Research report updates for grant recipients
Dr. Jonathan Brotchie $45,000 (1 year) Porridge for Parkinson’s Pilot Project Grant
University of Toronto
Project title: Evaluation of chloroquine as a disease modifying treatment for Parkinson’s disease
Nurr1 (also known as NR4A2) is one of the most exciting therapeutic targets for Parkinson’s disease (PD) to emerge in recent years and many pharmaceutical companies have programs to develop Nurr1 agonists as disease modifying therapies. This project will evaluate one of the most widely prescribed drugs ever, chloroquine, and repurpose it, using doses of chloroquine already approved by Health Canada, to provide a rapidly translatable means to engage Nurr1.
Chloroquine is a Health Canada approved medication for the treatment of malaria and other disorders including amoebiasis, rheumatoid arthritis and lupus erythematosus. It has a long history of use and, in rheumatoid arthritis patients, has been taken on a daily basis for many years, indicating its suitability for re-purposing as a chronically administered PD therapeutic. In addition to its anti-malarial properties, chloroquine is a brain-penetrant Nurr1activator that has demonstrated neuroprotective effects in cultured rat mesencephalic cultures. It is through this mechanism that we hypothesise that chloroquine has the potential to be a disease modifying therapy for PD.
Neuroprotective efficacy of chloroquine will be evaluated in an AAV1/2 A53T Î±-synuclein (Î±SYN) rat model of PD. The data obtained from this study will provide a go/no-go decision on whether to continue to develop chloroquine as a potential treatment for PD. The endpoints that will be evaluated in the proposed study will include behavioural (cylinder test), biochemical (striatal dopamine level) and histological (number of tyrosine hydroxylase positive cells in the substantia nigra) measures. We will also examine expression of genes known to be modulated by Nurr1 agonists in models of PD to ensure that chloroquine is engaging the intended target.
The strengths of this program are:
- Repositioning an already approved drug “ Minimal risk of failing for non-efficacy reasons and a faster and cheaper route to market.
- Validated preclinical target “ increasing Nurr1 activity has shown to provide neuroprotection in preclinical models of PD.
- If efficacy is demonstrated, it would provide a strong rationale for initiating additional preclinical studies intended to confirm efficacy in a second species and model of PD and to generate data that would allow optimal Phase II proof of-concept clinical studies to be performed. As chloroquine is already an approved drug in Canada, the clinical trials could be rapidly commenced should the preclinical data support such studies.Currently, there are no disease- modifying therapies for PD. Therefore, development of disease modifying treatments for PD is a serious unmet medical need.
Dr. Bradley McIntosh $45,000 (1 year) Porridge for Parkinson’s Pilot Project in Honour of Delphine Martin
University of Toronto, Sunnybrook Research Institute
Project title: Biomarkers of cognitive impairment in PD using orthostatic hypotension, white matter & grey matter
fMRI metrics: a PPMI study
This funding is supporting Dr. MacIntosh’s research in using imaging technology to track volatile blood flow in the brains of people with Parkinson’s disease. By correlating blood flow with fluctuations in white matter and cognitive decline, he hopes to create a diagnostic tool that could spot Parkinson’s disease early and potentially suggest ways of treating it by controlling blood pressure.
Dr. Bradley MacIntosh, a Scientist with the Brain Sciences Research Program at University of Toronto (Sunnybrook Research Institute) is studying the use of imaging technology to track blood flow in the brains of people living with Parkinson’s.
His work focuses on the role of blood flow in the development and management of Parkinson’s disease. Specifically, his work looks at fluctuations in white matter in the brain and periods of cognitive decline, hoping to correlate those with changes in blood flow.
If a correlation is found, the result could lead to diagnostic tools and also an ability to treat Parkinson’s disease through controlling blood pressure.
In many cases, non-motor symptoms of Parkinson’s (including orthostatic hypotension, caused by blood pressure concerns) appear before the more commonly thought of motor symptoms of the disease.
