Research Pillar: Clinical

A randomized controlled trial examining the effect of aerobic exercise on cognitive decline and brain region volumes in older men and women with mild cognitive impairment: Possible interaction between sex and BDNF polymorphisms

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

Worldwide, one new case of dementia is detected every four seconds; there is currently no effective drug therapy. Given the greater prevalence of Alzheimer's disease and its faster rate of progression from mild cognitive impairment to Alzheimer's disease in women compared to men, it is essential to assess sex differences in studies relating to dementia to foster development of successful sex-specific, non-pharmacological interventions.

Results from randomized controlled trials in older adults suggest that aerobic training can enhance functioning in certain cognitive domains. Importantly, exercise efficacy differs by sex, with women showing greater cognitive changes. The sex difference may be related to brain derived neurotrophic factor (BDNF), a growth factor involved in brain health and a mediator of the cognitive-enhancing effects of aerobic training. Women, compared to men, have greater declines in BDNF with increasing age.

The beneficial effects of aerobic training on cognitive decline are modified by the Val66Met polymorphism in the BDNF gene, which leads to altered secretion of BDNF. Furthermore, aerobic training alters stress hormones differently in women and men, and women Val66Met carriers have heightened stress responses compared to men.

The main aim of this project is to determine whether sex and the BDNF polymorphism influence aerobic training efficacy in ameliorating cognitive decline and brain tissue atrophy in older people with mild cognitive impairment, a risk factor for dementia. We will also consider whether the beneficial effects of aerobic training might be mediated through alterations in stress hormones in a sex- and Val66Met-dependent manner.

We will share the results of the effectiveness of aerobic training with practitioners and with policy makers in institutions such as Vancouver Coastal Health during educational sessions to help improve patient treatment and care.

Detecting neuroplasticity after spinal cord injury: Implications for neuropathic pain

Current interventions for neuropathic pain after spinal cord injury (SCI) have proven largely ineffective, an unfavorable outcome that can be partly attributed to poor understanding of mechanisms.

Through his research program, Dr. Kramer aims to shed light on this problem, focusing specifically on the hypothesis that changes in supraspinal (above the spine) structures contribute to neuropathic pain symptoms (e.g., burning sensation in the legs). In experiments using functional magnetic resonance imaging (MRI) and electroencephalography, a technique for measuring electrical activity in the brain, the brain activities following afferent stimulation in individuals with SCI will be investigated.

In an initial experiment, Dr. Kramer will explore how descending control of nociception, the neural processes of encoding and processing noxious stimuli, is affected by SCI. This will be done using behavioral manipulations to control awareness to noxious stimuli (e.g. placebo-analgesia, the inability to feel pain).

In the second experiment, Dr. Kramer will build on preliminary results, which indicate that neuropathic pain is associated with prominent changes in cortical functioning in brain areas involved in processing noxious stimuli. Beyond cortical functioning, he will also examine the role of plasticity in the brainstem in the maintenance of neuropathic pain.

In a final experiment, Dr. Kramer will delve further into the role of cortical and brainstem plasticity, determining the time course for when these changes occur. In proposed imaging experiments, the extent by which structural changes in the central nervous system accompany sensory deficits will be examined using quantitative anatomical MRI techniques.

As part of Dr. Kramer’s ongoing research program, quantitative approaches to objectively assess sensory function will continue to be developed. The focus of this work will be on validating novel neurophysiological and neuroimaging techniques to examine discrete elements of sensory impairments. Additionally, Dr. Kramer will continue to investigate the inter-relationship between neuropathic pain, other secondary complications (e.g., cardiovascular disease), and neurological recovery by analyzing large epidemiological SCI databases.

Overall, the research program will provide a clearer picture of the impact of neuropathic pain on neurological function, methods to improve objective measurement, and will enable implementation of novel interventions aimed at improving outcomes and quality of life for people with SCI.

Cardiac responses to spinal cord injury and exercise

The prognosis for the 2.5 million North Americans living with spinal cord injury (SCI) is poor. These wheelchair bound individuals are subjected to a number of physical, social, and environmental barriers that compound paralysis and limit daily physical activity. The five-fold increase in risk for heart disease reduces life-expectancy and costs the North American healthcare system $3 billion per annum.

