Blair Leavitt
Research Classification
Research Interests
Relevant Degree Programs
Affiliations to Research Centres, Institutes & Clusters
Recruitment
Mouse models of neurodegenerative diseases
Clinical biomarkers of neurodegenerative diseases (Imaging, CSF, Blood)
Gene silencing, gene editing and gene therapy for brain diseases
Transcriptional regulation of disease genes
Experimental therapeutics for neurodegenerative diseases
Induced pluripotent stem cells models of human brain diseases
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Supervision Enquiry
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - April 2022)
PLPHP deficiency is a recently discovered form of vitamin B6-dependent epilepsies (B6Es) that is caused by recessive mutations in PLPBP. PLPHP is involved in pyridoxal 5’-phosphate (PLP) homeostatic regulation. However, the mechanism by which PLPHP dysfunction disrupts PLP homeostasis and leads to the observed encephalopathy in patients was still elusive. We characterized the clinical, genomic and biochemical abnormalities in a new series of 12 PLPHP deficiency patients. Our results identified previously undescribed clinical features of PLPHP deficiency, including non-epileptic movement disorder, fatal mitochondrial encephalopathy and folinic acid-responsive seizures. We characterized the pathogenicity of patients’ PLPBP variants using in silico tools and 3D modelling of PLPHP and developed a system of clinical severity score. We generated and characterized PLPBP knockout models in HEK293 cells, yeast and zebrafish. Our plpbp-KO zebrafish model replicated the clinical phenotype of PLPHP-deficient patients by showing vitamin B6-dependent seizures and death in untreated KO larvae. Consistent with the biochemical picture in patients, Plphp-deficient fish displayed decreased systemic levels of PLP. In the future this model can be utilized as a tool for investigating the disease pathophysiology, drug screening and identifying diagnostic biomarkers. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is another form of B6Es that is caused by mutations in ALDH7A1, a gene which encodes an enzyme within the lysine catabolism pathway. We have successfully generated and characterized transgenic mouse strain with constitutive genetic ablation of Aldh7a1. Results showed that KO mice accumulated high concentrations of upstream lysine metabolites including ∆¹-piperideine-6-carboxylic acid (P6C), α-aminoadipic semialdehyde (α-AASA) and pipecolic acid (PIP), similar to the biochemical picture in ALDH7A1-defiecint patients. KO mice fed the regular diet (0.9% lysine) did not exhibit seizures based on EEG analysis. When KO mice are switched to a diet containing higher amount of lysine (4.7%), they developed severe recurrent seizures which led to their quick death. In analogy to the patients’ picture also, treating KO mice under high lysine diet with pyridoxine injections prevented seizures and prolonged their survival. This study provides a proof-of-concept for the utility of the model to study PDE-ALDH7A1 biochemistry and to test new therapeutics.
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Huntington’s disease (HD) is a devastating, late-onset neurodegenerative disorder that causes profound behavioral abnormalities, language impairment, and alterations in personality in affected patients. HD is an autosomal dominantly inherited disease, caused by a CAG trinucleotide repeat expansion in the huntingtin gene. HD effects up to 1 in 10,000 in populations of European ancestry, but with at least a 10 fold reduced prevalence rate in individuals in Asian or African descent. The critical mechanisms by which the expansion in the huntingtin gene leads to selective neurodegeneration in HD are poorly understood. The purpose of this thesis was to better understand the microglial dysfunction caused by mutant huntingtin and the potential role this microglial dysfunction may play in the pathogenesis of HD. Huntingtin, the protein (HTT) expressed from the huntingtin gene, is ubiquitously expressed in many tissues, with the highest expression levels in brain and testis. Over the last 20 years there have been multiple scientific breakthroughs allowing the development of an array of model systems to investigate HD pathogenesis. Immune dysfunction has recently been implicated in a number of neurodegenerative diseases, including HD. In conclusion, the mechanism of neurodegeneration is not well understood in HD, inflammation could play a pivotal role in the progression of the disease. Inflammation is altered in immune cells containing mutant HTT (mHTT), and although I was unable to provide conclusive evidence that mHTT-induced microglial dysfunction and related neuroinflammation are required for neurodegeneration in an HD mouse model, my work highlights the importance of critically evaluating proposed new disease mechanisms as many will not be directly involved in HD neurodegeneration. My research provides concrete evidence that immune dysfunction occurs in monocyte cells expressing mHTT, however, this cell intrinsic dysfunction does not play a major role in the HD phenotype of the BACHD mouse model.
