Imaging studies: towards understanding the complications related to advanced monoaminergic disease and treatment

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, estimated to affect 100,000 Canadians and is characterized by deficiency of the neurotransmitter dopamine (DA) as a consequence of dopaminergic neuronal death. Existing treatments ameliorate the symptoms, but they do not seem to alter disease progression. Furthermore, treatment often induces undesired side-effects such as motor complications and high risk taking behavior such as compulsive gambling. Positron emission tomography (PET) is a non-invasive imaging modality that uses radioactive tracers to obtain information about biological function in-vivo; depending on their chemical form, radiotracers tag different biochemical processes. PET is thus ideally suited to investigate the complex neurochemical changes associated with neurodegeneration. Using PET we have already provided significant insights into the motor aspects of disease-induced complications; an alteration in the pattern of the neuronal release of DA has been identified as being involved in the occurrence of motor complication. The main goal of this research program is to further develop and use novel imaging techniques to gain insights into the impact of different treatment strategies on motor complications and into treatment-induced psychiatric complications. Studies on human volunteers will be performed on a new, state-of-the art human PET brain scanner. This scanner, existing only in 15 PET centers worldwide, while providing and unprecedented amount of information, requires development of accurate data manipulation and interpretation algorithms, which are another part of this research program. A very important aspect in medical research is the ability to develop and investigate animal models of disease to be able to investigate disease in further detail in a more controlled environment. A third important part of this research program will be the in-vivo investigation of rodent models of PD and their relation to other diseases such as, for example, Alzheimer’s, since there is evidence of some clinical and pathological overlap between neurodegenerative diseases. A unique strength of this program is its ability to bridge advancement of knowledge with the advancement of methodological approaches. This aspect will contribute towards the establishment of a more comprehensive imaging environment aimed at the investigation of neurodegenerative and related disease, which is the program long term goal.

Involvement of ErbB4 in excitatory and inhibitory synapse maturation

Synapses are the junctions across which signals are passed from one neuron to another. Generally, the type of input received through synapses can be classified into two categories: excitatory input increases the signal transmission, while inhibitory input reduces signal transmission. Problems that disrupt the coordination of excitatory and inhibitory inputs have been associated with the development of many severe psychiatric disorders, including schizophrenia. Recently, genetic analysis of families with a history of schizophrenia identified two genes potentially responsible for the onset of the disorder: Neuregulin1 (NRG1) and its protein receptor ErbB4. Daria Krivosheya’s recent research indicates that the ErbB4 protein receptor may help to stabilize existing synapses. Previous research has shown that ErbB4 interacts with PSD-95, a protein involved in regulating other proteins involved with excitatory synapses. Krivosheya believes interaction of the ErbB4 protein receptor with the PSD-95 protein may regulate the number of excitatory and inhibitory synapses formed by the nerve cell, while interaction with the NRG1 gene may stabilize synapses and promote branching out of dendrites, extensions of a nerve cell that conduct impulses from neighbouring cells. Krivosheya is investigating the role of NRG1-ErbB4 interaction at the synapse, as well as involvement of PSD-95 in mediating this interaction. Her goal is to explain the mechanism through which these molecules control excitatory and inhibitory synaptic balance. She hopes her research will ultimately help explain some of the physical or behavioral abnormalities associated with schizophrenia, and lead to the development of new therapies.

Dynamic suppression of pathological brain oscillations in Parkinson's disease (PD) with virtual environments (VE)

Parkinson’s disease is a debilitating condition that affects millions of people worldwide, and is the second most prevalent neurodegenerative disorder in Canada. Typical symptoms include tremor, slowness of movement, difficulty in walking, and rigidity. Drug treatments and surgery are available to improve symptoms, but these forms of therapy are not always effective and can have serious side effects. As these options aren’t appropriate for all Parkinson’s patients, alternative, non-invasive treatments are needed. Parkinson’s symptoms are caused by a lack of the chemical messenger dopamine. Dopamine is normally released by neurons in the substantia nigra, allowing communication with the basal ganglia, an area of the brain that is responsible for the planning and smooth execution of movement. The lack of dopamine is believed to result in abnormal rhythms in the motor control areas of the brain, impeding movement. Recent studies have shown that appropriate stimuli can suppress the abnormal brain rhythms responsible for blocking movement in people with Parkinson’s and help improve the way people with the disease move and walk. Giorgia Tropini is researching the association between visual stimuli and ongoing brain rhythms. Using virtual environment technology and electroencephalogram (EEG) measurements, Giorgia is developing specific, precisely timed visual images to disrupt inappropriate brain rhythms. Ultimately, she aims to contribute to the development of a wearable, non-surgical, non-pharmacological device to treat Parkinson’s symptoms. Findings from her research could also be applied to other diseases that involve abnormal brain rhythms, such as epilepsy and depression.

