Much like how location can directly affect the price of a home, targeting specific areas of the brain can have an effect on the success of certain brain treatments. However, delivering treatment to the exact location in the brain that will provide the most benefit remains a daunting challenge.
To help address this challenge, researchers at Krembil Research Institute explored an emerging technique, known as magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy, for the treatment of essential tremor—a debilitating brain disorder that causes uncontrollable shaking. This study was done in collaboration with Sunnybrook Health Sciences Centre.
The approach uses high-resolution MR imaging to precisely target a tiny area of the brain called the thalamus. This brain region is responsible for relaying important motor and sensory signals in the brain and is a key target for essential tremor therapies.
By examining patients who underwent MRgFUS thalamotomy, the study found that clinical outcomes were largely dependent on the specific regions that were targeted within the thalamus. Just as in the real estate market, location seems to play a critical role in the clinical outcomes of these patients.
The researchers further mapped out areas that were associated with the best treatment responses, as well as those linked with an increased risk of detrimental side effects. Using standard assessment methods, the research team found that use of MRgFUS led to a ~42% improvement in tremor scores three months after treatment. The study also suggested that when smaller areas of the brain were targeted, side effects were less severe.
“These findings are a significant step toward improving the effectiveness of MRgFUS thalamotomy and will enable us to refine areas to target therapy so that we can improve outcomes and reduce adverse effects for patients,” says Dr. Andres M. Lozano, a neurosurgeon at Toronto Western Hospital and Krembil Senior Scientist.
This work was supported by Insightec and the Toronto General & Western Hospital Foundation. Dr. Lozano holds a Tier 1 Canada Research Chair in Neuroscience.
Boutet A, Ranjan M, Zhong J, Germann J, Xu D, Schwartz ML, Lipsman N, Hynynen K, Devenyi GA, Chakravarty M, Hlasny E, Llinas M, Lozano CS, Elias GJB, Chan J, Coblentz A, Fasano A, Kucharczyk W, Hodaie M, Lozano AM. Focused ultrasound thalamotomy location determines clinical benefits in patients with essential tremor. Brain. 2018 Dec 1. doi: 10.1093/brain/awy278.
Finland is known for its snowy landscapes and herds of reindeer.
In 2014, Finland became famous for a very different reason: researchers discovered Finnish people carrying a new type of mutation—known as A53E—in the SNCA gene that causes Parkinson disease (PD).
PD is a neurodegenerative disease characterized by progressive problems with movement. Many people with PD will also experience impaired mental function. Some hereditary forms of the disease are caused by mutations in the SNCA gene and may develop at a younger age than non-hereditary forms. To date, at least 6 different SNCA mutations have been detected in PD patients.
Until recently, the A53E mutation had only been found in Finnish families with PD.
In November 2018, Dr. Lorraine Kalia, a neurologist and Scientist at the Krembil Research Institute, reported the discovery of a Canadian family with PD caused by the A53E mutation. This work was done in collaboration with colleagues at the Krembil, the Morton and Gloria Shulman Movement Disorders Clinic and Edmond J. Safra Program in Parkinson’s Disease at Toronto Western Hospital, and the Tanz Centre for Research in Neurodegenerative Diseases at the University of Toronto.
Using genetic tests and the family’s medical history, Dr. Kalia and her colleagues found that the A53E mutation is likely to have occurred spontaneously and was not inherited from a Finnish ancestor. The tests also suggest that the pattern of methyl molecules ‘decorating’ the patients’ DNA might contribute to the earlier appearance of symptoms in PD patients with SNCA mutations.
Given that the SNCA gene provides the instructions for making the protein α-synuclein, Dr. Kalia and her colleagues also examined the effect of the A53E mutation on the protein’s behaviour in test tubes and in cells.
They showed that the mutated proteins had an increased tendency to form ‘clumps’ and that attaching a phosphoryl molecule onto the proteins caused them to assemble into ‘fibres’. Similar clumps and fibres of α-synuclein are typically found in the brains of PD patients and are believed to be toxic to brain cells and thus are key contributors to neurodegeneration.
Of the findings, Dr. Kalia says, “They show that the A53E mutation should not be ruled out as a cause of Parkinsonism outside of Finland. They also provide new insights into the mechanisms underpinning Parkinson disease, as well as other neurological diseases involving α-synuclein.”
This work was supported by the Canadian Institutes of Health Research, the Canadian Consortium on Neurodegeneration in Aging, and the Toronto General & Western Hospital Foundation (TGWHF).
