, McArthur AG, Wang B. Genotyping SARS-CoV-2 through an interactive web application. Lancet Digital Health. 2020 June 12. doi: 10.1016/S2589-7500(20)30140-0.
Welcome to the latest issue of Research Spotlight.
As Canada’s largest research hospital, UHN is a national and international source for discovery, education and patient care. This newsletter highlights top research advancements across UHN and from over 1000 researchers appointed at our institutes.
Stories in this month’s issue:
● COVID-19 and the Brain: Brain imaging in severe cases of COVID-19 reveals that the virus may cause microbleeding.
● Designed, Made and Tested Here: UHN fast-tracks on-site manufacturing of face shields, test swabs and ventilator components.
● A Fresh Pair of Eyes: Computer vision can accurately differentiate between sleep apneas and inform treatments.
● Searching the Blood for Cancer: Ground-breaking findings set the stage for blood tests to diagnose brain and kidney cancers.
Welcome to the latest issue of The Krembil.
The Krembil is the official newsletter of the Krembil Research Institute (formerly the Toronto Western Research Institute). Research at Krembil is focused on finding innovative treatments and cures for chronic debilitating disorders, including arthritis and diseases of the brain and eyes.
Stories in this month’s issue include:
● Krembil Researcher Retires: Community says farewell to world-renowned arthritis researcher Dr. Aileen Davis.
● Vision Researcher Recruited: Dr. Karun Singh, a neuroscientist and stem cell biologist, joins Krembil as a Senior Scientist.
● Tracing the Paths to Disease: New study reveals neuropathological patterns in progressive supranuclear palsy.
● Stronger Together: Partnership between UHN and company reveals a new putative treatment for spinal arthritis.
● Targeting Cancer at Its Roots: Protein in cancer stem cells could represent a new target to treat aggressive brain cancer.
● Investing in Infrastructure: The brain adjusts communication speed between its different regions to increase resilience.
Dr. Shaf Keshavjee, Senior Scientist at TGHRI, Director of the Latner Thoracic Research Laboratories and Surgeon-in-Chief, Sprott Department of Surgery at UHN, has been recognized with a Governor General’s Innovation Award for his invention of the Toronto Ex Vivo Lung Perfusion (EVLP) System. The prominent award recognizes individuals who have made transformative innovations that have a positive impact on the quality of life in Canada.
The EVLP system is designed to preserve donor lung function outside of the body by delivering a constant supply of oxygen and nutrients to the organ. By safely maintaining donor lungs in a fully functioning physiologic state outside of the human body, transplant surgeons can now assess, with much greater confidence, whether the donor lungs are suitable for life-saving transplantation.
This technology has been adopted worldwide, saving countless lives of individuals with end stage lung disease. EVLP helps to address the global shortage of donor lungs and critically reduce lung transplant wait times.
In addition to this award, Dr. Keshavjee has received numerous honours over his career, including a UHN Inventor of the Year Award for his work on developing the EVLP system and, in 2014, was named an Officer of the Order of Canada.
The Governor General’s Innovation Award is in its fifth year and 30 prestigious awards have been bestowed to date. Dr. Keshavjee will receive the award at a ceremony hosted by the Governor General at Rideau Hall in Ottawa later this year. To see the 2020 award winners, click here.
Congratulations Dr. Keshavjee!
Five researchers at UHN—Drs. Beate Sander, Myron Cybulsky, Jordan Feld, Andrea Iaboni and Patrick Lawler—have been awarded funding from the Government of Ontario for COVID-19 research. The Ontario COVID-19 Rapid Research Fund was launched in April to generate rapid solutions to fight the disease. The following funded projects will tackle ongoing challenges in screening and treatment of the disease, planning of health care resources, and management of long-term care homes.
Ontario’s Response to COVID-19: Balancing Trade-offs and Improving Outcomes for all Ontarians
Dr. Beate Sander, Scientist at Toronto General Hospital Research Institute
Dr. Sander’s team has developed the COvid19 Resource Estimator (CORE) model to support capacity planning and public health interventions. The model will be expanded to forecast COVID-19 case numbers and examine their effect on the acute care system and health outcomes for Ontarians. By examining a range of reopening scenarios, this research will help the province to plan mitigation strategies that balance health care system capacity, population health and broader societal outcomes, such as economic impact.
Development and Validation of Flexible Medium Throughput Solutions for COVID-19 Diagnostics
Dr. Myron Cybulsky, Senior Scientist at Toronto General Hospital Research Institute
As workplaces reopen, extensive screening of COVID-19 will be vital to identify asymptomatic and presymptomatic individuals. Dr. Cybulsky’s team will evaluate various methods of diagnosing COVID-19 that are adaptable to nasal swab, saliva and saline gargle testing. They will then develop tests based on rigorous clinical standards. The development of different diagnostic tests will help the province to manage outbreaks and shortages in test reagents while providing rapid and cost-effective testing strategies.
Interferon Lambda for Immediate Antiviral Therapy at Diagnosis (ILIAD): A Phase II Randomized, Open-label, Multicentre Trial to Evaluate the Effect of Peginterferon Lambda for the Treatment of COVID-19
Dr. Jordan Feld, Senior Scientist at Toronto General Hospital Research Institute
Dr. Feld will evaluate the drug peginterferon-lambda in ambulatory and hospitalized patients with mild to moderate cases of COVID-19. Peginterferon-lambda has been extensively studied and has been used to treat other viral diseases, such as hepatitis B and C. The trial will determine whether the drug improves the ability of individuals to clear the SARS-CoV-2 virus.
