59 results on '"Hsiao-Ying Wey"'
Search Results
2. Imaging Leucine-Rich Repeat Kinase 2 In Vivo with 18F-Labeled Positron Emission Tomography Ligand
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Zhen Chen, Jiahui Chen, Laigao Chen, Chi-Hyeon Yoo, Jian Rong, Hualong Fu, Tuo Shao, Karen Coffman, Stefanus J. Steyn, April T. Davenport, James B. Daunais, Ahmed Haider, Lee Collier, Lee Josephson, Hsiao-Ying Wey, Lei Zhang, and Steven H. Liang
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Drug Discovery ,Molecular Medicine - Published
- 2022
3. Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease
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Ping Bai, Prasenjit Mondal, Frederick A. Bagdasarian, Nisha Rani, Yan Liu, Ashley Gomm, Darcy R. Tocci, Se Hoon Choi, Hsiao-Ying Wey, Rudolph E. Tanzi, Can Zhang, and Changning Wang
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General Pharmacology, Toxicology and Pharmaceutics - Abstract
Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [
- Published
- 2022
4. Imaging regional histone deacetylase expression in dementia with Lewy bodies with [11C]Martinostat (P13-6.008)
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Anna Goodheart, Chi-Hyeon Yoo, Robin Striar, Moqing Quan, Hsiao-Ying Wey, Changning Wang, and Stephen Gomperts
- Published
- 2023
5. A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain
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Ping Bai, Liu Yan, Frederick A. Bagdasarian, Moses Q. Wilks, Hsiao-Ying Wey, and Changning Wang
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Metals and Alloys ,Nuclear Proteins ,Cell Cycle Proteins ,General Chemistry ,Article ,Catalysis ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Mice ,Protein Domains ,Positron-Emission Tomography ,Materials Chemistry ,Ceramics and Composites ,Animals ,Transcription Factors - Abstract
The two tandem bromodomains of BET (bromodomain and extra-terminal domain) proteins (BD1 and BD2) may play distinct and critical roles in neurological diseases. To better understand the underlying mechanisms of the BD1 bromodomain and facilitate brain permeable domain-selective inhibitor development, we describe here the development of the first BET BD1 positron emission tomography (PET) radioligand [(11)C]1a. Compound 1a was tested to possess potent binding affinities and good selectivity (>20-fold over BD2) for BD1 bromodomains of BRD2 (K(d) = 25 nM), BRD3 (K(d) = 24 nM), and BRD4 (K(d) = 19 nM). Physicochemical characterization of 1a indicated the brain permeability and specific binding. [(11)C]1a was radiosynthesized in a good radiochemical yield (RCY: 25–30%) and molar activity (258 GBq μmol(−1)). The PET imaging studies of [(11)C]1a in mice showed moderate brain uptake (with peak SUV = 0.7) and binding specificity. Furthermore, [(11)C]1a demonstrated translational potential in the non-human primate (NHP) PET imaging study, which sets the stage for clinical translation.
- Published
- 2022
6. Imaging Leucine-Rich Repeat Kinase 2 In Vivo with
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Zhen, Chen, Jiahui, Chen, Laigao, Chen, Chi-Hyeon, Yoo, Jian, Rong, Hualong, Fu, Tuo, Shao, Karen, Coffman, Stefanus J, Steyn, April T, Davenport, James B, Daunais, Ahmed, Haider, Lee, Collier, Lee, Josephson, Hsiao-Ying, Wey, Lei, Zhang, and Steven H, Liang
- Abstract
Leucine-rich repeat kinase 2 (LRRK2) has been demonstrated to be closely involved in the pathogenesis of Parkinson's disease (PD), and pharmacological blockade of LRRK2 represents a new opportunity for therapeutical treatment of PD and other related neurodegenerative conditions. The development of an LRRK2-specific positron emission tomography (PET) ligand would enable a target occupancy study in vivo and greatly facilitate LRRK2 drug discovery and clinical translation as well as provide a molecular imaging tool for studying physiopathological changes in neurodegenerative diseases. In this work, we present the design and development of compound
- Published
- 2022
7. Author Correction: [11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease
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Tharick A. Pascoal, Mira Chamoun, Elad Lax, Hsiao-Ying Wey, Monica Shin, Kok Pin Ng, Min Su Kang, Sulantha Mathotaarachchi, Andrea L. Benedet, Joseph Therriault, Firoza Z. Lussier, Frederick A. Schroeder, Jonathan M. DuBois, Baileigh G. Hightower, Tonya M. Gilbert, Nicole R. Zürcher, Changning Wang, Robert Hopewell, Mallar Chakravarty, Melissa Savard, Emilie Thomas, Sara Mohaddes, Sarah Farzin, Alyssa Salaciak, Stephanie Tullo, A. Claudio Cuello, Jean-Paul Soucy, Gassan Massarweh, Heungsun Hwang, Eliane Kobayashi, Bradley T. Hyman, Bradford C. Dickerson, Marie-Christine Guiot, Moshe Szyf, Serge Gauthier, Jacob M. Hooker, and Pedro Rosa-Neto
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Published
- 2022
8. [11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease
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Tharick A. Pascoal, Mira Chamoun, Elad Lax, Hsiao-Ying Wey, Monica Shin, Kok Pin Ng, Min Su Kang, Sulantha Mathotaarachchi, Andrea L. Benedet, Joseph Therriault, Firoza Z. Lussier, Frederick A. Schroeder, Jonathan M. DuBois, Baileigh G. Hightower, Tonya M. Gilbert, Nicole R. Zürcher, Changning Wang, Robert Hopewell, Mallar Chakravarty, Melissa Savard, Emilie Thomas, Sara Mohaddes, Sarah Farzin, Alyssa Salaciak, Stephanie Tullo, A. Claudio Cuello, Jean-Paul Soucy, Gassan Massarweh, Heungsun Hwang, Eliane Kobayashi, Bradley T. Hyman, Bradford C. Dickerson, Marie-Christine Guiot, Moshe Szyf, Serge Gauthier, Jacob M. Hooker, and Pedro Rosa-Neto
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Alzheimer’s disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1–3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology.
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- 2022
9. Molecular imaging of NAD + ‐dependent deacetylase SIRT1 in the brain
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Changning Wang, Can Zhang, Zude Chen, Yingxia Liang, Hsiao-Ying Wey, Rudolph E. Tanzi, and Yulong Xu
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0301 basic medicine ,Genetically modified mouse ,Brain uptake ,medicine.diagnostic_test ,Epidemiology ,Health Policy ,Nad dependent ,food and beverages ,Biology ,Nonhuman primate ,Biomarker (cell) ,03 medical and health sciences ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,Developmental Neuroscience ,Positron emission tomography ,medicine ,Neurology (clinical) ,Geriatrics and Gerontology ,Molecular imaging ,Neuroscience ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
Introduction Aging is an inevitable physiological process and the biggest risk factor of Alzheimer's disease (AD). Developing an imaging tracer to visualize aging-related changes in the brain may provide a useful biomarker in elucidating neuroanatomical mechanisms of AD. Methods We developed and characterized a new tracer that can be used to visualize SIRT1 in brains related to aging and AD by positron emission tomography imaging. Results The SIRT1 tracer displayed desirable brain uptake and selectivity, as well as stable metabolism and proper kinetics and distribution in rodent and nonhuman primate brains. This new tracer was further validated by visualizing SIRT1 in brains of AD transgenic mice, compared to nontransgenic animals. Discussion Our SIRT1 tracer not only enables, for the first time, the demonstration of SIRT1 in animal brains, but also allows visualization and recapitulation of AD-related SIRT1 neuropathological changes in animal brains.
- Published
- 2021
10. Shared intrinsic functional connectivity alterations as a familial risk marker for ADHD: a resting-state functional magnetic resonance imaging study with sibling design
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Wen-Yih Isaac Tseng, Hsiao-Ying Wey, Susan Shur-Fen Gau, and Huey-Ling Chiang
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Proband ,medicine.medical_specialty ,Precuneus ,Audiology ,03 medical and health sciences ,0302 clinical medicine ,Neural Pathways ,Humans ,Medicine ,Attention deficit hyperactivity disorder ,Genetic Predisposition to Disease ,Sibling ,Applied Psychology ,Brain Mapping ,medicine.diagnostic_test ,business.industry ,Siblings ,Brain ,Familial risk ,medicine.disease ,Magnetic Resonance Imaging ,030227 psychiatry ,Psychiatry and Mental health ,medicine.anatomical_structure ,Attention Deficit Disorder with Hyperactivity ,Posterior cingulate ,Analysis of variance ,business ,Functional magnetic resonance imaging ,030217 neurology & neurosurgery - Abstract
BackgroundAlthough aberrant intrinsic functional connectivity has been reported in attention-deficit/hyperactivity disorder (ADHD), we have a limited understanding of whether connectivity alterations are related to the familial risk of ADHD.MethodsFifty-three probands with ADHD, their unaffected siblings (n = 53) and typically developing controls (n = 53) underwent resting-state functional magnetic resonance imaging scans. A seed-based approach with the bilateral precuneus/posterior cingulate cortex (PCC) was used to derive a whole-brain functional connectivity map in each subject. The differences in functional connectivity among the three groups were tested with one-way ANOVA using randomized permutation. Comparisons between two groups were also performed to examine the increase or decrease in connectivity. The severity of ADHD symptoms was used to identify brain regions where symptom severity is correlated to the strength of intrinsic functional connectivity.ResultsWhen compared to controls, both probands and unaffected siblings showed increased functional connectivity in the left insula and left inferior frontal gyrus. The connectivity in these regions was linked to better performance in response inhibition in the control group but absent in other groups. Higher ADHD symptom severity was correlated with increased functional connectivity in bilateral fronto-parietal-temporal regions only noted in probands with ADHD.ConclusionsAlterations in resting-state functional connectivities with the precuneus/PCC, hubs of default-mode network, account for the underlying familial risks of ADHD. Since the left insula and left inferior frontal gyri are key regions of the salience and frontoparietal network, respectively, future studies focusing on alterations of cross-network functional connectivity as the familial risk of ADHD are suggested.
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- 2020
11. Classics in Neuroimaging: Imaging the Endocannabinoid Pathway with PET
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Steven H. Liang, Isabelle Boileau, Hsiao-Ying Wey, Neil Vasdev, and Cassis Varlow
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Cannabinoid receptor ,Physiology ,Cognitive Neuroscience ,Biochemistry ,Amidohydrolases ,03 medical and health sciences ,0302 clinical medicine ,Receptor, Cannabinoid, CB1 ,Neuroimaging ,Fatty acid amide hydrolase ,medicine ,Enzyme Inhibitors ,030304 developmental biology ,0303 health sciences ,Radiochemistry ,medicine.diagnostic_test ,business.industry ,Brain ,Cell Biology ,General Medicine ,medicine.disease ,Endocannabinoid system ,Monoacylglycerol Lipases ,Monoacylglycerol lipase ,Positron emission tomography ,Schizophrenia ,Positron-Emission Tomography ,Research studies ,lipids (amino acids, peptides, and proteins) ,business ,Neuroscience ,030217 neurology & neurosurgery ,Endocannabinoids - Abstract
This Viewpoint aims to highlight positron emission tomography (PET) research studies that have shaped our understanding of the endocannabinoid system (ECS) through radiopharmaceutical targeting of cannabinoid receptors 1 and 2 (CB1 and CB2), and the enzyme fatty acid amide hydrolase (FAAH), in several brain health illnesses including addiction, schizophrenia, eating disorders, and post-traumatic stress disorder. Advances in radiochemistry, including 11C-carbonylation and radiofluorination of nonactivated aromatic rings, are accelerating the translation of radiotracers with optimal kinetics, bringing us closer to clinical PET research studies to image the enzyme monoacylglycerol lipase (MAGL) and enabling the imaging of unexplored targets in the ECS.