Picillo M, Lizarraga KJ, Friesen EL, Chau H, Zhang M, Sato C, Rooke G, Munhoz RP, Rogaeva E, Fraser PE, Kalia SK, Kalia LV. Parkinsonism due to A53E α-synuclein gene mutation: Clinical, genetic, epigenetic, and biochemical features. Mov Disord. 2018 Nov 13. doi: 10.1002/mds.27506.
A team of researchers and clinicians specializing in head-and-neck cancer has identified a way to manipulate metabolism to potentially prevent skin fibrosis—a common side effect of radiotherapy affecting quality of life of cancer survivors.
The findings, from the laboratory of Princess Margaret Cancer Centre Senior Scientist Dr. Fei-Fei Liu, were published online today in Nature Metabolism.
First author Dr. Xiao Zhao, a resident in head-and- neck surgery who completed his PhD studies with Dr. Liu, says the research team wanted to find a way to reduce radiation-induced fibrosis, a condition where normal tissue progressively thickens causing pain and dysfunction. The underlying problem is the excess buildup of the extracellular matrix, a supporting structure for all tissues. There is currently no effective treatment to reduce this accumulation.
The team used human tissues with radiation-induced fibrosis and pre-clinical experiments to identify metabolic processes as key triggers and promoters of fibrosis. Metabolic processes are responsible for breaking down fats, proteins and sugars to provide cellular energy. Dr. Zhao explains, “We were surprised to see that metabolic abnormalities were predominant and consistently found in patients with skin fibrosis, even years after their original radiotherapy. Our question was: ‘Can we manipulate metabolism to reduce fibrosis?’”
The team identified two metabolic pathways that were consistently altered in skin with fibrosis: one pathway involved in the breakdown of fats was less active relative to healthy skin; and a second pathway involved in the breakdown of sugar was more active than in healthy skin.
Through uncovering this metabolic model of extracellular matrix regulation, the team also identified several metabolic drug compounds and potential cell therapy techniques that reduced fibrosis in pre-clinical models.
“We’re highlighting fibrosis from this new perspective, thereby opening the door to metabolic regulation as a way to treat this side effect of radiation,” says Dr. Zhao.
Source: UHN.ca
Xiao Zhao, Pamela Psarianos, Laleh Soltan Ghoraie, Kenneth Yip, David Goldstein, Ralph Gilbert, Ian Witterick, Hilary Pang, Ali Hussain, Ju Hee Lee, Justin Williams, Scott V. Bratman, Laurie Ailles, Benjamin Haibe-Kains and Fei-Fei Liu. Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis. Nature Metabolism, 2019; 1 (1): 147 DOI: 10.1038/s42255-018-0008-5
This work was supported by Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, Physicians Services Incorporated Foundation, the Harry Barberian Research Grant, the Jessie & Julie Rasch Foundation, the Strategic Training in Transdisciplinary Radiation Science for the 21st Century (STARS21), the Campbell Family Cancer Research Institute, the Ontario Ministry of Health and Long-Term Care, and The Princess Margaret Cancer Foundation.
Blood tests to measure 'bad’ cholesterol are common and used to identify the risk of a heart attack. Now researchers are exploring whether other types of fat molecules (ie, lipids) found in the blood can provide new insight into heart health.
One of the researchers advancing this field is Dr. Krista Lanctôt, an Affiliate Scientist at Toronto Rehabilitation Institute and Senior Scientist at Sunnybrook Health Sciences Centre.
Dr. Lanctôt led a recent study that showed that blood levels of lipids known as sphingolipids could serve as a readout of improvements in fitness in patients undergoing cardiac rehabilitation.
“Cardiac rehabilitation is an important way to improve the health of patients with coronary artery disease. However, patients’ response to these programs can be highly variable, which is why we explored whether we could identify a new, more objective way to gauge cardiac fitness in this these patients,” explains Dr. Lanctôt. “We focused on sphingolipids because levels of these lipids were recently shown to be elevated in elderly individuals with poor cardiopulmonary fitness.”
The study enrolled 100 patients with a history of coronary artery disease who were participating in a six-month cardiac rehabilitation program. In these patients, the researchers measured blood levels of 45 different sphingolipids, as well as cardiopulmonary fitness at the beginning of the program and then again at three and six months.
Cardiopulmonary fitness, which is a readout of how well the body uses oxygen during vigorous and sustained workout, was measured using a ‘stress test’, where participants wear a mask to measure oxygen levels while rigorously exercising.
“Our results revealed that blood levels of five key sphingolipids decrease as cardiopulmonary fitness improves during cardiac rehabilitation,” said Dr. Lanctôt. “The findings, while emphasizing the importance of lifestyle changes to improve heart health, also provide detailed data that will inform future studies on the role that sphingolipids play in cardiovascular health.”