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Huntington’s disease (HD) is a late onset, neurological, autosomal dominant genetic disorder. Despite being associated to a defined genetic mutation within the huntingtin gene (HTT), little is known about its transcriptional regulation. HTT is expressed, at varying levels, throughout the body. At the current time, the transcriptional regulation mechanisms controlling this differential expression pattern are unknown. Previous studies have focused on the genomic region directly preceding HTT’s transcriptional start site. The purpose of this thesis was to utilize the current understanding of mammalian transcriptional regulation to further characterize the HTT promoter and to expand the search for transcriptional regulatory regions outside the promoter. To direct this search a bioinfomatic screen was conducted, which identified 11 putative regions. Potential transcription factor binding sites (TFBSs) within these regions were identified through the use of available chIP-seq datasets. Curation of the TFBSs within the putative regions lead to selection of the 9th region, in addition to the promoter, for further study. To test the functionality of region 9 and identified candidate transcription factors (TFs), a panel of human kidney and rat neuronal cell lines were established. These cell lines stably expressed either the HTT promoter or region 9 luciferase constructs. Candidate TFs were tested using siRNA mediated knockdown. Knockdown of selected candidate TFs did not modulate HTT promoter function. The role of DNA methylation on transcriptional regulation of HTT was also explored using the Illumina 450K Methylation Array. Tissue specific DNA methylation of HTT using human cortex and liver tissues identified 33 differentially methylated sites. The role of the HD mutation on local and global DNA methylation was also investigated, finding no changes to local DNA and 15 differentially methylated regions globally. In conclusion, a data driven bioinfomatic search has expanded potential regulatory regions beyond that of the promoter of the HTT gene. A first attempt at identifying crucial TFs involved in HTT regulation was not successful, however additional candidates remain to be tested. A role for DNA methylation in tissue specific regulation of HTT has been identified, while the HD mutation itself does not appear to affect HTT DNA methylation.
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No abstract available.
The striatum is predominantly affected in Huntington disease (HD). To address this selective degeneration, we previously studied the gene expression profile in mouse brain and compared the striatum to other brain regions to identify novel striatal-enriched genes. One identified gene was Indoleamine 2,3 dioxygenase (Ido1), the first and the rate-limiting enzyme of the kynurenine pathway (KP), which was differentially expressed in the striatum of YAC128 mouse model of HD. KP leads to the production of both neuroprotective and neurotoxic metabolites, the imbalance of which has been implicated in several neurodegenerative disorders. This PhD thesis initially focuses on the age-dependent changes of the KP in YAC128 mice with a main focus on Ido1 expression and activity. I was able to demonstrate a chronic induction of Ido1 expression and activity in the striatum of YAC128 mice, which correlated with different substrate or product levels during the course of the disease. Using a liquid chromatography mass spectrometry method, I was also able to identify changes in the downstream metabolites, which seemed to follow a biphasic pattern where neurotoxic metabolites were reduced in presymptomatic mice and increased in symptomatic mice. We propose that the striatal-specfic induction of Ido1 and downstream KP alterations suggest involvement in HD pathogenesis, and should be taken into account in future therapeutic developments for HD. To follow up, this thesis project also assesses the sensitivity of brain to NMDA-mediated excitotoxicity in the absence of Ido1 expression under in vivo and ex vivo settings. I was able to demonstrate decreased sensitivity to NMDA receptor-mediated neurotoxicity in the brain of Ido1 constitutive null mice compared to that of WT. These data suggest that lack of Ido1 expression in vivo provides protection against NMDA-receptor-mediated excitotoxic stress, a well-described mechanism in HD pathogenesis.