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- 2020
12. [11C]PBR28 MR–PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder
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Anisha Bhanot, David Izquierdo-Garcia, L. Richey, Christopher J. McDougle, Jacob M. Hooker, Chieh-En Jane Tseng, Marco L. Loggia, Jonathan DuBois, Baileigh G. Hightower, Jennifer E Mullett, Christine J. Wu, Daniel B. Chonde, Anjali J. Parmar, Nouchine Hadjikhani, Ciprian Catana, Hsiao-Ying Wey, R. I. Butterfield, and Nicole R. Zürcher
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Precuneus ,Insular cortex ,behavioral disciplines and activities ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Cortex (anatomy) ,mental disorders ,Translocator protein ,Medicine ,Young adult ,Molecular Biology ,biology ,business.industry ,medicine.disease ,Psychiatry and Mental health ,030104 developmental biology ,medicine.anatomical_structure ,Autism spectrum disorder ,Posterior cingulate ,biology.protein ,Autism ,business ,030217 neurology & neurosurgery - Abstract
Mechanisms of neuroimmune and mitochondrial dysfunction have been repeatedly implicated in autism spectrum disorder (ASD). To examine these mechanisms in ASD individuals, we measured the in vivo expression of the 18 kDa translocator protein (TSPO), an activated glial marker expressed on mitochondrial membranes. Participants underwent scanning on a simultaneous magnetic resonance–positron emission tomography (MR–PET) scanner with the second-generation TSPO radiotracer [11C]PBR28. By comparing TSPO in 15 young adult males with ASD with 18 age- and sex-matched controls, we showed that individuals with ASD exhibited lower regional TSPO expression in several brain regions, including the bilateral insular cortex, bilateral precuneus/posterior cingulate cortex, and bilateral temporal, angular, and supramarginal gyri, which have previously been implicated in autism in functional MR imaging studies. No brain region exhibited higher regional TSPO expression in the ASD group compared with the control group. A subset of participants underwent a second MR–PET scan after a median interscan interval of 3.6 months, and we determined that TSPO expression over this period of time was stable and replicable. Furthermore, voxelwise analysis confirmed lower regional TSPO expression in ASD at this later time point. Lower TSPO expression in ASD could reflect abnormalities in neuroimmune processes or mitochondrial dysfunction.
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- 2020
13. Neuroepigenetic signatures of age and sex in the living human brain
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Jacob M. Hooker, Matthew Louis Hibert, Umar Mahmood, Changning Wang, Joshua L. Roffman, Maria A Di Biase, Nicole R. Zürcher, Minhae Kim, Baileigh G. Hightower, Tonya M. Gilbert, Anisha Bhanot, Amanda E. Lyall, Douglas N. Greve, Ofer Pasternak, Marek Kubicki, Mary C. Catanese, Frederick A. Schroeder, Chieh-En Jane Tseng, Christine J. Wu, Hsiao-Ying Wey, Steven M. Stufflebeam, Anjali J. Parmar, and Daphne J. Holt
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Male ,0301 basic medicine ,Emotions ,Histone Deacetylase 2 ,General Physics and Astronomy ,Hippocampus ,Adamantane ,Histone Deacetylase 1 ,02 engineering and technology ,Hydroxamic Acids ,Epigenesis, Genetic ,Carbon Radioisotopes ,Epigenetics in the nervous system ,lcsh:Science ,Sex Characteristics ,Martinostat ,Multidisciplinary ,biology ,Histone deacetylase 2 ,Age Factors ,Brain ,Human brain ,Middle Aged ,021001 nanoscience & nanotechnology ,White Matter ,Tissue Donors ,medicine.anatomical_structure ,Histone ,Female ,0210 nano-technology ,Sex characteristics ,Adult ,medicine.medical_specialty ,Adolescent ,Science ,Article ,General Biochemistry, Genetics and Molecular Biology ,White matter ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Epigenetics ,Aged ,General Chemistry ,030104 developmental biology ,Endocrinology ,biology.protein ,lcsh:Q ,Positron-emission tomography - Abstract
Age- and sex-related alterations in gene transcription have been demonstrated, however the underlying mechanisms are unresolved. Neuroepigenetic pathways regulate gene transcription in the brain. Here, we measure in vivo expression of the epigenetic enzymes, histone deacetylases (HDACs), across healthy human aging and between sexes using [11C]Martinostat positron emission tomography (PET) neuroimaging (n = 41). Relative HDAC expression increases with age in cerebral white matter, and correlates with age-associated disruptions in white matter microstructure. A post mortem study confirmed that HDAC1 and HDAC2 paralogs are elevated in white matter tissue from elderly donors. There are also sex-specific in vivo HDAC expression differences in brain regions associated with emotion and memory, including the amygdala and hippocampus. Hippocampus and white matter HDAC expression negatively correlates with emotion regulation skills (n = 23). Age and sex are associated with HDAC expression in vivo, which could drive age- and sex-related transcriptional changes and impact human behavior., Gene transcription is known to vary with age and sex, although the underlying mechanisms are unresolved. Here, the authors show that epigenetic enzymes known as HDACs, which regulate gene transcription, are increasingly expressed with age in the living human brain, with sex differences also observed.
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- 2019
14. Positron emission tomography probes targeting bromodomain and extra-terminal (BET) domains to enable in vivo neuroepigenetic imaging
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Yu Lan, Changning Wang, Stephen J. Haggarty, Xiaoxia Lu, Johanna Rokka, Hsiao-Ying Wey, Debasis Patnaik, Fiedler Stephanie, and Ping Bai
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Molecular Conformation ,Nerve Tissue Proteins ,Receptors, Cell Surface ,Crystallography, X-Ray ,010402 general chemistry ,01 natural sciences ,Catalysis ,Mice ,Protein Domains ,In vivo ,Materials Chemistry ,medicine ,Animals ,Carbon Radioisotopes ,Blood-Testis Barrier ,Neurons ,Brain uptake ,medicine.diagnostic_test ,010405 organic chemistry ,Chemistry ,Metals and Alloys ,Brain ,General Chemistry ,Pet imaging ,humanities ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Bromodomain ,Kinetics ,Positron emission tomography ,Positron-Emission Tomography ,Ceramics and Composites ,Biophysics ,Macaca ,Radiopharmaceuticals ,Preclinical imaging - Abstract
Here, we report the development of novel PET radiotracer ([11C]CW22) of BET proteins. In vivo imaging results in rodents and nonhuman primates (NHP) demonstrate that [11C]CW22 has excellent brain uptake, good specificity, good selectivity, suitable metabolism, appropriate kinetics and distribution in the brain. Our studies demonstrated that [11C]CW22 exhibits ideal properties as a PET imaging probe of BET proteins for further validation.
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- 2019
15. PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia
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Stephen J. Haggarty, Roy H. Perlis, Jacob M. Hooker, Baileigh G. Hightower, Minhae Kim, Tonya M. Gilbert, Anisha Bhanot, Joshua L. Roffman, Marco L. Loggia, Hsiao-Ying Wey, Thomas M. Morin, Changning Wang, Frederick A. Schroeder, Daphne J. Holt, Daniel S. Albrecht, Kamber L. Hart, Nicole R. Zürcher, Steven M. Stufflebeam, Amelia M. Pellegrini, Hannah E. Brown, Misha M. Riley, Anais Rodriguez-Thompson, and Christine J. Wu
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Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Prefrontal Cortex ,Neuroimaging ,Schizoaffective disorder ,Gene Expression Regulation, Enzymologic ,Histone Deacetylases ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Effects of sleep deprivation on cognitive performance ,Martinostat ,business.industry ,Cognition ,General Medicine ,Middle Aged ,medicine.disease ,Dorsolateral prefrontal cortex ,030104 developmental biology ,medicine.anatomical_structure ,Psychotic Disorders ,Schizophrenia ,Case-Control Studies ,Positron-Emission Tomography ,Female ,Histone deacetylase ,business ,030217 neurology & neurosurgery ,Research Article - Abstract
BACKGROUND. Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [(11)C]Martinostat positron emission tomography (PET). METHODS. In a case-control study, relative [((11))C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered. RESULTS. Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls. CONCLUSIONS. These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans. FUNDING. National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.
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- 2018
16. Molecular imaging of Alzheimer’s disease–related gamma-secretase in mice and nonhuman primates
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Robert E. Koegel, Robin Striar, Zude Chen, Yingxia Liang, Kevin D. Rynearson, Can Zhang, Chongzhao Ran, Changning Wang, Rudolph E. Tanzi, Steven L. Wagner, Stephanie A. Fiedler, Hsiao-Ying Wey, Se Hoon Choi, Daniela R. Bernales, and Yulong Xu
- Subjects
Male ,0301 basic medicine ,Transgene ,Immunology ,Mice, Transgenic ,Biology ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Neuroimaging ,Alzheimer Disease ,Positron Emission Tomography Computed Tomography ,Presenilin-1 ,medicine ,Animals ,Humans ,Immunology and Allergy ,Gamma secretase ,medicine.diagnostic_test ,Drug discovery ,Brief Definitive Report ,Brain ,Magnetic resonance imaging ,Macaca mulatta ,Magnetic Resonance Imaging ,Imaging agent ,Molecular Imaging ,030104 developmental biology ,Amyloid Precursor Protein Secretases ,Molecular imaging ,Neuroscience ,Human Disease Genetics ,030217 neurology & neurosurgery - Abstract
Alzheimer’s disease–related γ-secretase is a prime drug target whose brain regional expression and distribution remain largely unknown. This study describes the development of a molecular imaging probe to reveal γ-secretase in rodents and macaques with translational potentials in humans., The pathogenesis of Alzheimer’s disease (AD) is primarily driven by brain accumulation of the amyloid-β-42 (Aβ42) peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. γ-Secretase is a prime drug target for AD; however, its brain regional expression and distribution remain largely unknown. Here, we are aimed at developing molecular imaging tools for visualizing γ-secretase. We used our recently developed γ-secretase modulators (GSMs) and synthesized our GSM-based imaging agent, [11C]SGSM-15606. We subsequently performed molecular imaging in rodents, including AD transgenic animals, and macaques, which revealed that our probe displayed good brain uptake and selectivity, stable metabolism, and appropriate kinetics and distribution for imaging γ-secretase in the brain. Interestingly, rodents and macaques shared certain brain areas with high γ-secretase expression, suggesting a functional conservation of γ-secretase. Collectively, we have provided the first molecular brain imaging of γ-secretase, which may not only accelerate our drug discovery for AD but also advance our understanding of AD.
