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Morris ED, Emvalomenos GM, Hoye J, Meikle SR. Modeling PET Data Acquired During Nonsteady Conditions: What If Brain Conditions Change During the Scan? J Nucl Med 2024; 65:1824-1837. [PMID: 39448268 PMCID: PMC11619587 DOI: 10.2967/jnumed.124.267494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 09/11/2024] [Indexed: 10/26/2024] Open
Abstract
Researchers use dynamic PET imaging with target-selective tracer molecules to probe molecular processes. Kinetic models have been developed to describe these processes. The models are typically fitted to the measured PET data with the assumption that the brain is in a steady-state condition for the duration of the scan. The end results are quantitative parameters that characterize the molecular processes. The most common kinetic modeling endpoints are estimates of volume of distribution or the binding potential of a tracer. If the steady state is violated during the scanning period, the standard kinetic models may not apply. To address this issue, time-variant kinetic models have been developed for the characterization of dynamic PET data acquired while significant changes (e.g., short-lived neurotransmitter changes) are occurring in brain processes. These models are intended to extract a transient signal from data. This work in the PET field dates back at least to the 1990s. As interest has grown in imaging nonsteady events, development and refinement of time-variant models has accelerated. These new models, which we classify as belonging to the first, second, or third generation according to their innovation, have used the latest progress in mathematics, image processing, artificial intelligence, and statistics to improve the sensitivity and performance of the earliest practical time-variant models to detect and describe nonsteady phenomena. This review provides a detailed overview of the history of time-variant models in PET. It puts key advancements in the field into historical and scientific context. The sum total of the methods is an ongoing attempt to better understand the nature and implications of neurotransmitter fluctuations and other brief neurochemical phenomena.
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Affiliation(s)
- Evan D Morris
- Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut;
- Biomedical Engineering, Yale University, New Haven, Connecticut
- Psychiatry, Yale University, New Haven, Connecticut
| | | | - Jocelyn Hoye
- Psychiatry, Yale University, New Haven, Connecticut
| | - Steven R Meikle
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia; and
- Sydney Imaging Core Research Facility, University of Sydney, Sydney, Australia
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Stormezand GN, de Meyer E, Koopmans KP, Brouwers AH, Luurtsema G, Dierckx RAJO. Update on the Role of [ 18F]FDOPA PET/CT. Semin Nucl Med 2024; 54:845-855. [PMID: 39384519 DOI: 10.1053/j.semnuclmed.2024.09.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 09/19/2024] [Indexed: 10/11/2024]
Abstract
[18F]-dihydroxyphenylalanine ([18F]FDOPA) is a radiopharmaceutical used in a broad spectrum of diseases, including neuroendocrine tumors (NETs), congenital hyperinsulinism, parkinsonian syndromes and neuro-oncology. Genetic analysis and disease specific biomarkers may guide the optimum selection of patients that may benefit most from [18F]FDOPA PET in different stages of several neuroendocrine neoplasms and in congenital hyperinsulinism. For clinical routine in neuro-oncology, indications for [18F]FDOPA PET include tumor delineation and distinguishing between treatment related changes and recurrent disease. New developments as the advent of large axial field of view PET/CT or integrated PET/MRI systems may provide more unique opportunities, such as those related to detection of smaller lesions in primary staging of NETs, dose reduction in children with congenital hyperinsulinism, or possibilities to obtain more extensive noninvasive quantification of cerebral uptake by using image derived input functions. Although the widespread use of [18F]FDOPA has been hampered by complex synthesis methods and high production costs in the past, significant efforts have been undertaken to provide robust GMP compliant synthesis methods with high activity yield and molar activity.
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Affiliation(s)
- Gilles N Stormezand
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Eline de Meyer
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Klaas Pieter Koopmans
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Adrienne H Brouwers
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - G Luurtsema
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rudi A J O Dierckx
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Uenishi E, Seino Y, Nakashima A, Kato K, Kato M, Nagasaki H, Ishikawa K, Izumoto T, Yamamoto M, Takahashi Y, Sugimura Y, Oiso Y, Tsunekawa S. A novel mechanism of idiopathic orthostatic hypotension and hypocatecholaminemia due to autoimmunity against aromatic l-Amino acid decarboxylase. Biochem Biophys Res Commun 2024; 714:149940. [PMID: 38677008 DOI: 10.1016/j.bbrc.2024.149940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/09/2024] [Accepted: 04/12/2024] [Indexed: 04/29/2024]
Abstract
Orthostatic hypotension (OH) is a common condition. Many potential etiologies of OH have been identified, but in clinical practice the underlying cause of OH is often unknown. In the present study, we identified a novel and extraordinary etiology of OH. We describe a first case of acquired severe OH with syncope, and the female patient had extremely low levels of catecholamines and serotonin in plasma, urine and cerebrospinal fluid (CSF). Her clinical and biochemical evidence showed a deficiency of the enzyme aromatic l-amino acid decarboxylase (AADC), which converts l-DOPA to dopamine, and 5-hydroxytryptophan to serotonin, respectively. The consequence of pharmacologic stimulation of catecholaminergic nerves and radionuclide examination revealed her catecholaminergic nerves denervation. Moreover, we found that the patient's serum showed presence of autoantibodies against AADC, and that isolated peripheral blood mononuclear cells (PBMCs) from the patient showed cytokine-induced toxicity against AADC. These observations suggest that her autoimmunity against AADC is highly likely to cause toxicity to adrenal medulla and catecholaminergic nerves which contain AADC, resulting in hypocatecholaminemia and severe OH. Administration of vitamin B6, an essential cofactor of AADC, enhanced her residual AADC activity and drastically improved her symptoms. Our data thus provide a new insight into pathogenesis and pathophysiology of OH.
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Affiliation(s)
- Eita Uenishi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan; Uenishi Diabetes and Thyroid Clinic, Komaki, 485-0044, Japan
| | - Yusuke Seino
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan; Department of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan
| | - Akira Nakashima
- Department of Physiology I, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan
| | - Katsuhiko Kato
- Functional Medical Imaging, Biomedical Imaging Sciences, Division of Advanced Information Health Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, 461-8673, Japan
| | - Mitsuhiro Kato
- Department of Pediatrics, Showa University School of Medicine, Tokyo, 142-8555, Japan
| | - Hiroshi Nagasaki
- Department of Physiology I, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan
| | - Kota Ishikawa
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Takako Izumoto
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan; Department of Oral and Maxillofacial Surgery/ Protective Care for Masticatory Disorders, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Masaaki Yamamoto
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Yutaka Takahashi
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan; Department of Diabetes and Endocrinology, Nara Medical University, Nara, 634-8522, Japan
| | - Yoshihisa Sugimura
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan; Department of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan
| | - Yutaka Oiso
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Shin Tsunekawa
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan; Division of Diabetes, Department of Internal Medicine, Aichi Medical University, Nagakute, 480-1195, Japan.
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Zimmer L. Recent applications of positron emission tomographic (PET) imaging in psychiatric drug discovery. Expert Opin Drug Discov 2024; 19:161-172. [PMID: 37948046 DOI: 10.1080/17460441.2023.2278635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023]
Abstract
INTRODUCTION Psychiatry is one of the medical disciplines that suffers most from a lack of innovation in its therapeutic arsenal. Many failures in drug candidate trials can be explained by pharmacological properties that have been poorly assessed upstream, in terms of brain passage, brain target binding and clinical outcomes. Positron emission tomography can provide pharmacokinetic and pharmacodynamic data to help select candidate-molecules for further clinical trials. AREAS COVERED This review aims to explain and discuss the various methods using positron-emitting radiolabeled molecules to trace the cerebral distribution of the drug-candidate or indirectly measure binding to its therapeutic target. More than an exhaustive review of PET studies in psychopharmacology, this article highlights the contributions this technology can make in drug discovery applied to psychiatry. EXPERT OPINION PET neuroimaging is the only technological approach that can, in vivo in humans, measure cerebral delivery of a drug candidate, percentage and duration of target binding, and even the pharmacological effects. PET studies in a small number of subjects in the early stages of the development of a psychotropic drug can therefore provide the pharmacokinetic/pharmacodynamic data required for subsequent clinical evaluation. While PET technology is demanding in terms of radiochemical, radiopharmacological and nuclear medicine expertise, its integration into the development process of new drugs for psychiatry has great added value.
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Affiliation(s)
- Luc Zimmer
- Lyon Neuroscience Research Center, Université Claude Bernard, Lyon, France
- CERMEP, Hospices Civils de Lyon, Lyon, France
- Institut National des Sciences et Technologies Nucléaire, Saclay, France
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Ramesh S, Arachchige ASPM. Depletion of dopamine in Parkinson's disease and relevant therapeutic options: A review of the literature. AIMS Neurosci 2023; 10:200-231. [PMID: 37841347 PMCID: PMC10567584 DOI: 10.3934/neuroscience.2023017] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/27/2023] [Accepted: 08/02/2023] [Indexed: 10/17/2023] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects motor and cognition functions. The etiology of Parkinson's disease remains largely unknown, but genetic and environmental factors are believed to play a role. The neurotransmitter dopamine is implicated in regulating movement, motivation, memory, and other physiological processes. In individuals with Parkinson's disease, the loss of dopaminergic neurons leads to a reduction in dopamine levels, which causes motor impairment and may also contribute to the cognitive deficits observed in some patients. Therefore, it is important to understand the pathophysiology that leads to the loss of dopaminergic neurons, along with reliable biomarkers that may help distinguish PD from other conditions, monitor its progression, or indicate a positive response to a therapeutic intervention. Important advances in the treatment, etiology, and pathogenesis of Parkinson's disease have been made in the past 50 years. Therefore, this review tries to explain the different possible mechanisms behind the depletion of dopamine in PD patients such as alpha-synuclein abnormalities, mitochondrial dysfunction, and 3,4-dihydroxyphenylacetaldehyde (DOPAL) toxicity, along with the current therapies we have and the ones that are in development. The clinical aspect of Parkinson's disease such as the manifestation of both motor and non-motor symptoms, and the differential diagnosis with similar neurodegenerative disease are also discussed.
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Nordio G, Easmin R, Giacomel A, Dipasquale O, Martins D, Williams S, Turkheimer F, Howes O, Veronese M, and the FDOPA PET imaging working group:, Jauhar S, Rogdaki M, McCutcheon R, Kaar S, Vano L, Rutigliano G, Angelescu I, Borgan F, D’Ambrosio E, Dahoun T, Kim E, Kim S, Bloomfield M, Egerton A, Demjaha A, Bonoldi I, Nosarti C, Maccabe J, McGuire P, Matthews J, Talbot PS. An automatic analysis framework for FDOPA PET neuroimaging. J Cereb Blood Flow Metab 2023; 43:1285-1300. [PMID: 37026455 PMCID: PMC10369152 DOI: 10.1177/0271678x231168687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/23/2023] [Accepted: 02/05/2023] [Indexed: 04/08/2023]
Abstract
In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Kicer: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size.