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Master's Student Supervision (2010 - 2021)
Huntington’s disease (HD) is a late-onset neurodegenerative disorder characterized by motor deficits, behavioral abnormalities and psychiatric symptoms. HD is caused by a CAG trinucleotide repeat expansion in the HTT gene resulting in expression of a mutant polyglutamine stretch in the huntingtin protein. HD affects up to 14 per 100,000 people in British Columbia. This devastating disorder is characterized by relatively selective neuronal loss in the caudate and putamen, regions of the brain referred to collectively as the striatum. Numerous mechanisms leading to this selective neurodegeneration have been proposed but the pathways involved are still not well understood. The huntingtin protein (HTT) is ubiquitously expressed, meaning that it is present in all cell types in the central nervous system, prompting investigations into potential pathogenic mechanisms outside of the characteristic neuronal loss. The brain is composed of microglia and astrocyte cell populations that together, make up the central immune system. Immune system activation has been implicated in the disease pathogenesis of various neurodegenerative diseases, including HD. The purpose of this thesis was to establish a flow cytometry system to investigate potential HTT regulatory mechanisms as well as increase knowledge of immune cell dysfunction in HD. Following the establishment of the flow cytometry system I found that HTT expression does not vary across the cell cycle. Using an adapted technique, I identified robust but not absolute genetic knock-down in two microglia-specicfic conditional knock out mouse models. Adding to the neuroinflammation focus, I identified mutant-huntingtin specific changes in protein phosphorylation expression in microglia as a means of identifying potential signaling cascades involved in exaggerated cytokine release. Lastly, I investigated transcriptional dysregulation in HD microglia and astrocyte populations and the effect of a candidate therapeutic on gene expression in these cell types. My research provides additional insight into potential protein phosphorylation and genetic pathways involved in immune dysfunction in HD and will focus future experiments aimed at understanding the role of central inflammation in HD.
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Huntington's Disease (HD) is one of many neurodegenerative diseases with reported alterations in brain iron homeostasis. Many neurodegenerative diseases exist which are characterized by brain iron accumulation. Whether elevated brain iron occurs in HD, and whether it plays a significant contributory role in pathogenesis or is a secondary effect is currently unclear. Iron accumulation in specific brain areas of neurodegeneration in HD has been proposed based on observations in post-mortem tissue and magnetic resonance imaging (MRI) studies. Altered MRI signal within specific brain regions undergoing neurodegeneration has been consistently reported and interpreted as altered levels of brain iron. Biochemical studies using various techniques to measure iron species in human samples, mouse tissue, or in vitro has generated equivocal data to support such an association. I have reviewed previous and current published literature reporting iron alterations and summarized the findings in this dissertation. Current consensus remains unclear if iron plays a contributing role, and further studies that modulate iron levels in HD models to assess the effects of iron are required.The experimental aim of this thesis was to measure iron-related changes in the YAC128 HD mouse model with the hypothesis that this mouse model will develop elevated striatal iron levels compared with wild-type littermates. Using analytical techniques to measure levels of elemental brain iron, no significant differences were observed in various brain regions of aged HD mice and in post-mortem HD samples.
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Huntington Disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the Huntingtin gene. Patients typically present in mid-life with progressive motor dysfunction, cognitive deficits, and neuropsychiatric abnormalities. Recently, researchers have provided evidence that HD is associated with significant pathology in peripheral tissues as well. At the current time no effective treatment has been proven to alter or cure progression of HD which leads to complete loss of independence and eventual death an average of 20 years after disease onset. The ability to model Huntington disease in animals has enabled studies which have provided new insights into the mechanisms of HD pathogenesis. However, the development of simple cell culture-based systems will be useful to accelerate our research efforts into the basic underlying pathogenic pathways of HD and will allow dissection of cellular interactions and the identification of novel targets for intervention that offer the greatest hope of a cure. The YAC mouse model of HD expresses full-length human Huntingtin with either 18 polyglutamines (YAC18) or 128 polyglutamines (YAC128), and develops age-dependent cognitive deficits, motor dysfunction, and selective striatal neurodegeneration similar to that seen in human HD patients. I have generated novel embryonic stem (ES) cell lines from wild-type, YAC18 and YAC128 mice on two genetic backgrounds. These cell lines have been cultured under defined conditions over long periods of time, and express characteristic markers of pluripotency, such as alkaline phosphatase, Oct-4 and Nanog. Neurons and macrophages derived from these novel cell lines using established in vitro protocols have been characterized via immunocytochemistry and challenged in functional assays.To confirm results attained from functional assays in our ES-derived macrophages, I examined primary macrophages and microglia cultures derived from the YAC mice and determined the functional response of these cells to endotoxin stimulation. Primary cell cultures isolated from YAC128 mice produced significantly more IL-6 than wild-type cultures. In comparison, with the same endotoxin stimulation, YAC18 primary macrophages and microglia responded with similar levels of IL-6 release as cultures of wild-type cells, suggesting that the over-activity in the YAC128 cytokine response is caused by the mutant Huntingtin transgene.