Dr. MacIntosh is using imaging technology to try to identify people with these early symptoms of Parkinson’s. MacIntosh is using functional Magnetic Resonance Imaging (fMRI) to scan the brains of people who have difficulty regulating their blood pressure.
The scans MacIntosh is conducting will track how often the brain is pulsating “ a measure of blood flow to the brain. He believes the volatility of that blood flow is bad for the brain, and may be either depriving brain cells of oxygen or flooding them with too much oxygen, at different times.
“The brain is like Jello, and it’s pulsating with every heartbeat. Too much of this jiggling, we think, is related to blood vessels that have lost their ability to cushion the blood flow,” he says.
MacIntosh hopes to correlate rates of pulsatility with fluctuations in white matter in the brains of people who have already been diagnosed clinically as being in the early stages of Parkinson’s disease. He and his team will also test their cognitive functioning to see if that is also declining. If he can confirm an association with the volatility of blood flow to the brain, and show cognitive decline, he will not only have developed a way to help diagnose Parkinson’s disease, he may also open up treatment avenues. Treating the volatile blood pressure early might prove beneficial.
“What we’re aiming for right now is a non-invasive diagnostic tool using information that is already out there,’’ says MacIntosh. “It’s just a matter of finding and proving that this can be helpful.”
Dr. MacIntosh’s work continues, with final findings expected in early 2018.
Dr. MacIntosh works closely with scientists in the fields of neurology and psychiatry. His areas of research interest include
functional & vascular imaging techniques using magnetic resonance imaging, notably the arterial spin labeling perfusion technique, and he studies stroke and neurodegenerative diseases. In addition to using neuroimaging measurements as outcome measures for aerobic exercise trials, his laboratory is actively developing new forms of physiological images, such as cardiac pulsatility effects on the brain.
Dr. Natasha Radhu $80,000 (2 years) Porridge for Parkinson’s Basic Research Fellowship Award
University of Toronto (CAMH)
Project title: Interactions between motor cortical inhibitory and excitatory circuits in Parkinson’s disease using
transcranial magnetic stimulation
Postdoctoral fellow Dr. Radhu uses Transcranial Magnetic Stimulation (TMS) to study the brain’s excitatory
and inhibitory circuits. She is investigating whether an imbalance in the circuits in the motor cortex, the section
of the brain that governs movement, leaves people with Parkinson’s disease unable to calm a barrage of signals
to the area of the brain that directs movement. If she can demonstrate this imbalance, she hopes her research
will lead to a diagnostic tool and a way to see if medication used to treat Parkinson’s is effective.
Ms. Sarah Coakeley $40,000 (2 years) Porridge for Parkinson’s Graduate Student Award
University of Toronto (CAMH)
Project title: Positron Emission Tomography Imaging of Pathological Tau in Parkinsonisms
Master’s student Sarah Coakeley is using medical imaging technology to scan the brains of people with Parkinson’s disease
and compare them to brain images of people who are healthy and those who have two rare disorders, multiple system
atrophy and progressive supranuclear palsy (PSP). Using radioactive dye that binds to a protein that accumulates
in the brain cells of people with these diseases, she hopes to develop a diagnostic test for PSP.
2015 Porridge for Parkinson’s Graduate Student Award recipient Sarah Coakeley continues to be hard at work with her colleagues at the University of Toronto with a goal of developing a diagnostic test for Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA).
Specifically, Ms. Coakeley, a Master’s student, is using Positron Emission Tomography Imaging to track the presence of Pathological Tau in forms of Parkinsonism.
Access to medical imaging technology is critical to deepening her understanding of the accumulation of protein in the brains of people living with MSA or PSP. By using a radioactive dye that binds to a protein that accumulates in the brain cells of people living with MSA and PSP, she is able to track the presence of this protein in disease affected subjects and healthy controls. Developing this understanding helps to distinguish protein formation in brains living with MSA and PSP from those of healthy subjects, and this could ultimately lead to a diagnostic test.
Your support is critical to this process. Coakeley hopes to find a correlation between how much dye binds to Tau in the brains of the people in the different groups in her study. If there are more clumps of the protein in the brains of people with progressive supranuclear palsy, as she suspects, the imaging test would help to diagnose that disease.
“It will give them a more accurate prognosis, so they are prepared for this rapid disease progression,” she says.
Development of a diagnostic test is essential for better understanding of how to diagnose these two rare forms of Parkinsonism, but also to help avoid misdiagnosis of Parkinson’s disease. Relying on clinical diagnosis can lead to cases of misdiagnosis, leaving people unsure of the most appropriate course of treatment and families uncertain about disease progression and how to best prepare for what lies ahead.
Her ties to Parkinson Canada, and the broader Parkinson Community continue to grow. Sarah has attended Parkinson SuperWalk, and Parkinson Canada’s annual research recognition event in the Fall of 2015. With a goal of ensuring that Graduate Student Award recipients continue to serve the Parkinson Community beyond the scope of their funding, these relationships are another important measure of the value of your support.
Ms. Coakeley’s final report is due to Parkinson Canada in October of 2017.
Ms. Chelsie Kadgien $30,000 Dr. Robert Lorne Alexander Graduate Student Award
University of British Columbia
Project title: Vacuolar protein sorting 35 (VPS35) neurobiology: Novel retromer cargo trafficking, synapse maintenance,
and plasticity in the context of Parkinson’s disease mutations.
PhD student Chelsie Kadgien is zeroing in on the function of a particular gene that, when mutated, is linked
to late-onset Parkinson’s disease. Kadgien investigates VPS35 to see if its role in transporting proteins that help
brain cells communicate could eventually become the target for a drug that could disrupt or repair the problems
that damaged forms of the gene cause.
Ms. Chelsie Kadgien, a PhD student at the University of British Columbia is investigating gene mutation in late-onset Parkinson’s disease.
Specifically, she’s investigating protein VPS35 to try to understand its role in transporting proteins that help brain cells communicate. With current research indicating that the formation of protein clusters, or aggregates, could lead to the type of cell death that causes Parkinson’s disease understanding the way in which they are transported is a critical part of the future course of treatment.
“Neurons have an ideal amount of communication that they receive from other cells,” Kadgien says. If brain cells don’t get enough communication, they can die. If they get too much, they use up so much energy trying to interpret that communication that they become exhausted, which can also kill them.
Kadgien believes brain cells that contain mutant forms of VPS35 have too many receptors on their surface, causing them to receive too much communication. If she can confirm her theory, using not only cell cultures, but animal models, she will open up avenues for new drugs that might disrupt or correct this particular pathway in the brain that is damaging communication and killing brain cells.
“We want to understand how this particular mutation is affecting cells,” she says. “Ideally, we would like to find a good target for a therapeutic intervention.”
The first step understands how the process works, and the funding provided for the Dr. Robert Lorne Alexander Graduate Student Award directly contributes to that.
Dr. Mark Carpenter $45,000 (1 year) Porridge for Parkinson’s Pilot Project Grant
Project title: A novel fMRI approach to investigating the pathophysiology of postural instability in Parkinson’s disease
This funding is supporting Dr. Carpenter’s investigation of using imaging technology to scan the brains of people with Parkinson’s disease as they perform a balancing task, to discover what structures of the brain control balance and might be receptive to new treatments to restore balance and reduce falls.
The final findings from this project are expected early 2017.
Dr. Carpenter’s research focuses on identifying the factors in the mind, the brain, and the body which contribute to losing balance and falling. In particular, he examines the elements associated with age, Parkinson’s disease, damage to the inner ear, and spinal cord injury (SCI). His second focus is on identifying the best exercise, training, and treatment strategies to improve these conditions and thereby reduce the occurrence and impact of falls.
Dr. Carpenter is an investigator at ICORD (a spinal cord injury research centre of the UBC Faculty of Medicine and VCH Research Institute); and Associate Professor, School of Kinesiology, Faculty of Education, University of British Columbia.
Mr. Jean-Francois Daneault $30,000 (2 years) In memory of Delphine Martin Graduate Student Award
Project title: Subthalamic deep brain stimulation in Parkinson’s disease: Effect on the mobility of patients and their caregiver
This funding allowed Dr. Daneault to complete his PhD studies on the impact of subthalamic deep brain stimulation
on mobility in PD patients. The results of this study (published in Movement Disorder) along with the results of
another study (published in the Journal of Parkinson’s Disease) have direct clinical implications for the management
of patients with PD scheduled for deep brain stimulation.
Dr. Jean-Francois Daneault is currently pursuing a postdoctoral fellowship from the Canadian Institutes of
Health Research, at Harvard Medical School where he will be developing new techniques and methods for the
detection and management of PD.
Mr. Karl Grenier $30,000 (2 years) Porridge for Parkinson’s Graduate Student Award
Project title: The interaction between PINK1 and the Mitochondrial Processing Peptidase: Defining the role of Mitochondrial import defects in Parkinson’s Disease
This funding allowed Dr. Grenier to complete his PhD studies on neurodegeneration mechanisms in PD. Specifically,
he helped identify the nature of the protein that helps stabilize PINK1, and his results provided a novel view on how
PINK1 is imported into the mitochondria. These novel results give us essential information on how the loss-of function
of PINK1 might lead to neuronal death by knowing where PINK1 is and what important role it plays in the cell.
The progress achieved has been substantial and will drive novel ideas of how PINK1 contributes to mitochondrial
quality control, and adds essential information to a pathway that is now a primary suspect in causing Parkinson’s disease.
Karl Grenier vividly recalls his first encounter with Parkinson’s disease at six years of age, when he was convinced he might be suffering from this illness.
“I was watching a television documentary about it, and afterward I was crying when I went downstairs to see my Mom,” he says. “I had been looking at my hands and they had the slightest of movements, so I told her I had Parkinson’s disease.”
She assured him these movements were perfectly normal. Even more importantly, she told him that if he maintained an interest in the problem, he could eventually find a way to help people who did have Parkinson’s disease. Today, more than 20 years later, he is doing just that.
Grenier launched his Porridge for Parkinson’s (Toronto) supported project examining two proteins that help our body’s cells deal with damaged components. One of those proteins is responsible for detecting trouble within a cell, when the structure that provides energy to the cell breaks down. If that happens, the second protein takes over and eliminates this structure before it becomes toxic, poisoning the rest of the cell.
When these proteins function properly, this process of detection and disposal takes place all the time. But when they stop doing their job, cells become contaminated by waste products until they can no longer operate. When those cells are in the brain, the effect sets the stage for Parkinson’s disease.
The research conducted as part of this Graduate Student Award offered significant findings. Specifically, Dr. Grenier successfully identified the nature of the protein that helps stabilize the protein PINK1, and identified a previously unknown route by which PINK1 is imported into the mitochondria. These novel results provide essential information on how the loss-of-function of PINK1 might lead to cell death.
The biggest impact of this research is that it provides fundamental knowledge on neurodegeneration mechanisms in Parkinson’s. The results directly contribute to the understanding of what goes wrong in neurons before they start to die. Specifically the results provide a new viewpoint as to how PINK1 interacts with the mitochondrial import machinery and adds essential information to a pathway that is now a primary suspect in causing Parkinson’s.
With a better understanding of how these proteins work, it should be possible to design drugs to restore their function, and stop the disease at the cellular level. In the meantime, Grenier is grateful for the opportunity to acquire such an understanding, provided through the Porridge for Parkinson’s (Toronto) Graduate Student Award.
Grenier noted his gratitude to Porridge for Parkinson’s supporters “In the first few years of my PhD I learned a lot, but things are really coming together now,” he says. “This is where you make most of your discoveries, and it’s key to have someone to support you when things matter most.”
Dr. Karl Grenier is continuing his research at the Fon lab while he studies medicine at McGill University.
Dr. Edward Fon $45,000 (1 year) Porridge for Parkinson’s Pilot Project Grant
Project title: Regulation of Parkin function by deubiquitination
The research from this funding led to identification of specific proteins and genes as central players in the regulation of quality control of neurons specific to PD. This work will now lead to future studies focused on these protein and gene targets that have the potential to be exploited in designing new PD neuroprotective therapies.
Dr. Fon and his team were able to translate the findings from this project into a collaboration with Iprogen, a Vancouver based company research protein-based therapeutics. They also successfully obtained funding from the Michael J Fox foundation for a rapid response program in the amount of $75,000.
The Fon lab studies the molecular mechanisms leading to the neuronal degeneration in Parkinson’s disease (PD). Their focus is on understanding the cellular functions of the genes responsible for familial forms of PD and how the dysfunction of these genes leads to disease.
Dr. Fon is is a neurologist and scientist who serves as the Scientific Director of the Montreal Neurological Institute,
a National Parkinson Foundation Centre of Excellence, as well as Associate Professor, McGill University. He is also Past Chair
of Parkinson Canada’s Scientific Advisory Board.
Dr. Abbas Sadikot $44,722 (1 year) Porridge for Parkinson’s Pilot Project Grant
Montreal Neurological Institute, McGill University
Project title: Creation of a Novel Computerized MRI-Integrated 3-D Histochemical Atlas of Parkinson’s Disease Brain
This funding is supporting the development of a more comprehensive and higher resolution reference image that could be superimposed on the MRI scan of a patient’s brain. This tool would serve the same function as the common atlas to enhance precision and to increase the chances of success in neurosurgery.
Dr. Sadikot’s research interest lies in determining how the developing brain forms complex networks, information that can be used to develop new therapies for repairing the damaged nervous system. He is particularly interested in cell and growth-factor replacement strategies. His work has implications for neurodegenerative diseases such as Parkinson’s disease and maldevelopmental conditions that lead to epilepsy.
Dr. Sadikot is a neurosurgeon with the Montreal Neurological Institute and a professor at McGill University. He is also a member of Parkinson Canada’s Scientific Advisory Board.
Dr. Michael Schlossmacher $45,000 Porridge for Parkinson’s Pilot Project Grant/Area of Research: Causes
Project title: Characterization and validation of pharmacologically-driven signaling pathways to lower alpha-synuclein:
Implications for Parkinson
This funding supported the screening of 45 approved drugs (already on the market for other purposes) for their ability to
reduce aSyn in brain cells that are most susceptible to PD. A number of compounds were short-listed for further validation
in vivo. The funds also enabled the purchase of an a-Syn mouse model to be used in future PD-related studies. ]Dr. Schlossmacher’s research continues to identify and test already approved drugs that can be repurposed for Parkinson’s disease
Dr. Schlossmacher and his team’s research currently focuses on:
(i) modeling of the pathogenesis of PD and DLB in mouse models;
(ii) validation of drug targets to lower alpha-synuclein concentrations; and (iii) biomarker exploration in PD, DLB and MSA based on alpha-synuclein metabolism.
Dr. Schlossmacher is Senior Scientist, Neuroscience Program, Ottawa Hospital Research Institute; Neurologist, Division of Neurology, Department of Medicine, The Ottawa Hospital; Associate Professor of Medicine (Neurology), and Director of the MD/PhD Program, Faculty of Medicine, University of Ottawa. He is also a member of Parkinson Canada’s Scientific Advisory Board.