Alex Zijdenbos | McGill University (original) (raw)

Papers by Alex Zijdenbos

Research paper thumbnail of Spatially Distributed Amyloid-β Reduces Glucose Metabolism in Mild Cognitive Impairment

Journal of Alzheimer's Disease, 2020

Background: Several positron emission tomography (PET) studies have explored the relationship bet... more Background: Several positron emission tomography (PET) studies have explored the relationship between amyloid-␤ (A␤), glucose metabolism, and the APOE 4 genotype. It has been reported that APOE 4, and not aggregated A␤, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer's disease (AD) pathology. Objective: We hypothesize that typical measurements of A␤ taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of A␤ are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI). Methods: We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the crosscorrelation structure between glucose metabolism, as measured by [ 18 F]2-fluoro-2-deoxyglucose (FDG) PET, and A␤, as measured by [ 18 F]florbetapir PET, from the Alzheimer's Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of A␤. Results: From an older population of CN and MCI subjects, we found that the SVD-based A␤ score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding A␤ network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of A␤ deposition. Conclusions: Our approach uncovered hidden patterns of the glucose metabolism-A␤ relationship. We showed that the SVD-based A␤ score produces a stronger relationship with decreasing glucose metabolism than either APOE 4 genotype or global measures of A␤ burden.

Research paper thumbnail of Imaging the spatial distribution of proximal femoral response to one year of teriparatide therapy: the OPTAMISE study

Research paper thumbnail of Correlation between cerebral lesion load and EDSS in relapsing remitting multiple sclerosis: results of the application of automatic 3D image analysis

Research paper thumbnail of Automatic quantification of multiple sclerosis lesion volume using stereotaxic space

Lecture Notes in Computer Science, 1996

... 2B4. Emaih alex~bic.mni.mcgill.ca Abstract. ... trial. The processing chain employs a convent... more ... 2B4. Emaih alex~bic.mni.mcgill.ca Abstract. ... trial. The processing chain employs a conventional multi-spectral (multi-feature) classifier combined with explicit registration of all image volumes to a standardized 3D coordinate space. ...

Research paper thumbnail of A Data-driven Approach for Estimating the Spatial Resolution of Brain PET images (4301)

Objective: The main objective is to estimate the spatial resolution of brain PET images. Backgrou... more Objective: The main objective is to estimate the spatial resolution of brain PET images. Background: The spatial resolution of brain PET images is often estimated using Hoffman phantom data. Unfortunately, Hoffman phantom images may not always be readily available, and phantom-based approaches may yield sub-optimal results. We propose a new, computational approach that allows estimation of spatial resolution directly from the PET image itself. Design/Methods: We generalized the logarithmic intensity plots reported by Mizutani and colleagues (Mizutani, 2016) in order to perform spatial resolution estimation in both axial and in-plane directions. The FWHMs are estimated from multiple regression of the logarithm of the square norm of the image Fourier transform against the square distance from the origin in the Fourier domain. The proposed approach was applied to Amyloid and FDG PET images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Results: We obtained in-plane and axial FWHMs resolution estimators that vary between 3.5 mm and 8 mm for both [18F]florbetapir and [18F]FDG images. In both cases, we observed a low within-scan variability. We also obtained a strong cross-tracer consistency in FWHM resolution estimators, which is an expected result since the spatial resolution does not depend on the particular 18F-labeled tracer. Conclusions: We obtained small (less than a voxel size) across-subject variability in groups of subjects sharing the same PET site and reconstruction parameters. Our novel approach not only eliminates the need for surrogate brain phantom data, but also provides a general framework that can be applied to a wide range of tracers and other image modalities, such as SPECT. Disclosure: Dr. Carbonell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biospective Inc.. Dr. Zijdenbos has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biospective Inc.. Dr. Zijdenbos holds stock and/or stock options in Biospective Inc. which sponsored research in which Dr. Zijdenbos was involved as an investigator. Dr. Bedell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee: Biospective Inc.. Dr. Bedell holds stock and/or stock options in Stock: Biospective Inc. which sponsored research in which Dr. Bedell was involved as an investigator.

