Drs. Cathy Barr and Paul Sandor at the Krembil Research Institute contributed to a landmark study on the genetic underpinnings of brain disorders. The study was published in Science and involved over 400 researchers from around the world.
As part of the study, the international team led by researchers at Harvard University examined the genetic information of more than 200,000 patients, each affected by one of 25 common brain disorders.
The research team found that psychiatric disorders, such as bipolar disorder and major depressive disorder, appear to be more genetically similar than originally thought. In contrast, neurological disorders such as Alzheimer disease tend to be more genetically distinct.
The study’s findings will help researchers improve the diagnosis and treatment of brain disorders.
Drs. Barr and Sandor are experts on the genetics of Tourette syndrome, a neurodevelopmental disorder that causes a person to make involuntary movements and sounds. Tourette syndrome was one of the 25 brains disorders examined in the study.
Brainstorm Consortium et al. Analysis of shared heritability in common disorders of the brain. Science. 2018 Jun 22. doi: 10.1126/science.aap8757.
Imagine superheroes who can destroy their enemies by engulfing them whole, acquire new powers to ward off unfamiliar threats and enlist the help of others when the going gets tough.
To find such superheroes, you’d have to look no further than your own body. Monocytes—the largest cells circulating in the blood—have all of these capabilities and more. They patrol the blood for disease-causing bacteria and viruses and use their ‘special powers’ to eliminate them.
Dr. Nigil Haroon, a Scientist at Krembil Research Institute, has recently shown that instead of fighting disease, some monocytes contribute to it. He and his team have found evidence suggesting that some monocytes worsen the symptoms of ankylosing spondylitis (AS)—a form of spinal arthritis.
AS is characterized by inflammation, stiffness of the spine and chronic back pain. Unusually, over half of those with the condition also have gut inflammation. Researchers have been trying to understand the mechanisms behind this puzzling connection.
By analyzing spinal tissues of AS patients who have gut inflammation, Dr. Haroon’s team made a startling discovery: while patrolling for threats in the gut, some monocytes pick up information that causes them to travel to the spine where they promote inflammation.
“It’s as if these monocytes were tricked into over-reacting, thus exacerbating the symptoms of AS,” explains Dr. Francesco Ciccia, who led the study with Dr. Haroon.
“Our results suggest that monocytes from the gut could play an important role in AS pathogenesis. Moreover, they’re providing new insight into the complex relationship between AS and gut inflammation, one factor at a time,” comments Dr. Haroon. “Our goal is to eventually develop specific drugs to help alleviate the symptoms in these patients.”
This work was supported by the Italian Ministero dell’Istruzione, dell’Università e della ricerca Scientifica and the Toronto General & Western Hospital Foundation.
Ciccia F, Guggino G, Zeng M, Thomas R, Ranganathan V, Rahman A, Alessandro R, Rizzo A, Saieva L, Macaluso F, Peralta S, Di Liberto D, Dieli F, Cipriani P, Giacomelli R, Baeten D, Haroon N. Pro-inflammatory CX3CR1+ CD59+ TL1A+ IL-23+ monocytes are expanded in patients with Ankylosing Spondylitis and modulate ILC3 immune functions. Arthritis Rheumatol. 2018 June 5. doi: 10.1002/art.40582.
Type 2 diabetes (T2D) and Alzheimer disease are linked.
People with T2D, a chronic condition characterized by high blood sugar levels, are at a higher risk of developing Alzheimer disease than those who don’t have it. Moreover, high blood sugar levels have been implicated in brain dysfunction—such as deficits in attention, memory and information processing—which are hallmarks of Alzheimer disease and other forms of dementia.
Several clinical studies suggest that some anti-diabetic medications, which lower blood sugar levels, might improve brain function in Alzheimer disease and slow its progression. However, it’s unclear which of the approximately 20 anti-diabetic medications currently available would be most effective.
To begin to narrow down this list, a team led by Krembil Clinician Investigator Dr. Roger McIntyre performed a study that examined relevant clinical trials completed within the past 13 years. Dr. McIntyre was named one of ‘the world’s most influential scientific minds’ by Clarivate Analytics/Thomson Reuters in 2014, 2015, 2016 and 2017.