Heart disease is the number one cause of illness and death in the SCI population. On a daily basis, these individuals are tasked with managing abnormal blood pressure control, fatigue, and a host of other bowel and bladder problems. Chronic management of these ‘secondary’ conditions can be poor, owing primarily to a lack of understanding of the underlying mechanisms. In able-bodied individuals, regular physical activity has multiple cardiovascular benefits. Although numerous attempts have been made to engage SCI individuals in regular physical activity, there is limited information available on the cardiovascular benefits of exercise in SCI individuals.

The primary aim of this research project is to investigate the effects of daily physical activity and structured exercise on heart function after SCI.

To improve our understanding of how the heart changes after SCI and the effectiveness of exercise, Dr. West will conduct simultaneous studies in rodents and humans with SCI. The use of a clinically relevant rodent model of SCI will allow Dr. West to answer fundamental questions about cardiac structure and function, and what mechanisms are responsible for the changes that occur after SCI and exercise. The findings will then be translated through conducting assessments of the heart in individuals with SCI.

This project is unique as it will be the first to use ultrasound to make identical measures of heart function in both rodents and humans. Additionally, Dr. West will be able to conduct direct assessments of heart function in the rodent model and follow this up with a detailed examination of the structure of the heart. Finally, he will conduct novel experiments into the effect of lower-limb passive cycling in rodents with SCI and follow this up by assessing how the heart responds to a novel passive leg energetic arm exercise intervention in humans.

Results from this study will yield vital information that can be used to assist in the rehabilitation and management of individuals with SCI.

Screening and development of molecules targeting presynaptic SNARE protein-protein interactions as novel pharmacological strategy in schizophrenia and other mental illnesses

Screening and development of molecules targeting presynaptic SNARE protein-protein interactions as novel pharmacological strategy in schizophrenia and other mental illnesses Schizophrenia is one of the major disabling mental disorders with a worldwide prevalence of about one percent. Although the cause  of schizophrenia remains unclear, converging data indicate that dysfunctions altering neurotransmitter levels in the synaptic cleft, the tiny space between nerve cells in which nerve impulses are conducted, might be at the core of this disorder. In presynaptic cells, neurotransmitter release is governed by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor).  Findings in the schizophrenic postmortem brain have revealed increased SNARE protein-protein interactions, which may explain the unbalanced neurotransmitter levels in schizophrenia, and reduced SNARE complexes in antipsychotic-treated patients. In accordance, genetic differences in SNARE-coding genes have been associated with schizophrenia.

Despite the growing evidence involving presynaptic dysfunction in mental illnesses, no attempts have been made to develop a pharmacological approach targeting the SNARE complex. Furthermore, the sole active agent against SNARE proteins, Botox cannot be used due to its irreversible, and lethal effects, presenting a challenge to finding SNARE-interfering compounds and pharmaceutically treating schizophrenia.

Against this background, the objective of Dr. Ramos-Miguel’s clinical research project is to find SNARE-interfering compounds, and further address their potential benefits in the pharmacological management of schizophrenia.

To meet this goal, an  agreement involving UBC, the Centre for Drug Research and Development (CDRD), and Roche-Canada, will allow Dr. Ramos-Miguel’s team to  screen the company’s largest library, containing more than one million compounds. Additionally, an immunoassay-derived method has been automated for high throughput screening of compounds modifying SNARE interactions. This assay successfully screened the CDRD 26,000-compound library, and identified at least two SNARE “inhibitors”. Further hits from the screening project will be subjected to a number of preclinical tests, including immunological, electrophysiological, toxicological and behavioral assays.

Identification of SNARE-interfering substances may have potential to improve pharmacological treatment of schizophrenia through a completely novel strategy.

Brain strain: Effect of autonomic dysreflexia on cerebral blood flow and cognition

Spinal cord injury (SCI) is a devastating chronic condition resulting not only in paralysis but severe autonomic cardiovascular dysfunction. In fact, cardiovascular disease is the leading cause of death in those living with SCI. Autonomic dysreflexia (AD) is a life-threatening condition characterized by episodes of extreme hypertension accompanied by pounding headaches, confusion, seizures, strokes and even death. Despite the high incidence of AD in individuals with cervical or high thoracic SCI and the negative impact this condition has on on the brain, there has been no prior studies examining the relationship between AD and cognition or cerebral blood flow.