Research paper thumbnail of IC-P-047: Cortical laminar analysis of beta-amyloid deposition, astrogliosis and neuronal density in a mouse model of Alzheimer's disease

Alzheimers & Dementia, Jul 1, 2013

Research paper thumbnail of A 3D probabilistic atlas of normal human neuroanatomy

Research paper thumbnail of Impact of Reference and Target Region Selection on Amyloid PET SUV Ratios in the Phase 1b PRIME Study of Aducanumab

The Journal of Nuclear Medicine, May 18, 2018

Research paper thumbnail of Improved correlation between scores on the expanded disability status scale and cerebral lesion load in relapsing-remitting multiple sclerosis. Results of the application of new imaging methods

Research paper thumbnail of Slice-Wise Three-Dimensional Reconstruction of Myocardial Contrast Perfusion from Simulated Biplane Views

Springer eBooks, 1989

ABSTRACT

Research paper thumbnail of Spatially Distributed Amyloid-β Reduces Glucose Metabolism in Mild Cognitive Impairment

Journal of Alzheimer's Disease, Jan 21, 2020

Research paper thumbnail of Genome-wide association studies of cerebral white matter lesion burden: The CHARGE consortium

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2011

Objective-White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)are p... more Objective-White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMH are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. Methods-We performed a meta-analysis of genome-wide association studies (GWAS) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. Results-We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs)in one locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (P discovery = 4.0×10 −9 ; P replication =1.3×10 −7 ; P combined =4.0×10 −15). Other SNPs in this region also reaching genome-wide significance are rs9894383 (P=5.3×10 −9), rs11869977 (P=5.7×10 −9), rs936393 (P=6.8×10 −9), rs3744017 (P=7.3×10 −9), and rs1055129 (P=4.1×10 −8). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample). Interpretation-This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

Research paper thumbnail of P2-182: Amyloid-associated alterations in metabolic connectivity patterns in ADNI participants

Alzheimers & Dementia, Jul 1, 2013

Research paper thumbnail of Hierarchical Multivariate Covariance Analysis of Metabolic Connectivity

Journal of Cerebral Blood Flow and Metabolism, Oct 8, 2014

Research paper thumbnail of A fully automatic and robust brain MRI tissue classification method

Medical Image Analysis, Dec 1, 2003

Research paper thumbnail of Fast and robust parameter estimation for statistical partial volume models in brain MRI

Research paper thumbnail of Common variants at 6q22 and 17q21 are associated with intracranial volume

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2012

Research paper thumbnail of P2-227: Beta-Amyloid-Related Alterations of Metabolic Connectivity in Adni MCI Subjects: A Multivariate Covariance Analysis

Alzheimers & Dementia, Jul 1, 2014

IC-P-051 LONGITUDINAL, MULTI-MODALITY, MRI STUDIESOFGAMMA-SECRETASE INHIBITION IN AN APP-SW MOUSE... more IC-P-051 LONGITUDINAL, MULTI-MODALITY, MRI STUDIESOFGAMMA-SECRETASE INHIBITION IN AN APP-SW MOUSE MODEL OFALZHEIMER’S DISEASE Barry J. Bedell, Simone P. Zehntner, Thomas Rosahl, Kathleen Wood, Kelly R. Bales, Michael A. Marconi, Eric Parker, Felix Carbonell, Alex P. Zijdenbos, Biospective Inc. & McGill University, Montreal, Quebec, Canada; Biospective Inc., Montreal, Quebec, Canada; Merck & Co., Rahway, New Jersey, United States; Pfizer Inc., Cambridge, Massachusetts, United States; Merck Research Laboratories, Kenilworth, New Jersey, United States. Contact e-mail: bbedell@biospective.com

Research paper thumbnail of A probabilistic approach to mapping human neuroanatomy

Biological Psychiatry, Jul 1, 1997

Research paper thumbnail of IC-P-001: Amyloid-associated alterations in metabolic connectivity patterns in ADNI participants