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Affiliation(s)
- Giovanna Nordio
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Rubaida Easmin
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Alessio Giacomel
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Ottavia Dipasquale
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Daniel Martins
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Steven Williams
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Federico Turkheimer
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Oliver Howes
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- MRC London Institute of Medical Sciences, Hammersmith Hospital, London, UK
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, UK
| | - Mattia Veronese
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- Department of Information Engineering (DEI), University of Padua, Padua, Italy
| | - and the FDOPA PET imaging working group:
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- MRC London Institute of Medical Sciences, Hammersmith Hospital, London, UK
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, UK
- Department of Information Engineering (DEI), University of Padua, Padua, Italy
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College, Imperial College London, London, UK
- South London and Maudsley NHS Foundation Trust, London, UK
- COMPASS Pathways plc, London, UK
- Psychiatric Neuroscience Group, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, Italy
- Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK
- Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
- Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea
- Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
- Division of Psychiatry, Faculty of Brain Sciences, University College of London, London, UK
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neurosicences, King’s College London, London, UK
- Centre for the Developing Brain, Division of Imaging Sciences & Biomedical Engineering, King's College London, London, UK
- Early Intervention Psychosis Clinical Academic Group, South London & Maudsley NHS Trust, London, UK
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Sameer Jauhar
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College, Imperial College London, London, UK
| | - Maria Rogdaki
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Robert McCutcheon
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College, Imperial College London, London, UK
- South London and Maudsley NHS Foundation Trust, London, UK
| | - Stephen Kaar
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, UK
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK
- South London and Maudsley NHS Foundation Trust, London, UK
| | - Luke Vano
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK
| | - Grazia Rutigliano
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK
| | - Ilinca Angelescu
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Faith Borgan
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- COMPASS Pathways plc, London, UK
| | - Enrico D’Ambrosio
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- Psychiatric Neuroscience Group, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, Italy
| | - Tarik Dahoun
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College, Imperial College London, London, UK
- Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK
| | - Euitae Kim
- Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
- Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea
- Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
| | - Seoyoung Kim
- Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Micheal Bloomfield
- Division of Psychiatry, Faculty of Brain Sciences, University College of London, London, UK
| | - Alice Egerton
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Arsime Demjaha
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Ilaria Bonoldi
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Chiara Nosarti
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neurosicences, King’s College London, London, UK
- Centre for the Developing Brain, Division of Imaging Sciences & Biomedical Engineering, King's College London, London, UK
| | - James Maccabe
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Philip McGuire
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- Early Intervention Psychosis Clinical Academic Group, South London & Maudsley NHS Trust, London, UK
| | - Julian Matthews
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Peter S Talbot
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Pakula RJ, Scott PJH. Applications of radiolabeled antibodies in neuroscience and neuro-oncology. J Labelled Comp Radiopharm 2023; 66:269-285. [PMID: 37322805 DOI: 10.1002/jlcr.4049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 06/17/2023]
Abstract
Positron emission tomography (PET) is a powerful tool in medicine and drug development, allowing for non-invasive imaging and quantitation of biological processes in live organisms. Targets are often probed with small molecules, but antibody-based PET is expanding because of many benefits, including ease of design of new antibodies toward targets, as well as the very strong affinities that can be expected. Application of antibodies to PET imaging of targets in the central nervous system (CNS) is a particularly nascent field, but one with tremendous potential. In this review, we discuss the growth of PET in imaging of CNS targets, present the promises and progress in antibody-based CNS PET, explore challenges faced by the field, and discuss questions that this promising approach will need to answer moving forward for imaging and perhaps even radiotherapy.
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Affiliation(s)
- Ryan J Pakula
- Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Peter J H Scott
- Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA
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Cogswell PM, Fan AP. Multimodal comparisons of QSM and PET in neurodegeneration and aging. Neuroimage 2023; 273:120068. [PMID: 37003447 PMCID: PMC10947478 DOI: 10.1016/j.neuroimage.2023.120068] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/17/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Quantitative susceptibility mapping (QSM) has been used to study susceptibility changes that may occur based on tissue composition and mineral deposition. Iron is a primary contributor to changes in magnetic susceptibility and of particular interest in applications of QSM to neurodegeneration and aging. Iron can contribute to neurodegeneration through inflammatory processes and via interaction with aggregation of disease-related proteins. To better understand the local susceptibility changes observed on QSM, its signal has been studied in association with other imaging metrics such as positron emission tomography (PET). The associations of QSM and PET may provide insight into the pathophysiology of disease processes, such as the role of iron in aging and neurodegeneration, and help to determine the diagnostic utility of QSM as an indirect indicator of disease processes typically evaluated with PET. In this review we discuss the proposed mechanisms and summarize prior studies of the associations of QSM and amyloid PET, tau PET, TSPO PET, FDG-PET, 15O-PET, and F-DOPA PET in evaluation of neurologic diseases with a focus on aging and neurodegeneration.
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Affiliation(s)
- Petrice M Cogswell
- Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
| | - Audrey P Fan
- Department of Biomedical Engineering and Department of Neurology, University of California, Davis, 1590 Drew Avenue, Davis, CA 95618, USA
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9
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Morley V, Dolt KS, Alcaide-Corral CJ, Walton T, Lucatelli C, Mashimo T, Tavares AAS, Kunath T. In vivo18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation. Front Neurosci 2023; 17:1095761. [PMID: 37292159 PMCID: PMC10244711 DOI: 10.3389/fnins.2023.1095761] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 05/03/2023] [Indexed: 06/10/2023] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative condition with several major hallmarks, including loss of substantia nigra neurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations in SNCA, encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous rat SNCA gene. SNCAG51D/+ and SNCAG51D/G51D rats were born in Mendelian ratios and did not exhibit any severe behavourial defects. L-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT), SNCAG51D/+ and SNCAG51D/G51D rats were characterized over the course of ageing (5, 11, and 16 months old) using 18F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (Ki) and effective distribution volume ratio (EDVR) of 18F-DOPA in the striatum relative to the cerebellum in WT, SNCAG51D/+ and SNCAG51D/G51D rats. A significant reduction in EDVR was observed in SNCAG51D/G51D rats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in EDVR between the left and right striatum in aged SNCAG51D/G51D rats. The increased and asymmetric dopamine turnover observed in the striatum of aged SNCAG51D/G51D rats reflects one aspect of prodromal PD, and suggests the presence of compensatory mechanisms. SNCAG51D rats represent a novel genetic model of PD, and kinetic modelling of 18F-DOPA PET data has identified a highly relevant early disease phenotype.
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Affiliation(s)
- Victoria Morley
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom
| | - Karamjit Singh Dolt
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom
| | - Carlos J. Alcaide-Corral
- University/BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Tashfeen Walton
- University/BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Christophe Lucatelli
- University/BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Tomoji Mashimo
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Adriana A. S. Tavares
- University/BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Tilo Kunath
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom
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10
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Orlovskaya VV, Fedorova OS, Viktorov NB, Vaulina DD, Krasikova RN. One-Pot Radiosynthesis of [18F]Anle138b—5-(3-Bromophenyl)-3-(6-[18F]fluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazole—A Potential PET Radiotracer Targeting α-Synuclein Aggregates. Molecules 2023; 28:molecules28062732. [PMID: 36985703 PMCID: PMC10052605 DOI: 10.3390/molecules28062732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/12/2023] [Accepted: 03/13/2023] [Indexed: 03/22/2023] Open
Abstract
Availability of PET imaging radiotracers targeting α-synuclein aggregates is important for early diagnosis of Parkinson’s disease and related α-synucleinopathies, as well as for the development of new therapeutics. Derived from a pyrazole backbone, 11C-labelled derivatives of anle138b (3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole)—an inhibitor of α-synuclein and prion protein oligomerization—are currently in active development as the candidates for PET imaging α-syn aggregates. This work outlines the synthesis of a radiotracer based on the original structure of anle138b, labelled with fluorine-18 isotope, eminently suitable for PET imaging due to half-life and decay energy characteristics (97% β+ decay, 109.7 min half-life, and 635 keV positron energy). A three-step radiosynthesis was developed starting from 6-[18F]fluoropiperonal (6-[18F]FP) that was prepared using (piperonyl)(phenyl)iodonium bromide as a labelling precursor. The obtained 6-[18F]FP was used directly in the condensation reaction with tosylhydrazide followed by 1,3-cycloaddition of the intermediate with 3′-bromophenylacetylene eliminating any midway without any intermediate purifications. This one-pot approach allowed the complete synthesis of [18F]anle138b within 105 min with RCY of 15 ± 3% (n = 3) and Am in the range of 32–78 GBq/µmol. The [18F]fluoride processing and synthesis were performed in a custom-built semi-automated module, but the method can be implemented in all the modern automated platforms. While there is definitely space for further optimization, the procedure developed is well suited for preclinical studies of this novel radiotracer in animal models and/or cell cultures.