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News Releases
Publications
- Author Correction: The current landscape of nucleic acid therapeutics (2021)
Nature Nanotechnology, - Composite UHDRS Correlates With Progression of Imaging Biomarkers in Huntington's Disease (2021)
Movement Disorders, 36 (5), 1259--1264 - Safety and feasibility of research lumbar puncture in Huntington’s disease: the HDClarity cohort and bioresource (2021)
- The current landscape of nucleic acid therapeutics (2021)
Nature Nanotechnology, 16 (6), 630--643 - Antisense oligonucleotides for neurodegeneration (2020)
Science (New York, N.Y.), - Apathy predicts rate of cognitive decline over 24 months in premanifest Huntington's disease (2020)
Psychological medicine, - Early deficits in olfaction are associated with structural and molecular alterations in the olfactory system of a Huntington disease mouse model (2020)
Human molecular genetics, - Huntingtin-Lowering Therapies for Huntington Disease: A Review of the Evidence of Potential Benefits and Risks (2020)
JAMA neurology, - Longitudinal Structural MRI in Neurologically Healthy Adults (2020)
Journal of magnetic resonance imaging : JMRI, - Spontaneous, solvent-free entrapment of siRNA within lipid nanoparticles (2020)
Nanoscale, - A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes (2019)
EBioMedicine, - Association of CAG Repeats With Long-term Progression in Huntington Disease (2019)
JAMA neurology, - Huntingtin Lowering Strategies for Disease Modification in Huntington's Disease (2019)
Neuron, - Isolating cells from adult murine brain for validation of cell-type specific cre-mediated deletion (2019)
Journal of neuroscience methods, - Movement Disorder Society Task Force Viewpoint: Huntington's Disease Diagnostic Categories. (2019)
Movement Disorders Clinical Practice, - Mutant huntingtin expression in microglia is neither required nor sufficient to cause the Huntington's disease-like phenotype in BACHD mice (2019)
Human molecular genetics, - Targeting Huntingtin Expression in Patients with Huntington's Disease (2019)
The New England journal of medicine, - Altered Intracortical T1-Weighted/T2-Weighted Ratio Signal in Huntington's Disease (2018)
Frontiers in neuroscience, - Brain Regions Showing White Matter Loss in Huntington's Disease Are Enriched for Synaptic and Metabolic Genes (2018)
Biological Psychiatry, - Computational Analysis of Transcriptional Regulation Sites at the HTT Gene Locus (2018)
Journal of Huntington's disease, - Cross-sectional and longitudinal voxel-based grey matter asymmetries in Huntington's disease (2018)
NeuroImage. Clinical, - Editorial on Clinical Trial's Corner. (2018)
Journal of Huntington's disease, - Executive impairment is associated with unawareness of neuropsychiatric symptoms in premanifest and early Huntington's disease (2018)
Neuropsychology, - Murine Models of Huntington's Disease for Evaluating Therapeutics (2018)
Methods in molecular biology (Clifton, N.J.), - Neurofilament light protein in blood predicts regional atrophy in Huntington disease (2018)
Neurology, - Testing a longitudinal compensation model in premanifest Huntington's disease (2018)
Brain : a journal of neurology, - Transcriptional Regulation of the Huntingtin Gene. (2018)
Journal of Huntington's disease, - Conditional loss of progranulin in neurons is not sufficient to cause neuronal ceroid lipofuscinosis-like neuropathology in mice (2017)
Neurobiology of disease, - Conditional loss of progranulin in neurons is not sufficient to cause neuronal ceroid lipofuscinosis-like neuropathology in mice (2017)
Neurobiology of Disease, 106, 14--22 - Design optimization for clinical trials in early-stage manifest Huntington's disease (2017)
Movement disorders : official journal of the Movement Disorder Society, - Epidemiology of Huntington disease. (2017)
Handbook of clinical neurology, - Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study (2017)
The Lancet. Neurology, - Introducing the "Clinical Trials Corner" (2017)
Journal of Huntington's disease, - KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients (2017)
Proceedings of the National Academy of Sciences of the United States of America, - Motor, cognitive, and functional declines contribute to a single progressive factor in early HD (2017)
Neurology, - Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis (2017)
The Lancet. Neurology, - Operationalizing compensation over time in neurodegenerative disease (2017)
Brain : a journal of neurology, - p35 hemizygosity activates Akt but does not improve motor function in the YAC128 mouse model of Huntington's disease (2017)
Neuroscience, - Recommendations for the Use of Automated Gray Matter Segmentation Tools: Evidence from Huntington's Disease (2017)
Frontiers in neurology, - Selective depletion of microglial progranulin in mice is not sufficient to cause neuronal ceroid lipofuscinosis or neuroinflammation (2017)