Supported by the Canadian Institutes of Health Research, the Alzheimer's Society of Canada, the National Institutes of Health (including the National Institute on Aging), and the Toronto Rehab Foundation. AC Andreazza holds a Tier 2 Canada Research Chair in Molecular Pharmacology of Mood Disorders.
Saleem M, Herrmann N, Dinoff A, Marzolini S, Mielke MM, Andreazza A, Oh [no-lexicon]PI[/no-lexicon], Vattem Venkata SL, Haughey NJ, Lanctôt KL. Association between sphingolipids and cardiopulmonary fitness in coronary artery disease patients undertaking cardiac rehabilitation. J Gerontol A Biol Sci Med Sci. 2018 Dec 8. doi:10.1093/gerona/gly273.
Krembil Senior Scientist Dr. Anthony Lang was presented with the 2018 Weston Brain Institute International Outstanding Achievement Award.
The award is valued at $40,000 and recognizes an exceptional researcher who has made significant advances in accelerating the development of therapeutics for neurodegenerative diseases of aging through translational research. The award also recognizes outstanding leadership contributions and citizenship in the research community. The prize was open to all researchers nationally and was provided by The W. Garfield Weston Foundation.
Dr. Lang is considered a world leader in movement disorders such as Parkinson disease (PD) and progressive supranuclear palsy (PSP), as evidenced by his more than 700 publications and 87,000 citations in the area.
He is a founding member of the Parkinson Study group, the largest worldwide network of PD clinicians focused on clinical trials for Parkinson's treatments. His work was critical in bringing several drugs to market for Parkinson disease. Dr. Lang has also been involved in developing cutting-edge therapeutic interventions for PD and PSP including implementing neuronal growth factors as neuroprotective agents, and neurosurgical interventions such as pallidotomy and deep brain stimulation. Another key contribution was his role as a leader in the creation of MDS-UPDRS, the most commonly used scale globally to help diagnose PD and PSP patients and to determine their stage of disease progression.
Other honours bestowed upon Dr. Lang include his role as President of the International Parkinson and Movement Disorder Society (MDS) from 2007-2009, his appointment as an Officer of the Order of Canada in 2010, his election as a Fellow of the Canadian Academy of Health Sciences and the Royal Society of Canada in 2011, and his selection as an Honorary Member by the MDS in 2014.
Congratulations Dr. Lang!
Scientists at the Peter Munk Cardiac Centre have identified a cell that is key to helping the heart repair and potentially regenerate following a heart attack.
The study, published in Nature Immunology, characterized a type of white blood cell—referred to as a cardiac macrophage—that resides in our hearts. Macrophages are well-known for their ability to fight infections and promote tissue repair.
"Using a combination of single-cell technologies, we found that instead of a single type of macrophage, there are at least four types that live within the un-injured heart,” says senior author Dr. Slava Epelman, staff cardiologist and scientist at Toronto General Hospital Research Institute. “That number increases to 11 after a heart attack, which indicates the immune system behaves in a much more complex fashion than we ever imagined."
One type of macrophage was found to be in a neonatal-like (or newborn) state, a time in life where these cells would normally aid in the growth and development of organs, meaning that they could be channeled to help repair the heart following a heart attack. These macrophages are lost after a heart attack in adults, which could be a contributing factor as to why the adult heart may not heal itself as well as the neonatal heart.
"Genetically removing neonatal-like macrophages at the time of the heart attack in experimental models worsens heart function most profoundly at the region of the heart separating injured and un-injured heart muscle—the only zone of the adult heart where this macrophage type increases in number," says Dr. Epelman, explaining the important role that these newly identified cardiac macrophages play in repair.
These findings represent an instrumental step forward in finding effective strategies to promote repair following a heart attack.
This work was supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation, March of Dimes, The Ted Rogers Centre for Heart Research, the Peter Munk Cardiac Centre, the National Institutes of Health and the Toronto General & Western Hospital Foundation. M Cybulsky holds a Tier 1 Canada Research Chair in Arterial Wall Biology and Atherogenesis.
Dick SA, Macklin JA, Nejat S, Momen A, Clemente-Casares X, Althagafi MG, Chen J, Kantores C, Hosseinzadeh S, Aronoff L, Wong A, Zaman R, Barbu I, Besla R, Lavine KJ, Razani B, Ginhoux F, Husain M, Cybulsky MI, Robbins CS, Epelman S. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat Immunol. 2019 Jan;20(1):29-39. doi: 10.1038/s41590-018-0272-2.