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Affiliation(s)
- Viktoriya V. Orlovskaya
- N.P. Bechtereva Institute of the Human Brain, Russian Academy of Science, 197376 St. Petersburg, Russia
| | - Olga S. Fedorova
- N.P. Bechtereva Institute of the Human Brain, Russian Academy of Science, 197376 St. Petersburg, Russia
| | - Nikolai B. Viktorov
- St. Petersburg State Technological Institute, Technical University, 190013 St. Petersburg, Russia
| | - Daria D. Vaulina
- N.P. Bechtereva Institute of the Human Brain, Russian Academy of Science, 197376 St. Petersburg, Russia
| | - Raisa N. Krasikova
- N.P. Bechtereva Institute of the Human Brain, Russian Academy of Science, 197376 St. Petersburg, Russia
- Correspondence:
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Hazut Krauthammer S, Cohen D, Even-Sapir E, Lerman H. Beyond Visual Assessment of Basal Ganglia Uptake: Can Automated Method and Pineal Body Uptake Assessment Improve Identification of Nigrostriatal Dysfunction on 18F-DOPA PET/CT? Int J Mol Sci 2023; 24:ijms24065683. [PMID: 36982756 PMCID: PMC10056028 DOI: 10.3390/ijms24065683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/13/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
The interpretation of 18F-DOPA PET/CT performed for assessing nigrostriatal dysfunction (NSD) is usually based on visual assessment of the uptake in the basal ganglia (VA-BG). In the present study, we evaluate the diagnostic performance of an automated method that assesses BG uptake (AM-BG) and of methods that assess pineal body uptake, and examine whether these methods can enhance the diagnostic performance of VA-BG alone. We retrospectively included 112 scans performed in patients with clinically suspected NSD who also had a subsequent final clinical diagnosis provided by a movement disorder specialist (69 NSD and 43 non-NSD patients). All scans were categorized as positive or negative based on (1) VA-BG, (2) AM-BG, and (3) qualitative and semiquantitative assessment of pineal body uptake. VA-BG, AM-BG, assessment of pineal body 18F-DOPA uptake by VA (uptake > background), by SUVmax (≥0.72), and by pineal to occipital ratio (POR ≥ 1.57) could all significantly differentiate NSD from non-NSD patients (Pv < 0.01 for all five methods). Of these methods, VA-BG provided the highest sensitivity (88.4%) and accuracy (90.2%). Combining VA-BG with AM-BG did not improve diagnostic accuracy. An interpretation algorithm that combines VA-BG with pineal body uptake assessment by POR calculation increased sensitivity to 98.5%, at the expense of decreased specificity. In conclusion, an automated method that assesses 18F-DOPA uptake in the BG and assessment of pineal body 18F-DOPA uptake can significantly separate NSD from non-NSD patients, with apparent inferior diagnostic performance when applied alone compared with VA-BG. When VA-BG categorizes a scan as negative or equivocal, assessment of the 18F-DOPA uptake in the pineal body has the potential to minimize the rate of false negative reports. Further research is essential to validate this approach and to study the pathophysiologic relationship between 18F-DOPA uptake in the pineal body and nigrostriatal dysfunction.
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Affiliation(s)
- Shir Hazut Krauthammer
- Department of Nuclear Medicine, Tel-Aviv Sourasky Medical Center, 6 Weizmann St., Tel Aviv 6423906, Israel
- Correspondence:
| | - Dan Cohen
- Department of Nuclear Medicine, Tel-Aviv Sourasky Medical Center, 6 Weizmann St., Tel Aviv 6423906, Israel
| | - Einat Even-Sapir
- Department of Nuclear Medicine, Tel-Aviv Sourasky Medical Center, 6 Weizmann St., Tel Aviv 6423906, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Hedva Lerman
- Department of Nuclear Medicine, Tel-Aviv Sourasky Medical Center, 6 Weizmann St., Tel Aviv 6423906, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
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12
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Haider A, Elghazawy NH, Dawoud A, Gebhard C, Wichmann T, Sippl W, Hoener M, Arenas E, Liang SH. Translational molecular imaging and drug development in Parkinson's disease. Mol Neurodegener 2023; 18:11. [PMID: 36759912 PMCID: PMC9912681 DOI: 10.1186/s13024-023-00600-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/23/2023] [Indexed: 02/11/2023] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects elderly people and constitutes a major source of disability worldwide. Notably, the neuropathological hallmarks of PD include nigrostriatal loss and the formation of intracellular inclusion bodies containing misfolded α-synuclein protein aggregates. Cardinal motor symptoms, which include tremor, rigidity and bradykinesia, can effectively be managed with dopaminergic therapy for years following symptom onset. Nonetheless, patients ultimately develop symptoms that no longer fully respond to dopaminergic treatment. Attempts to discover disease-modifying agents have increasingly been supported by translational molecular imaging concepts, targeting the most prominent pathological hallmark of PD, α-synuclein accumulation, as well as other molecular pathways that contribute to the pathophysiology of PD. Indeed, molecular imaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can be leveraged to study parkinsonism not only in animal models but also in living patients. For instance, mitochondrial dysfunction can be assessed with probes that target the mitochondrial complex I (MC-I), while nigrostriatal degeneration is typically evaluated with probes designed to non-invasively quantify dopaminergic nerve loss. In addition to dopaminergic imaging, serotonin transporter and N-methyl-D-aspartate (NMDA) receptor probes are increasingly used as research tools to better understand the complexity of neurotransmitter dysregulation in PD. Non-invasive quantification of neuroinflammatory processes is mainly conducted by targeting the translocator protein 18 kDa (TSPO) on activated microglia using established imaging agents. Despite the overwhelming involvement of the brain and brainstem, the pathophysiology of PD is not restricted to the central nervous system (CNS). In fact, PD also affects various peripheral organs such as the heart and gastrointestinal tract - primarily via autonomic dysfunction. As such, research into peripheral biomarkers has taken advantage of cardiac autonomic denervation in PD, allowing the differential diagnosis between PD and multiple system atrophy with probes that visualize sympathetic nerve terminals in the myocardium. Further, α-synuclein has recently gained attention as a potential peripheral biomarker in PD. This review discusses breakthrough discoveries that have led to the contemporary molecular concepts of PD pathophysiology and how they can be harnessed to develop effective imaging probes and therapeutic agents. Further, we will shed light on potential future trends, thereby focusing on potential novel diagnostic tracers and disease-modifying therapeutic interventions.
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Affiliation(s)
- Achi Haider
- Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
- Department of Radiology and Imaging Sciences, Emory University, 101 Woodruff Circle, Atlanta, GA, 30322, USA.
| | - Nehal H Elghazawy
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Main Entrance of Al-Tagamoa Al-Khames, Cairo, 11835, Egypt
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Main Entrance of Al-Tagamoa Al-Khames, Cairo, 11835, Egypt
| | - Alyaa Dawoud
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Main Entrance of Al-Tagamoa Al-Khames, Cairo, 11835, Egypt
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Main Entrance of Al-Tagamoa Al-Khames, Cairo, 11835, Egypt
| | - Catherine Gebhard
- Department of Nuclear Medicine, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Thomas Wichmann
- Department of Neurology/School of Medicine, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA
| | - Wolfgang Sippl
- Institute of Pharmacy, Department of Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, W.-Langenbeck-Str. 4, 06120, Halle, Germany
| | - Marius Hoener
- Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Ernest Arenas
- Karolinska Institutet, MBB, Molecular Neurobiology, Stockholm, Sweden
| | - Steven H Liang
- Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
- Department of Radiology and Imaging Sciences, Emory University, 101 Woodruff Circle, Atlanta, GA, 30322, USA.
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Li M, An H, Wang W, Wei D. Biomolecular Markers of Brain Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1419:111-126. [PMID: 37418210 DOI: 10.1007/978-981-99-1627-6_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 07/08/2023]
Abstract
Characterized by the gradual loss of physiological integrity, impaired function, and increased susceptibility to death, aging is considered the primary risk factor for major human diseases, such as cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. The time-dependent accumulation of cellular damage is widely considered the general cause of aging. While the mechanism of normal aging is still unresolved, researchers have identified different markers of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Theories of aging can be divided into two categories: (1) aging is a genetically programmed process, and (2) aging is a random process caused by gradual damage to the organism over time as a result of its vital activities. Aging affects the entire human body, and aging of the brain is undoubtedly different from all other organs, as neurons are highly differentiated postmitotic cells, and the lifespan of most neurons in the postnatal period is equal to the lifespan of the brain. In this chapter, we discuss the conserved mechanisms of aging that may underlie the changes observed in the aging brain, with a focus on mitochondrial function and oxidative stress, autophagy and protein turnover, insulin/IGF signaling, target of rapamycin (TOR) signaling, and sirtuin function.
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Affiliation(s)
- Min Li
- State Key Laboratory of Cognitive Neuroscience and Learning, Faculty of Psychology, Beijing Normal University, Beijing, China
- Beijing Aging Brain Rejuvenation Initiative (BABRI) Centre, Beijing Normal University, Beijing, China
| | - Haiting An
- Beijing Aging Brain Rejuvenation Initiative (BABRI) Centre, Beijing Normal University, Beijing, China
- Beijing Neurosurgical Institute, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China
| | - Wenxiao Wang
- Beijing Aging Brain Rejuvenation Initiative (BABRI) Centre, Beijing Normal University, Beijing, China
- School of Systems Science, Beijing Normal University, Beijing, China
| | - Dongfeng Wei
- Beijing Aging Brain Rejuvenation Initiative (BABRI) Centre, Beijing Normal University, Beijing, China
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
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14
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Waśniowski P, Czuczejko J, Chuchra M, Wędrowski M, Marciniak D, Sobiak S, Małkowski B. Automatic Production of [ 18F]F-DOPA Using the Raytest SynChrom R&D Module. Pharmaceuticals (Basel) 2022; 16:ph16010010. [PMID: 36678506 PMCID: PMC9865388 DOI: 10.3390/ph16010010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
[18F]F-DOPA is widely used in PET diagnostics. Diseases diagnosed with this tracer are schizophrenia, Parkinson's disease, gliomas, neuroendocrine tumors, pheochromocytomas, and pancreatic adenocarcinoma. It should be noted that the [18F]F-DOPA tracer has been known for over 30 years. However, the methods of radiosynthesis applied in the past did not allow its clinical use due to low efficiency and purity. Currently, in the market, one encounters different types of radiosynthesis using the fluorine 18F isotope and variants of the same method. The synthesis and its modifications were carried out using a Raytest Synchrom R&D module. The synthesis consists of the following steps: (a) binding of the fluoride anion 18F- on an anion exchange column; (b) elution with TBAHCO3-; (c) nucleophilic fluorination to the ABX 1336 precursor; (d) purification of the intermediate product on the C18ec column; (e) Baeyer-Villiger oxidation; (f) hydrolysis; and (gfinal purification of the crude product on a semipreparative column. The nucleophilic synthesis of [18F]F-DOPA was successfully performed in 120 min, using the ABX 1336 precursor on the Raytest SynChrom R&D module, with a radiochemical yield (RCY) of 15%, radiochemical purity (RCP) ≥ 97%, and enantiomeric purity (ee) ≥ 96%.