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- 2020
17. Synthesis of a11C-labeledD-amino acid oxidase inhibitor for PET imaging
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Deng, Xiaoyun, Shao, Tuo, Shao, Yihan, Josephson, Lee, Hsiao-Ying, Wey, Ming-Rong, Zhang, and Liang, Huan
- Abstract
Objectives: We have identified 4-hydroxy-6-(3-methoxyphenethyl)pyridazin-3(2H)-one (1) as a lead molecule for D-amino acid oxidase (DAAO)-specific PET ligand. It has been reported that inhibitory activity of compound 1 for human, mouse and rat DAAOs showed dose-dependent responses with IC50 valves of 8.8, 4.4 and 5.6 nM, respectively. [1] The goal of the project was to synthesize the standard and precursor molecules for this target and perform radiolabeling of compound 1 with carbon-11. Methods: The leading compound 1 was synthesized in the following procedures. The cyclization of 3,4,6-trichloropyridazine 2 and pyrocatechol 3 led to intermediate 4 in 80% yield. Through the Sonagashira coupling reaction of compound 4 and 1-ethynyl-3-methoxybenzene 5, the alkyne 6 was obtained in 40% yield. Exchanged with phenylmethanol under base, compound 6 was converted to benzyl-protected ether 7 in 58% yield. After Pd-mediated hydrogenation of compound 7, the desired product 1 was obtained in 77% yield (Scheme 1A). The synthesis of the labeling precursor for compound 1 was showed in Scheme 1B. Phenylmethanol was used to react with compound 4 to get benzyl-protected ether 8 in 48% yield. After hydrogenation of compound 8 under hydrogen using palladium/carbon catalysis, 6-chloro-4-hydroxypyridazin-3(2H)-one 9 was obtained in 84% yield. Hydroxy groups were then protected by the treatment with chloromethyl methyl ether to give compound 10 in 40% yield, followed by the Sonagashira coupling reaction with alkyne 12 to produce compound 13 in 38% yield. At the end, benzyl protecting group was removed by palladium hydroxide/carbon catalysis under hydrogen to yield the precursor 14 in 71% yield. Preliminary 11C-labeling was carried out using precursor (14; 1.6 mg) with [11C]methyl iodide in the presence of Cs2CO3 in DMF (0.4 mL) at 80°C for 5 min to generate [11C]15 (Scheme 1C). Then, 4 M HCl in dioxane was added to remove the MOM group and the mixture was neutralized with NaHCO3 aqueous solution to get [11C]1. Results: The synthesis of candidate compound 1 was obtained from commercially available 3,4,6-trichloropyridazine 2 and pyrocatechol 3 in four steps with overall yield of 14%. The radioligand [11C]1 was synthesized in 13 ± 3% radiochemical yield based on [11C]CH3I (decay corrected). The tracer was obtained at end-of-synthesis (70 min synthesis time) with high radiochemical purity (>99%) and molar activity (> 1.0 Ci/μmol; 37 GBq/μmol). No radiolysis was observed within 90 min. Conclusions: We have successfully prepared one potent and selective DAAO ligand and performed 11C-labeling with a reasonable radiochemical yield and high molar activity. Preliminary in vivo evaluation by PET are underway. References: [1] T. Hondo, M. Warizaya, T. Niimi, I. Namatame, T. Yamaguchi, K. Nakanishi, T. Hamajima, K. Harada, H. Sakashita, Y. Matsumoto, J. Med. Chem. 2013, 56, 3582., SNMMI 2020 Annual Meeting
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- 2020
18. Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[11C]methoxyphenethyl)pyridazin-3(2H)-one, a 11C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging
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Deng, Xiaoyun, Zhang, Yiding, Chen, Zhen, Kumata, Katsushi, Van, Richard, Rong, Jian, Shao, Tuo, Hatori, Akiko, Mori, Wakana, Yu, Qingzhen, Kuan, Hu, Fujinaga, Masayuki, Hsiao-Ying, Wey, Shao, Yihan, Josephson, Lee, Murtas, Giulia, Pollegioni, Loredano, Ming-Rong, Zhang, and Liang, Huan
- Abstract
Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer’s patients with early phase. Herein we report the synthesis and preliminary evaluation of a 11C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). 11C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [11C]8 failed to cross the blood–brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding.
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- 2020
19. Advances in simultaneous PET/MR for imaging neuroreceptor function
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Hsiao-Ying Wey, Hanne D. Hansen, and Christin Y. Sander
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Sensory Receptor Cells ,Functional dynamics ,Neuroimaging ,Mri studies ,Multimodal Imaging ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Review Articles ,Brain function ,business.industry ,Brain ,Human brain ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Pharmacological interventions ,Neurology ,Positron-Emission Tomography ,Molecular targets ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Hybrid imaging using PET/MRI has emerged as a platform for elucidating novel neurobiology, molecular and functional changes in disease, and responses to physiological or pharmacological interventions. For the central nervous system, PET/MRI has provided insights into biochemical processes, linking selective molecular targets and distributed brain function. This review highlights several examples that leverage the strengths of simultaneous PET/MRI, which includes measuring the perturbation of multi-modal imaging signals on dynamic timescales during pharmacological challenges, physiological interventions or behavioral tasks. We discuss important considerations for the experimental design of dynamic PET/MRI studies and data analysis approaches for comparing and quantifying simultaneous PET/MRI data. The primary focus of this review is on functional PET/MRI studies of neurotransmitter and receptor systems, with an emphasis on the dopamine, opioid, serotonin and glutamate systems as molecular neuromodulators. In this context, we provide an overview of studies that employ interventions to alter the activity of neuroreceptors or the release of neurotransmitters. Overall, we emphasize how the synergistic use of simultaneous PET/MRI with appropriate study design and interventions has the potential to expand our knowledge about the molecular and functional dynamics of the living human brain. Finally, we give an outlook on the future opportunities for simultaneous PET/MRI.
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- 2020
20. Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[11C]methoxyphenethyl)pyridazin-3(2H)-one, a 11C-labeled D-amino acid oxidase (DAAO) inhibitor for PET imaging
- Author
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Tuo Shao, Masayuki Fujinaga, Qingzhen Yu, Hsiao-Ying Wey, Richard Van, Steven H. Liang, Loredano Pollegioni, Giulia Murtas, Xiaoyun Deng, Yiding Zhang, Kuan Hu, Wakana Mori, Lee Josephson, Ming-Rong Zhang, Zhen Chen, Yihan Shao, Katsushi Kumata, Akiko Hatori, and Jian Rong
- Subjects
Clinical Biochemistry ,D-amino acid oxidase ,Pharmaceutical Science ,Carbon-11 ,01 natural sciences ,Biochemistry ,In vivo ,Drug Discovery ,medicine ,Molecular Biology ,D-Amino acid oxidase (DAAO) ,Cerebellum function ,Positron emission tomography (PET) ,Schizophrenia ,medicine.diagnostic_test ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Pet imaging ,Ligand (biochemistry) ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Positron emission tomography ,Molecular Medicine ,Efflux ,Early phase - Abstract
Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer’s patients with early phase. Herein we report the synthesis and preliminary evaluation of a 11C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). 11C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [11C]8 failed to cross the blood–brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding.
- Published
- 2020
21. Effects of flow changes on radiotracer binding: Simultaneous measurement of neuroreceptor binding and cerebral blood flow modulation
- Author
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Jacob M. Hooker, Hsiao-Ying Wey, Christin Y. Sander, Ciprian Catana, Joseph B. Mandeville, and Bruce R. Rosen
- Subjects
Male ,Sensory Receptor Cells ,Multimodal Imaging ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Dopamine receptor D3 ,Dopamine receptor D2 ,medicine ,Animals ,Computer Simulation ,Raclopride ,Behavior, Animal ,medicine.diagnostic_test ,Receptors, Dopamine D2 ,Chemistry ,business.industry ,Receptors, Dopamine D3 ,Original Articles ,Blood flow ,Magnetic Resonance Imaging ,Neurology ,Cerebral blood flow ,Fallypride ,Positron emission tomography ,Cerebrovascular Circulation ,Positron-Emission Tomography ,Benzamides ,Biophysics ,Female ,Spin Labels ,Neurology (clinical) ,Radiopharmaceuticals ,Cardiology and Cardiovascular Medicine ,Nuclear medicine ,business ,Functional magnetic resonance imaging ,Psychomotor Performance ,030217 neurology & neurosurgery ,Papio ,medicine.drug - Abstract
The potential effects of changes in blood flow on the delivery and washout of radiotracers has been an ongoing question in PET bolus injection studies. This study provides practical insight into this topic by experimentally measuring cerebral blood flow (CBF) and neuroreceptor binding using simultaneous PET/MRI. Hypercapnic challenges (7% CO2) were administered to non-human primates in order to induce controlled increases in CBF, measured with pseudo-continuous arterial spin labeling. Simultaneously, dopamine D2/D3 receptor binding of [11C]raclopride or [18F]fallypride was monitored with dynamic PET. Experiments showed that neither time activity curves nor quantification of binding through binding potentials ( BPND) were measurably affected by CBF increases, which were larger than two-fold. Simulations of experimental procedures showed that even large changes in CBF should have little effect on the time activity curves of radiotracers, given a set of realistic assumptions. The proposed method can be applied to experimentally assess the flow sensitivity of other radiotracers. Results demonstrate that CBF changes, which often occur due to behavioral tasks or pharmacological challenges, do not affect PET [11C]raclopride or [18F]fallypride binding studies and their quantification. The results from this study suggest flow effects may have limited impact on many PET neuroreceptor tracers with similar properties.
- Published
- 2017
22. Nasal neuron PET imaging quantifies neuron generation and degeneration
- Author
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Tracey K. Murray, Mark W. Albers, Genevieve C. Van de Bittner, Hsiao-Ying Wey, Emily L. Ricq, Changning Wang, Zeshan Ahmed, Michael J. O'Neill, Janina Ehses, Frederick A. Schroeder, Scott P. Herrick, Misha M. Riley, Jaclyn E. Smith, Jacob M. Hooker, and Luxiang Cao
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Aging ,Olfactory Nerve ,Population ,Sensory system ,Neuroprotection ,Rats, Sprague-Dawley ,03 medical and health sciences ,Olfaction Disorders ,0302 clinical medicine ,medicine ,Animals ,Cognitive decline ,Radioactive Tracers ,education ,education.field_of_study ,business.industry ,Neurodegeneration ,Neurogenesis ,General Medicine ,Olfactory Pathways ,respiratory system ,medicine.disease ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Tauopathies ,Positron-Emission Tomography ,Tauopathy ,Neuron ,sense organs ,business ,Neuroscience ,030217 neurology & neurosurgery ,Research Article - Abstract
Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [11C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [11C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [11C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [18F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics.