The researchers identified 19 clinical trials that evaluated the effect of six different diabetes medications in patients with either Alzheimer disease or mild forms of dementia.
By performing a comprehensive analysis of the studies’ findings, the researchers found that all six diabetic medications produced significant improvements in the mental function of participants. The two drugs that produced the most improvement–pioglitazone and rosiglitazone—lower blood sugar through the same mechanism: by stimulating cells to absorb more sugar and use it as a source of energy.
“Our study provides compelling evidence that anti-diabetic drugs, especially piglitazone, help protect brain function in Alzheimer disease. However, before these findings can be applied in the clinic, they need to be replicated and confirmed in large-scale clinical trials,” says Dr. McIntyre.
This work was supported by the China Scholarship Council and the Toronto General & Western Hospital Foundation.
Cao B, Rosenblat JD, Brietzke E, Park C, Lee Y, Musial N, Pan Z, Mansur RB, McIntyre RS. Comparative efficacy and acceptability of antidiabetic agents for Alzheimer's disease and mild cognitive impairment: A systematic review and network meta-analysis. Diabetes Obes Metab. 2018 May 23. doi: 10.1111/dom.13373.
An international team of leukemia scientists has discovered a way to identify which healthy individuals are at risk of developing acute myeloid leukemia (AML), an aggressive and often deadly blood cancer.
The findings, published today in Nature, illuminate the ‘black box of leukemia’ and answer the question of where, when and how the disease begins, says co-principal investigator Dr. John Dick, Senior Scientist at Princess Margaret Cancer Centre, University Health Network.
“We have been able to identify people in the general population who have traces of mutations in their blood that represent the first steps in how normal blood cells begin on a pathway of becoming increasingly abnormal and puts them at risk of progressing to AML. We can find these traces up to 10 years before AML actually develops,” says Dr. Dick. “This extended window of time gives us the first opportunity to think about how to prevent AML.”
Dr. Dick is also a Professor in the Department of Molecular Genetics at the University of Toronto, he holds the Canada Research Chair in Stem Cell Biology, and is Co-Leader of the Acute Leukemia Translational Research Initiative at the Ontario Institute for Cancer Research.
Study author Dr. Sagi Abelson, a post-doctoral fellow in the Dick laboratory, says: “AML is a devastating disease diagnosed too late, with a 90% mortality rate after the age of 65. Our findings show it is possible to identify individuals in the general population who are at high risk of developing AML through a genetic test on a blood sample.” Drs. Dick and Abelson talk about the research in this video.
“The ultimate goal is to identify these individuals and study how we can target the mutated blood cells long before the disease actually begins.”
The study builds on Dr. Dick’s 2014 discovery that a pre-leukemic stem cell could be found lurking amongst all the leukemia cells that are present in the blood sample taken when a person is first diagnosed with AML. The pre-leukemic stem cell still functions normally but it has taken the first step in generating a pathway through which blood cells become more and more abnormal resulting in AML (Nature, February 12, 2014).
“Our 2014 study predicted that people with early mutations in their blood stem cells, long before the disease appears and makes them sick, should be able to be detected within the general population by testing a blood sample for the presence of the mutation.” says Dr. Dick.
Co-principal investigator Dr. Liran Shlush, a former fellow in the Dick lab, and now Senior Scientist at the Weizmann Institute in Israel, led the approach to use data from a large European population health and lifestyle study that tracked 550,000 people over 20 years to determine correlations to cancer.
The leukemia team extracted the data from more than 100 participants who developed AML six to 10 years after joining the study, plus the data from an age-matched cohort of more than 400 who did not develop the disease.
Dr. Dick says: “We wanted to know if there was any difference between these two groups in the genetics of their ‘normal’ blood samples taken at enrollment. To find out, we developed a gene sequencing tool that captured the most common genes that get altered in AML and sequenced all 500 blood samples.”
The answer was “Yes”. The seeds of the blood system started picking up mutations years before an individual was diagnosed with AML, a finding that enabled the team to accurately predict those at risk of disease progression.