Journal of neuroinflammation, - Structural and functional brain network correlates of depressive symptoms in premanifest Huntington's disease (2017)
Human brain mapping, - Survival End Points for Huntington Disease Trials Prior to a Motor Diagnosis (2017)
JAMA neurology, - The reliability of commonly used electrophysiology measures (2017)
Brain stimulation, - Topological length of white matter connections predicts their rate of atrophy in premanifest Huntington's disease (2017)
JCI insight, - Validation of Ultrasensitive Mutant Huntingtin Detection in Human Cerebrospinal Fluid by Single Molecule Counting Immunoassay (2017)
Journal of Huntington's disease, - White matter predicts functional connectivity in premanifest Huntington's disease (2017)
Annals of clinical and translational neurology, - Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington's disease (2016)
Journal of neurochemistry, - Core neuropathological abnormalities in progranulin-deficient mice are penetrant on multiple genetic backgrounds (2016)
Neuroscience, - DNA methylation profiling in human Huntington's disease brain (2016)
Human molecular genetics, - Enhanced immune response to MMP3 stimulation in microglia expressing mutant huntingtin (2016)
Neuroscience, - Large-scale brain network abnormalities in Huntington's disease revealed by structural covariance (2016)
Human Brain Mapping, - Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease (2016)
Human brain mapping, - Potential biomarkers to follow the progression and treatment response of Huntington's disease (2016)
The Journal of experimental medicine, - Visuospatial Processing Deficits Linked to Posterior Brain Regions in Premanifest and Early Stage Huntington's Disease (2016)
Journal of the International Neuropsychological Society : JINS, - A longitudinal study of magnetic resonance spectroscopy Huntington's disease biomarkers (2015)
Movement disorders : official journal of the Movement Disorder Society, - A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease (2015)
Nature neuroscience, - Characterisation of immune cell function in fragment and full-length Huntington's disease mouse models (2015)
Neurobiology of disease, - Compensation in Preclinical Huntington's Disease: Evidence From the Track-On HD Study (2015)
EBioMedicine, - Detection of Motor Changes in Huntington's Disease Using Dynamic Causal Modeling (2015)
Frontiers in human neuroscience, - Direct intracerebral delivery of a miR-33 antisense oligonucleotide into mouse brain increases brain ABCA1 expression. [Corrected] (2015)
Neuroscience letters, - Huntington disease. (2015)
Nature Reviews. Disease Primers, - Indoleamine 2,3 Dioxygenase as a Potential Therapeutic Target in Huntington's Disease (2015)
Journal of Huntington's disease, - Neurobiology of Huntington's Disease (2015)
Current topics in behavioral neurosciences, - Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery (2015)
Journal of neurochemistry, - Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients (2015)
The Journal of clinical investigation, - Reliability and factor structure of the Short Problem Behaviors Assessment for Huntington's disease (PBA-s) in the TRACK-HD and REGISTRY studies (2015)
The Journal of neuropsychiatry and clinical neurosciences, - Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial (2015)
The Lancet. Neurology, - The impact of occipital lobe cortical thickness on cognitive task performance: An investigation in Huntington's Disease (2015)
Neuropsychologia, - Treatment of Huntington Disease and Comorbid Trichotillomania With Aripiprazole (2015)
The Journal of neuropsychiatry and clinical neurosciences, - Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression (2015)
Scientific reports, - Aquatherapy for neurodegenerative disorders (2014)
Journal of Huntington's disease, - Clinical utility gene card for: Huntington's disease (2014)
European journal of human genetics : EJHG, - Correction of inter-scanner and within-subject variance in structural MRI based automated diagnosing (2014)
NeuroImage, - Diagnostic criteria for Huntington's disease based on natural history (2014)
Movement disorders : official journal of the Movement Disorder Society, - Huntington disease: natural history, biomarkers and prospects for therapeutics (2014)
Nature reviews. Neurology, - Huntington's disease: a field on the move. Introduction (2014)
Movement disorders : official journal of the Movement Disorder Society, - Iron dysregulation in Huntington's disease (2014)
Journal of neurochemistry, - p53 increases caspase-6 expression and activation in muscle tissue expressing mutant huntingtin (2014)
Human molecular genetics, - Progranulin in neurodegenerative disease (2014)
Trends in neurosciences, - The catalytic function of hormone-sensitive lipase is essential for fertility in male mice (2014)
Endocrinology, - The potential of composite cognitive scores for tracking progression in Huntington's disease (2014)
Journal of Huntington's disease, - 8OHdG is not a biomarker for Huntington disease state or progression (2013)