- Published
- 2017
23. Synthesis and preliminary evaluation of [(11)C]GNE-1023 as a novel potent PET probe for imaging leucine-rich repeat kinase 2 (LRRK2) in Parkinson’s disease
- Author
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Hsiao-Ying Wey, Jian Rong, April T. Davenport, James B. Daunais, Zhen Chen, Steven H. Liang, Tuo Shao, Yihan Shao, Qingzhen Yu, Xiaoyun Deng, Lee Josephson, Hualong Fu, Wen‐Wei Qiu, Wei Gao, Thomas Lee Collier, and Xiaofei Zhang
- Subjects
Biodistribution ,Parkinson's disease ,Morpholines ,Leucine-rich repeat ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Ligands ,01 natural sciences ,Biochemistry ,Article ,Rats, Sprague-Dawley ,Mice ,Drug Discovery ,medicine ,Radioligand ,Animals ,Humans ,Carbon Radioisotopes ,General Pharmacology, Toxicology and Pharmaceutics ,Kinase activity ,Protein Kinase Inhibitors ,Pharmacology ,medicine.diagnostic_test ,010405 organic chemistry ,Chemistry ,Kinase ,Organic Chemistry ,Brain ,Parkinson Disease ,medicine.disease ,LRRK2 ,Macaca mulatta ,0104 chemical sciences ,nervous system diseases ,010404 medicinal & biomolecular chemistry ,Pyrimidines ,Positron emission tomography ,Positron-Emission Tomography ,Cancer research ,Molecular Medicine ,Female ,Radiopharmaceuticals - Abstract
Leucin-rich repeat kinase 2 (LRRK2) is a large protein that is involved in the pathogenesis of Parkinson’s disease (PD). It has been demonstrated that LRRK2 mutations mainly confers PD, which bring about increased kinase activity of LRRK2. As a consequence, selective inhibition of LRRK2 may help to recover the normal functions of LRRK2, and thereafter serve as an alternatively promising therapeutic target for PD treatment. The mapping of LRRK2 with PET studies allows a deep understanding of PD and other LRRK2-related disorders, as well as helps to validate and translate novel LRRK2 inhibitors. However, to date no LRRK2 PET probes have been reported in the primary literature. In this study, we present a facile synthesis and preliminary evaluation of [(11)C]GNE-1023 as a novel potent PET probe for LRRK2 imaging in PD. [(11)C]GNE-1023 was synthesized in good radiochemical yield (10% non-decay corrected RCY), excellent radiochemical purity (>99%) and high molar activity (>37 GBq / μmol). Excellent in vitro binding specificity of [(11)C]GNE-1023 towards LRRK2 was demonstrated in cross species studies, including rat and nonhuman primate brain tissues by autoradiography experiments. Subsequent whole-body biodistribution studies indicated limited brain uptake and urinary and hepatobiliary elimination of this radioligand. This study may pave the way for the further development of a new generation of LRRK2 PET probes.
- Published
- 2019
24. A regularized full reference tissue model for PET neuroreceptor mapping
- Author
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Bruce R. Rosen, Jacob M. Hooker, Joseph B. Mandeville, Hsiao-Ying Wey, Gitte M. Knudsen, Christin Y. Sander, Claus Svarer, and Hanne D. Hansen
- Subjects
Work (thermodynamics) ,Reference tissue ,Cognitive Neuroscience ,Models, Neurological ,Value (computer science) ,Receptors, Cell Surface ,Shuttle Radar Topography Mission ,Article ,030218 nuclear medicine & medical imaging ,Reduction (complexity) ,03 medical and health sciences ,0302 clinical medicine ,Statistics ,Image Processing, Computer-Assisted ,Calibration ,Animals ,Humans ,Mathematics ,Brain Mapping ,Brain ,Signal Processing, Computer-Assisted ,Neurology ,Positron-Emission Tomography ,Reference Region ,Constant (mathematics) ,Biological system ,030217 neurology & neurosurgery - Abstract
The full reference tissue model (FRTM) is a PET analysis framework that includes both free and specifically bound compartments within tissues, together with rate constants defining association and dissociation from the specifically bound compartment. The simplified reference tissue model (SRTM) assumes instantaneous exchange between tissue compartments, and this “1-tissue” approximation reduces the number of parameters and enables more robust mapping of non-displaceable binding potentials. Simulations based upon FRTM have shown that SRTM exhibits biases that are spatially dependent, because biases depend upon binding potentials. In this work, we describe a regularized model (rFRTM) that employs a global estimate of the dissociation rate constant from the specifically bound compartment (k4). The model provides an internal calibration for optimizing k4 through the reference-region outflow rate k2′, a model parameter that should be a global constant but varies regionally in SRTM. Estimates of k4 by rFRTM are presented for four PET radioligands. We show that SRTM introduces bias in parameter estimates by assuming an infinite value for k4, and that rFRTM ameliorates bias with an appropriate choice of k4. Theoretical considerations and simulations demonstrate that rFRTM reduces bias in non-displaceable binding potentials. A two-parameter reduction of the model (rFRTM2) provides robust mapping at a voxel-wise level. With a structure similar to SRTM, the model is easily implemented and can be applied as a PET reference region analysis that reduces parameter bias without substantially altering parameter variance.
- Published
- 2016
25. PET Neurochemical Imaging Modes
- Author
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Hsiao-Ying Wey, Jacob M. Hooker, Thomas M. Morin, Michael S. Placzek, and Wenjun Zhao
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Brain tumor ,Article ,03 medical and health sciences ,0302 clinical medicine ,Neurochemical ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Neurochemistry ,Radioactive Tracers ,Neurotransmitter Agents ,medicine.diagnostic_test ,business.industry ,Proteins ,Pet imaging ,Human brain ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Positron emission tomography ,Positron-Emission Tomography ,Proteins metabolism ,Research questions ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Positron emission tomography (PET) has deep roots in neuroscience stemming from its first applications in brain tumor and brain metabolism imaging. Over the past few decades, PET emerged and continues to play a prominent role in the study of neurochemistry in the living human brain. Over time, neurochemical imaging with PET has been expanded to address a host of research questions related to among many others, protein density, drug occupancy and endogenous neurochemical release. Each of these imaging modes has distinct design and analysis considerations that are critical for enabling quantitative measurements. The number of considerations required for a neurochemical PET study can make it unapproachable. This seminar aims to orient those interested in neurochemical PET imaging to three of the common imaging modes and to provide some perspective on needs that exist for expansion of neurochemical PET imaging.
- Published
- 2016
26. Discrepancies in Kappa Opioid Agonist Binding Revealed through PET Imaging
- Author
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Ramesh Neelamegam, Michael S. Placzek, Hsiao-Ying Wey, Jacob M. Hooker, Changning Wang, Tao Che, Bryan L. Roth, and Frederick A. Schroeder
- Subjects
Agonist ,Male ,Pyrrolidines ,Physiology ,medicine.drug_class ,Cognitive Neuroscience ,(+)-Naloxone ,Pharmacology ,Biochemistry ,κ-opioid receptor ,Binding, Competitive ,Naltrexone ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Carbon Radioisotopes ,030304 developmental biology ,0303 health sciences ,Dose-Response Relationship, Drug ,business.industry ,Receptors, Opioid, kappa ,Binding potential ,Cell Biology ,General Medicine ,Human brain ,JDTic ,Rats ,Analgesics, Opioid ,medicine.anatomical_structure ,chemistry ,Positron-Emission Tomography ,Benzamides ,business ,030217 neurology & neurosurgery ,Kappa ,medicine.drug - Abstract
Kappa opioid receptor (KOR) modulation has been pursued in many conceptual frameworks for the treatment of human pain, depression, and anxiety. As such, several imaging tools have been developed to characterize the density of KORs in the human brain and its occupancy by exogenous drug-like compounds. While exploring the pharmacology of KOR tool compounds using positron emission tomography (PET), we observed discrepancies in the apparent competition binding as measured by changes in binding potential (BPND, binding potential with respect to non-displaceable uptake). This prompted us to systematically look at the relationships between baseline BPND maps for three common KOR PET radioligands, the antagonists [11C]LY2795050 and [11C]LY2459989, and the agonist [11C]GR103545. We then measured changes in BPND using kappa antagonists (naloxone, naltrexone, LY2795050, JDTic, nor-BNI), and found BPND was affected similarly between [11C]GR103545 and [11C]LY2459989. Longitudinal PET studies with nor-BNI and JDTic wer...
- Published
- 2018
27. A population stereotaxic positron emission tomography brain template for the macaque and its application to ischemic model
- Author
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Steven H. Liang, Chai Pei, Hsiao-Ying Wey, Yongjin Tang, Gong Jianxian, Chao Zheng, Shengxiang Liang, Zhangsheng Pan, Xudong Zhao, Zhiqiang Tan, Baoci Shan, Yichao Hu, Lu Wang, Xiaofei Zhang, Jingjie Shang, Hao Xu, and Binbin Nie
- Subjects
Male ,Computer science ,Cognitive Neuroscience ,Population ,Ischemia ,Macaque ,050105 experimental psychology ,Brain Ischemia ,03 medical and health sciences ,Atlases as Topic ,0302 clinical medicine ,Imaging Tool ,Species Specificity ,Neuroimaging ,biology.animal ,Image Processing, Computer-Assisted ,medicine ,T1 weighted ,Animals ,0501 psychology and cognitive sciences ,education ,Brain Mapping ,education.field_of_study ,medicine.diagnostic_test ,biology ,business.industry ,05 social sciences ,Brain atlas ,Brain ,Pattern recognition ,medicine.disease ,Macaca mulatta ,Magnetic Resonance Imaging ,Macaca fascicularis ,Neurology ,Positron emission tomography ,Positron-Emission Tomography ,Female ,Artificial intelligence ,business ,030217 neurology & neurosurgery - Abstract
Purpose Positron emission tomography (PET) is a non-invasive imaging tool for the evaluation of brain function and neuronal activity in normal and diseased conditions with high sensitivity. The macaque monkey serves as a valuable model system in the field of translational medicine, for its phylogenetic proximity to man. To translation of non-human primate neuro-PET studies, an effective and objective data analysis platform for neuro-PET studies is needed. Materials and methods A set of stereotaxic templates of macaque brain, namely the Institute of High Energy Physics & Jinan University Macaque Template (HJT), was constructed by iteratively registration and averaging, based on 30 healthy rhesus monkeys. A brain atlas image was created in HJT space by combining sub-anatomical regions and defining new 88 bilateral functional regions, in which a unique integer was assigned for each sub-anatomical region. Results The HJT comprised a structural MRI T1 weighted image (T1WI) template image, a functional FDG-PET template image, intracranial tissue segmentations accompanied with a digital macaque brain atlas image. It is compatible with various commercially available software tools, such as SPM and PMOD. Data analysis was performed on a stroke model compared with a group of healthy controls to demonstrate the usage of HJT. Conclusion We have constructed a stereotaxic template set of macaque brain named HJT, which standardizes macaque neuroimaging data analysis, supports novel radiotracer development and facilitates translational neuro-disorders research.
- Published
- 2019
28. Associations between cerebral blood flow and structural and functional brain imaging measures in individuals with neuropsychologically defined mild cognitive impairment
- Author
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Elizabeth C. Leritz, Dany J.J. Wang, Rachel L. Alvarado, Hsiao-Ying Wey, Kimberly A. Stephens, David H. Salat, and Chan Mi Kim
- Subjects
0301 basic medicine ,Male ,Aging ,medicine.medical_specialty ,White matter lesion ,Disease ,Neuropsychological Tests ,Article ,Vascular health ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Internal medicine ,medicine ,Humans ,Cognitive Dysfunction ,Cognitive impairment ,Aged ,business.industry ,General Neuroscience ,Organ Size ,Middle Aged ,Magnetic Resonance Imaging ,White Matter ,Hyperintensity ,Functional Brain Imaging ,030104 developmental biology ,Cerebral blood flow ,nervous system ,Cerebrovascular Circulation ,Cardiology ,cardiovascular system ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,human activities ,030217 neurology & neurosurgery ,Developmental Biology ,circulatory and respiratory physiology - Abstract
Reduced cerebral blood flow (CBF), an indicator of neurovascular processes and metabolic demands, is a common finding in Alzheimer's disease. However, little is known about what contributes to CBF deficits in individuals with mild cognitive impairment (MCI). We examine regional CBF differences in 17 MCI compared with 21 age-matched cognitively healthy older adults. Next, we examined associations between CBF, white matter lesion (WML) volume, amplitude of low-frequency fluctuations, and cortical thickness to better understand whether altered CBF was detectable before other markers and the potential mechanistic underpinnings of CBF deficits in MCI. MCI had significantly reduced CBF, whereas cortical thickness and amplitude of low-frequency fluctuation were not affected. Reduced CBF was associated with the WML volume but not associated with other measures. Given the presumed vascular etiology of WML and relative worsening of vascular health in MCI, it may suggest CBF deficits result from early vascular as opposed to metabolic deficits in MCI. These findings may support vascular mechanisms as an underlying component of cognitive impairment.
