Barry J Bedell

McGill University, Montréal, Quebec, Canada

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Publications (44)349.89 Total impact

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    ABSTRACT: We provide a detailed morphometric analysis of eight transmission electron micrographs (TEMs) obtained from the corpus callosum of one cynomolgus macaque. The raw TEM images are included in the article, along with the distributions of the axon caliber and the myelin g-ratio in each image. The distributions are analyzed to determine the relationship between axon caliber and g-ratio, and compared against the aggregate metrics (myelin volume fraction, fiber volume fraction, and the aggregate g-ratio), as defined in the accompanying research article entitled ‘In vivo histology of the myelin g-ratio with magnetic resonance imaging’ [1].
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    ABSTRACT: The myelin g-ratio, defined as the ratio between the inner and the outer diameter of the myelin sheath, is a fundamental property of white matter that can be computed from a simple formula relating the myelin volume fraction to the fiber volume fraction or the axon volume fraction. In this paper, a unique combination of magnetization transfer, diffusion imaging and histology is presented, providing a novel method for in vivo magnetic resonance imaging of the axon volume fraction and the myelin g-ratio. Our method was demonstrated in the corpus callosum of one cynomolgus macaque, and applied to obtain full-brain g-ratio maps in one healthy human subject and one multiple sclerosis patient. In the human subjects, the g-ratio in multiple sclerosis lesions was higher than in normal appearing white matter, which was in turn higher than in healthy white matter. Measuring the g-ratio brings us one step closer to fully characterizing white matter non-invasively, making it possible to perform in vivo histology of the human brain during development, aging, disease and treatment. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 05/2015; 118. DOI:10.1016/j.neuroimage.2015.05.023 · 6.13 Impact Factor
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    ABSTRACT: Conventional brain connectivity analysis is typically based on the assessment of interregional correlations. Given that correlation coefficients are derived from both covariance and variance, group differences in covariance may be obscured by differences in the variance terms. To facilitate a comprehensive assessment of connectivity, we propose a unified statistical framework that interrogates the individual terms of the correlation coefficient. We have evaluated the utility of this method for metabolic connectivity analysis using [18F]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. As an illustrative example of the utility of this approach, we examined metabolic connectivity in angular gyrus and precuneus seed regions of mild cognitive impairment (MCI) subjects with low and high β-amyloid burdens. This new multivariate method allowed us to identify alterations in the metabolic connectome, which would not have been detected using classic seed-based correlation analysis. Ultimately, this novel approach should be extensible to brain network analysis and broadly applicable to other imaging modalities, such as functional magnetic resonance imaging (MRI).Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 October 2014; doi:10.1038/jcbfm.2014.165.
    Journal of Cerebral Blood Flow & Metabolism 10/2014; 34(12). DOI:10.1038/jcbfm.2014.165 · 5.34 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P385. DOI:10.1016/j.jalz.2014.05.460 · 17.47 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P30. DOI:10.1016/j.jalz.2014.05.058 · 17.47 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P708-P709. DOI:10.1016/j.jalz.2014.05.1303 · 17.47 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P557-P558. DOI:10.1016/j.jalz.2014.05.904 · 17.47 Impact Factor
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    ABSTRACT: Abnormal neuronal accumulation and modification of TAR DNA binding protein 43 (TDP-43) have recently been discovered to be defining histopathological features of particular subtypes of frontotemporal dementia and amyotrophic lateral sclerosis, and are also common in aging, particularly coexisting with hippocampal sclerosis and Alzheimer's disease pathology. This case report describes a 72 year old Hispanic male with no family history of neurological disease, who presented at age 59 with obsessive behavior, anxiety, agitation, and dysphasia. Positron emission tomography imaging using the amyloid ligand 18F florbetapir (Amyvid) was positive. Postmortem examination revealed frequent diffuse and neuritic amyloid plaques throughout the cerebral cortex, thalamus, and striatum, Braak stage II neurofibrillary degeneration, and frequent frontal and temporal cortex TDP-43-positive neurites with rare nuclear inclusions. The case is unusual and instructive because of the co-existence of frequent cortical and diencephalic amyloid plaques with extensive TDP-43-positive histopathology in the setting of early-onset dementia and because it demonstrates that a positive cortical amyloid imaging signal in a subject with dementia does not necessarily establish that Alzheimer's disease is the sole cause.
