UBC MRI Research Centre Room M10, Purdy Pavilion/ECU 2221 Wesbrook Mall Vancouver, BC Canada, V6T 2B5 Tel:

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1 April 11, 2008 UBC MRI Research Centre Room M10, Purdy Pavilion/ECU 2221 Wesbrook Mall Vancouver, BC Canada, V6T 2B5 Tel: Sharon Johnstone PO Box 6086 Lancaster, PA USA Re: MACPAD 2008 Research Fund Grant Application: Can novel MR techniques distinguish which individuals with phenylketonuria are at risk for cognitive decline? Dear Ms. Johnstone, Please find attached a completed application for MACPAD Research Fund Grant that includes a four-page description along with a budget justification. As background, we have developed a long-term interdisciplinary research collaboration between faculty members of various departments at the University of British Columbia to investigate methods for improving clinical care provided to people with phenylketonuria (PKU). The adult PKU population in British Columbia is followed by the Adult Metabolic Disease Clinic (AMDC) at Vancouver General Hospital in Vancouver, BC and is the largest clinic in North America for adults with inborn errors of metabolism (IEM). The clinical currently follows over 1,000 individuals with various IEMs of which over 100 individuals over 18 years of age have PKU. We are interested in the ability of magnetic resonance (MR) imaging techniques to help predict which individuals with PKU are at risk for cognitive compromise, and by extension, to assist people with PKU and their caregivers in making decisions about treatment needs. We are very interested in this topic because, as you know, adults with PKU are typically advised to follow a lifelong, expensive and strict diet to avoid neurological and cognitive complications. The literature is clear that children with PKU must remain on diet. However, within the population of adults who choose to discontinue the restrictive diet there is a range of complications from few to severe. Accordingly, the development of a standard technique which can identify those individuals with PKU who are at risk for developing cognitive or neurological decline is therefore of significant clinical importance. Based on our pilot project 1 we published findings that our specialized MR techniques reliably distinguished between people with and without PKU. We were also able to demonstrate an association between MRI findings and cognitive compromise that has important consequences for treatment considerations, optimal health and quality of life. Our pilot project brought new questions to light and we have since refined our techniques and equipment. We are confident that information from this second, larger study will provide data critical to understanding disease process and will set the stage for expansion of our research mandate to include a wider age range of people with PKU, including children. We hope that you find our research of significant interest to warrant support from the MACPAD Research Fund. If you have any questions, please do not hesitate to contact us. Kind regards, Sandra Sirrs Co-principal Investigator (sandra.sirrs@vch.ca) Cornelia Laule Co-principal Investigator (claule@physics.ubc.ca) 1 Vancouver General Hospital Interdisciplinary Grant: Determining the correlation between brain myelin content and current neurological status in patients with phenylketonuria.

2 Synopsis of Study Goals Development of novel magnetic resonance techniques that inform people with phenylkentonuria about risk for cognitive decline The diet protocol for people with PKU is often difficult and expensive to maintain, especially for young adults. While some people with PKU who discontinue a low-phe diet develop significant cognitive deficits, others appear to be unaffected. In our previous studies using magnetic resonance imaging (MRI), we observed unique brain changes in people with PKU and found that these changes were associated with cognitive difficulties. By refining our novel MRI methods, we seek to identify which individuals with PKU are at risk for cognitive changes when they go off diet as adults. Our ultimate goal is to develop an MRI test that can help people with PKU make informed choices about long term dietary therapy. Expertise and Roles of co-principal Investigators and Co-Investigators Name Training Academic Position, Expertise Sandra Sirrs MD FRCPC Clinical Associate Professor, Endocrinology/Inborn Errors of Metabolism Cornelia Laule PhD Research Associate, Physics/Radiology Alex Mackay DPhil Professor, Physics/Radiology Elana Brief PhD Research Associate, Physics David Li MD FRCPC Professor, Radiology Carole Bishop PhD Clinical Assistant Professor, Neuropsychology Campbell Clark PhD Professor, Psychiatry Study Responsibilities Co-Principal Investigator, identifying and recruiting patients for the study, data Co-Principal Investigator, MR experimental design, protocol development and MR analysis MRS data analysis and radiological design and neuropsychological testing and statistical analysis and Current Role Medical Director, Adult Metabolic Disease Clinic (AMDC)* Research manager, UBC MRI Research Group Director, UBC MRI Research Centre** Research Associate, UBC MRI Research Group Staff Radiologist, UBC Clinical Psychologist, Adult Metabolic Disease Clinic Psychologist and Statistician *The Adult Metabolic Disease Clinic (AMDC) is the largest clinic in North America for adults with inborn errors of metabolism (IEM), currently following more than 1,000 patients with various IEMs and well over 100 adults with PKU. **The UBC MRI Research Centre is a state of the art MRI centre equipped with a 3.0 Tesla Philips Achieva MR scanner and provides services to researchers responsible for over $17 million funding brought into the University of British Columbia Contact Information for co-principal Investigators Dr. Sandra Sirrs (co-principal Investigator) Clinical Associate Professor, UBC Medical Director, Adult Metabolic Diseases Clinic Level Laurel Street, Vancouver, BC, V5Z 1M9 Tel: Fax: sandra.sirrs@vch.ca Dr. Cornelia Laule (co-principal Investigator) Research Associate, UBC Department of Radiology, UBC MRI Research Centre Room M10, 2221 Wesbrook Mall Vancouver, BC, V6T 2B5 Tel: Fax: claule@physics.ubc.ca MACPAD Funding: Can novel MR techniques distinguish individuals with phenylketonuria are at risk for cognitive decline? Page 1 of 5