- Published
- 2018
29. A Manganese-Based Alternative to Gadolinium: Contrast Enhanced MR Angiography, Pharmacokinetics, and Metabolism
- Author
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Hsiao-Ying Wey, Yi-Fen Yen, David E. Sosnovik, Peter Caravan, Ian Ramsay, and Eric M. Gale
- Subjects
Gadolinium DTPA ,Gadolinium ,chemistry.chemical_element ,Contrast Media ,Manganese ,010402 general chemistry ,Kidney ,01 natural sciences ,Hepatobiliary Elimination ,Article ,030218 nuclear medicine & medical imaging ,Excretion ,03 medical and health sciences ,0302 clinical medicine ,Renal Artery ,Pharmacokinetics ,biology.animal ,Image Processing, Computer-Assisted ,Organometallic Compounds ,Medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Aorta, Abdominal ,biology ,business.industry ,Kidney metabolism ,Metabolism ,0104 chemical sciences ,chemistry ,Female ,business ,Nuclear medicine ,Magnetic Resonance Angiography ,Baboon ,Half-Life ,Papio - Abstract
Purpose To compare intravascular contrast enhancement produced by the manganese-based magnetic resonance (MR) imaging contrast agent manganese-N-picolyl-N,N',N'-trans-1,2-cyclohexenediaminetriacetate (Mn-PyC3A) to gadopentetate dimeglumine (Gd-DTPA) and to evaluate the excretion, pharmacokinetics, and metabolism of Mn-PyC3A. Materials and Methods Contrast material-enhanced MR angiography was performed in baboons (Papio anubis; n = 4) by using Mn-PyC3A and Gd-DTPA. Dynamic imaging was performed for 60 minutes following Mn-PyC3A injection to monitor distribution and elimination. Serial blood sampling was performed to quantify manganese and gadolinium plasma clearance by using inductively coupled plasma mass spectrometry and to characterize Mn-PyC3A metabolism by using high-performance liquid chromatography. Intravascular contrast enhancement in the abdominal aorta and brachiocephalic artery was quantified by measuring contrast-to-noise ratios (CNRs) versus muscle at 9 seconds following Mn-PyC3A or Gd-DTPA injection. Plasma pharmacokinetics were modeled with a biexponential function, and data were compared with a paired t test. Results Aorta versus muscle CNR (mean ± standard deviation) with Mn-PyC3A and Gd-DTPA was 476 ± 77 and 538 ± 120, respectively (P = .11). Brachiocephalic artery versus muscle CNR was 524 ± 55 versus 518 ± 140, respectively (P = .95). Mn-PyC3A was eliminated via renal and hepatobiliary excretion with similar pharmacokinetics to Gd-DTPA (area under the curve between 0 and 30 minutes, 20.2 ± 3.1 and 17.0 ± 2.4, respectively; P = .23). High-performance liquid chromatography revealed no evidence of Mn-PyC3A biotransformation. Conclusion Mn-PyC3A enables contrast-enhanced MR angiography with comparable contrast enhancement to gadolinium-based agents and may overcome concerns regarding gadolinium-associated toxicity and retention.
- Published
- 2017
30. Immediate and Persistent Effects of Salvinorin A on the Kappa Opioid Receptor in Rodents, Monitored In Vivo with PET
- Author
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Scott E. Lukas, Hsiao-Ying Wey, Genevieve C. Van de Bittner, Jacob M. Hooker, and Michael S. Placzek
- Subjects
Male ,Agonist ,Pyrrolidines ,medicine.drug_class ,Pharmacology ,Toxicology ,Binding, Competitive ,κ-opioid receptor ,Piperazines ,Diterpenes, Clerodane ,Time ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Pharmacokinetics ,In vivo ,Opioid receptor ,Opioid Receptor Binding ,medicine ,Animals ,Pharmacology (medical) ,Carbon Radioisotopes ,Dose-Response Relationship, Drug ,Chemistry ,Receptors, Opioid, kappa ,Brain ,Binding potential ,Salvinorin A ,Analgesics, Opioid ,Psychiatry and Mental health ,Opioid ,Positron-Emission Tomography ,Original Article ,Radiopharmaceuticals ,medicine.drug - Abstract
Monitoring changes in opioid receptor binding with positron emission tomography (PET) could lead to a better understanding of tolerance and addiction because altered opioid receptor dynamics following agonist exposure has been linked to tolerance mechanisms. We have studied changes in kappa opioid receptor (KOR) binding availability in vivo with PET following kappa opioid agonist administration. Male Sprague-Dawley rats (n=31) were anesthetized and treated with the (KOR) agonist salvinorin A (0.01-1.8 mg/kg, i.v.) before administration of the KOR selective radiotracer [(11)C]GR103545. When salvinorin A was administered 1 min prior to injection of the radiotracer, [(11)C]GR103545 binding potential (BPND) was decreased in a dose-dependent manner, indicating receptor binding competition. In addition, the unique pharmacokinetics of salvinorin A (half-life ~8 min in non-human primates) allowed us to study the residual impact on KOR after the drug had eliminated from the brain. Salvinorin A was administered up to 5 h prior to [(11)C]GR103545, and the changes in BPND were compared with baseline, 2.5 h, 1 h, and 1 min pretreatment times. At lower doses (0.18 mg/kg and 0.32 mg/kg) we observed no prolonged effect on KOR binding but at 0.60 mg/kg salvinorin A induced a sustained decrease in KOR binding (BPND decreased by 40-49%) which persisted up to 2.5 h post administration, long after salvinorin A had been eliminated from the brain. These data point towards an agonist-induced adaptive response by KOR, the dynamics of which have not been previously studied in vivo with PET.
- Published
- 2015
31. Kinetic Analysis and Quantification of [11C]Martinostat for in Vivo HDAC Imaging of the Brain
- Author
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Julie C. Price, Hsiao-Ying Wey, Jacob M. Hooker, Changning Wang, Jean Logan, and Frederick A. Schroeder
- Subjects
Male ,Physiology ,Cognitive Neuroscience ,Kinetic analysis ,Adamantane ,Hydroxamic Acids ,Biochemistry ,Article ,Histone Deacetylases ,Neuroimaging ,In vivo ,Image Processing, Computer-Assisted ,medicine ,Animals ,Carbon Radioisotopes ,Epigenetics ,Martinostat ,biology ,medicine.diagnostic_test ,Brain ,Cell Biology ,General Medicine ,Nonhuman primate ,Histone ,Positron emission tomography ,Positron-Emission Tomography ,biology.protein ,Female ,Radiopharmaceuticals ,Neuroscience ,Papio - Abstract
Epigenetic mechanisms mediated by histone deacetylases (HDACs) have been implicated in a wide-range of CNS disorders and may offer new therapeutic opportunities. In vivo evaluation of HDAC density and drug occupancy has become possible with [(11)C]Martinostat, which exhibits selectivity for a subset of class I/IIb HDAC enzymes. In this study, we characterize the kinetic properties of [(11)C]Martinostat in the nonhuman primate (NHP) brain in preparation for human neuroimaging studies. The goal of this work was to determine whether classic compartmental analysis techniques were appropriate and to further determine if arterial plasma is required for future NHP studies. Using an arterial plasma input function, several analysis approaches were evaluated for robust outcome measurements. [(11)C]Martinostat showed high baseline distribution volume (VT) ranging from 29.9 to 54.4 mL/cm(3) in the brain and large changes in occupancy (up to 99%) with a blocking dose approaching full enzyme saturation. An averaged nondisplaceable tissue uptake (VND) of 8.6 ± 3.7 mL/cm(3) suggests high specific binding of [(11)C]Martinostat. From a two-tissue compartment model, [(11)C]Martinostat exhibits a high K1 (averaged K1 of 0.65 mL/cm(3)/min) and a small k4 (average of 0.0085 min(-1)). Our study supports that [(11)C]Martinostat can be used to detect changes in HDAC density and occupancy in vivo and that simplified analysis not using arterial blood could be appropriate.
- Published
- 2015
32. Simultaneous fMRI–PET of the opioidergic pain system in human brain
- Author
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Ciprian Catana, Danny J.J. Wang, Daniel B. Chonde, Bruce R. Rosen, Darin D. Dougherty, Hsiao-Ying Wey, Jacob M. Hooker, Jian Kong, Randy L. Gollub, and Gitte M. Knudsen
- Subjects
Adult ,Male ,Haemodynamic response ,Narcotic Antagonists ,Cognitive Neuroscience ,Diprenorphine ,Pain ,Brain mapping ,Article ,Young Adult ,Thalamus ,Neuroimaging ,medicine ,Humans ,Endogenous opioid ,Opioidergic ,Brain Mapping ,medicine.diagnostic_test ,Brain ,Magnetic resonance imaging ,Human brain ,Magnetic Resonance Imaging ,Corpus Striatum ,medicine.anatomical_structure ,nervous system ,Neurology ,Positron-Emission Tomography ,Receptors, Opioid ,Female ,Psychology ,Neuroscience ,psychological phenomena and processes ,medicine.drug - Abstract
MRI and PET provide complementary information for studying brain function. While the potential use of simultaneous MRI/PET for clinical diagnostic and disease staging has been demonstrated recently; the biological relevance of concurrent functional MRI-PET brain imaging to dissect neurochemically distinct components of the blood oxygenation level dependent (BOLD) fMRI signal has not yet been shown. We obtained sixteen fMRI-PET data sets from eight healthy volunteers. Each subject participated in randomized order in a pain scan and a control (nonpainful pressure) scan on the same day. Dynamic PET data were acquired with an opioid radioligand, [(11)C]diprenorphine, to detect endogenous opioid releases in response to pain. BOLD fMRI data were collected at the same time to capture hemodynamic responses. In this simultaneous human fMRI-PET imaging study, we show co-localized responses in thalamus and striatum related to pain processing, while modality specific brain networks were also found. Co-localized fMRI and PET signal changes in the thalamus were positively correlated suggesting that pain-induced changes in opioid neurotransmission contribute a significant component of the fMRI signal change in this region. Simultaneous fMRI-PET provides unique opportunities allowing us to relate specific neurochemical events to functional hemodynamic activation and to investigate the impacts of neurotransmission on neurovascular coupling of the human brain in vivo.