Furthermore, the team used advanced computational technology to assay the information obtained from routinely collected blood tests taken over 15 years in Israel and housed in a massive database of 3.4 million electronic health records.
The study has deepened our understanding of the distinction between AML and a common feature of aging called ARCH–age-related clonal hematopoiesis–whereby blood stem cells acquire mutations and become a little more proliferative. For the vast majority of people this is just a completely benign feature of aging.
“Every AML patient has ARCH but not everyone with ARCH gets AML,” explains Dr. Dick.
Sagi Abelson, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature, 2018. doi: 10.1038/s41586-018-0317-6.
The UHN research team was funded by the Leukemia and Lymphoma Society, the Ontario Institute for Cancer Research, the Canadian Cancer Society, the Canadian Institutes of Health Research, the International Development Research Centre, the Terry Fox Research Institute, Medicine by Design – Canada First Research Excellence Fund, the Benjamin Pearl Fellowship from the McEwen Centre for Regenerative Medicine, the Ontario Ministry of Health and Long-term Care, and The Princess Margaret Cancer Foundation. Major international collaborators included the Wellcome Sanger Institute and the University of Cambridge in the UK; and the Weizmann Institute of Science and Clalit Research Institute in Israel.
Researchers at the University of Toronto and University Health Network have uncovered new information that could accelerate post-surgical healing for procedures involving medical devices as diverse as dental implants and skin dressings.
Their paper, published in Nature Communications Biology describes how different surface textures on medical implants affect a fundamental process in the body’s ability to heal the area surrounding the implant.
“We have known for decades that creating nano-scale implant surface texture improves clinical success rates,” said John E. Davies, a professor in University of Toronto’s Faculty of Dentistry and Institute of Biomaterials & Biomedical Engineering (IBBME)—the senior author of this study. “However, little was known of the cellular mechanisms by which the implant surface affects the healing process.”
The team was co-led by Dr. Ralph DaCosta, a Scientist at Princess Margaret Cancer Centre and Research Faculty at the Techna Institute at University Health Network, who looked at the effect of implant surface texture on neovascularization—the process of blood vessel formation— around implants.
“The ability for blood vessels to form around an implant is a key factor in its successful tissue integration,” said Niloufar Khosravi, a PhD candidate in Davies’ lab and the study’s first author. “Indeed, neovascularization is vital for tissue healing and regeneration around the implant.”
To study this effect, the team built a model that allowed them to observe the implant healing process in real-time using intravital optical microscopic imaging systems developed in DaCosta’s lab. Their experiments monitored the formation of new blood vessels around a series of medical-grade titanium implants at the cellular level, and how the distribution of these vessels changed according to different surface textures on the implants.
“We did not initially expect blood vessels to be clearly visible in this model,” said Khosravi. “We decided to add an imaging contrast agent after a few pilot studies and the resulting resolution was remarkably higher than we expected. It allowed us to monitor not only the rate, but also the location, shape, function and pattern of new blood vessels around implants over a six week period.”
In addition to providing new insights into how medical implants can be better designed, the team’s findings could also address other health related challenges.
“We can use this knowledge to build broader implantable biomaterials to improve the quality of life for people who have impaired healing conditions, such as the elderly or persons with diabetes,” said Dr. DaCosta, who is also an assistant professor in the University of Toronto’s Department of Medical Biophysics. “We now have new tools and strategies to better support the body’s natural repair process.”
Story source: Luke Ng, University of Toronto.
Our thoughts and actions—no matter how simple—are underpinned by a complex network of chemical traffic in our brain. This traffic consists of chemical messages that are exchanged between brain cells, a process that enables thousands of cells in the brain to communicate and share information with each other.
Although this ‘chemical communication’ is crucial for brain function, we know relatively little about the machinery responsible for sending and receiving these messages.
Recently, Dr. Shuzo Sugita, a Senior Scientist at the Krembil Research Institute, found that the protein syntaxin 4 is important for the exchange of chemical messages in the hippocampus, a part of the brain that helps us store memories long-term and keep track of the location of objects in space.