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Affiliation(s)
- Paweł Waśniowski
- Department of Inorganic and Analytical Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, ul. Jagiellonska 13-15, 85-067 Bydgoszcz, Poland
- Nuclear Medicine Department, Oncology Centre Professor Franciszek Łukaszczyk Memorial, dr I. Romanowskiej 2 Street, 85-796 Bydgoszcz, Poland
- Correspondence: ; Tel.: +48-52-374-3781
| | - Jolanta Czuczejko
- Nuclear Medicine Department, Oncology Centre Professor Franciszek Łukaszczyk Memorial, dr I. Romanowskiej 2 Street, 85-796 Bydgoszcz, Poland
- Department of Psychiatry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, ul. Jagiellonska 13-15, 85-067 Bydgoszcz, Poland
| | - Michał Chuchra
- Nuclear Medicine Department, Oncology Centre Professor Franciszek Łukaszczyk Memorial, dr I. Romanowskiej 2 Street, 85-796 Bydgoszcz, Poland
| | - Mateusz Wędrowski
- Nuclear Medicine Department, Oncology Centre Professor Franciszek Łukaszczyk Memorial, dr I. Romanowskiej 2 Street, 85-796 Bydgoszcz, Poland
- Department of Diagnostic Imaging, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, ul. Jagiellonska 13-15, 85-067 Bydgoszcz, Poland
| | - Dawid Marciniak
- Department of Manufacturing Techniques, Bydgoszcz University of Science and Technology, ul. Kaliskiego 7, 85-796 Bydgoszcz, Poland
| | - Stanisław Sobiak
- Department of Inorganic and Analytical Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, ul. Jagiellonska 13-15, 85-067 Bydgoszcz, Poland
| | - Bogdan Małkowski
- Nuclear Medicine Department, Oncology Centre Professor Franciszek Łukaszczyk Memorial, dr I. Romanowskiej 2 Street, 85-796 Bydgoszcz, Poland
- Department of Diagnostic Imaging, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, ul. Jagiellonska 13-15, 85-067 Bydgoszcz, Poland
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15
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Halff EF, Natesan S, Bonsall DR, Veronese M, Garcia-Hidalgo A, Kokkinou M, Tang SP, Riggall LJ, Gunn RN, Irvine EE, Withers DJ, Wells LA, Howes OD. Evaluation of Intraperitoneal [ 18F]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity. Mol Imaging 2022; 2022:4419221. [PMID: 36721730 PMCID: PMC9881672 DOI: 10.1155/2022/4419221] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/08/2022] [Indexed: 02/05/2023] Open
Abstract
Positron emission tomography (PET) using the radiotracer [18F]-FDOPA provides a tool for studying brain dopamine synthesis capacity in animals and humans. We have previously standardised a micro-PET methodology in mice by intravenously administering [18F]-FDOPA via jugular vein cannulation and assessment of striatal dopamine synthesis capacity, indexed as the influx rate constant K i Mod of [18F]-FDOPA, using an extended graphical Patlak analysis with the cerebellum as a reference region. This enables a direct comparison between preclinical and clinical output values. However, chronic intravenous catheters are technically difficult to maintain for longitudinal studies. Hence, in this study, intraperitoneal administration of [18F]-FDOPA was evaluated as a less-invasive alternative that facilitates longitudinal imaging. Our experiments comprised the following assessments: (i) comparison of [18F]-FDOPA uptake between intravenous and intraperitoneal radiotracer administration and optimisation of the time window used for extended Patlak analysis, (ii) comparison of Ki Mod in a within-subject design of both administration routes, (iii) test-retest evaluation of Ki Mod in a within-subject design of intraperitoneal radiotracer administration, and (iv) validation of Ki Mod estimates by comparing the two administration routes in a mouse model of hyperdopaminergia induced by subchronic ketamine. Our results demonstrate that intraperitoneal [18F]-FDOPA administration resulted in good brain uptake, with no significant effect of administration route on Ki Mod estimates (intraperitoneal: 0.024 ± 0.0047 min-1, intravenous: 0.022 ± 0.0041 min-1, p = 0.42) and similar coefficient of variation (intraperitoneal: 19.6%; intravenous: 18.4%). The technique had a moderate test-retest validity (intraclass correlation coefficient (ICC) = 0.52, N = 6) and thus supports longitudinal studies. Following subchronic ketamine administration, elevated K i Mod as compared to control condition was measured with a large effect size for both methods (intraperitoneal: Cohen's d = 1.3; intravenous: Cohen's d = 0.9), providing further evidence that ketamine has lasting effects on the dopamine system, which could contribute to its therapeutic actions and/or abuse liability.
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Affiliation(s)
- Els F. Halff
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, London, UK
| | - Sridhar Natesan
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, London, UK
| | - David R. Bonsall
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, London, UK
- Invicro, Burlington Danes, Hammersmith Hospital, London, UK
| | - Mattia Veronese
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Department of Information Engineering, University of Padua, Italy
| | - Anna Garcia-Hidalgo
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Michelle Kokkinou
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Sac-Pham Tang
- Invicro, Burlington Danes, Hammersmith Hospital, London, UK
| | - Laura J. Riggall
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Roger N. Gunn
- Invicro, Burlington Danes, Hammersmith Hospital, London, UK
| | - Elaine E. Irvine
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
- Metabolic Signalling Group, MRC London Institute of Medical Sciences, London, UK
| | - Dominic J. Withers
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
- Metabolic Signalling Group, MRC London Institute of Medical Sciences, London, UK
| | - Lisa A. Wells
- Invicro, Burlington Danes, Hammersmith Hospital, London, UK
| | - Oliver D. Howes
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
- South London and Maudsley NHS Foundation Trust, Camberwell, London, UK
- H. Lundbeck A/S, St Albans AL1 2PS, UK
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Zhu J, Pan F, Cai H, Pan L, Li Y, Li L, Li Y, Wu X, Fan H. Positron emission tomography imaging of lung cancer: An overview of alternative positron emission tomography tracers beyond F18 fluorodeoxyglucose. Front Med (Lausanne) 2022; 9:945602. [PMID: 36275809 PMCID: PMC9581209 DOI: 10.3389/fmed.2022.945602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
Lung cancer has been the leading cause of cancer-related mortality in China in recent decades. Positron emission tomography-computer tomography (PET/CT) has been established in the diagnosis of lung cancer. 18F-FDG is the most widely used PET tracer in foci diagnosis, tumor staging, treatment planning, and prognosis assessment by monitoring abnormally exuberant glucose metabolism in tumors. However, with the increasing knowledge on tumor heterogeneity and biological characteristics in lung cancer, a variety of novel radiotracers beyond 18F-FDG for PET imaging have been developed. For example, PET tracers that target cellular proliferation, amino acid metabolism and transportation, tumor hypoxia, angiogenesis, pulmonary NETs and other targets, such as tyrosine kinases and cancer-associated fibroblasts, have been reported, evaluated in animal models or under clinical investigations in recent years and play increasing roles in lung cancer diagnosis. Thus, we perform a comprehensive literature review of the radiopharmaceuticals and recent progress in PET tracers for the study of lung cancer biological characteristics beyond glucose metabolism.
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Affiliation(s)
- Jing Zhu
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China,Respiratory and Critical Care Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China,NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Fei Pan
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Huawei Cai
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lili Pan
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yalun Li
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Li
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - YunChun Li
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China,Department of Nuclear Medicine, The Second People’s Hospital of Yibin, Yibin, China
| | - Xiaoai Wu
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China,Xiaoai Wu,
| | - Hong Fan
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Hong Fan,
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Gjedde A, Wong DF. Four decades of mapping and quantifying neuroreceptors at work in vivo by positron emission tomography. Front Neurosci 2022; 16:943512. [PMID: 36161158 PMCID: PMC9493011 DOI: 10.3389/fnins.2022.943512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/18/2022] [Indexed: 11/16/2022] Open
Abstract
Decryption of brain images is the basis for the necessary translation of the findings from imaging to information required to meet the demands of clinical intervention. Tools of brain imaging, therefore, must satisfy the conditions dictated by the needs for interpretation in terms of diagnosis and prognosis. In addition, the applications must serve as fundamental research tools that enable the understanding of new therapeutic drugs, including compounds as diverse as antipsychotics, antidepressants, anxiolytics, and drugs serving the relief of symptoms from neurochemical disorders as unrelated as multiple sclerosis, stroke, and dementia. Here we review and explain the kinetics of methods that enable researchers to describe the brain’s work and functions. We focus on methods invented by neurokineticists and expanded upon by practitioners during decades of experimental work and on the methods that are particularly useful to predict possible future approaches to the treatment of neurochemical disorders. We provide an overall description of the basic elements of kinetics and the underlying quantification methods, as well as the mathematics of modeling the recorded brain dynamics embedded in the images we obtain in vivo. The complex presentation to follow is necessary to justify the contribution of modeling to the development of methods and to support the specifications dictated by the proposed use in clinical settings. The quantification and kinetic modeling processes are equally essential to image reconstruction and labeling of brain regions of structural or functional interest. The procedures presented here are essential tools of scientific approaches to all conventional and novel forms of brain imaging. The foundations of the kinetic and quantitative methods are keys to the satisfaction of clinicians that actively engage in treating the neurochemical disorders of mammalian brains in the fields of neurology, neurosurgery, and neuropsychiatry.
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Affiliation(s)
- Albert Gjedde
- Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- *Correspondence: Albert Gjedde,
| | - Dean F. Wong
- Department of Radiology, Psychiatry, Neurology, and Neuroscience, Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, United States
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18
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Nanabala R, Pillai MRA, Gopal B. Experience of 6-l-[18F]FDOPA Production Using Commercial Disposable Cassettes and an Automated Module. Nucl Med Mol Imaging 2022; 56:127-136. [DOI: 10.1007/s13139-022-00742-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/27/2022] [Accepted: 02/08/2022] [Indexed: 11/29/2022] Open
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Golan H, Volkov O, Shalom E. Nuclear imaging in Parkinson's disease: The past, the present, and the future. J Neurol Sci 2022; 436:120220. [DOI: 10.1016/j.jns.2022.120220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 02/15/2022] [Accepted: 03/02/2022] [Indexed: 01/15/2023]
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20
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Karaboğa MNS, Sezgintürk MK. Biosensor approaches on the diagnosis of neurodegenerative diseases: Sensing the past to the future. J Pharm Biomed Anal 2022; 209:114479. [PMID: 34861607 DOI: 10.1016/j.jpba.2021.114479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/05/2021] [Accepted: 11/14/2021] [Indexed: 12/12/2022]
Abstract
Early diagnosis of neurodegeneration-oriented diseases that develop with the aging world is essential for improving the patient's living conditions as well as the treatment of the disease. Alzheimer's and Parkinson's diseases are prominent examples of neurodegeneration characterized by dementia leading to the death of nerve cells. The clinical diagnosis of these diseases only after the symptoms appear, delays the treatment process. Detection of biomarkers, which are distinctive molecules in biological fluids, involved in neurodegeneration processes, has the potential to allow early diagnosis of neurodegenerative diseases. Studies on biosensors, whose main responsibility is to detect the target analyte with high specificity, has gained momentum in recent years with the aim of high detection of potential biomarkers of neurodegeneration process. This study aims to provide an overview of neuro-biosensors developed on the basis of biomarkers identified in biological fluids for the diagnosis of neurodegenerative diseases such as Alzheimer's disease (AD), and Parkinson's disease (PD), and to provide an overview of the urgent needs in this field, emphasizing the importance of early diagnosis in the general lines of the neurodegeneration pathway. In this review, biosensor systems developed for the detection of biomarkers of neurodegenerative diseases, especially in the last 5 years, are discussed.