Toolkit to Prevent COVID-19 Transmission among Persons with Dementia in Long-Term Care
Dr. Andrea Iaboni, Senior Scientist at KITE Research Institute
Dr. Iaboni’s team will develop, implement and evaluate a Dementia Isolation Toolkit for long-term care homes. A series of methods and approaches will be designed to support the compassionate, safe and effective isolation of individuals with dementia without compromising their dignity and personhood. The toolkit will help improve the implementation of infection control protocols in long-term care homes, reduce community spread of the virus and protect health care workers. The team will support the implementation of the toolkit through ongoing evaluation and consultation.
The Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC) Trial: A Multinational Randomized, Adaptive, Controlled Clinical Trial – Support for Personnel at the International Clinical Coordinating Centre in Ontario
Dr. Patrick Lawler, Scientist at Toronto General Hospital Research Institute
Dr. Ewan Goligher, Scientist at Toronto General Hospital Research Institute
In partnership with Dr. Ryan Zarychanski (University of Manitoba) and researchers from Canada, the United States, Brazil and Mexico, Drs. Lawler and Goligher will test a blood thinner called heparin for its effectiveness in treating severe COVID-19 infection. Heparin may also have anti-viral and anti-inflammatory effects, and has the potential to reduce mortality and the need for mechanical ventilation in hospitalized patients.
Can you diagnose cancer with a blood test? The answer is now yes for brain and kidney tumours, according to new research from UHN and Harvard Medical School.
Published in the latest issue of Nature Medicine, the tests were developed based on findings by Dr. Daniel De Carvalho, a Senior Scientist and Canada Research Chair at Princess Margaret Cancer Centre.
His research group studies a genetic change known as DNA methylation—a process through which the cell attaches a chemical group known as methyl to DNA. This process can change cell behaviour by affecting which genes get turned on or off. In cancer cells, DNA methylation patterns are disrupted and lead to unregulated cancer growth.
“We took advantage of the fact that there are hundreds of thousands of DNA fragments from cancer cells circulating in the blood,” says Dr. De Carvalho. “Using this knowledge, we developed advanced approaches to profile or ‘read’ DNA methylation in this circulating DNA and combined them with machine learning analysis.” The result: a highly sensitive test that can classify multiple solid tumours, including brain and kidney cancers.
The approach was applied to brain cancer, through a collaboration with Dr. Gelareh Zadeh, Senior Scientist at the Princess Margaret Cancer Centre and Medical Director of the Krembil Brain Institute.
The team analyzed blood samples paired with brain cancer tumour samples. Machine learning was used to analyze DNA methylation in the blood samples and to classify the brain tumour type.
"Because this test is so sensitive in picking up even small amounts of highly specific tumour-derived signals in the blood, we now have a new, non-invasive way of detecting and discriminating between common brain tumours—something which was long thought impossible,” says Dr. Zadeh.
To apply the approach to detect kidney cancer, Dr. De Carvalho worked with Drs. Toni Choueiri and Matthew Freedman at the Dana-Farber Cancer Institute in Boston.
The team reported accurate classification of all the various stages of kidney cancer using blood plasma and demonstrated that the method could also be applied to urine samples to identify individuals with renal cell carcinoma—the most common type of kidney cancer in adults.
"DNA methylation is a type of epigenetic change that, unlike mutations or other genetic changes, does not alter the sequence of the DNA. Our findings reveal that these epigenetic changes represent a powerful tool in the fight against cancer—one that could be combined with traditional genetic testing to develop more accurate and more sensitive cancer tests,” says Dr. De Carvalho.
These findings lay the groundwork for the development of blood tests, which are less invasive than traditional biopsies, to detect and diagnose kidney and brain cancers. Future work will validate these findings clinically and explore the application of this strategy to other solid tumours.
Nassiri F, Chakravarthy A, Feng S, et al. Detection and discrimination of intracranial tumors using plasma cell-free DNA methylomes. Nat Med. 2020 Jun 22. doi:10.1038/s41591-020-0932-2. This work was supported by the Canadian Institutes of Health Research, the Brain Tumour Charity (UK), the Princess Margaret Cancer Foundation, the Natural Sciences and Engineering Research Council of Canada and the Province of Ontario. D De Carvalho holds a Tier 2 Canada Research Chair in Neoplasms.
Nuzzo PV, Berchuck JE, Korthauer K, et al. Detection of renal cell carcinoma using plasma and urine cell-free DNA. Nat Med. 2020 Jun 22. doi:10.1038/s41591-020-0933-1. This work was supported by Rebecca and Nathan Milikowsky, Dana-Farber Cancer Institute, H.L. Snyder Medical Foundation, BC Children’s Hospital Research Institute, BC Provincial Health Services Authority, Children’s & Women’s Health Centre of British Columbia, BC Children’s Hospital Foundation and the Canadian Institutes of Health Research.
Research conducted at UHN's research institutes spans the full spectrum of diseases and disciplines, including cancer, cardiovascular sciences, transplantation, neural and sensory sciences, musculoskeletal health, rehabilitation sciences, and community and population health.
Learn more about our institutes by clicking below: