Research Location: University of British Columbia - Vancouver Campus

Influence of community rehabilitation services on community reintegration and health utilization after stroke

Stroke is a leading cause of long-term disability in adults, and community reintegration is the pivotal outcome of successful rehabilitation.

Physical and cognitive impairments after stroke impact reintegration of patients into the community and place a burden on caregivers. The current system seeks to address this with health care services aimed at improving physical and cognitive functioning, as well as providing access to information and resources to facilitate improvement. These services are costly, and it is not known if such services benefit community reintegration or could potentially reduce the usage and cost of other health and social services.

The primary purpose of this study is to determine the impact of rehabilitation services on community reintegration and health after stroke.

This study will include 100 community-dwelling stroke patients and their caregivers. They will be assessed at several timepoints following stroke, and the hours and type of community rehabilitation services will be documented within this 12-month period. We will use the framework from the World Health Organization International Classification of Functioning to assess impairments and activity. We will compare the extent of the use and cost of health and social services, community services, and medications used by the patient with their degree of community reintegration.

The study protocol has been reviewed and approved by the local Clinical Research Ethics Board.

The results from this research could help to inform the effective delivery of health care services for stroke survivors.

Using aerobic exercise to enhance motor learning and cortical excitability after stroke

The severity of motor impairments due to stroke vary markedly in different people, and with therapy, a degree of recovery is possible. Understanding the underlying neural mechanisms supporting motor recovery from stroke would inform development of more effective therapies.

The overall objective of the proposed work is to determine whether priming exercise (bouts of aerobic exercise) can alter cortical structure and excitability and prepare the brain to enhance motor learning after stroke. Testing hypotheses based on studies of healthy individuals, we will investigate whether for individuals with stroke:

  1. Neurobiological changes occur following priming exercise
  2. Motor learning is enhanced by repeated pairings of priming exercise with skilled motor practice
  3. There is capacity for neuroplastic change in brain white matter (myelin) following repeated pairings of priming exercise with skilled motor practice

This work could aid in predicting how priming exercise may alter the neurobiology of the brain and impact capacity for motor learning in different individuals.

Pairing rehabilitation with priming exercise could prove to be an effective approach to improving outcomes after stroke. This research may serve as a starting point for using structural imaging information to personalize this approach patient-by-patient for optimal outcomes.

Multimodal characterization of airway remodeling with label-free nonlinear optical imaging

Michael Smith Foundation for Health Research/AllerGen Post-Doctoral Fellowship Award

The number of Canadians who will die from asthma is estimated at 200 per year and over 3 million suffer daily with the disease. A better understanding of the disease could give rise to more effective treatments.

Within the normal lung, collagen and elastin fibers provide the structural components of the airways. In asthmatic airways, the collagen and elastin fibers are disorganized and more collagen accumulates within the airway, making the airway more narrow and harder to breath through.

We will use nonlinear optical microscopy (NLOM) to understand the changes in the three-dimentional structure of the airways' elastin and collagen fibres that occur within asthma. Additionally, we will observe changes that occur inside these fibers by transmission electron microscopy (TEM).

Thus, if collagen were a "rope", we would be taking images of this rope with NLOM, and then images of each thread that composes the rope with TEM. To study the spatial distribution of the "ropes" and the ratio of collagen to elastin in asthmatic airway tissue, we will use textural analysis.

This study will give rise to results that could aid researchers in developing better asthma therapies, this improving the quality of life for millions of asthma patients.

Are there indicators of Alzheimer’s disease in the eye?: New computational imaging and analysis algorithms

Michael Smith Foundation for Health Research/The Pacific Alzheimer Research Foundation Post-Doctoral Fellowship Award

 

Alzheimer’s disease (AD) is progressive degeneration of the brain that results in loss of memory and cognitive abilities. The prevalence of the disease presents a daunting challenge — as of 2015, 46.8 million people in the world live with AD, with the number expected to double by 2035. In Canada, 14.9 percent of those 65 and older have the disease. The global health-care cost for dementia has exceeded 1 percent of the global gross domestic product (GDP).