Dr. Phillips’ research comprehensively examines cerebral blood flow during progressive AD and relates chronic AD severity to cognitive function. The vast majority of men with SCI experience sexual dysfunction and difficulty with ejaculation. Vibrostimulation is a standard medical procedure that helps with obtaining sperm for the purpose of family-planning. However, this procedure elicits AD in 96 percent of individuals with SCI above T6 and requires careful monitoring. Nonetheless, vibrostimulation offers a unique and ideal model through which it is possible to study the influence of AD on a number of cerebrovascular parameters.

As pilot data for this proposal, Dr. Phillips recorded spontaneously occurring AD bouts in individuals with SCI. In Project 1, Dr. Phillips will examine and measure cerebral blood flow during AD (induced by vibrostimulation) using Transcranial Doppler tests in the middle and posterior cerebral arteries, as well as a newly-developed volumetric technique using duplex ultrasound of the internal carotid and vertebral arteries. In Project 2, Dr. Phillips will examine the relationship between severity of AD (from 24 hour blood pressure monitoring) and cognitive function in SCI.

Ultimately, Dr. Phillips’ study will greatly contribute to the understanding of the cerebrovascular and cognitive effects of AD.

A prospective investigation of the relationship between depressed mood, sexual pleasure and desire in women with Sexual Interest/Arousal Disorder (SIAD)

Sexual Interest/Arousal Disorder (SIAD) is the most widespread sexual complaint in women, with reduced pleasure during sexual activity as one of the most common features. SIAD is associated with elevated depression symptoms, relationship distress, and presents a significant health care burden. Although low sexual desire is a common symptom of depression, little is known about how less severe depressed mood influences sexual desire in women who do not have depression.

The goal of Dr. Paterson’s study is to clarify how a depressed mood and reduced sexual pleasure and desire interact in women with SIAD.

Two studies will compare premenopausal women with SIAD but without depression to a healthy control group. In the first study, participants will complete electronic daily diaries for one month, in which they will provide ratings of sexual desire, sexual pleasure experienced with a partner and depressed mood. It is expected that women with SIAD will report less sexual desire, greater depressed mood, and less sexual pleasure than healthy women, and that the depressed mood will contribute to low desire by decreasing both the experience and memories of sexual pleasure. In the second study, women seeking help for SIAD and who also have depressed mood will receive mindfulness-based cognitive-behavioural therapy in a group format. This therapy will target sexual desire and depressed mood, and is expected to significantly improve both problems.

The results will help improve treatment options for women with SIAD by also demonstrating the importance of addressing depressed mood.

A preventive parenting program for family reunification

Out-of-home care accomodates children who face serious distruptions in their family environment, including severely impaired, abusive, and/or neglectful parenting, and elevated behavioural and emotional problems in children. The most common and desired goal for children in out-of-home care is to achieve a timely and safe family reunification (FR), i.e. the process of returning children to their families of origin. The risk for developing or exacerbating mental health problems that impacts behavioural conduct in these children increases relative to the number of significant disruptions (e.g. multiple placements) they experience while waiting for FR. There are two significant impediments to achieving a well-timed and stable FR: (1) children’s conduct problems and (2) parents’ lack of confidence or skills in managing their child’s behaviour. Though decades of research suggests that parent management training programs can significantly improve parenting skills and self-efficacy while effectively treating and/or preventing conduct problems in young children, there is no existing research investigating whether these programs may be effective with birth parents of children in out-of-home care, specifically for the purpose of FR.

Accordingly, Dave Pasalich’s research will examine the feasibility and efficacy of a parenting program for FR.

Through intervention, Pasalich will focus on improving parent-child interactions between young children (aged 3 to 7) in out-of-home care and their birth parents.

It is envisioned that the short-term effects of the parenting program on improving the quality of the parent-child relationship, parenting, and reducing conduct problems in children, will (1) increase the likelihood of achieving FR; (2) decrease the time taken to achieve FR; and (3) decrease the need for these children to re-enter the out-of-home care system at a later stage, or at least delay the need for re-entry.