    Journal of Alzheimer's disease: JAD 06/2014; 42(3). DOI:10.3233/JAD-140162 · 3.61 Impact Factor
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    ABSTRACT: Hyperhomocysteinemia can contribute to cognitive impairment and brain atrophy. Methionine synthase reductase (MTRR) activates methionine synthase, which catalyzes homocysteine remethylation to methionine. Severe MTRR deficiency results in homocystinuria with cognitive and motor impairments. An MTRR polymorphism may influence homocysteine levels and reproductive outcomes. The goal of this study was to determine whether mild hyperhomocysteinemia impacts neurologic function in a mouse model with Mtrr deficiency. Three-month-old Mtrr+/+, Mtrr+/gt and Mtrrgt/gt mice were assessed for short-term memory, brain volumes and hippocampal morphology. We also measured DNA methylation, apoptosis, neurogenesis, choline metabolites and expression of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in hippocampus. Mtrrgt/gt mice exhibited short-term memory impairment on 2 tasks. They had global DNA hypomethylation and decreased choline, betaine and acetylcholine levels. Expression of ChAT and AChE was increased and decreased, respectively. At 3 weeks of age, they showed increased neurogenesis. In cerebellum, mutant mice had DNA hypomethylation, decreased choline and increased expression of ChAT. Our work demonstrates that mild hyperhomocysteinemia is associated with memory impairment. We propose a mechanism whereby a deficiency in methionine synthesis leads to hypomethylation and compensatory disturbances in choline metabolism in hippocampus. This disturbance affects the levels of acetylcholine, a critical neurotransmitter in learning and memory.
    Biochemical Journal 05/2014; DOI:10.1042/BJ20131568 · 4.78 Impact Factor
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    ABSTRACT: Positron emission tomography (PET) studies using [18F]2-fluoro-2-deoxyglucose (FDG) have identified a well-defined pattern of glucose hypometabolism in Alzheimer's disease (AD). The assessment of the metabolic relationship among brain regions has the potential to provide unique information regarding the disease process. Previous studies of metabolic correlation patterns have demonstrated alterations in AD subjects relative to age-matched, healthy control subjects. The objective of this study was to examine the associations between β-amyloid, apolipoprotein E ɛ4 (APOE ɛ4) genotype, and metabolic correlations patterns in subjects diagnosed with mild cognitive impairment (MCI). Mild cognitive impairment subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were categorized into β-amyloid-low and β-amyloid-high groups, based on quantitative analysis of [18F]florbetapir PET scans, and APOE ɛ4 non-carriers and carriers based on genotyping. We generated voxel-wise metabolic correlation strength maps across the entire cerebral cortex for each group, and, subsequently, performed a seed-based analysis. We found that the APOE ɛ4 genotype was closely related to regional glucose hypometabolism, while elevated, fibrillar β-amyloid burden was associated with specific derangements of the metabolic correlation patterns.Journal of Cerebral Blood Flow & Metabolism advance online publication, 16 April 2014; doi:10.1038/jcbfm.2014.66.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2014; 34(7). DOI:10.1038/jcbfm.2014.66 · 5.34 Impact Factor
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    ABSTRACT: Persistent pain is a central characteristic of neuropathic pain conditions in humans. Knowing whether rodent models of neuropathic pain produce persistent pain is therefore crucial to their translational applicability. We investigated the Spared Nerve Injury (SNI) model of neuropathic pain and the formalin pain model in rats using Positron Emission Tomography (PET) with the metabolic tracer [18F]fluorodeoxyglucose (FDG) to determine if there is ongoing brain activity suggestive of persistent pain. For the formalin model, under brief anesthesia we injected one hindpaw with 5% formalin and the FDG tracer into a tail vein. We then allowed the animals to awaken and observed pain behavior for 30min during the FDG uptake period. The rat was then anesthetized and placed in the scanner for static image acquisition, which took place between minutes 45 and 75 post-tracer injection. A single reference rat brain magnetic resonance image (MRI) was used to align the PET images with the Paxinos and Watson rat brain atlas. Increased glucose metabolism was observed in the somatosensory region associated with the injection site (S1 hindlimb contralateral), S1 jaw/upper lip and cingulate cortex. Decreases were observed in the prelimbic cortex and hippocampus. Second, SNI rats were scanned 3 weeks post-surgery using the same scanning paradigm, and region-of-interest analyses revealed increased metabolic activity in the contralateral S1 hindlimb. Finally, a second cohort of SNI rats were scanned while anesthetized during the tracer uptake period, and the S1 hindlimb increase was not observed. Increased brain activity in the somatosensory cortex of SNI rats resembled the activity produced with the injection of formalin, suggesting that the SNI model may produce persistent pain. The lack of increased activity in S1 hindlimb with general anesthetic demonstrates that this effect can be blocked, as well as highlights the importance of investigating brain activity in awake and behaving rodents.
    NeuroImage 01/2014; 91. DOI:10.1016/j.neuroimage.2014.01.020 · 6.13 Impact Factor
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    ABSTRACT: Neuropathologic heterogeneity is often present among Alzheimer disease (AD) patients. We sought to determine whether amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinically and pathologically defined AD and 17 nondemented patients with quantitative florbetapir F-18 (F-AV-45) positron emission tomography (PET) imaging during life and postmortem histological β-amyloid quantification and neuropathologic examination were assessed. AD patients were divided on the basis of concurrent pathologies, including those with Lewy bodies (LBs) (n = 21), white matter rarefaction (n = 27), severe cerebral amyloid angiopathy (n = 11), argyrophilic grains (n = 5), and TAR DNA binding protein-43 inclusions (n = 18). Many patients exhibited more than 1 type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in 6 cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p < 0.001). All AD subgroups had significantly greater amyloid measures versus nondemented patients, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with LBs had significantly lower SUVr measures versus AD cases without LBs (p = 0.002); there were no other paired comparison differences. These findings indicate that florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.
    12/2013; DOI:10.1097/NEN.0000000000000028
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    ABSTRACT: Objective: To define the functional significance of increased mir-155 expression in myeloid cells in multiple sclerosis. Methods: Mir-155 expression levels were measured in CD14+ monocytes from untreated RRMS patients and compared to healthy controls. Similar miRNA analyses were performed in laser-captured CD68+ cells from perivascular (blood-derived macrophages) and parenchymal (microglia) brain regions in both active MS lesions and non-inflammatory cases. Using human adult blood-derived macrophages and brain-derived microglia, in vitro experiments were performed to demonstrate how mir-155 influences polarization state, phenotype and functional properties of myeloid cells, in addition to their ability to subsequently impact adaptive T cell responses. Results: In multiple sclerosis, mir-155 expression was significantly increased in both peripheral circulating CD14+ monocytes and active lesions (CD68+ cells) compared to control donor monocytes and parenchymal microglia respectively. In vitro, mir-155 was significantly increased in both M1-polarized primary human macrophages and microglia. Transfection of a mir-155 mimic increased pro-inflammatory cytokine secretion and co-stimulatory surface marker expression in both cell types; mir-155 inhibitors decreased pro-inflammatory cytokine expression. Co-culture experiments demonstrated that allogeneic T cell responses were significantly enhanced in the presence of mir-155 transfected myeloid cells compared to controls. Interpretation: Our results demonstrate that mir-155 regulates pro-inflammatory responses in both blood-derived and CNS-resident myeloid cells, in addition to impacting subsequent adaptive immune responses. Differential miRNA expression may therefore provide insight into mechanisms responsible for distinct phenotypic and functional properties of myeloid cells, thus impacting their ability to influence CNS injury and repair. ANN NEUROL 2013. © 2013 American Neurological Association.
    Annals of Neurology 11/2013; DOI:10.1002/ana.23967 · 11.91 Impact Factor
  • American Journal of Geriatric Psychiatry 03/2013; 21(3):S138-S139. DOI:10.1016/j.jagp.2012.12.183 · 3.52 Impact Factor