- Published
- 2014
33. Positron Emission Tomography Assessment of the Intranasal Delivery Route for Orexin A
- Author
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Ramalinga Dharanipragada, John Hoekman, Xiaoyou Ying, Hsiao-Ying Wey, Jacob M. Hooker, Kyle C. Van de Bittner, Genevieve C. Van de Bittner, Wayne Rowe, Kim Alving, Andrew Giovanni, Anurag Gupta, and William J Hurst
- Subjects
0301 basic medicine ,Drug ,Male ,Physiology ,Cognitive Neuroscience ,media_common.quotation_subject ,Neuropeptide ,Pharmacology ,Biochemistry ,Methylation ,Rats, Sprague-Dawley ,03 medical and health sciences ,Orexin-A ,0302 clinical medicine ,Pharmacokinetics ,medicine ,Animals ,Carbon Radioisotopes ,Administration, Intranasal ,media_common ,Orexins ,medicine.diagnostic_test ,Molecular Structure ,business.industry ,Brain ,Cell Biology ,General Medicine ,Wakefulness-Promoting Agents ,Macaca mulatta ,Bioavailability ,030104 developmental biology ,Positron emission tomography ,Raclopride ,Positron-Emission Tomography ,Drug delivery ,Nasal administration ,business ,030217 neurology & neurosurgery - Abstract
Intranasal drug delivery is a noninvasive drug delivery route that can enhance systemic delivery of therapeutics with poor oral bioavailability by exploiting the rich microvasculature within the nasal cavity. The intranasal delivery route has also been targeted as a method for improved brain uptake of neurotherapeutics, with a goal of harnessing putative, direct nose-to-brain pathways. Studies in rodents, nonhuman primates, and humans have pointed to the efficacy of intranasally delivered neurotherapeutics, while radiolabeling studies have analyzed brain uptake following intranasal administration. In the present study, we employed carbon-11 radioactive methylation to assess the pharmacokinetic mechanism of intranasal delivery of Orexin A, a native neuropeptide and prospective antinarcoleptic drug that binds the orexin receptor 1. Using physicochemical and pharmacological analysis, we identified the methylation sites and confirmed the structure and function of methylated Orexin A (CH3-Orexin A) prior to mo...
- Published
- 2017
34. Dynamic functional imaging of brain glucose utilization using fPET-FDG
- Author
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Christin Y. Sander, Ciprian Catana, Joanna S. Fowler, Hsiao-Ying Wey, Daniel B. Chonde, Bruce R. Rosen, Nicole R. Zürcher, Marjorie Villien, Jacob M. Hooker, Joseph B. Mandeville, and Jonathan R. Polimeni
- Subjects
Adult ,Blood Glucose ,Glucose utilization ,Brain activity and meditation ,Computer science ,Cognitive Neuroscience ,Carbohydrate metabolism ,Multimodal Imaging ,Article ,Hypercapnia ,Fluorodeoxyglucose F18 ,Functional neuroimaging ,medicine ,Animals ,Humans ,medicine.diagnostic_test ,business.industry ,Functional Neuroimaging ,Brain ,Magnetic resonance imaging ,Magnetic Resonance Imaging ,Functional imaging ,Neurology ,Positron emission tomography ,Positron-Emission Tomography ,Temporal resolution ,Visual Perception ,Feasibility Studies ,Female ,medicine.symptom ,Nuclear medicine ,business ,Papio ,Biomedical engineering - Abstract
Glucose is the principal source of energy for the brain and yet the dynamic response of glucose utilization to changes in brain activity is still not fully understood. Positron emission tomography (PET) allows quantitative measurement of glucose metabolism using 2-[(18)F]-fluorodeoxyglucose (FDG). However, FDG PET in its current form provides an integral (or average) of glucose consumption over tens of minutes and lacks the temporal information to capture physiological alterations associated with changes in brain activity induced by tasks or drug challenges. Traditionally, changes in glucose utilization are inferred by comparing two separate scans, which significantly limits the utility of the method. We report a novel method to track changes in FDG metabolism dynamically, with higher temporal resolution than exists to date and within a single session. Using a constant infusion of FDG, we demonstrate that our technique (termed fPET-FDG) can be used in an analysis pipeline similar to fMRI to define within-session differential metabolic responses. We use visual stimulation to demonstrate the feasibility of this method. This new method has a great potential to be used in research protocols and clinical settings since fPET-FDG imaging can be performed with most PET scanners and data acquisition and analysis are straightforward. fPET-FDG is a highly complementary technique to MRI and provides a rich new way to observe functional changes in brain metabolism.
- Published
- 2014
35. PET Imaging Demonstrates Histone Deacetylase Target Engagement and Clarifies Brain Penetrance of Known and Novel Small Molecule Inhibitors in Rat
- Author
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Jennifer P. Gale, W. R. Takakura, Surya A. Reis, Clay C. C. Wang, Stephen J. Haggarty, Jacob M. Hooker, Edward B. Holson, Hsiao-Ying Wey, Frederick Albert Schroeder, Ramesh Neelamegam, Yan Ling Zhang, A. Karunakaran, and G. C. Van de Bittner
- Subjects
Physiology ,Cognitive Neuroscience ,Motor Activity ,Biology ,Biochemistry ,Histone Deacetylases ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,preclinical ,Animals ,Carbon Radioisotopes ,030304 developmental biology ,chemistry.chemical_classification ,Depressive Disorder ,0303 health sciences ,Histone deacetylase 5 ,translational ,rodent ,Brain ,Cell Biology ,General Medicine ,radiotracer ,Penetrance ,Small molecule ,Antidepressive Agents ,Rats ,Neuroimaging epigenetics ,3. Good health ,Chromatin ,Histone Deacetylase Inhibitors ,Disease Models, Animal ,Enzyme ,chemistry ,Positron-Emission Tomography ,Benzamides ,Histone deacetylase ,Radiopharmaceuticals ,Neuroscience ,030217 neurology & neurosurgery ,Homeostasis ,Research Article - Abstract
Histone deacetylase (HDAC) enzymes have been demonstrated as critical components in maintaining chromatin homeostasis, CNS development, and normal brain function. Evidence in mouse models links HDAC expression to learning, memory, and mood-related behaviors; small molecule HDAC inhibitor tool compounds have been used to demonstrate the importance of specific HDAC subtypes in modulating CNS-disease-related behaviors in rodents. So far, no direct evidence exists to understand the quantitative changes in HDAC target engagement that are necessary to alter biochemistry and behavior in a living animal. Understanding the relationship between target engagement and in vivo effect is essential in refining new ways to alleviate disease. We describe here, using positron emission tomography (PET) imaging of rat brain, the in vivo target engagement of a subset of class I/IIb HDAC enzymes implicated in CNS-disease (HDAC subtypes 1, 2, 3, and 6). We found marked differences in the brain penetrance of tool compounds from the hydroxamate and benzamide HDAC inhibitor classes and resolved a novel, highly brain penetrant benzamide, CN147, chronic treatment with which resulted in an antidepressant-like effect in a rat behavioral test. Our work highlights a new translational path for understanding the molecular and behavioral consequences of HDAC target engagement.
- Published
- 2014
36. In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs
- Author
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Ronald Borra, Frederick A. Schroeder, Hsiao-Ying Wey, Stephen J. Haggarty, Edward B. Holson, Florence F. Wagner, Sung Won Kim, Changning Wang, Surya A. Reis, and Jacob M. Hooker
- Subjects
Epigenomics ,Male ,Central nervous system ,Context (language use) ,Pharmacology ,Biology ,Kidney ,Histone Deacetylases ,Article ,Rats, Sprague-Dawley ,Drug Discovery ,medicine ,Animals ,Humans ,Epigenetics ,Dose-Response Relationship, Drug ,Drug discovery ,Myocardium ,Brain ,Imaging agent ,Rats ,3. Good health ,Histone Deacetylase Inhibitors ,medicine.anatomical_structure ,Histone ,Positron-Emission Tomography ,biology.protein ,Autoradiography ,Molecular Medicine ,Neuroscience ,Preclinical imaging ,Papio - Abstract
Epigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute to disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting in the context of cardiovascular disease and central nervous system dysfunction. Development of a molecular agent for non-invasive imaging to elucidate the distribution and functional roles of HDACs in humans will accelerate medical research and drug discovery in this domain. Herein, we describe the synthesis and validation of an HDAC imaging agent, [(11)C]6. Our imaging results demonstrate that this probe has high specificity, good selectivity, and appropriate kinetics and distribution for imaging HDACs in the brain, heart, kidney, pancreas, and spleen. Our findings support the translational potential for [(11)C]6 for human epigenetic imaging.
- Published
- 2014
37. PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates
- Author
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Steven H. Liang, Alan A. Wilson, Timothy M. Shoup, Jacob M. Hooker, Benjamin H. Rotstein, Hsiao-Ying Wey, and Neil Vasdev
- Subjects
Primates ,Fluorine Radioisotopes ,positron emission tomography ,Brief Article ,Pharmaceutical Science ,Pharmacology ,Blood–brain barrier ,Amidohydrolases ,chemistry.chemical_compound ,Pharmacokinetics ,[18F]DOPP ,Fatty acid amide hydrolase ,Drug Discovery ,fatty acid amide hydrolase ,medicine ,Animals ,Distribution (pharmacology) ,Tissue Distribution ,FAAH ,Oxazoles ,Human studies ,Brain ,Pet imaging ,URB597 ,kinetic modeling ,Magnetic Resonance Imaging ,Endocannabinoid system ,PET ,medicine.anatomical_structure ,Models, Chemical ,Biochemistry ,chemistry ,Blood-Brain Barrier ,Positron-Emission Tomography ,Benzamides ,Molecular Medicine ,Carbamates ,Endocannabinoids ,Papio - Abstract
Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [(11)C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [(18)F]DOPP ([(18)F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising (18)F-labeled analogue based on rodent studies. The goal of this work is to evaluate [(18)F]DOPP in nonhuman primates to support its clinical translation. High specific activity [(18)F]DOPP (5-6 Ci·μmol(-1)) was administered intravenously (iv) to three baboons (2M/1F, 3-4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [(18)F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ∼95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [(18)F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [(11)C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [(18)F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm(3)/min; 300 μg/kg URB597: 0.058 mL/cm(3)/min), suggesting that [(18)F]DOPP binding is specific for FAAH, consistent with previous rodent data.
- Published
- 2014
38. Functional connectivity of the frontoparietal network predicts cognitive modulation of pain
- Author
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Alexandra Cheetham, Randy L. Gollub, Bruce R. Rosen, Hsiao-Ying Wey, Karin B. Jensen, Ted J. Kaptchuk, Rita E. Loiotile, Jian Kong, Ying Tan, and Jordan W. Smoller
- Subjects
Adult ,Male ,Nociception ,Hot Temperature ,Emotions ,Pain ,Posterior parietal cortex ,Gyrus Cinguli ,Article ,Young Adult ,Cognition ,Parietal Lobe ,Neural Pathways ,medicine ,Humans ,Prefrontal cortex ,Sensory cue ,Anterior cingulate cortex ,Pain Measurement ,Resting state fMRI ,medicine.diagnostic_test ,Parietal lobe ,Anticipation, Psychological ,Magnetic Resonance Imaging ,Anticipation ,Frontal Lobe ,Forearm ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Neurology ,Female ,Neurology (clinical) ,Cues ,Nerve Net ,Functional magnetic resonance imaging ,Psychology ,Neuroscience ,Photic Stimulation - Abstract
The experience of pain can be significantly influenced by expectancy (predictive cues). This ability to modulate pain has the potential to affect therapeutic analgesia substantially and constitutes a foundation for nonpharmacological pain relief. In this study, we investigated (1) brain regions involved in visual cue modulation of pain during anticipation of pain, pain administration, and pain rating; and (2) the association between pretest resting state functional connectivity and the magnitude of cue effects on pain ratings. We found that after cue conditioning, visual cues can significantly modulate subjective pain ratings. Functional magnetic resonance imaging results suggested that brain regions pertaining to the frontoparietal network (prefrontal and parietal cortex) and a pain/emotion modulatory region (rostral anterior cingulate cortex) are involved in cue modulation during both pain anticipation and administration stage. Most interestingly, we found that pretest resting state functional connectivity between the frontoparietal network (as identified by independent component analysis) and the rostral anterior cingulate cortex/medial prefrontal cortex was positively associated with cue effects on pain rating changes. We believe that these findings will shed new light on our understanding of variable cue/expectancy effects across individuals and how the intrinsic connectivity of the brain may influence expectancy-induced modulation of pain.