Investigation of aging-related pathways associated with an increased risk of emphysema in HIV-infected patients

Because antiretroviral therapy has enabled people to live longer, those with HIV now face a growing epidemic of age-related chronic diseases such as chronic obstructive pulmonary disease (COPD). The reason for this increased risk, however, remains unknown. Compelling evidence suggests that HIV infection triggers an inflammatory process which causes the premature aging of inflammatory and structural cells due to cell exhaustion from repeated divisions and oxidative stress. This concept of “inflamm-aging” (coined by Claudio Franceschi) applies fittingly to the development of COPD as well, where the primary trigger is cigarette smoke.

Given the dual pro-inflammatory states of HIV and COPD, Dr. Leung hypothesizes that the accelerated development of emphysema in HIV is driven in part by inflammation-induced cell aging related to the HIV infection and potentiated in the lungs by cigarette smoke. Dr. Leung's laboratory has found peripheral leukocyte telomere lengths, a marker of cell senescence, are shorter in HIV-infected patients who also have COPD compared to HIV-infected patients without COPD. Those with the most severe airflow obstruction on spirometry and those with the greatest extent of emphysema as visualized on CT scanning also appear to have the shortest telomere lengths. The laboratory group is now exploring whether similar relationships hold in lung cells obtained from HIV-infected patients.

Structural and functional correlates of neuroplastic change associated with stroke

In Canada, stroke is the third leading cause of neurological disease and death. Although improved acute care has resulted in greater survival rates, an increased number of Canadians suffer long-term neurological disability and a decreased quality of life following a stroke. With an aging Canadian population, the need for efficient and effective diagnostic tools and rehabilitation strategies are critical so that stroke survivors can maintain independence and a high quality of life. Currently, the assessment of recovery and motor learning after a stroke focuses on neuroimaging techniques that indicate the status of gray matter within the central nervous system, which consists primarily of cell bodies. However, data characterizing how white matter supports motor learning and recovery after a stroke has been notably absent.

The goal of the study is to explore and understand the mechanisms associated with learning-dependent changes of white matter in the central nervous system. The proposed research plan will attempt to, firstly, understand whether motor learning is associated with changes in the white matter micro-structure and, secondly, relate changes in brain structure and neurophysiology to learning and functional recovery after stroke.

The intended research will provide unprecedented insight into areas of the stroke-injured brain that respond to motor learning. More importantly, this work will enhance the understanding of the effects of motor learning on functional recovery and generate the opportunity to develop novel therapeutic interventions for the growing population of individuals living with the after-effects of stroke.

Evolutionary dynamics and driver mutations underlying histological transformation and treatment resistance in follicular lymphoma

Lymphoid cancers arise from lymphocytes, a subset of white blood cells, and represent the fifth most common cause of cancer. Follicular lymphoma (FL) is a common subtype of lymphoid cancers. For ten percent of FL patients, the disease either does not respond to primary therapy or progresses early after treatment. These patients have poor outcomes and often require aggressive therapeutic interventions.

With regards to its origin, FL demonstrates how cancers arise through the successive acquisition of changes in their genomes. In his research, Dr. Kridel’s group has identified highly recurrent mutations in certain genes which delineate disease-initiating mechanisms. Yet, the biological underpinnings of treatment resistance and transformation in FL are only partially understood.

Dr. Kridel hypothesizes that both resistance to therapy and transformation can be explained by genetic alterations that are either present at diagnosis and get selected for during therapy, or that arise during the course of the disease. Thus, Dr. Kridel’s team will apply high-throughput genome sequencing technology to paired FL and progressed/transformed lymphoma samples. Dr. Kridel will leverage the availability of tumour specimens from the tissue repository of the Centre for Lymphoid Cancer at the BC Cancer Agency and collaborate with the Computational Biology group of Dr. Sohrab Shah, who has developed cutting-edge tools to examine genome-wide mutational changes.

The goal is to improve patient outcomes by understanding the genetic mechanisms that drive treatment resistance, early progression and transformation in FL.