Alzheimers & Dementia, Jul 1, 2013

Background: While regional glucose hypometabolism is characteristic of Alzheimer’s disease (AD), ... more Background: While regional glucose hypometabolism is characteristic of Alzheimer’s disease (AD), this feature has been shown to be primarily associated with the ApoE4 genotype, rather than fibrillar b-amyloid, during the pre-clinical/early stages of the disease process. However, derangements of metabolic connectivity are intimately related to b-amyloid plaque burden. In order to assess the specific alterations in metabolic connectivity in early disease, we have performed a quantitative analysis of correlation patterns derived from FDG positron emission tomography (PET) images from ADNI subjects with different levels of cortical b-amyloid. Methods: [18F]florbetapir PET, [18F]FDG PET, and 3D T1-weighted MR images were obtained from ADNI-GO/-2 study subjects classified as cognitively normal or mild cognitive impairment (MCI). PET volumes were registered to a customized MRI template in MNI stereotaxic space, and standardized uptake value ratio (SUVR) images were generated and projected onto each subject’s cortical surface using Biospective’s fully-automated PIANO TM image processing software. The amyloid burden for each subject was determined from a composite region-of-interest (ROI) on [18F]florbetapir images, and subjects were categorized into Amyloid-Low (Ab L) and Amyloid-High (Ab H) groups. We generated vertexwise correlation strength maps across the entire cerebral cortex, controlling for ApoE4 genotype, and assessed the relative alterations in short-/long-range and intra-/interhemispheric metabolic connections in each group. Results: We observed statistically significant differences in short-/long-range and intra-/interhemispheric metabolic connections between the Ab L and Ab H groups in multiple cortical regions. For example, the entorhinal cortex showed greater reductions in interthan intra-hemispheric correlations (especially with the contralateral medial temporal lobe, precuneus, and posterior lateral temporal-parietal cortex) in the Ab H group. The angular gyrus demonstrated greater loss of longthan short-range metabolic correlations in the Ab H group.Conclusions:We have employed metabolic connectivity analysis to examine disruptions of the cortical correlation architecture as a function of b-amyloid burden. The aberrant metabolic connections observed in the Ab H group may be a consequence of variable spatio-temporal patterns of compensatory responses and/or cortical remodeling during the early stages of AD. The quantitative approach employed in this study may serve as a powerful, non-invasive imaging biomarker for early diagnosis/prognosis and objective evaluation of the efficacy of novel amyloid-lowering therapeutic agents.

Research paper thumbnail of Spatially Distributed Amyloid-β Reduces Glucose Metabolism in Mild Cognitive Impairment

Journal of Alzheimer's Disease, 2020

Background: Several positron emission tomography (PET) studies have explored the relationship bet... more Background: Several positron emission tomography (PET) studies have explored the relationship between amyloid-␤ (A␤), glucose metabolism, and the APOE 4 genotype. It has been reported that APOE 4, and not aggregated A␤, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer's disease (AD) pathology. Objective: We hypothesize that typical measurements of A␤ taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of A␤ are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI). Methods: We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the crosscorrelation structure between glucose metabolism, as measured by [ 18 F]2-fluoro-2-deoxyglucose (FDG) PET, and A␤, as measured by [ 18 F]florbetapir PET, from the Alzheimer's Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of A␤. Results: From an older population of CN and MCI subjects, we found that the SVD-based A␤ score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding A␤ network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of A␤ deposition. Conclusions: Our approach uncovered hidden patterns of the glucose metabolism-A␤ relationship. We showed that the SVD-based A␤ score produces a stronger relationship with decreasing glucose metabolism than either APOE 4 genotype or global measures of A␤ burden.

Research paper thumbnail of Imaging the spatial distribution of proximal femoral response to one year of teriparatide therapy: the OPTAMISE study

Research paper thumbnail of Correlation between cerebral lesion load and EDSS in relapsing remitting multiple sclerosis: results of the application of automatic 3D image analysis

Research paper thumbnail of Automatic quantification of multiple sclerosis lesion volume using stereotaxic space

Lecture Notes in Computer Science, 1996

... 2B4. Emaih alex~bic.mni.mcgill.ca Abstract. ... trial. The processing chain employs a convent... more ... 2B4. Emaih alex~bic.mni.mcgill.ca Abstract. ... trial. The processing chain employs a conventional multi-spectral (multi-feature) classifier combined with explicit registration of all image volumes to a standardized 3D coordinate space. ...