- Published
- 2013
39. Changes in Cerebral Blood Flow during an Alteration in Glycemic State in a Large Non-human Primate (
- Author
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Peter, Kochunov, Hsiao-Ying, Wey, Peter T, Fox, Jack L, Lancaster, Michael D, Davis, Danny J J, Wang, Ai-Ling, Lin, Raul A, Bastarrachea, Marcia C R, Andrade, Vicki, Mattern, Patrice, Frost, Paul B, Higgins, Anthony G, Comuzzie, and Venkata S, Voruganti
- Subjects
cerebral blood flow ,perfusion imaging ,resting state network ,hyperglycemic challenge ,default state network ,arterial spin labeling ,Neuroscience ,Original Research - Abstract
Changes in cerebral blood flow (CBF) during a hyperglycemic challenge were mapped, using perfusion-weighted MRI, in a group of non-human primates. Seven female baboons were fasted for 16 h prior to 1-h imaging experiment, performed under general anesthesia, that consisted of a 20-min baseline, followed by a bolus infusion of glucose (500 mg/kg). CBF maps were collected every 7 s and blood glucose and insulin levels were sampled at regular intervals. Blood glucose levels rose from 51.3 ± 10.9 to 203.9 ± 38.9 mg/dL and declined to 133.4 ± 22.0 mg/dL, at the end of the experiment. Regional CBF changes consisted of four clusters: cerebral cortex, thalamus, hypothalamus, and mesencephalon. Increases in the hypothalamic blood flow occurred concurrently with the regulatory response to systemic glucose change, whereas CBF declined for other clusters. The return to baseline of hypothalamic blood flow was observed while CBF was still increasing in other brain regions. The spatial pattern of extra-hypothalamic CBF changes was correlated with the patterns of several cerebral networks including the default mode network. These findings suggest that hypothalamic blood flow response to systemic glucose levels can potentially be explained by regulatory activity. The response of extra-hypothalamic clusters followed a different time course and its spatial pattern resembled that of the default-mode network.
- Published
- 2016
40. IC‐P‐166: Olfactory Sensory Neuron Monitoring in Alzheimer’s Disease: Toward Human Translation of a Pet Imaging Agent
- Author
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Genevieve C. Van de Bittner, Jacob M. Hooker, Hsiao-Ying Wey, Ramesh Neelamegam, Janina Ehses, Misha M. Riley, Mark W. Albers, and Luxiang Cao
- Subjects
Epidemiology ,business.industry ,Health Policy ,Translation (biology) ,Disease ,Pet imaging ,Sensory neuron ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,Developmental Neuroscience ,medicine ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,Neuroscience - Published
- 2016
41. O1‐06‐06: Olfactory Sensory Neuron Monitoring in Alzheimer’s Disease: Toward Human Translation of a Pet Imaging Agent
- Author
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Genevieve C. Van de Bittner, Misha M. Riley, Luxiang Cao, Janina Ehses, Ramesh Neelamegam, Mark Albers, Jacob M. Hooker, and Hsiao-Ying Wey
- Subjects
Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2016
42. Multimodal MRI of Nonhuman Primate Stroke
- Author
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Hsiao-Ying Wey and Timothy Q. Duong
- Subjects
medicine.medical_specialty ,Pathology ,Neurology ,medicine.diagnostic_test ,business.industry ,General Neuroscience ,MEDLINE ,Magnetic resonance imaging ,Vascular surgery ,medicine.disease ,Article ,Nonhuman primate ,medicine ,cardiovascular diseases ,Neurology (clinical) ,Neurosurgery ,Cardiology and Cardiovascular Medicine ,Intensive care medicine ,business ,Stroke ,Cause of death - Abstract
Stroke is the fourth leading cause of death. Despite decades of research, no neuroprotective drug has proven to be effective clinically. One widely accepted view to account for this negative outcome is that the rodent stroke model simply does not adequately reflect the complexity of human stroke. Recent failures of several high-profile neuroprotective drugs for stroke treatment in phase III clinical trials further underscore the importance of developing adequate animal models for stroke research. The brain organization and vascular circuitry of nonhuman primates (NHPs) are more homologous with humans than the widely used rodent for stroke modeling. The Stroke Therapy Academic Industry Roundtable, a national committee commissioned by the American Heart Association, recommended that clinically relevant NHP stroke models be established for developing and assessing neuroprotective drugs. The aim of this article is to review the challenges and applications of magnetic resonance imaging studies of NHP stroke models.
- Published
- 2012
43. Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance
- Author
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Michael S. Placzek, Jacob M. Hooker, Frederick A. Schroeder, Martin G. Strebl, Ramesh Neelamegam, Hsiao-Ying Wey, Changning Wang, and Genevieve C. Van de Bittner
- Subjects
0301 basic medicine ,Male ,Physiology ,Cognitive Neuroscience ,Adamantane ,Biology ,Hydroxamic Acids ,01 natural sciences ,Biochemistry ,Rats sprague dawley ,Histone Deacetylases ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,Animals ,Epigenetics ,Brain uptake ,Martinostat ,Psychiatric Disease ,010405 organic chemistry ,Brain ,Cell Biology ,General Medicine ,Penetrance ,0104 chemical sciences ,030104 developmental biology ,Positron-Emission Tomography ,Female ,Histone deacetylase ,Radiopharmaceuticals ,Neuroscience ,Papio - Abstract
Despite major efforts, our knowledge about many brain diseases remains remarkably limited. Epigenetic dysregulation has been one of the few leads toward identifying the causes and potential treatments of psychiatric disease over the past decade. A new positron emission tomography radiotracer, [(11)C]Martinostat, has enabled the study of histone deacetylase in living human subjects. A unique property of [(11)C]Martinostat is its profound brain penetrance, a feature that is challenging to engineer intentionally. In order to understand determining factors for the high brain-uptake of Martinostat, a series of compounds was evaluated in rodents and nonhuman primates. The study revealed the major structural contributors to brain uptake, as well as a more clinically relevant fluorinated HDAC radiotracer with comparable behavior to Martinostat, yet longer half-life.
- Published
- 2015
44. Insights into neuroepigenetics through human histone deacetylase PET imaging
- Author
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Hsiao-Ying Wey, Anisha Bhanot, Frederick A. Schroeder, Changing Wang, Nicole R. Zürcher, Angela She, Brendan D. Taillon, Tonya M. Gilbert, Stephen J. Haggarty, and Jacob M. Hooker
- Subjects
0301 basic medicine ,Adult ,Male ,Synaptophysin ,Adamantane ,Bioinformatics ,Hydroxamic Acids ,Histone Deacetylases ,Article ,Histone H4 ,03 medical and health sciences ,Histone H3 ,Young Adult ,0302 clinical medicine ,Progranulins ,medicine ,Humans ,Protein Isoforms ,Epigenetics ,Vorinostat ,Martinostat ,biology ,Brain-Derived Neurotrophic Factor ,Neurodegeneration ,Brain ,General Medicine ,medicine.disease ,Healthy Volunteers ,Cell biology ,030104 developmental biology ,Histone ,Positron-Emission Tomography ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Female ,Histone deacetylase ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Epigenetic dysfunction is implicated in many neurological and psychiatric diseases, including Alzheimer’s disease and schizophrenia. Consequently, histone deacetylases (HDACs) are being aggressively pursued as therapeutic targets. However, a fundamental knowledge gap exists regarding the expression and distribution of HDACs in healthy individuals for comparison to disease states. Here, we report the first-in-human evaluation of neuroepigenetic regulation in vivo. Using positron emission tomography (PET) with [11C]Martinostat, an imaging probe selective for class I HDACs (isoforms 1–3), we found HDAC expression is higher in cortical gray matter than white matter with strikingly conserved regional distribution patterns within and between healthy individuals. Among gray matter regions, HDAC expression is lowest in the hippocampus and amygdala. Through biochemical profiling of postmortem human brain tissue, we confirmed [11C]Martinostat selectively binds HDAC isoforms 1–3, the HDAC subtypes most implicated in regulating neuroplasticity and cognitive function. To relate the PET imaging signal to the epigenetic regulation of gene transcription, we measured mRNA expression changes elicited by Martinostat in human stem cell-derived neural progenitor cells. We demonstrate that genes closely associated with synaptic plasticity, including BDNF (brain derived neurotrophic factor) and SYP (synaptophysin), as well as genes implicated in neurodegeneration, including GRN (progranulin), were markedly increased at the transcript level in concert with increased acetylation at both histone H3 lysine 9 and histone H4 lysine 12. This study provides the first quantification of HDAC expression in the living human brain, and provides the foundation for gaining unprecedented in vivo epigenetic information in the healthy and diseased human brain.
- Published
- 2015
45. MRI of Perfusion-Diffusion Mismatch in Non-Human Primate (Baboon) Stroke: A Preliminary Report
- Author
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Timothy Q. Duong, Jinqi Li, Ghazwan M. Kroma, Lisa Jones, Hsiao-Ying Wey, and M. Michelle Leland
- Subjects
medicine.medical_specialty ,middle cerebral artery occlusion ,nonhuman primate ,Balloon ,Article ,cerebral ischemia ,perfusion ,magnetic resonance imaging ,03 medical and health sciences ,0302 clinical medicine ,Penumbra ,Internal medicine ,biology.animal ,Occlusion ,medicine ,Radiology, Nuclear Medicine and imaging ,cardiovascular diseases ,Stroke ,030304 developmental biology ,0303 health sciences ,medicine.diagnostic_test ,biology ,business.industry ,diffusion ,Balloon catheter ,Magnetic resonance imaging ,medicine.disease ,Surgery ,cardiovascular system ,Cardiology ,Neurology (clinical) ,business ,Perfusion ,030217 neurology & neurosurgery ,Baboon - Abstract
The goal of this study was to develop a clinically relevant non-human primate (baboon) stroke model and multi-parametric MRI protocols on a clinical scanner with long-term goals to better model human stroke and facilitate clinical translations of novel therapeutic strategies. Baboons were chosen because of their relatively large brain volume and that they are evolutionarily close to humans. Middle cerebral artery occlusion (MCAO) was induced using a minimally invasive endovascular approach to guide an inflatable balloon catheter into the MCA and followed by permanently or transiently inflate the balloon. Using multimodal MRI, including perfusion and diffusion imaging, the spatiotemporal dynamic evolution of the ischemic lesions in permanent and transient occlusion experiments in baboons were investigated. Perfusion-diffusion mismatch, which approximates the ischemic penumbra, was detected. In the permanent MCAO group (n = 2), the mean infarct volume was 29 ml (17% of total brain volume) whereas in the transient MCAO group (n = 2, 60 or 90 min of occlusion), the mean infarct volume was 15 ml (9% of total brain volume). Substantial perfusion-diffusion mismatch tissue (~50%) was salvaged by reperfusion compared to permanent MCAO. This baboon stroke model has the potential to become a translational platform to better design clinical studies, guide clinical diagnosis and improve treatment time windows in patients.