 

AD significantly affects the quality of life for the patients and caregivers, and this makes early detection critical. However, the brain imaging required for the diagnosis is costly, and AD is often discovered only after it has progressed considerably.

 

The overarching theme of this project is finding the connection between the eye and AD, by investigating it for potential biomarkers of the disease. The eye is an extension of the brain, with the optic nerve forming a direct physical connection between the retina and the brain’s visual cortex. Recent advances in ophthalmic imaging techniques, such as optical coherence tomography (OCT), provides high-resolution 3D visualization of the inner structures of the eye, including the retina, nerve fibres, and blood vessels, in a noninvasive manner. OCT and other imaging techniques give us a comprehensive picture of the eye’s health and function.

 

We will develop image processing and analysis tools to examine chemical biomarkers, structural degradation, and functional loss in the eye that may be associated with AD. The project will potentially lead to discovery of novel AD biomarkers in the eye, and a cost-effective and accessible diagnostic tool for early detection of AD.

 

End of Award Update

Source: CLEAR Foundation

 

What did we learn?

We know that amyloid beta, a hallmark of Alzheimer’s disease, is present not only in the brain but also in the retina of the patients, and its deposition can vary by location and comorbidity such as cerebral amyloid atrophy.

 

Why is this knowledge important?

Retina can be readily imaged in high detail, and it contains rich information about the person’s neuronal health. Retinal imaging has potential as an early and accessible screening tool for neurodegenerative diseases. Studying the mechanisms of Alzheimer’s disease pathology in the retina also gives us insight into those in the brain.

 

What are the next steps?

Professor Joanne A. Matsubara’s group at the University of British Columbia and I are continuing to collaborate to study retinal biomarkers of Alzheimer’s disease. We are currently looking into how amyloid beta affects glial cells and blood vessels in the retina.

 

Publications

Women and the criminalization of HIV – An ethnographic investigation of gendered power relations, violence and access to health care

Women living with HIV/AIDS (WLWH) have been identified as a key population of interest by the Federal Initiative to address HIV/AIDS in Canada. An October 2012 ruling of the Supreme Court of Canada upheld the criminalization of HIV nondisclosure except where both a condom is used and the person has a 'low' HIV viral load. The decision has drawn criticism as being 'gender-blind' for failing to consider the gender imbalance in negotiation of male condom use and in associated risks for violence and livelihood.

Given the prevalence of gender-based violence and ongoing HIV-related stigma, there is a need to better understand how the criminalization of HIV non-disclosure uniquely affects WLWH.

The central objectives of the proposed study are to investigate how the criminalization of HIV non-disclosure shapes: 

  1. The gendered power dynamics of negotiating HIV disclosure, safer sex practices, and violence among WLWH
  2. HIV-related stigma and access to HIV treatment and care among WLWH

To do this, we will observe participants (e.g. in health care settings) and conduct in-depth individual interviews with WLWH, legal advisors, and health and social service providers.

There is potential to translate the findings of this research into evidence-based HIV policy that better considers gendered power dynamics and HIV-related stigma.

Optimizing anti-cancer peptides for use as novel cancer therapies

Anticancer peptides (ACPs) are small peptides (short chains of amino acids) that kill cancer cells by puncturing them or by triggering programmed cell suicide. In the lab, certain ACPs kill slow-growing and multidrug-resistant cancer cells, enhance action of anticancer drugs, and trigger the immune system to attack tumours. However, many also kill normal cells.

The goal of this work is to understand how the amino acid sequence contributes to selective cancer cell killing. This project will:

  1. Screen large numbers of ACPs to identify amino acids that maximize cancer cell selectivity
  2. Explore mechanisms of anti-tumour activity of our lead peptide Mastoparan

Peptide arrays allow hundreds of ACPs to be tested inexpensively. We will create many variant forms of the highly active ACP Mastoparan by substituting every amino acid in its chain with every other naturally occurring amino acid. A peptide array will be used to test which amino acids are vital for cancer cell killing and which ones harm normal cells.