Using a variety of experimental models, Dr. Sugita and his team showed that the loss of syntaxin 4 disrupted the communication between brain cells within the hippocampus. This in turn impaired learning—a process that involves storing and retrieving memories.
Upon closer examination, the researchers discovered why syntaxin 4 is important for communication and learning: the protein helps to add sensors that receive chemical messages to the surface of brain cells. Moreover, when a lot of information needs to be communicated from one cell to another, syntaxin 4 recruits more chemical sensors to the surface of the receiving cell to help it capture the extra incoming messages.
“It’s like adding more lanes to the road during rush-hour traffic,” explains Dr. Na-Ryum Bin, who led the study with Dr. Sugita.
These findings show that syntaxin 4 is important for learning because it is involved in the receipt of chemical messages in brain cells within the hippocampus.
Of his work, Dr. Sugita says, “It takes us one step closer to understanding what happens in the hippocampus when we learn and remember. The eventual goal is to design personalized medicine to help restore these functions when they are lost.”
This work was supported by the Natural Sciences and Engineering Research Council of Canada, the Heart and Stroke Foundation of Ontario, the Canadian Institutes of Health Research and the Toronto General & Western Hospital Foundation.
Bin N-R, Ma K, Harada H, Tien C-W, Bergin F, Sugita K, Luyben TT, Narimatsu M, Jia Z, Wrana JL, Monnier PP, Zhang L, Okamoto K, Sugita S. Crucial role of postsynaptic syntaxin 4 in mediating basal neurotransmission and synaptic plasticity in hippocampal CA1 Neurons. Cell Rep. 2018 June 5. doi: doi.org/10.1016/j.celrep.2018.05.026.
On June 20, UHN established the Krembil Brain Institute to formally create an academic health sciences entity that harmonizes the clinical and research priorities in the neurosciences.
This new Institute will help clinicians, scientists and researchers based at Toronto Western Hospital and across UHN work together to seek better treatments and cures for diseases of the brain, spine and nerves.
Dr. Gelareh Zadeh, neurosurgeon, Scientist and Program Medical Director, Krembil Neuroscience Centre at UHN, and Dr. Donald Weaver, dementia neurologist, medicinal chemist and Director of the Krembil Research Institute, will act as co-directors of the Krembil Brain Institute.
"Aligning the clinical and research priorities at Krembil is crucial to making a bigger impact in our field, the community we serve, and for improving outcomes and wellness of the aging brain," said Dr. Zadeh.
"It is important we devise strategies that accelerate and focus our research discoveries, education and training towards improving clinical outcomes and standards of care in order to advance early detection, prevention and treatment of brain conditions," she said.
The Krembil Neuroscience Centre and the Krembil Research Institute will remain as operational entities within UHN alongside the Krembil Brain Institute; however, UHN will move towards the use of a single Krembil Brain Institute brand for neuroscience activities.
It is estimated that one in three Canadians will be affected by a brain disease, disorder or injury in their lifetime and that 3.6 million Canadians are currently affected by a neurological condition.
Giving UHN a competitive advantage
"In this coming century, the diagnosis and treatment of brain diseases will emerge as one of the pre-eminent pursuits of modern medicine," said Dr. Weaver.
The Krembil Brain Institute will give UHN a competitive advantage over other organizations by establishing a single identity and offering integrated, multidisciplinary, comprehensive neuroscience health care that is second to none in Canada and among the best in the world.
The new Institute is also expected to help UHN recruit leaders in the neuroscience field, attract high-quality students and build on pre-existing partnerships with the Toronto Rehabilitation Institute, The Centre for Addiction and Mental Health (CAMH) and other organizations provincially, nationally and internationally.
"We have the expertise, the people power and the ambition to take neurosciences to the next phase, which is to understand where we can make the biggest impact on outcomes," said Dr. Zadeh.
"Establishing the Krembil Brain Institute allows us to position ourselves to be the predominant leader in brain medicine now, and in the years to come," added Dr. Weaver.
This is an adaptation of a story originally published by UHN News on www.uhn.ca.