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21
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A reliable and automated synthesis of 6-[18F]fluoro-L-DOPA and the clinical application on the imaging of congenital hyperinsulinism of infants. Med Chem Res 2022. [DOI: 10.1007/s00044-022-02850-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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22
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Chen W, Wang H, Tay NES, Pistritto VA, Li KP, Zhang T, Wu Z, Nicewicz DA, Li Z. Arene radiofluorination enabled by photoredox-mediated halide interconversion. Nat Chem 2022; 14:216-223. [PMID: 34903859 PMCID: PMC9617144 DOI: 10.1038/s41557-021-00835-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 10/08/2021] [Indexed: 02/03/2023]
Abstract
Positron emission tomography (PET) is a powerful imaging technology that can visualize and measure metabolic processes in vivo and/or obtain unique information about drug candidates. The identification of new and improved molecular probes plays a critical role in PET, but its progress is somewhat limited due to the lack of efficient and simple labelling methods to modify biologically active small molecules and/or drugs. Current methods to radiofluorinate unactivated arenes are still relatively limited, especially in a simple and site-selective way. Here we disclose a method for constructing C-18F bonds through direct halide/18F conversion in electron-rich halo(hetero)arenes. [18F]F- is introduced into a broad spectrum of readily available aryl halide precursors in a site-selective manner under mild photoredox conditions. Notably, our direct 19F/18F exchange method enables rapid PET probe diversification through the preparation and evaluation of an [18F]-labelled O-methyl tyrosine library. This strategy also results in the high-yielding synthesis of the widely used PET agent L-[18F]FDOPA from a readily available L-FDOPA analogue.
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Affiliation(s)
- Wei Chen
- Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Hui Wang
- Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nicholas E S Tay
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Vincent A Pistritto
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kang-Po Li
- Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Tao Zhang
- Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Zhanhong Wu
- Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - David A Nicewicz
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Zibo Li
- Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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23
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PET imaging in dementia. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00089-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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24
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Brücke T, Brücke C. Dopamine transporter (DAT) imaging in Parkinson's disease and related disorders. J Neural Transm (Vienna) 2021; 129:581-594. [PMID: 34910248 DOI: 10.1007/s00702-021-02452-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 11/30/2021] [Indexed: 11/27/2022]
Abstract
This review gives an insight into the beginnings of dopamine transporter (DAT) imaging in the early 1990s, focussing on single photon emission tomography (SPECT). The development of the method and its consolidation as a now widely used clinical tool is described. The role of DAT-SPECT in the diagnosis and differential diagnosis of PD, atypical parkinsonian syndromes and several other different neurological disorders is reviewed. Finally the clinical research using DAT-SPECT as a biomarker for the progression of PD, for the detection of a preclinical dopaminergic lesion and its correlation with neuropathological findings is outlined.
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Affiliation(s)
- Thomas Brücke
- Ottakring Clinic, Neurological Department, Verein zur Förderung der Wissenschaftlichen Forschung am Wilhelminenspital (FWFW), Montleartstrasse 37, 1160, Vienna, Austria.
- , Linke Wienzeile 12, 1060, Vienna, Austria.
| | - Christof Brücke
- Department for Neurology, Medical University Vienna, Währingergürtel 18-20, 1090, Vienna, Austria
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25
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The effect and safety of levodopa alone versus levodopa sparing therapy for early Parkinson's disease: a systematic review and meta-analysis. J Neurol 2021; 269:1834-1850. [PMID: 34652505 DOI: 10.1007/s00415-021-10830-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/27/2021] [Accepted: 09/28/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND The best choice between levodopa alone and levodopa sparing medications for early Parkinson's disease (PD) remains controversial. We aimed to evaluate the effect and safety of levodopa alone and levodopa sparing therapy in symptom relief, neuroimage results and complications. METHODS A systematic search was performed in PubMed, The Cochrane Library, EMBASE, and Web of Science for randomized controlled trials of early PD patients comparing levodopa-alone with levodopa-sparing therapy. The mean difference (MD) and the risk ratio (RR) were meta-analyzed. RESULTS Twenty-three articles with 4913 patients were included. Significantly greater benefit was detected for the levodopa group in the changes of Unified Parkinson's Disease Rating Scale part II (p < 0.00001), III (p < 0.00001), and total (p < 0.00001) scores, and the between-group MD in part III score increased over time. The loss of the radioligands uptake in levodopa-alone group was also increasingly greater over time. Patients treated with levodopa alone were at higher risk for wearing-off (p < 0.001) and dyskinesia (p < 0.001), but the RR for dyskinesia between the two groups decreased after 2 years of follow-up. CONCLUSION Levodopa-alone therapy might be superior in motor symptom relief than levodopa-sparing therapy for early PD patients, and the motor advantage of levodopa-alone might grow over time. Sparing therapy might be associated with less risk of wearing-off and dyskinesia, but the events between the two groups might not be different in the long run. Overall, levodopa alone therapy might bring more net benefit to early PD patients compared with levodopa sparing strategies. The clinical and imaging findings are conflicting, which requires further investigation.
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Bidesi NSR, Vang Andersen I, Windhorst AD, Shalgunov V, Herth MM. The role of neuroimaging in Parkinson's disease. J Neurochem 2021; 159:660-689. [PMID: 34532856 PMCID: PMC9291628 DOI: 10.1111/jnc.15516] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 09/09/2021] [Accepted: 09/10/2021] [Indexed: 11/29/2022]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Two hallmarks of PD are the accumulation of alpha-synuclein and the loss of dopaminergic neurons in the brain. There is no cure for PD, and all existing treatments focus on alleviating the symptoms. PD diagnosis is also based on the symptoms, such as abnormalities of movement, mood, and cognition observed in the patients. Molecular imaging methods such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) can detect objective alterations in the neurochemical machinery of the brain and help diagnose and study neurodegenerative diseases. This review addresses the application of functional MRI, PET, and SPECT in PD patients. We provide an overview of the imaging targets, discuss the rationale behind target selection, the agents (tracers) with which the imaging can be performed, and the main findings regarding each target's state in PD. Molecular imaging has proven itself effective in supporting clinical diagnosis of PD and has helped reveal that PD is a heterogeneous disorder, which has important implications for the development of future therapies. However, the application of molecular imaging for early diagnosis of PD or for differentiation between PD and atypical parkinsonisms has remained challenging. The final section of the review is dedicated to new imaging targets with which one can detect the PD-related pathological changes upstream from dopaminergic degeneration. The foremost of those targets is alpha-synuclein. We discuss the progress of tracer development achieved so far and challenges on the path toward alpha-synuclein imaging in humans.
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Affiliation(s)
- Natasha S R Bidesi
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Ida Vang Andersen
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Albert D Windhorst
- Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Vladimir Shalgunov
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Matthias M Herth
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen, Denmark
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An Y, Fan F, Jiang X, Sun K. Recent Advances in Liquid Biopsy of Brain Cancers. Front Genet 2021; 12:720270. [PMID: 34603383 PMCID: PMC8484876 DOI: 10.3389/fgene.2021.720270] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/23/2021] [Indexed: 11/13/2022] Open
Abstract
Brain cancers are among the top causes of death worldwide. Although, the survival rates vary widely depending on the type of the tumor, early diagnosis could generally benefit in better prognosis outcomes of the brain cancer patients. Conventionally, neuroimaging and biopsy are the most widely used approaches in diagnosis, subtyping, and prognosis monitoring of brain cancers, while emerging liquid biopsy assays using peripheral blood or cerebrospinal fluid have demonstrated many favorable characteristics in this task, especially due to their minimally invasive and easiness in sampling nature. Here, we review the recent studies in the liquid biopsy of brain cancers. We discuss the methodologies and performances of various assays on diagnosis, tumor subtyping, relapse prediction as well as prognosis monitoring in brain cancers, which approaches have made a big step toward clinical benefits of brain cancer patients.
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Affiliation(s)
- Yunyun An
- Shenzhen Bay Laboratory, Shenzhen, China
| | - Fei Fan
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaobing Jiang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Sun
- Shenzhen Bay Laboratory, Shenzhen, China
- BGI-Shenzhen, Shenzhen, China
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28
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Lin J, Kang X, Xiong Y, Zhang D, Zong R, Yu X, Pan L, Lou X. Convergent structural network and gene signatures for MRgFUS thalamotomy in patients with Parkinson's disease. Neuroimage 2021; 243:118550. [PMID: 34481084 DOI: 10.1016/j.neuroimage.2021.118550] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/07/2021] [Accepted: 09/01/2021] [Indexed: 12/30/2022] Open
Abstract
MRgFUS has just been made available for the 1.7 million Parkinson's disease patients in China. Despite its non-invasive and rapid therapeutic advantages for involuntary tremor, some concerns have emerged about outcomes variability, non-specificity, and side-effects, as little is known about its impact on the long-term plasticity of brain structure. We sought to dissect the characteristics of long-term changes in brain structure caused by MRgFUS lesion and explored potential biological mechanisms. One-year multimodal imaging follow-ups were conducted for nine tremor-dominant Parkinson's disease patients undergoing unilateral MRgFUS thalamotomy. A structural connectivity map was generated for each patient to analyze dynamic changes in brain structure. The human brain transcriptome was extracted and spatially registered for connectivity vulnerability. Genetic functional enrichment analysis was performed and further clarified using in vivo emission computed tomography data. MRgFUS not only abolished tremors but also significantly disrupted the brain network topology. Network-based statistics identified a U-shape MRgFUS-sensitive subnetwork reflective of hand tremor recovery and surgical process, accompanied by relevant cerebral blood flow and gray matter alteration. Using human brain gene expression data, we observed that dopaminergic signatures were responsible for the preferential vulnerability associated with these architectural alterations. Additional PET/SPECT data not only validated these gene signatures, but also suggested that structural alteration was significantly correlated with D1 and D2 receptors, DAT, and F-DOPA measures. There was a long-term dynamic loop between structural alteration and dopaminergic signature for MRgFUS thalamotomy, which may be closely related to the long-term improvements in clinical tremor.