Neurology, - A randomized, double-blind, placebo-controlled study of latrepirdine in patients with mild to moderate Huntington disease (2013)
JAMA neurology, - A systematic review and meta-analysis of clinical variables used in Huntington disease research (2013)
Movement disorders : official journal of the Movement Disorder Society, - Age-dependent alterations of the kynurenine pathway in the YAC128 mouse model of Huntington disease (2013)
Journal of neurochemistry, - Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy (2013)
Human brain mapping, - Corpus callosal atrophy in premanifest and early Huntington's disease (2013)
Journal of Huntington's disease, - Frontotemporal degeneration, the next therapeutic frontier: molecules and animal models for frontotemporal degeneration drug development (2013)
Alzheimer's & dementia : the journal of the Alzheimer's Association, - Postnatal muscle modification by myogenic factors modulates neuropathology and survival in an ALS mouse model (2013)
Nature communications, - Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data (2013)
The Lancet. Neurology, - Progranulin promotes activation of microglia/macrophage after pilocarpine-induced status epilepticus (2013)
Brain research, - Quality of life in Huntington's disease: a comparative study investigating the impact for those with pre-manifest and early manifest disease, and their partners (2013)
Journal of Huntington's disease, - Sensitivity to neurotoxic stress is not increased in progranulin-deficient mice (2013)
Neurobiology of aging, - The absence of indoleamine 2,3-dioxygenase expression protects against NMDA receptor-mediated excitotoxicity in mouse brain (2013)
Experimental neurology, - The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier) (2013)
Alzheimer's & dementia : the journal of the Alzheimer's Association, - We are pleased to introduce this next volume of the Journal of Huntington's Disease. Introduction (2013)
Journal of Huntington's disease, - 8OHdG as a marker for Huntington disease progression (2012)
Neurobiology of disease, - Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease (2012)
Neurobiology of disease, - Decreasing Levels of the cdk5 Activators, p25 and p35, Reduces Excitotoxicity in Striatal Neurons (2012)
Journal of Huntington's disease, - Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington's disease (2012)
Journal of neurology, neurosurgery, and psychiatry, - Forkhead box protein p1 is a transcriptional repressor of immune signaling in the CNS: implications for transcriptional dysregulation in Huntington disease (2012)
Human molecular genetics, - Journal of Huntington's Disease (2012)
Journal of Huntington's disease, - Synaptic dysfunction in progranulin-deficient mice (2012)
Neurobiology of disease, - Visual Working Memory Impairment in Premanifest Gene-Carriers and Early Huntington's Disease (2012)
Journal of Huntington's disease, - Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis (2011)
The Lancet. Neurology, - Cystamine and ethyl-eicosapentaenoic acid treatment fail to prevent malonate-induced striatal toxicity in mice (2011)
Neurobiology of aging, - Development of biomarkers for Huntington's disease (2011)
The Lancet. Neurology, - The structural involvement of the cingulate cortex in premanifest and early Huntington's disease (2011)
Movement disorders : official journal of the Movement Disorder Society, - YB-1 bridges neural stem cells and brain tumor-initiating cells via its roles in differentiation and cell growth (2011)
Cancer research, - Expression analysis of novel striatal-enriched genes in Huntington disease (2010)
Human molecular genetics, - Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression (2010)
Human molecular genetics, - Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease (2010)
Neurology, - Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A (2010)
The Journal of neuroscience : the official journal of the Society for Neuroscience, - Progranulin expression in the developing and adult murine brain (2010)
The Journal of comparative neurology, - Tapping linked to function and structure in premanifest and symptomatic Huntington disease (2010)
Neurology, - The clinical and genetic features of Huntington disease (2010)
Journal of geriatric psychiatry and neurology, - Transcriptional changes in Huntington disease identified using genome-wide expression profiling and cross-platform analysis (2010)
Human molecular genetics, - Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease (2009)
The Journal of neuroscience : the official journal of the Society for Neuroscience, - Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data (2009)
The Lancet. Neurology, - Brain-specific proteins decline in the cerebrospinal fluid of humans with Huntington disease (2009)
Molecular & cellular proteomics : MCP, - Differential susceptibility to excitotoxic stress in YAC128 mouse models of Huntington disease between initiation and progression of disease (2009)