Research paper thumbnail of A Data-driven Approach for Estimating the Spatial Resolution of Brain PET images (4301)

Objective: The main objective is to estimate the spatial resolution of brain PET images. Backgrou... more Objective: The main objective is to estimate the spatial resolution of brain PET images. Background: The spatial resolution of brain PET images is often estimated using Hoffman phantom data. Unfortunately, Hoffman phantom images may not always be readily available, and phantom-based approaches may yield sub-optimal results. We propose a new, computational approach that allows estimation of spatial resolution directly from the PET image itself. Design/Methods: We generalized the logarithmic intensity plots reported by Mizutani and colleagues (Mizutani, 2016) in order to perform spatial resolution estimation in both axial and in-plane directions. The FWHMs are estimated from multiple regression of the logarithm of the square norm of the image Fourier transform against the square distance from the origin in the Fourier domain. The proposed approach was applied to Amyloid and FDG PET images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Results: We obtained in-plane and axial FWHMs resolution estimators that vary between 3.5 mm and 8 mm for both [18F]florbetapir and [18F]FDG images. In both cases, we observed a low within-scan variability. We also obtained a strong cross-tracer consistency in FWHM resolution estimators, which is an expected result since the spatial resolution does not depend on the particular 18F-labeled tracer. Conclusions: We obtained small (less than a voxel size) across-subject variability in groups of subjects sharing the same PET site and reconstruction parameters. Our novel approach not only eliminates the need for surrogate brain phantom data, but also provides a general framework that can be applied to a wide range of tracers and other image modalities, such as SPECT. Disclosure: Dr. Carbonell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biospective Inc.. Dr. Zijdenbos has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biospective Inc.. Dr. Zijdenbos holds stock and/or stock options in Biospective Inc. which sponsored research in which Dr. Zijdenbos was involved as an investigator. Dr. Bedell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee: Biospective Inc.. Dr. Bedell holds stock and/or stock options in Stock: Biospective Inc. which sponsored research in which Dr. Bedell was involved as an investigator.

Research paper thumbnail of IC-P-047: Cortical laminar analysis of beta-amyloid deposition, astrogliosis and neuronal density in a mouse model of Alzheimer's disease

Alzheimers & Dementia, Jul 1, 2013

Research paper thumbnail of A 3D probabilistic atlas of normal human neuroanatomy

Research paper thumbnail of Impact of Reference and Target Region Selection on Amyloid PET SUV Ratios in the Phase 1b PRIME Study of Aducanumab

The Journal of Nuclear Medicine, May 18, 2018

Research paper thumbnail of Improved correlation between scores on the expanded disability status scale and cerebral lesion load in relapsing-remitting multiple sclerosis. Results of the application of new imaging methods

Research paper thumbnail of Slice-Wise Three-Dimensional Reconstruction of Myocardial Contrast Perfusion from Simulated Biplane Views

Springer eBooks, 1989

ABSTRACT

Research paper thumbnail of Spatially Distributed Amyloid-β Reduces Glucose Metabolism in Mild Cognitive Impairment

Journal of Alzheimer's Disease, Jan 21, 2020

Research paper thumbnail of Genome-wide association studies of cerebral white matter lesion burden: The CHARGE consortium

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2011

Objective-White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)are p... more Objective-White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMH are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. Methods-We performed a meta-analysis of genome-wide association studies (GWAS) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. Results-We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs)in one locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (P discovery = 4.0×10 −9 ; P replication =1.3×10 −7 ; P combined =4.0×10 −15). Other SNPs in this region also reaching genome-wide significance are rs9894383 (P=5.3×10 −9), rs11869977 (P=5.7×10 −9), rs936393 (P=6.8×10 −9), rs3744017 (P=7.3×10 −9), and rs1055129 (P=4.1×10 −8). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample). Interpretation-This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

Research paper thumbnail of P2-182: Amyloid-associated alterations in metabolic connectivity patterns in ADNI participants

Alzheimers & Dementia, Jul 1, 2013

Research paper thumbnail of Hierarchical Multivariate Covariance Analysis of Metabolic Connectivity

Journal of Cerebral Blood Flow and Metabolism, Oct 8, 2014

Research paper thumbnail of A fully automatic and robust brain MRI tissue classification method