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Affiliation(s)
- Jiaji Lin
- Department of Radiology, Chinese PLA General Hospital, No.28 Fuxing Road, Beijing, 100853, China.
| | - Xiaopeng Kang
- School of Artificial Intelligence, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100876, China; Brainnetome Center & National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China
| | - Yongqin Xiong
- Department of Radiology, Chinese PLA General Hospital, No.28 Fuxing Road, Beijing, 100853, China
| | - Dekang Zhang
- Department of Radiology, Chinese PLA General Hospital, No.28 Fuxing Road, Beijing, 100853, China
| | - Rui Zong
- Department of Neurosurgery, Chinese PLA General Hospital, No.28 Fuxing Road, Beijing, 100853, China
| | - Xinguang Yu
- Department of Neurosurgery, Chinese PLA General Hospital, No.28 Fuxing Road, Beijing, 100853, China
| | - Longsheng Pan
- Department of Neurosurgery, Chinese PLA General Hospital, No.28 Fuxing Road, Beijing, 100853, China.
| | - Xin Lou
- Department of Radiology, Chinese PLA General Hospital, No.28 Fuxing Road, Beijing, 100853, China.
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Pontoriero AD, Nordio G, Easmin R, Giacomel A, Santangelo B, Jahuar S, Bonoldi I, Rogdaki M, Turkheimer F, Howes O, Veronese M. Automated Data Quality Control in FDOPA brain PET Imaging using Deep Learning. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2021; 208:106239. [PMID: 34289438 PMCID: PMC8404039 DOI: 10.1016/j.cmpb.2021.106239] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 06/10/2021] [Indexed: 06/07/2023]
Abstract
INTRODUCTION With biomedical imaging research increasingly using large datasets, it becomes critical to find operator-free methods to quality control the data collected and the associated analysis. Attempts to use artificial intelligence (AI) to perform automated quality control (QC) for both single-site and multi-site datasets have been explored in some neuroimaging techniques (e.g. EEG or MRI), although these methods struggle to find replication in other domains. The aim of this study is to test the feasibility of an automated QC pipeline for brain [18F]-FDOPA PET imaging as a biomarker for the dopamine system. METHODS Two different Convolutional Neural Networks (CNNs) were used and combined to assess spatial misalignment to a standard template and the signal-to-noise ratio (SNR) relative to 200 static [18F]-FDOPA PET images that had been manually quality controlled from three different PET/CT scanners. The scans were combined with an additional 400 scans, in which misalignment (200 scans) and low SNR (200 scans) were simulated. A cross-validation was performed, where 80% of the data were used for training and 20% for validation. Two additional datasets of [18F]-FDOPA PET images (50 and 100 scans respectively with at least 80% of good quality images) were used for out-of-sample validation. RESULTS The CNN performance was excellent in the training dataset (accuracy for motion: 0.86 ± 0.01, accuracy for SNR: 0.69 ± 0.01), leading to 100% accurate QC classification when applied to the two out-of-sample datasets. Data dimensionality reduction affected the generalizability of the CNNs, especially when the classifiers were applied to the out-of-sample data from 3D to 1D datasets. CONCLUSIONS This feasibility study shows that it is possible to perform automatic QC of [18F]-FDOPA PET imaging with CNNs. The approach has the potential to be extended to other PET tracers in both brain and non-brain applications, but it is dependent on the availability of large datasets necessary for the algorithm training.
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Affiliation(s)
- Antonella D Pontoriero
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Giovanna Nordio
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
| | - Rubaida Easmin
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Alessio Giacomel
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Barbara Santangelo
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Sameer Jahuar
- Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Ilaria Bonoldi
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Maria Rogdaki
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Federico Turkheimer
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Oliver Howes
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; H. Lundbeck UK, Ottiliavej 9 2500 Valby, Denmark; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
| | - Mattia Veronese
- Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Department of Information Engineering, University of Padua, Padua, Italy
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Sipos D, László Z, Tóth Z, Kovács P, Tollár J, Gulybán A, Lakosi F, Repa I, Kovács A. Additional Value of 18F-FDOPA Amino Acid Analog Radiotracer to Irradiation Planning Process of Patients With Glioblastoma Multiforme. Front Oncol 2021; 11:699360. [PMID: 34295825 PMCID: PMC8290215 DOI: 10.3389/fonc.2021.699360] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 06/11/2021] [Indexed: 01/25/2023] Open
Abstract
PURPOSE To investigate the added value of 6-(18F]-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) PET to radiotherapy planning in glioblastoma multiforme (GBM). METHODS From September 2017 to December 2020, 17 patients with GBM received external beam radiotherapy up to 60 Gy with concurrent and adjuvant temozolamide. Target volume delineations followed the European guideline with a 2-cm safety margin clinical target volume (CTV) around the contrast-enhanced lesion+resection cavity on MRI gross tumor volume (GTV). All patients had FDOPA hybrid PET/MRI followed by PET/CT before radiotherapy planning. PET segmentation followed international recommendation: T/N 1.7 (BTV1.7) and T/N 2 (BTV2.0) SUV thresholds were used for biological target volume (BTV) delineation. For GTV-BTVs agreements, 95% of the Hausdorff distance (HD95%) from GTV to the BTVs were calculated, additionally, BTV portions outside of the GTV and coverage by the 95% isodose contours were also determined. In case of recurrence, the latest MR images were co-registered to planning CT to evaluate its location relative to BTVs and 95% isodose contours. RESULTS Average (range) GTV, BTV1.7, and BTV2.0 were 46.58 (6-182.5), 68.68 (9.6-204.1), 42.89 (3.8-147.6) cm3, respectively. HD95% from GTV were 15.5 mm (7.9-30.7 mm) and 10.5 mm (4.3-21.4 mm) for BTV1.7 and BTV2.0, respectively. Based on volumetric assessment, 58.8% (28-100%) of BTV1.7 and 45.7% of BTV2.0 (14-100%) were outside of the standard GTV, still all BTVs were encompassed by the 95% dose. All recurrences were confirmed by follow-up imaging, all occurred within PTV, with an additional outfield recurrence in a single case, which was not DOPA-positive at the beginning of treatment. Good correlation was found between the mean and median values of PET/CT and PET/MRI segmented volumes relative to corresponding brain-accumulated enhancement (r = 0.75; r = 0.72). CONCLUSION 18FFDOPA PET resulted in substantial larger tumor volumes compared to MRI; however, its added value is unclear as vast majority of recurrences occurred within the prescribed dose level. Use of PET/CT signals proved to be feasible in the absence of direct segmentation possibilities of PET/MR in TPS. The added value of 18FFDOPA may be better exploited in the context of integrated dose escalation.
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Affiliation(s)
- David Sipos
- Dr. József Baka Diagnostic, Radiation Oncology, Research and Teaching Center, “Moritz Kaposi” Teaching Hospital, Kaposvár, Hungary
- Doctoral School of Health Sciences, University of Pécs, Pécs, Hungary
- Department of Medical Imaging, Faculty of Health Sciences, University of Pécs, Pécs, Hungary
| | - Zoltan László
- Dr. József Baka Diagnostic, Radiation Oncology, Research and Teaching Center, “Moritz Kaposi” Teaching Hospital, Kaposvár, Hungary
| | - Zoltan Tóth
- Doctoral School of Health Sciences, University of Pécs, Pécs, Hungary
- MEDICOPUS Healthcare Provider and Public Nonprofit Ltd., Somogy County Moritz Kaposi Teaching Hospital, Kaposvár, Hungary
| | - Peter Kovács
- Dr. József Baka Diagnostic, Radiation Oncology, Research and Teaching Center, “Moritz Kaposi” Teaching Hospital, Kaposvár, Hungary
- Department of Medical Imaging, Faculty of Health Sciences, University of Pécs, Pécs, Hungary
| | - Jozsef Tollár
- Department of Medical Imaging, Faculty of Health Sciences, University of Pécs, Pécs, Hungary
- Department of Neurology, Somogy County Moritz Kaposi Teaching Hospital, Kaposvár, Hungary
| | - Akos Gulybán
- Medical Physics Department, Institut Jules Bordet, Bruxelles, Belgium
| | - Ferenc Lakosi
- Dr. József Baka Diagnostic, Radiation Oncology, Research and Teaching Center, “Moritz Kaposi” Teaching Hospital, Kaposvár, Hungary
- Department of Medical Imaging, Faculty of Health Sciences, University of Pécs, Pécs, Hungary
| | - Imre Repa
- Dr. József Baka Diagnostic, Radiation Oncology, Research and Teaching Center, “Moritz Kaposi” Teaching Hospital, Kaposvár, Hungary
- Doctoral School of Health Sciences, University of Pécs, Pécs, Hungary
| | - Arpad Kovács
- Doctoral School of Health Sciences, University of Pécs, Pécs, Hungary
- Department of Medical Imaging, Faculty of Health Sciences, University of Pécs, Pécs, Hungary
- Department of Oncoradiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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Tandon A, Singh SJ, Chaturvedi RK. Nanomedicine against Alzheimer's and Parkinson's Disease. Curr Pharm Des 2021; 27:1507-1545. [PMID: 33087025 DOI: 10.2174/1381612826666201021140904] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/06/2020] [Accepted: 08/18/2020] [Indexed: 11/22/2022]
Abstract
Alzheimer's and Parkinson's are the two most rampant neurodegenerative disorders worldwide. Existing treatments have a limited effect on the pathophysiology but are unable to fully arrest the progression of the disease. This is due to the inability of these therapeutic molecules to efficiently cross the blood-brain barrier. We discuss how nanotechnology has enabled researchers to develop novel and efficient nano-therapeutics against these diseases. The development of nanotized drug delivery systems has permitted an efficient, site-targeted, and controlled release of drugs in the brain, thereby presenting a revolutionary therapeutic approach. Nanoparticles are also being thoroughly studied and exploited for their role in the efficient and precise diagnosis of neurodegenerative conditions. We summarize the role of different nano-carriers and RNAi-conjugated nanoparticle-based therapeutics for their efficacy in pre-clinical studies. We also discuss the challenges underlying the use of nanomedicine with a focus on their route of administration, concentration, metabolism, and any toxic effects for successful therapeutics in these diseases.