The Journal of neuroscience : the official journal of the Society for Neuroscience, - Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infection (2009)
Proceedings of the National Academy of Sciences of the United States of America, - Tetrabenazine. (2009)
Nature reviews. Drug discovery, - A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease (2008)
The Journal of experimental medicine, - Re: Autopsy-proven Huntington's disease with 29 trinucleotide repeats (2008)
Movement disorders : official journal of the Movement Disorder Society, - Ataxia and the role of antigliadin antibodies (2007)
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, - CAG-encoded polyglutamine length polymorphism in the human genome (2007)
BMC genomics, - Chapter 15 Juvenile amyotrophic lateral sclerosis (2007)
Handbook of clinical neurology, - Cocaine- and amphetamine-regulated transcript is increased in Huntington disease (2007)
Movement disorders : official journal of the Movement Disorder Society, - Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage (2007)
Human molecular genetics, - Phenotypic abnormalities in the YAC128 mouse model of Huntington disease are penetrant on multiple genetic backgrounds and modulated by strain (2007)
Neurobiology of disease, - Proteomic profiling of plasma in Huntington's disease reveals neuroinflammatory activation and biomarker candidates (2007)
Journal of proteome research, - Testicular degeneration in Huntington disease (2007)
Neurobiology of disease, - Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities (2006)
Proceedings of the National Academy of Sciences of the United States of America, - Body weight is modulated by levels of full-length huntingtin (2006)
Human molecular genetics, - Cerebrospinal fluid levels of orexin-A are not a clinically useful biomarker for Huntington disease (2006)
Clinical genetics, - Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin (2006)
Cell, - Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice (2006)
Neurobiology of disease, - Familial frontotemporal dementia with neuronal intranuclear inclusions is not a polyglutamine expansion disease (2006)
BMC neurology, - Huntingtin inhibits caspase-3 activation (2006)
The EMBO journal, - Is tetrabenazine safe and effective for suppressing chorea in Huntington's disease? (2006)
Nature clinical practice. Neurology, - Levels of mutant huntingtin influence the phenotypic severity of Huntington disease in YAC128 mouse models (2006)
Neurobiology of disease, - Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease (2006)
Neurobiology of disease, - Wild-type huntingtin ameliorates striatal neuronal atrophy but does not prevent other abnormalities in the YAC128 mouse model of Huntington disease (2006)
BMC neuroscience, - Wild-type huntingtin protects neurons from excitotoxicity (2006)
Journal of neurochemistry, - Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions (2005)
Proceedings of the National Academy of Sciences of the United States of America, - Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington's disease (2005)
The Journal of neuroscience : the official journal of the Society for Neuroscience, - Cross-species characterization of the ALS2 gene and analysis of its pattern of expression in development and adulthood (2005)
Neurobiology of disease, - Cystamine treatment is neuroprotective in the YAC128 mouse model of Huntington disease (2005)
Journal of neurochemistry, - Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial (2005)
Neurology, - Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease (2005)
Experimental neurology, - Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease (2005)
Human molecular genetics, - Satellog: a database for the identification and prioritization of satellite repeats in disease association studies (2005)
BMC bioinformatics, - Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease (2005)
Human molecular genetics, - Treatment of YAC128 mice and their wild-type littermates with cystamine does not lead to its accumulation in plasma or brain: implications for the treatment of Huntington disease (2005)
Journal of neurochemistry, - Novel ventriculo-peritoneal shunt in Alzheimer's disease cerebrospinal fluid biomarkers. (2004)
Expert review of neurotherapeutics, - Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington's disease. (2004)
Molecular and cellular neurosciences, - Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease. (2002)
Human molecular genetics, - Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. (2001)
Science (New York, N.Y.), - A one-hit model of cell death in inherited neuronal degenerations. (2000)
Nature, - Huntington disease: new insights on the role of huntingtin cleavage. (2000)
Journal of neural transmission. Supplementum, - A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. (1999)
Neuron, - Differentiation of transplanted neural precursors varies regionally in adults striatum. (1999)
Neuroreport,
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