Computer analysis will generate new ACP sequences with better predicted selectivity for cancer cells. The ACPs predicted to be most selective for cancer cells will be synthesized and screened, and the most promising ones will be tested for toxicity against human cancer cells and normal cells.

In addition, the immune system component of the anti-tumour activity of Mastoparan L will be explored further in vivo.

Ultimately, this project could give rise to peptides that selectively target cancer cells and induce an anti-tumour immune response.

Development of novel indolmycin derivatives for the treatment of MRSA

Since the discovery of antibiotics over 80 years ago, bacterial infections have been relatively straightforward to treat. However, the improper use of antibiotics has caused bacteria to develop antibiotic resistance, posing a serious global threat to preventing and treating common bacterial infections.

This project seeks to combat multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) by improving on an antimicrobial compound that naturally occurs in the environment. Indolmycin is naturally produced by Streptomyces griseus and is active against multi-drug resistant MRSA strains.

We aim to develop forms of indolmycin that are more potent against MRSA by feeding Streptomyces griseus with variant amino acids. In addition, we will perform structure-based studies to elucidate the molecular mechanism of anti-MRSA activity in indolmycin. This will allow for rational design of more effective forms of indolmycin.

Ultimately, this research could give rise to novel antibiotics to treat infections such as MRSA that are developing resistance to our current toolkit.

Altered glutamate dynamics in a mouse model of Alzheimer’s disease: Novel early biomarkers with therapeutic potential

Michael Smith Foundation for Health Research/The Pacific Alzheimer Research Foundation Post-Doctoral Fellowship Award

 

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. With no cure available, it imposes a major burden on society. In AD, a protein called amyloid beta accumulates into plaques in the brain. This event is an early and predictive marker for AD and can be detected up to 20 years before clinical symptoms arise.

 

We are exploring the dysfunction and hyperactivity of various cell types in the presence of amyloid plaques. We will investigate the possible role of altered glutamate dynamics in mouse models of AD. Fluorescent labelling will shed light on changes in glutamate signalling in awake and behaving AD mice. We will also test whether Ceftriaxone can restore normal glutamate dynamics in these mice.

 

Ultimately, our work with AD mouse models and novel glutamate imaging could shed light on possible drug targets and enable early intervention for people with Alzheimer’s disease.

End of Award Update

Source: CLEAR Foundation

 

What did we learn?

During our study it became clear that amyloid deposits have a drastic impact on glutamate signaling. This early cellular signaling deficit was only visible using in vivo 2-Photon imaging and a region-specific analysis of real time glutamate transients in direct proximity to amyloid plaques. We found areas of chronically high glutamate levels directly surrounding amyloid plaques and adjacent areas in which glutamate signaling was impaired. In larger scale wide-field real-time imaging experiments this effect was lost, indicating the importance of region-specific effects on cellular function in the early stages of the disease. Moreover, we used luminescent conjucated oligothiophens (provided by Dr. Peter Nilson, Linköping University) to visualize prefibrillary forms of amyloid. We found a direct overlap of these prefibrillary forms of amyloid surrounding the dense core plaque and a decrease in astrocytic GLT-1 transporter. We hypothesized that this decrease in GLT-1 is responsible for the observed glutamate dysfunction that was found in our experiments using stimulation experiments in awake and anesthetized animals. We thus used Ceftriaxone to restore GLT-1 expression in our mouse model of AD. We provided longitudinal imaging data of glutamate transients before and after Ceftriaxone treatment and could show that this partially restores glutamate signaling.

 

Why is this knowledge important?

As prefibrillary species are present in the brain before dense core plaques are formed it is important to further our understanding of their impact on cellular function. Moreover, it is essential to develop strategies that aim at the earlies stage that amyloids have on cellular function as these can be treated. Once neurons and other cells undergo cell death, strategies of recovery are much harder to implement. Our results provided a new therapeutical target that not only treats the disease on a symptomatic level but in an amyloid centric way that prevents/delays cellular dysfunction at an early stage in the disease.