3 Title and Summary of the Project Can novel MR techniques distinguish individuals with phenylketonuria are at risk for cognitive decline? Background PKU Potential Neurological Sequelae from Discontinued Diet Phenylketonuria (PKU) is an inborn genetic disorder characterized by the body s inability to metabolize the amino acid phenylalanine (PHE). Treatment of PKU involves rigid dietary restriction of PHE along with specific nutritional supplementation that is both expensive and challenging to maintain 1. People with PKU untreated by a diet restricted in PHE may have high blood PHE levels which could result in neurological symptoms that include tremor, ataxia, hyper-reflexia, psychiatric disorders and/or cognitive impairment. However, not all people with PKU who choose to discontinue diet therapy develop these complications 2-4 despite high PHE blood levels. In part, this may be related to reduced PHE transport into the brain 5, 6. A noninvasive method of quantifying risk of neurological sequelae would therefore be useful to assist people with PKU make informed decisions about long-term dietary therapy. How can we use MRI to study PKU? Conventional magnetic resonance imaging (MRI) of people with PKU often reveals widespread white matter changes, thought to represent the formation of structurally altered and less stable myelin, a condition referred to as dysmyelination 7 (Figure 1). Unfortunately, conventional MRI does not predict neurological status as white matter changes correlate poorly with blood PHE levels and neurological findings in adults with PKU 7. Figure 1: White matter hyperintensities (brighter spots as indicated by the arrows) on a conventional MR image in one person with PKU. New MR methods have been developed that provide greater specificity about widespread white matter changes than the simple pictures one obtains with conventional imaging. The MR signal from brain arises almost entirely from water. A new method, T 2 relaxation imaging, is able to measure water in different tissue structures, including myelin, based on an MR property described by T 2 relaxation time (Figure 2). Measures of myelin water made using this technique have been shown to correlate with histological staining for myelin 8, 9. Another technique, magnetic resonance spectroscopy (MRS), measures the signal from brain chemicals including those related to neuronal integrity and osmotic processes. We use both techniques, T 2 relaxation imaging and MRS, to understand the white matter changes associated with PKU. Myelin Water Intra/ extra cellular water T 2 time (s) CSF Figure 2: Cross section through a myelinated axon (inset) showing different water environments with corresponding peaks on the T 2 relaxation time distribution (from the MR data). The area under each peak corresponds to the amount of water in that component as measured by the MRI technique. The dotted component is present in PKU but not controls (discussed below). T 2 relaxation can measure the total amount of water in brain, which, in healthy brain, can then be separated into 3 components: a very long T 2 component (~2 s) due to cerebrospinal fluid, an intermediate component (~100 ms) arising from intra- and extracellular water, and a short T 2 component (~20 ms) attributed to water trapped between the myelin bilayers (known as myelin water ) 10. MACPAD Funding: Can novel MR techniques distinguish individuals with phenylketonuria are at risk for cognitive decline? Page 2 of 5