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Affiliation(s)
- Ankit Tandon
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Sangh J Singh
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Rajnish K Chaturvedi
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
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32
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Scroggie KR, Perkins MV, Chalker JM. Reaction of [ 18F]Fluoride at Heteroatoms and Metals for Imaging of Peptides and Proteins by Positron Emission Tomography. Front Chem 2021; 9:687678. [PMID: 34249861 PMCID: PMC8262615 DOI: 10.3389/fchem.2021.687678] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/07/2021] [Indexed: 12/11/2022] Open
Abstract
The ability to radiolabel proteins with [18F]fluoride enables the use of positron emission tomography (PET) for the early detection, staging and diagnosis of disease. The direct fluorination of native proteins through C-F bond formation is, however, a difficult task. The aqueous environments required by proteins severely hampers fluorination yields while the dry, organic solvents that promote nucleophilic fluorination can denature proteins. To circumvent these issues, indirect fluorination methods making use of prosthetic groups that are first fluorinated and then conjugated to a protein have become commonplace. But, when it comes to the radiofluorination of proteins, these indirect methods are not always suited to the short half-life of the fluorine-18 radionuclide (110 min). This review explores radiofluorination through bond formation with fluoride at boron, metal complexes, silicon, phosphorus and sulfur. The potential for these techniques to be used for the direct, aqueous radiolabeling of proteins with [18F]fluoride is discussed.
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Affiliation(s)
| | | | - Justin M. Chalker
- Institute for Nanoscale Science and Technology, College of Science and Engineering, Flinders University, Adelaide, SA, Australia
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Andersen VL, Soerensen MA, Dam JH, Langkjaer N, Petersen H, Bender DA, Fugloe D, Huynh THV. GMP production of 6-[ 18F]Fluoro-L-DOPA for PET/CT imaging by different synthetic routes: a three center experience. EJNMMI Radiopharm Chem 2021; 6:21. [PMID: 34117961 PMCID: PMC8197687 DOI: 10.1186/s41181-021-00135-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/20/2021] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND The radiofluorinated levodopa analogue 6-[18F]F-L-DOPA (3,4-dihydroxy-6-18F-L-phenylalanine) is a commonly employed radiotracer for PET/CT imaging of multiple oncological and neurological indications. An unusually large number of different radiosyntheses have been published to the point where two different Ph. Eur. monographs exist depending on whether the chemistry relies on electrophilic or nucleophilic radiosubstitution of appropriate chemical precursors. For new PET imaging sites wishing to adopt [18F]FDOPA into clinical practice, selecting the appropriate production process may be difficult and dependent on the clinical needs of the site. METHODS Data from four years of [18F]FDOPA production at three different clinical sites are collected and compared. These three sites, Aarhus University Hospital (AUH), Odense University Hospital (OUH), and Herlev University Hospital (HUH), produce the radiotracer by different radiosynthetic routes with AUH adopting an electrophilic strategy, while OUH and HUH employ two different nucleophilic approaches. Production failure rates, radiochemical yields, and molar activities are compared across sites and time. Additionally, the clinical use of the radiotracer over the time period considered at the different sites are presented and discussed. RESULTS The electrophilic substitution route suffers from being demanding in terms of cyclotron operation and maintenance. This challenge, however, was found to be compensated by a production failure rate significantly below that of both nucleophilic approaches; a result of simpler chemistry. The five-step nucleophilic approach employed at HUH produces superior radiochemical yields compared to the three-step approach adopted at OUH but suffers from the need for more comprehensive synthesis equipment given the multi-step nature of the procedure, including HPLC purification. While the procedure at OUH furnishes the lowest radiochemical yield of the synthetic routes considered, it produces the highest molar activity. This is of importance across the clinical applications of the tracer discussed here, including dopamine synthesis in striatum of subjects with schizophrenia and congenital hyperinsulinism in infants. CONCLUSION For most sites either of the two nucleophilic substitution strategies should be favored. However, which of the two will depend on whether a given site wishes to optimize the radiochemical yield or the ease of the use.
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Affiliation(s)
- Valdemar L Andersen
- Department of Nuclear Medicine, Copenhagen University Hospital Herlev and Gentofte, Borgmester Ib Juuls vej 31, DK-2730, Herlev, Denmark
| | - Mikkel A Soerensen
- Department of Nuclear Medicine, Copenhagen University Hospital Herlev and Gentofte, Borgmester Ib Juuls vej 31, DK-2730, Herlev, Denmark
| | - Johan Hygum Dam
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Niels Langkjaer
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark
| | - Henrik Petersen
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Dirk Andreas Bender
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark
| | - Dan Fugloe
- Department of Nuclear Medicine, Copenhagen University Hospital Herlev and Gentofte, Borgmester Ib Juuls vej 31, DK-2730, Herlev, Denmark
| | - Tri Hien Viet Huynh
- Department of Nuclear Medicine, Copenhagen University Hospital Herlev and Gentofte, Borgmester Ib Juuls vej 31, DK-2730, Herlev, Denmark.
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Abstract
Two pathologically distinct neurodegenerative conditions, progressive supranuclear palsy and corticobasal degeneration, share in common deposits of tau proteins that differ both molecularly and ultrastructurally from the common tau deposits diagnostic of Alzheimer disease. The proteinopathy in these disorders is characterized by fibrillary aggregates of 4R tau proteins. The clinical presentations of progressive supranuclear palsy and of corticobasal degeneration are often confused with more common disorders such as Parkinson disease or subtypes of frontotemporal lobar degeneration. Neither of these 4R tau disorders has effective therapy, and while there are emerging molecular imaging approaches to identify patients earlier in the course of disease, there are as yet no reliably sensitive and specific approaches to diagnoses in life. In this review, aspects of the clinical syndromes, neuropathology, and molecular biomarker imaging studies applicable to progressive supranuclear palsy and to corticobasal degeneration will be presented. Future development of more accurate molecular imaging approaches is proposed.
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Affiliation(s)
- Kirk A Frey
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, The University of Michigan Health System, Ann Arbor, MI.
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Zitser J, Casaletto KB, Staffaroni AM, Sexton C, Weiner-Light S, Wolf A, Brown JA, Miller BL, Kramer JH. Mild Motor Signs Matter in Typical Brain Aging: The Value of the UPDRS Score Within a Functionally Intact Cohort of Older Adults. Front Aging Neurosci 2021; 13:594637. [PMID: 33643020 PMCID: PMC7904682 DOI: 10.3389/fnagi.2021.594637] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 01/11/2021] [Indexed: 11/20/2022] Open
Abstract
Objectives: To characterize the clinical correlates of subclinical Parkinsonian signs, including longitudinal cognitive and neural (via functional connectivity) outcomes, among functionally normal older adults. Methods: Participants included 737 functionally intact community-dwelling older adults who performed prospective comprehensive evaluations at ~15-months intervals for an average of 4.8 years (standard deviation 3.2 years). As part of these evaluations, participants completed the Unified Parkinson's Disease Rating Scale (UPDRS) longitudinally and measures of processing speed, executive functioning and verbal episodic memory. T1-weighted structural scans and task-free functional MRI scans were acquired on 330 participants. We conducted linear mixed-effects models to determine the relationship between changes in UPDRS with cognitive and neural changes, using age, sex, and education as covariates. Results: Cognitive outcomes were processing speed, executive functioning, and episodic memory. Greater within-person increases in UPDRS were associated with more cognitive slowing over time. Although higher average UPDRS scores were significantly associated with overall poorer executive functions, there was no association between UPDRS and executive functioning longitudinally. UPDRS scores did not significantly relate to longitudinal memory performances. Regarding neural correlates, greater increases in UPDRS scores were associated with reduced intra-subcortical network connectivity over time. There were no relationships with intra-frontoparietal or inter-subcortical-frontoparietal connectivity. Conclusions: Our findings add to the aging literature by indicating that mild motor changes are negatively associated with cognition and network connectivity in functionally intact adults.
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Affiliation(s)
- Jennifer Zitser
- Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States.,Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, United States.,Movement Disorders Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Kaitlin B Casaletto
- Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
| | - Adam M Staffaroni
- Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
| | - Claire Sexton
- Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States.,Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, United States
| | - Sophia Weiner-Light
- Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
| | - Amy Wolf
- Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
| | - Jesse A Brown
- Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
| | - Bruce L Miller
- Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States.,Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, United States
| | - Joel H Kramer
- Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States.,Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, United States
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36
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Snyder SE, Butch ER, Shulkin BL. Radiopharmaceuticals in Pediatric Nuclear Medicine. HANDBOOK OF RADIOPHARMACEUTICALS 2020:653-701. [DOI: 10.1002/9781119500575.ch21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Abstract
The major applications for molecular imaging with PET in clinical practice concern cancer imaging. Undoubtedly, 18F-FDG represents the backbone of nuclear oncology as it remains so far the most widely employed positron emitter compound. The acquired knowledge on cancer features, however, allowed the recognition in the last decades of multiple metabolic or pathogenic pathways within the cancer cells, which stimulated the development of novel radiopharmaceuticals. An endless list of PET tracers, substantially covering all hallmarks of cancer, has entered clinical routine or is being investigated in diagnostic trials. Some of them guard significant clinical applications, whereas others mostly bear a huge potential. This chapter summarizes a selected list of non-FDG PET tracers, described based on their introduction into and impact on clinical practice.
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Krasikova RN. Nucleophilic Synthesis of 6-l-[ 18F]FDOPA. Is Copper-Mediated Radiofluorination the Answer? Molecules 2020; 25:E4365. [PMID: 32977512 PMCID: PMC7582790 DOI: 10.3390/molecules25194365] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/18/2020] [Accepted: 09/20/2020] [Indexed: 02/07/2023] Open
Abstract
Positron emission tomography employing 6-l-[18F]fluoro-3,4-dihydroxyphenylalanine (6-l-[18F]FDOPA) is currently a highly relevant clinical tool for detection of gliomas, neuroendocrine tumors and evaluation of Parkinson's disease progression. Yet, the deficiencies of electrophilic synthesis of 6-l-[18F]FDOPA hold back its wider use. To fulfill growing clinical demands for this radiotracer, novel synthetic strategies via direct nucleophilic 18F-radiloabeling starting from multi-Curie amounts of [18F]fluoride, have been recently introduced. In particular, Cu-mediated radiofluorination of arylpinacol boronates and arylstannanes show significant promise for introduction into clinical practice. In this short review these current developments will be discussed with a focus on their applicability to automation.