Medical Image Analysis, Dec 1, 2003

Research paper thumbnail of Fast and robust parameter estimation for statistical partial volume models in brain MRI

Research paper thumbnail of Common variants at 6q22 and 17q21 are associated with intracranial volume

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2012

Research paper thumbnail of P2-227: Beta-Amyloid-Related Alterations of Metabolic Connectivity in Adni MCI Subjects: A Multivariate Covariance Analysis

Alzheimers & Dementia, Jul 1, 2014

IC-P-051 LONGITUDINAL, MULTI-MODALITY, MRI STUDIESOFGAMMA-SECRETASE INHIBITION IN AN APP-SW MOUSE... more IC-P-051 LONGITUDINAL, MULTI-MODALITY, MRI STUDIESOFGAMMA-SECRETASE INHIBITION IN AN APP-SW MOUSE MODEL OFALZHEIMER’S DISEASE Barry J. Bedell, Simone P. Zehntner, Thomas Rosahl, Kathleen Wood, Kelly R. Bales, Michael A. Marconi, Eric Parker, Felix Carbonell, Alex P. Zijdenbos, Biospective Inc. & McGill University, Montreal, Quebec, Canada; Biospective Inc., Montreal, Quebec, Canada; Merck & Co., Rahway, New Jersey, United States; Pfizer Inc., Cambridge, Massachusetts, United States; Merck Research Laboratories, Kenilworth, New Jersey, United States. Contact e-mail: bbedell@biospective.com

Research paper thumbnail of A probabilistic approach to mapping human neuroanatomy

Biological Psychiatry, Jul 1, 1997

Research paper thumbnail of IC-P-001: Amyloid-associated alterations in metabolic connectivity patterns in ADNI participants

Alzheimers & Dementia, Jul 1, 2013

Background: While regional glucose hypometabolism is characteristic of Alzheimer’s disease (AD), ... more Background: While regional glucose hypometabolism is characteristic of Alzheimer’s disease (AD), this feature has been shown to be primarily associated with the ApoE4 genotype, rather than fibrillar b-amyloid, during the pre-clinical/early stages of the disease process. However, derangements of metabolic connectivity are intimately related to b-amyloid plaque burden. In order to assess the specific alterations in metabolic connectivity in early disease, we have performed a quantitative analysis of correlation patterns derived from FDG positron emission tomography (PET) images from ADNI subjects with different levels of cortical b-amyloid. Methods: [18F]florbetapir PET, [18F]FDG PET, and 3D T1-weighted MR images were obtained from ADNI-GO/-2 study subjects classified as cognitively normal or mild cognitive impairment (MCI). PET volumes were registered to a customized MRI template in MNI stereotaxic space, and standardized uptake value ratio (SUVR) images were generated and projected onto each subject’s cortical surface using Biospective’s fully-automated PIANO TM image processing software. The amyloid burden for each subject was determined from a composite region-of-interest (ROI) on [18F]florbetapir images, and subjects were categorized into Amyloid-Low (Ab L) and Amyloid-High (Ab H) groups. We generated vertexwise correlation strength maps across the entire cerebral cortex, controlling for ApoE4 genotype, and assessed the relative alterations in short-/long-range and intra-/interhemispheric metabolic connections in each group. Results: We observed statistically significant differences in short-/long-range and intra-/interhemispheric metabolic connections between the Ab L and Ab H groups in multiple cortical regions. For example, the entorhinal cortex showed greater reductions in interthan intra-hemispheric correlations (especially with the contralateral medial temporal lobe, precuneus, and posterior lateral temporal-parietal cortex) in the Ab H group. The angular gyrus demonstrated greater loss of longthan short-range metabolic correlations in the Ab H group.Conclusions:We have employed metabolic connectivity analysis to examine disruptions of the cortical correlation architecture as a function of b-amyloid burden. The aberrant metabolic connections observed in the Ab H group may be a consequence of variable spatio-temporal patterns of compensatory responses and/or cortical remodeling during the early stages of AD. The quantitative approach employed in this study may serve as a powerful, non-invasive imaging biomarker for early diagnosis/prognosis and objective evaluation of the efficacy of novel amyloid-lowering therapeutic agents.