4 Previous Work In our previous studies we developed unique protocols using both of these two novel MR techniques to study white matter in the brains of people with PKU for determining brain water content, brain myelin water and brain chemicals. These data were evaluated in concert with cognitive status and neurological findings in a small cohort of people with PKU compared to matched controls. We found that people with PKU had a number of changes in the brain relative to people without PKU, including: Increased relative water content 11. Decreased myelin water content (i.e. suggesting people with PKU had less myelin) 11. A different distribution of water which shows up as intermediate T 2 peak between intra and extracellular water and CSF 11, 12 (Figure 2). Reduced myo-inositol (an osmolyte) which may cause the observed redistribution of water 11. An association of between brain water content and general cognitive functioning 13. These findings are remarkable for: The ability to reliably distinguish between people with PKU and controls using T 2 relaxation 11 Identification of an abnormal water signal in people with PKU 11, 12, a finding which has since be replicated by other investigators 14 Demonstration of a relationship between MRI findings and cognitive status 13 These findings also generated new questions in furthering understanding of how PKU affects the brain, specifically: 1. To what extent are changes in brain chemicals, water content and myelin water related to each other in different brain structures? 2. In which ways are these changes in brain chemicals, water content and myelin water related to higher order cognitive processes (e.g. attentional capacity, learning and memory, reasoning, visual-perception)? 3. How do these changes evolve over time in people with PKU? Abbreviated Research Plan Since our pilot study, we have significantly advanced our techniques. We now have access to a state of the art 3 Tesla MR scanner (located in the UBC MRI Research Centre) that acquires superior data (greater signal-to-noise ratio) to that acquired in our pilot study that used an older (1.5 Tesla) scanner. With the new scanner we are now able to co-localize our data acquisition in the same structures throughout the brain. Our initial findings also demonstrated the need to utilize more sensitive neuropsychological measures to evaluate higher-order cognitive processes (complex attentional capacity, abstract reasoning, complex learning and memory, visual-perceptual processes) 4. Given these advancements, we propose to: 1. Recruit 20 individuals with PKU from across the province of British Columbia through the Vancouver General Hospital AMDC database (including as many people as possible from the pilot study cohort still residing in the province) and 20 age- and gender-matched peer-controls. 2. Perform multi-slice T 2 relaxation and multi-voxel MRS measurement on all 40 study participants (the previous study was single slice and single voxel) 3. Perform complete comprehensive neuropsychological evaluations on all participants (details provided within budget justification). 4. Determine the relation of MRI findings with neuropsychological data. This new study will enable us to build on findings from our pilot studies as follows: Greater sensitivity to measuring abnormal water signals using the 3 Tesla MR scanner. Better absolute water content measurements given protocol refinement and technical superiority (i.e., improvement over our previous relative water content measurement). Determination of neuropsychological status in people with PKU over time in relation to MR findings. Determination of the relation of brain water and brain chemicals in individual brain structures (given our unique ability to now co-register multi-slice T 2 relaxation and MRS data) (Figure 3). MACPAD Funding: Can novel MR techniques distinguish individuals with phenylketonuria are at risk for cognitive decline? Page 3 of 5

5 MRS (Single box) MRS (multi-slice, multi-box) T 2 (single slice) T 2 (multi-slice) Original pilot study: T 2 data and MRS data was collected from single locations, in different anatomical locations in the brain. Proposed new study: T 2 data and MRS data will be collected from multiple locations, in the same anatomical locations in the brain. Figure 3: Example of a sagital MRI scan showing the locations of data acquisition for the T 2 relaxation experiment (water content and myelin water) and MRS (brain chemicals) from the original pilot study (left) and the proposed new study (right). With technological advancements we are now able to collect T 2 relaxation data from many slices and MRS data from many locations. This study is intended to serve as a foundation for further developing and refining our MR and cognitive evaluation protocols. In future, we plan to apply these protocols to include a wider developmental range that includes children to chart the course of PKU-related brain changes across the lifespan. As this emerging field of inquiry has yet no model, we are confident that these studies will yield important information about the ability of MR techniques to predict cognitive changes from white matter disease. We believe that we are well positioned to address these questions which have broad ranging clinical applications. MACPAD Funding: Can novel MR techniques distinguish individuals with phenylketonuria are at risk for cognitive decline? Page 4 of 5