Topographical disorientation as a predictor of Alzheimer's Disease in patients affected by Mild Cognitive Impairment

While mild cognitive impairment (MCI) is common among elderly individuals, most continue to function moderately well in carrying out their usual activities. However, over the following three years after diagnoses of MCI, about 30 per cent of patients develop Alzheimer disease — a neurodegenerative disorder that seriously impairs thinking and memory. Some studies suggest that analyzing cerebrospinal fluid or brain imaging may predict the risk of Alzheimer dementia in patients with MCI, but these techniques are costly and, in some cases, not routinely available. The earliest degeneration of brain tissue with Alzheimer disease occurs in the hippocampus, a region of the brain important for learning, memory and topographical orientation, that is our ability to orient within the environment Dr. Giuseppe Iaria is investigating whether a computerized virtual reality test assessing topographical orientation skills is able to predict the progression of Alzheimer’s disease in patients diagnosed with MCI. If effective, this inexpensive test could be administered in any clinic to identify MCI patients at high risk for developing Alzheimer dementia. With early detection, it may be possible for medication to prevent or slow the progression of nerve cell degeneration because once the damage has occurred, it is generally irreversible.

In Vivo Evaluation of the Potential Role of Anti-Inflammatory Factors Involved in the Survival and Mechanism of Action of hRPE-Cell Implants for Parkinson's Disease

Parkinson’s disease is a neurodegenerative disorder that causes tremors, muscular rigidity, slowness of movement and postural instability. Affecting up to three per cent of the elderly population, Parkinson’s is characterized by depletion of the neurotransmitter dopamine and chronic inflammation in the substantia nigra region of the brain. While various pharmacological treatments alleviate symptoms of the disease, these medications eventually lose effectiveness and cause debilitating side effects. Cell-based transplantation therapies are being studied as alternative treatment options for Parkinson’s disease, but the routine use of these therapies has been delayed by mixed clinical results, safety and logistical concerns, and ethical issues. Recently, human retinal pigment epithelial (hRPE) cells have been proposed as a tissue transplant alternative for Parkinson’s disease and are currently being used in Phase II clinical trials. Found in the inner retina, hRPE cells are easily grown in culture so that a single donor can provide sufficient tissue for multiple recipients. Several studies have shown sustained reversal of Parkinsonian symptoms after hRPE implants with minimal side effects. Especially interesting is early evidence suggesting that transplanted cells may have the potential for long-term survival without requiring immunosuppressive drugs. However, little is known about the mechanisms of action of hRPE cells. Joseph Flores is researching the survival of implanted hRPE cells and the ability of implanted hRPE cells to replace depleted dopamine and induce a long-term anti-inflammatory response. A better understanding of hRPE-cell implants may lead to its routine use as a therapeutic alternative for Parkinson’s disease and improved outcomes for patients.

The excitatory and inhibitory synaptic balance in neurodevelopmental disorders: the role of neuroligins

Neurodevelopmental disorders result from gaps, delays or variations in the way a child’s brain develops, often interfering with learning, behaviour and adaptability. Research has shown that neurodevelopmental disorders have a strong genetic basis, yet the genes involved have not been clearly identified. The onset of disorders such as autism, fragile-x and Rett syndrome occurs after neurons have developed, during the time connections between neurons (synapses) are being formed to facilitate transmission of signals from one neuron to another. These disorders may, therefore, result from altered synapse formation and maintenance. Some of the genes thought to be associated with these disorders produce proteins involved in synapse formation and maintenance. Alterations in the size, form and structure of synaptic components have been demonstrated in fragile-x syndrome, Rett syndrome and autistic spectrum disorders. This suggests that these diseases are associated with abnormal or halted synaptic development and maturation. Building on her MSFHR-funded Master’s research, Rochelle Hines is studying specific proteins involved in synapse formation and maintenance to assess whether and how they contribute to the development of neurodevelopmental disorders.