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    ABSTRACT: Magnetic resonance imaging (MRI) studies have identified aberrant cortical structure in Alzheimer's disease (AD). The association between MRI-derived cortical morphometry measures and β-amyloid, however, remains poorly understood. In this study, we explored the potential relationship between early alterations in cortical thickness and later stage β-amyloid deposition, using a novel approach, in a transgenic AD mouse model. We acquired longitudinal anatomical MRI scans from mutant amyloid precursor protein (APP) transgenic mice and age-matched wild-type mice at 1 and 3.5 months-of-age, and employed fully-automated image processing methods to derive objective, quantitative measures of cortical thickness on a region-of-interest basis. We also generated 3D quantitative immunohistochemistry (qIHC) volumes of deposited β-amyloid burden from 18 month-old transgenic mice using an automated, production-level process. These studies revealed thinner cortex in most regions in the 1 month-old transgenic mice relative to age-matched wild-types, with the exception of the frontal, perirhinal/entorhinal, posterior cingulate, and retrosplenial cortical regions. Betweeen 1 and 3.5 months-of-age, the transgenic mice demonstrated stable or increasing cortical thickness, while the wild-type mice showed cortical thinning. Based on data from co-registered 3D MRI and qIHC volumes, we identified an association between abnormal, early, regional cortical thickness change over 2.5 months and later β-amyloid deposition. These observations suggest that the spatio-temporal pattern of early (pre-plaque) alterations in cerebral cortical structure is indicative of regional predisposition to later β-amyloid pathology in a transgenic AD mouse model.
    Neurobiology of Disease 02/2013; 54. DOI:10.1016/j.nbd.2013.02.005 · 5.20 Impact Factor
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    ABSTRACT: Magnetic resonance imaging studies have revealed distinct patterns of cortical atrophy and hypoperfusion in patients with Alzheimer's disease. The relationship between these in vivo imaging measures and the corresponding underlying pathophysiological changes, however, remains elusive. Recently, attention has turned to neuroimaging of mouse models of Alzheimer's disease in which imaging-pathological correlations can be readily performed. In this study, anatomical and arterial spin labeling perfusion magnetic resonance imaging scans of amyloid precursor protein transgenic and age-matched wild-type mice were acquired at 3, 12, and 18 months of age. Fully-automated image processing methods were used to derive quantitative measures of cortical thickness and perfusion. These studies revealed increased regional cortical thickness in young transgenic mice relative to age-matched wild-type mice. However, the transgenic mice generally demonstrated a greater rate of cortical thinning over 15 months. Cortical perfusion was significantly reduced in young transgenic mice in comparison with wild-type mice across most brain regions. Previously unreported regional genotype differences and age-related changes in cortical thickness and cerebral perfusion were identified in amyloid precursor protein transgenic and wild-type mice.
    Neurobiology of aging 12/2012; 34(6). DOI:10.1016/j.neurobiolaging.2012.11.022 · 4.85 Impact Factor
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    ABSTRACT: Although significant improvements have been made regarding the visualization and characterization of cortical multiple sclerosis (MS) lesions using magnetic resonance imaging (MRI), cortical lesions (CL) continue to be under-detected in vivo, and we have a limited understanding of the causes of GM pathology. The objective of this study was to characterize the MRI signature of CLs to help interpret the changes seen in vivo and elucidate the factors limiting their visualization. A quantitative 3D high-resolution (350 μm isotropic) MRI study at 3 Tesla of a fixed post mortem cerebral hemisphere from a patient with MS is presented in combination with matched immunohistochemistry. Type III subpial lesions are characterized by an increase in T1, T2 and M0, and a decrease in MTR in comparison to the normal appearing cortex (NAC). All quantitative MR parameters were associated with cortical GM myelin content, while T1 showed the strongest correlation. The histogram analysis showed extensive overlap between CL and NAC for all MR parameters and myelin content. This is due to the poor contrast in myelin content between CL and NAC in comparison to the variability in myelo-architecture throughout the healthy cortex. This latter comparison is highlighted by the representation of T1 times on cortical surfaces at several laminar depths.
    11/2012; 2012:742018. DOI:10.1155/2012/742018
  • Alzheimer's and Dementia 07/2012; 8(4):P12. DOI:10.1016/j.jalz.2012.05.036 · 17.47 Impact Factor

Publication Stats

667 Citations
349.89 Total Impact Points

Institutions

  • 2005–2015
    • McGill University
      • • Department of Neurology and Neurosurgery
      • • McConnell Brain Imaging Centre
      Montréal, Quebec, Canada
  • 2007–2012
    • Montreal Heart Institute
      Montréal, Quebec, Canada
    • Royal Perth Hospital
      Perth City, Western Australia, Australia
  • 2010
    • Biospective, Inc.
      Montréal, Quebec, Canada