- Published
- 2011
46. Anatomical, blood oxygenation level-dependent, and blood flow MRI of nonhuman primate (baboon) retina
- Author
-
Timothy Q. Duong, Yi Zhang, Hsiao-Ying Wey, Bryan H. De La Garza, Qi Peng, and Oscar San Emeterio Nateras
- Subjects
Retina ,genetic structures ,medicine.diagnostic_test ,media_common.quotation_subject ,Retinal ,Blood flow ,Anatomy ,Biology ,Magnetic resonance angiography ,Ganglion ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,biology.animal ,medicine ,Contrast (vision) ,Radiology, Nuclear Medicine and imaging ,sense organs ,Choroid ,media_common ,Baboon - Abstract
The goal of this study was to demonstrate high-resolution anatomical, BOLD (blood-oxygenation-level-dependent), and blood-flow (BF) MRI on large non-human primate (NHP) retinas using a 3-Tesla clinical scanner as a first step toward translation. Baboon was chosen because of its evolutionary similarity to human. Anesthetized preparation, free of eye-movement artifacts, was used to evaluate clinical scanner hardware feasibility. Anatomical MRI (0.1×0.2×2.0 mm) before contrast-agent injection detected three alternating bright-dark-bright layers. The hyperintense inner strip nearest to the vitreous was enhanced by an intravascular contrast agent, likely included the ganglion and bipolar cell layer and the embedded retinal vessels. The hypointense middle strip showed no contrast enhancement, likely included the avascular outer unclear layer and photoreceptor segments. The hyperintense outer strip showed contrast enhancement, likely corresponded to the choroid vascular layer. In the posterior retina, the total thickness including the choroid was 617±101µm (±SD, n=7). BOLD fMRI (0.3×0.6×2.0 mm) of oxygen inhalation relative to air increased 6.5±1.4%. Basal BF (2×2×2mm) was 83±30mL/100g/min (air), and hypercapnia increased BF by 25±9% (P
- Published
- 2011
47. Striatal and Cortical BOLD, Blood Flow, Blood Volume, Oxygen Consumption, and Glucose Consumption Changes in Noxious Forepaw Electrical Stimulation
- Author
-
Bryan H. De La Garza, Yen-Yu Ian Shih, Hsiao-Ying Wey, and Timothy Q. Duong
- Subjects
Male ,Haemodynamic response ,Pain ,Hemodynamics ,Blood volume ,Striatum ,Somatosensory system ,Rats, Sprague-Dawley ,Oxygen Consumption ,Fluorodeoxyglucose F18 ,Forelimb ,medicine ,Animals ,Cerebral Cortex ,Blood Volume ,medicine.diagnostic_test ,business.industry ,Magnetic Resonance Imaging ,Corpus Striatum ,Electric Stimulation ,Rats ,Oxygen ,Functional imaging ,Glucose ,medicine.anatomical_structure ,nervous system ,Neurology ,Regional Blood Flow ,Cerebral cortex ,Positron-Emission Tomography ,Original Article ,Neurology (clinical) ,Radiopharmaceuticals ,Cardiology and Cardiovascular Medicine ,business ,Functional magnetic resonance imaging ,Neuroscience - Abstract
Recent reports showed noxious forepaw stimulation in rats evoked an unexpected sustained decrease in cerebral blood volume (CBV) in the bilateral striatum, whereas increases in spike activity and Fos-immunoreactive cells were observed. This study aimed to further evaluate the hemodynamic and metabolic needs in this model and the sources of negative functional magnetic resonance imaging (fMRI) signals by measuring blood oxygenation-level-dependent (BOLD), cerebral-blood-flow (CBF), CBV, and oxygen-consumption (i.e., cerebral metabolic rate of oxygen (CMRO2)) changes using an 11.7-T MRI scanner, and glucose-consumption (i.e., cerebral metabolic rate of glucose (CMRglc)) changes using micro-positron emission tomography. In the contralateral somatosensory cortex, BOLD, CBF, CBV, CMRO2 ( n=7, P2 decreased slightly, although not significantly from baseline, and CMRglc was not statistically significant from baseline ( P>0.05). These multimodal functional imaging findings corroborate the unexpected negative hemodynamic changes in the striatum during noxious forepaw stimulation, and support the hypothesis that striatal hemodynamic response is dominated by neurotransmitter-mediated vasoconstriction, overriding the stimulus-evoked fMRI signal increases commonly accompany elevated neuronal activity. Multimodal functional imaging approach offers a means to probe the unique attributes of the striatum, providing novel insights into the neurovascular coupling in the striatum. These findings may have strong implications in fMRI studies of pain.
- Published
- 2010
48. Baseline CBF, and BOLD, CBF, and CMRO2 fMRI of Visual and Vibrotactile Stimulations in Baboons
- Author
-
Hsiao-Ying Wey, Danny J.J. Wang, and Timothy Q. Duong
- Subjects
Haemodynamic response ,Perfusion Imaging ,Perfusion scanning ,Somatosensory system ,Vibration ,Hypercapnia ,White matter ,Oxygen Consumption ,Physical Stimulation ,Image Processing, Computer-Assisted ,medicine ,Animals ,Anesthesia ,Anesthetics, Dissociative ,Isoflurane ,medicine.diagnostic_test ,Brain ,Blood flow ,Magnetic Resonance Imaging ,Oxygen ,Kinetics ,medicine.anatomical_structure ,nervous system ,Neurology ,Cerebral blood flow ,Touch ,Cerebrovascular Circulation ,Anesthetics, Inhalation ,Calibration ,Original Article ,Female ,Ketamine ,Spin Labels ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,Functional magnetic resonance imaging ,Psychology ,Algorithms ,Photic Stimulation ,Papio ,medicine.drug - Abstract
Neurovascular coupling associated with visual and vibrotactile stimulations in baboons anesthetized sequentially with isoflurane and ketamine was evaluated using multimodal functional magnetic resonance imaging (fMRI) on a clinical 3-Tesla scanner. Basal cerebral blood flow ( CBF), and combined blood-oxygenation-level-dependent ( BOLD) and CBF fMRI of visual and somatosensory stimulations were measured using pseudo-continuous arterial spin labeling. Changes in stimulus-evoked cerebral metabolic rate of oxygen ( CMRO2) were estimated using calibrated fMRI. Arterial transit time for vessel, gray matter (GM), and white matter (WM) were 250, 570, and 823 ms, respectively. Gray matter and WM CBF, respectively, were 107.8 ± 7.9 and 47.8 ± 3.8 mL per 100 g per minute under isoflurane, and 108.8 ± 10.3 and 48.7 ± 4.2 mL per 100 g per minute under ketamine (mean ± s.e.m., N = 8 sessions, five baboons). The GM/WM CBF ratio was not statistically different between the two anesthetics, averaging 2.3 ± 0.1. Hypercapnia evoked global BOLD and CBF increases. Blood-oxygenation-level-dependent, CBF, and CMRO2 signal changes by visual and vibrotactile stimulations were 0.19% to 0.22%, 18% to 23%, and 4.9% to 6.7%, respectively. The CBF/CMRO2 ratio was 2.9 to 4.7. Basal CBF and fMRI responses were not statistically different between the two anesthetics. This study establishes a multimodal fMRI protocol to probe clinically relevant functional, physiological and metabolic information in large nonhuman primates.
- Published
- 2010
49. Fetal brain during a binge drinking episode: a dynamic susceptibility contrast MRI fetal brain perfusion study
- Author
-
Donald J. Dudley, Peter Kochunov, Peter T. Fox, Gerald Schatten, Duff M. Davis, David E. Purdy, Calvin Simerly, Hsiao-Ying Wey, and Carlos A. Castro
- Subjects
Gadolinium DTPA ,medicine.medical_specialty ,Time Factors ,Perfusion Imaging ,Fetal alcohol syndrome ,Contrast Media ,Binge drinking ,Perfusion scanning ,Article ,Pregnancy ,Fetal membrane ,Internal medicine ,Animals ,Medicine ,Fetus ,Ethanol ,medicine.diagnostic_test ,business.industry ,General Neuroscience ,Uterus ,Brain ,Central Nervous System Depressants ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Endocrinology ,Cerebral blood flow ,Cerebrovascular Circulation ,Myometrium ,Female ,Papio hamadryas ,business ,Alcoholic Intoxication ,Perfusion - Abstract
We assessed the effects of a single episode of maternal alcohol intoxication on fetal brain blood perfusion in three pregnant dams (baboons) at the 24th week of pregnancy using dynamic susceptibility contrast magnetic resonance imaging. After the oral administration of alcohol, there was a four-fold increase in the peak contrast concentrations in the fetal brain. In addition, we observed a two- to three-fold increase in the contrast uptake and washout rates in the fetal brain. The underlying mechanisms of these changes are unknown, but we hypothesized that these could include the alcohol-mediated changes in placental permeability and fetal cerebral blood flow. Our findings indicate that alcohol intoxication produces profound changes, which may detrimentally influence neurodevelopmental processes in the brain.
- Published
- 2010
50. Synthesis and Imaging Validation of [18F]MDL100907 Enabled by Ni-Mediated Fluorination
- Author
-
Hsiao-Ying Wey, Tobias Ritter, Ramesh Neelamegam, Hong Ren, Jacob M. Hooker, and Martin G. Strebl
- Subjects
Fluorine Radioisotopes ,Time Factors ,Halogenation ,Physiology ,Cognitive Neuroscience ,Biochemistry ,Unmet needs ,Piperidines ,medicine ,Animals ,Receptor, Serotonin, 5-HT2A ,Single scan ,Carbon Radioisotopes ,medicine.diagnostic_test ,business.industry ,Chemistry ,Brain ,Cell Biology ,General Medicine ,Pet imaging ,Magnetic Resonance Imaging ,Papio anubis ,Nonhuman primate ,Fluorobenzenes ,High specific activity ,Positron emission tomography ,Positron-Emission Tomography ,Serotonin 5-HT2 Receptor Antagonists ,Radiopharmaceuticals ,Nuclear medicine ,business ,Biomedical engineering - Abstract
Several voids exist in reliable positron emission tomography (PET) radioligands for quantification of the serotonin (5HT) receptor system. Even in cases where 5HT radiotracers exist, challenges remain that have limited the utility of 5HT imaging in clinical research. Herein we address an unmet need in 5HT2a imaging using innovative chemistry. We report a scalable and robust synthesis of [(18)F]MDL100907, which was enabled by a Ni-mediated oxidative fluorination using [(18)F]fluoride. This first demonstration of a Ni-mediated fluorination used for PET imaging required development of a new reaction strategy that ultimately provided high specific activity [(18)F]MDL100907. Using the new synthetic strategy and optimized procedure, [(18)F]MDL100907 was evaluated against [(11)C]MDL100907 for reliability to quantify 5HT₂a in the nonhuman primate brain and was found to be superior based on a single scan analysis using the same nonhuman primate. The use of this new 5HT₂a radiotracer will afford clinical neuroscience research the ability to distinguish 5HT₂a receptor abnormalities binding between healthy subjects and patients even when group differences are small.
- Published
- 2014
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