The effect of reward expectation and dopamine release on the mechanism of the placebo effect in Parkinson's disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and affects about 100,000 Canadians. It occurs when cells that produce dopamine in the brain die. Without enough dopamine to send signals to the striatum, an area of the brain that controls movement, people with Parkinson’s develop tremors, stiffness and balance problems. Patients take medication to replace the missing dopamine, but this often produces troubling side effects. Interestingly, a significant placebo effect can occur in patients with Parkinson’s, with patents showing an improvement in symptoms due to their belief that a particular treatment will be beneficial. Sarah Lidstone is expanding on her earlier MSFHR-funded research to study how patients’ expectations for an improvement in symptoms actually produce measurable improvement. Using positron emission tomography (PET), a powerful brain scanning technique, Sarah has shown that patients with Parkinson’s disease release dopamine in the brain when given a placebo they thought was medication. Dopamine is also released in the same brain areas when people anticipate receiving a reward such as money or food, a response also generated in drug addiction. Sarah is examining whether the placebo mechanism in Parkinson’s taps into the same process as reward anticipation. If so, this research could lead to better treatments for the disorder. It could also inform treatment for drug addiction and other conditions influenced by a placebo effect or dopamine, including pain management, depression and obsessive-compulsive disorder.

Signaling Pathways Underlying Spreading Depression and Ischemic Depolarization

The visual aura some people experience with migraine headaches is caused by “spreading depression,” a wave that begins in the outer portion of the brain and spreads throughout the gray matter. During the wave, nerve cell activity lessens and brain tissue swells. A similar wave, called ischemic depolarization (ID), occurs during a stroke. Ischemic strokes cause the sudden death of brain cells when blood flow to the brain is blocked. Although spreading depression was first reported more than 60 years ago, researchers are still unclear about how the wave is generated. Ning Zhou is using a new imaging technique, called two-photon laser scanning microscopy, to examine detailed changes in individual cells when brain tissue suffers from spreading depression or ischemia (insufficient blood supply). Although these two events are similar, brain cells do not die during the wave of spreading depression. Zhou will examine the differences to discover why nerve cells undergo unusual swelling during spreading depression, and how this contributes to cell death during stroke. This research could provide insight into how to prevent tissue damage induced by strokes.

Novel Antimicrobial Surface Coatings for Urologic Devices

Health Issue:Urinary catheters provide drainage of the bladder to an external collecting device and are the most commonly placed medical devices. Ureteral stents provide drainage of urine from the kidney to the bladder and are used in the treatment of kidney stones. Both of these devices are foreign bodies in the urinary tract and allow bacteria to adhere and result in urinary tract infections and encrustations leading to device blockage and malfunction. Catheter and ureteral stent-associated infections prolong hospital stay, result in greater health care costs and may result in blood-borne bacterial infections possibly resulting in death. Antibiotics may be given for the duration that the drainage devices remain in the body, but there is great concern that the overuse of antibiotics will lead to the development of antibiotic resistant bacteria, or superbugs. Novel ways to reduce catheter and stent related infections would certainly improve patient care and decrease costs to the health care system without inducing resistant superbugs. Project Objective: To develop and test a novel peptide (protein) coating on urinary devices to reduce device-related urinary tract infection. Work to Undertake: Urinary catheters and stents will be coated with this novel peptide and evaluated for their ability to resist infection and encrustation using test tubes, bacterial cultures, and animals. Ultimately, human trials will be required. Unique to this research program/proposal of research: This novel peptide coating was discovered at the University of British Columbia by two researchers and is already being applied to artificial joints and implants used in orthopaedics. This will be the first use of this novel, promising technique in protecting urologic devices from infection and encrustation.