 

What are the next steps?

We are currently expanding our research to investigate the impact of prefibrillary amyloid species on vessel function to search for more potential therapeutic targets.

 

Publications

Characterizing Arm Recovery in People with Severe Stroke (CARPSS)

In Canada, there are over 50,000 new strokes reported every year. The prevalence and severity of subsequent upper limb disability is increasing and the prospect of complete recovery is poor. Stroke survivors who lack early indicators of a good prognosis, such as movement at the shoulder or wrist, are considered unlikely to regain much arm function through rehabilitation. However, a growing body of evidence suggests that untapped recovery potential may be better assessed from brain scans.

This project will create a data set that sheds light on 'who recovers' and 'who does not recover' by examining how the severely damaged brain changes over the first year post stroke. A series of brain scans and clinical tests of motor recovery will be performed for fifty adults with severe upper limb impairment after their first stroke. Their upper limb use during training and real world settings will also be documented.

This research will support the development of personalized training approaches that maximize functional recovery following stroke.

The role and regulation of pannexin ion channels during cytotoxic edema

A primary and often fatal consequence of stroke, traumatic brain injury, and other brain insults is edema: an increase in brain tissue water content. Cytotoxic edema is a component of this process and occurs when excess ions and water enter across the neuronal plasma membrane -the semi-permeable barrier separating the intra- and extracellular space. This increase in cell volume causes membrane swelling and ultimately results in cell death.    

Presently, the cascade of events by which neuronal swelling triggers cell death remains obscure. Preliminary evidence from Dr. Brian MacVicar's lab (the host) indicates that swelling triggers cell death by activating pannexins- a class of large transmembrane ion channels. Following activation, pannexins form large pores in the membrane and allow ions and small molecules to diffuse between the intra- and extracellular compartments. Consequently, pannexins can initiate cell death by collapsing the transmembrane electrochemical gradient and/or promoting the loss of essential cellular components. The precise mechanism by which swelling triggers the opening of pannexins is unknown. Interestingly, these ion channels can be mechanically activated by membrane stretch. Moreover, membrane stretch also leads to the production of reactive oxygen species (ROS)-a group of harmful chemical agents that can directly activate pannexins.    

For the present proposal, we will test the hypothesis that pannexin activation is a crucial step underlying cell death following cytotoxic edema. Furthermore, we hypothesize that pannexins are activated by neuronal swelling through direct mechanical stimulation and/or the production of ROS.   

These hypotheses will be tested in acutely prepared rat brain slices using advanced microscopy/imaging and electrophysiology techniques. As there are few effective treatments for edema, this research could reveal new avenues for therapeutic intervention following a variety of brain insults. Considering the implications of this project for basic biomedical and clinical research, it will be essential to diffuse and disseminate our knowledge to a variety of communities. This will be done largely through symposiums/presentations at the Society for Neuroscience as well as publication in peer-reviewed scientific journals.

A primary and often fatal consequence of brain insults such as stroke and traumatic injury is edema: an increase in brain tissue water content. Cytotoxic edema is a component of this process, which occurs at the level of individual brain cells, or neurons. The cells swell up as excess ions and water enter, causing them to die. This project will build on earlier work carried out under the project supervisor, which suggests that cytotoxic edema is caused by the action of pannexins.

Pannexins are activated through unknown mechanisms when the cell membrane is caused to stretch, either chemically through the production of reactive oxygen species or mechanically. Following activation, pannexins form large pores in the cell membrane that allow ions and small molecules to pass through. They are believed to cause cell death by collapsing the transmembrane electrochemical gradient and/or by promoting the loss of essential cellular components.

We will study tissue samples using advanced imaging and electrophysiology techniques to test the hypotheses that:

  1. Pannexin activation is a crucial step underlying neuronal cell death in the brain following cytotoxic edema
  2. Pannexins are activated by neuronal swelling through direct mechanical stimulation and/or the production of reactive oxygen species

New lines of research for therapies for damage to the brain are greatly needed and some could arise from this work.