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Affiliation(s)
- Raisa N Krasikova
- N.P. Bechtereva Institute of the Human Brain Russian Academy of Science, 197376 St. Petersburg, Russia
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Horimoto Y, Hayashi E, Ito Y, Iida A, Goto Y, Kato S, Okita K, Kako T, Sato C, Tajima T, Inagaki A, Nokura K, Hibino H, Matsukawa N, Yamada K, Kabasawa H. Dopaminergic function in spinocerebellar ataxia type 6 patients with and without parkinsonism. J Neurol 2020; 267:2692-2696. [PMID: 32440919 DOI: 10.1007/s00415-020-09908-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 05/08/2020] [Accepted: 05/11/2020] [Indexed: 11/30/2022]
Abstract
BACKGROUND Although pure cerebellar ataxia is usually emphasized as the characteristic clinical feature of spinocerebellar ataxia type 6 (SCA6), parkinsonism has been repeatedly described in patients with genetically confirmed SCA6. METHODS We conducted a positron emission tomography study using a combination of [18F]fluoro-L-dopa for dopamine synthesis and [11C]raclopride for dopamine D2 receptor function on six genetically confirmed SCA6 patients, both with and without parkinsonism. To the best of our knowledge, this is the first dopamine receptor imaging study of patients with SCA6. RESULTS Most patients had somewhat decreased dopaminergic function, and this decrease was significant in the caudate nucleus. In addition, one SCA6 patient with parkinsonism had whole striatal dysfunction of both dopamine synthesis and dopamine D2 receptor function. CONCLUSIONS The pathology of SCA6 may not be restricted to the cerebellum, but may also be distributed across various regions, including in both presynaptic and postsynaptic dopaminergic neurons to some degree. Patients with SCA6 may show apparent parkinsonism after the progression of neurodegeneration.
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Affiliation(s)
- Yoshihiko Horimoto
- Department of Neurology, Nagoya City Rehabilitation Center, 1-2, Mikan-yama, Yatomi-cho, Mizuho, Nagoya, 467-8622, Japan.
| | - Emi Hayashi
- Department of Radiology, Nagoya City Rehabilitation Center, Nagoya, Japan.,Department of Planning and Research, Nagoya City Rehabilitation Center, Nagoya, Japan
| | - Yoshihiro Ito
- Department of Radiology, Nagoya City Rehabilitation Center, Nagoya, Japan.,Department of Planning and Research, Nagoya City Rehabilitation Center, Nagoya, Japan
| | - Akihiko Iida
- Department of Radiology, Nagoya City Rehabilitation Center, Nagoya, Japan
| | - Yoji Goto
- Department of Neurology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan
| | - Shigenori Kato
- Department of Neurology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
| | - Kenji Okita
- Department of Neurology, Nagoya City University, Nagoya, Japan
| | - Tetsuharu Kako
- Department of Neurology, Bantane Hospital, Fujita Health University, Nagoya, Japan
| | - Chikako Sato
- Department of Neurology, Nagoya City Rehabilitation Center, 1-2, Mikan-yama, Yatomi-cho, Mizuho, Nagoya, 467-8622, Japan
| | - Toshihisa Tajima
- Department of Neurology, Nagoya City Rehabilitation Center, 1-2, Mikan-yama, Yatomi-cho, Mizuho, Nagoya, 467-8622, Japan.,Department of Planning and Research, Nagoya City Rehabilitation Center, Nagoya, Japan
| | - Aki Inagaki
- Department of Neurology, Nagoya City Rehabilitation Center, 1-2, Mikan-yama, Yatomi-cho, Mizuho, Nagoya, 467-8622, Japan
| | - Kazuya Nokura
- Department of Neurology, Bantane Hospital, Fujita Health University, Nagoya, Japan
| | - Hiroaki Hibino
- Department of Neurology, Nagoya City Rehabilitation Center, 1-2, Mikan-yama, Yatomi-cho, Mizuho, Nagoya, 467-8622, Japan
| | | | - Kazuo Yamada
- Department of Neurosurgery, Nagoya City Rehabilitation Center, Nagoya, Japan
| | - Hidehiro Kabasawa
- Department of Neurology, Nagoya City Rehabilitation Center, 1-2, Mikan-yama, Yatomi-cho, Mizuho, Nagoya, 467-8622, Japan
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Mossine AV, Tanzey SS, Brooks AF, Makaravage KJ, Ichiishi N, Miller JM, Henderson BD, Erhard T, Bruetting C, Skaddan MB, Sanford MS, Scott PJH. Synthesis of high-molar-activity [ 18F]6-fluoro-L-DOPA suitable for human use via Cu-mediated fluorination of a BPin precursor. Nat Protoc 2020; 15:1742-1759. [PMID: 32269382 PMCID: PMC7333241 DOI: 10.1038/s41596-020-0305-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 01/27/2020] [Indexed: 11/09/2022]
Abstract
[18F]6-fluoro-L-DOPA ([18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) and high molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.
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Affiliation(s)
- Andrew V Mossine
- Department of Radiology, University of Michigan, Ann Arbor, MI, USA
- Curium Pharma, Nuclear Medicine Manufacturing, Noblesville, IN, USA
| | - Sean S Tanzey
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA
| | - Allen F Brooks
- Department of Radiology, University of Michigan, Ann Arbor, MI, USA
| | - Katarina J Makaravage
- Department of Chemistry, University of Michigan, Ann Arbor, MI, USA
- Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA
| | - Naoko Ichiishi
- Department of Chemistry, University of Michigan, Ann Arbor, MI, USA
- Takeda Pharmaceuticals International Co., Process Chemistry, Boston, MA, USA
| | - Jason M Miller
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA
- Environmental Analysis Branch, US Army Corps of Engineers, Detroit, MI, USA
| | | | - Thomas Erhard
- AbbVie Deustschland GmbH & Co. KG Ludwigschafen, Ludwigshafen, Germany
| | | | | | - Melanie S Sanford
- Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
| | - Peter J H Scott
- Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
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Miyamoto M, Miyamoto T, Saitou J, Sato T. Longitudinal study of striatal aromatic l-amino acid decarboxylase activity in patients with idiopathic rapid eye movement sleep behavior disorder. Sleep Med 2020; 68:50-56. [PMID: 32028226 DOI: 10.1016/j.sleep.2019.09.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/15/2019] [Accepted: 09/20/2019] [Indexed: 12/20/2022]
Abstract
STUDY OBJECTIVES To determine if nigrostriatal dopaminergic system function, evaluated by aromatic l-amino acid decarboxylase (AADC) activity using 6-[18F]fluoro-meta-tyrosine brain positron emission tomography (FMT-PET) can accurately and efficiently identify idiopathic rapid-eye-movement behavior disorder (IRBD) individuals at risk for conversion to a clinical diagnosis of Parkinson's disease (PD) or dementia with Lewy bodies (DLB). METHODS We assessed prospectively striatal aromatic l-amino acid decarboxylase activity using FMT brain PET imaging in IRBD patients who were followed systematically every 1-3 months for 1-10 years. IRBD patients (n = 27) were enrolled in this prospective cohort study starting in 2009. Those who underwent follow-up scans between January 2011 and September 2014 (n = 24) were analyzed in the present study. RESULTS Of the 24 IRBD patients with baseline and follow-up FMT-PET scans, 11 (45.8%) developed PD (n = 6) or DLB (n = 5). Compared to IRBD patients who were still disease-free, those who developed PD (n = 5) or DLB with parkinsonism (n = 1) had significantly reduced bilateral putaminal FMT uptake during the follow-up. Furthermore, the rate of FMT decline between baseline and follow-up scans was higher in all converted patients, even for those with DLB without parkinsonism, than in IRBD patients who remained disease-free. CONCLUSIONS FMT-PET, which represents a dynamic change in AADC activity over time, may also be a useful predictor for the risk of conversion to PD or DLB over short-term clinical follow-up periods, or when testing neuroprotective and restorative strategies in the prodromal phases of PD or DLB.
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Affiliation(s)
- Masayuki Miyamoto
- Department of Neurology, Center of Sleep Medicine, Dokkyo Medical University, Japan
| | - Tomoyuki Miyamoto
- Department of Neurology, Dokkyo Medical University Saitama Medical Center, Japan.
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Gallezot JD, Lu Y, Naganawa M, Carson RE. Parametric Imaging With PET and SPECT. IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES 2020. [DOI: 10.1109/trpms.2019.2908633] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Beaurain M, Salabert AS, Ribeiro MJ, Arlicot N, Damier P, Le Jeune F, Demonet JF, Payoux P. Innovative Molecular Imaging for Clinical Research, Therapeutic Stratification, and Nosography in Neuroscience. Front Med (Lausanne) 2019; 6:268. [PMID: 31828073 PMCID: PMC6890558 DOI: 10.3389/fmed.2019.00268] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 11/01/2019] [Indexed: 01/06/2023] Open
Abstract
Over the past few decades, several radiotracers have been developed for neuroimaging applications, especially in PET. Because of their low steric hindrance, PET radionuclides can be used to label molecules that are small enough to cross the blood brain barrier, without modifying their biological properties. As the use of 11C is limited by its short physical half-life (20 min), there has been an increasing focus on developing tracers labeled with 18F for clinical use. The first such tracers allowed cerebral blood flow and glucose metabolism to be measured, and the development of molecular imaging has since enabled to focus more closely on specific targets such as receptors, neurotransmitter transporters, and other proteins. Hence, PET and SPECT biomarkers have become indispensable for innovative clinical research. Currently, the treatment options for a number of pathologies, notably neurodegenerative diseases, remain only supportive and symptomatic. Treatments that slow down or reverse disease progression are therefore the subject of numerous studies, in which molecular imaging is proving to be a powerful tool. PET and SPECT biomarkers already make it possible to diagnose several neurological diseases in vivo and at preclinical stages, yielding topographic, and quantitative data about the target. As a result, they can be used for assessing patients' eligibility for new treatments, or for treatment follow-up. The aim of the present review was to map major innovative radiotracers used in neuroscience, and explain their contribution to clinical research. We categorized them according to their target: dopaminergic, cholinergic or serotoninergic systems, β-amyloid plaques, tau protein, neuroinflammation, glutamate or GABA receptors, or α-synuclein. Most neurological disorders, and indeed mental disorders, involve the dysfunction of one or more of these targets. Combinations of molecular imaging biomarkers can afford us a better understanding of the mechanisms underlying disease development over time, and contribute to early detection/screening, diagnosis, therapy delivery/monitoring, and treatment follow-up in both research and clinical settings.
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Affiliation(s)
- Marie Beaurain
- CHU de Toulouse, Toulouse, France.,ToNIC, Toulouse NeuroImaging Center, Inserm U1214, Toulouse, France
| | - Anne-Sophie Salabert
- CHU de Toulouse, Toulouse, France.,ToNIC, Toulouse NeuroImaging Center, Inserm U1214, Toulouse, France
| | - Maria Joao Ribeiro
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.,Inserm CIC 1415, University Hospital, Tours, France.,CHRU Tours, Tours, France
| | - Nicolas Arlicot
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.,Inserm CIC 1415, University Hospital, Tours, France.,CHRU Tours, Tours, France
| | - Philippe Damier
- Inserm U913, Neurology Department, University Hospital, Nantes, France
| | | | - Jean-François Demonet
- Leenards Memory Centre, Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Pierre Payoux
- CHU de Toulouse, Toulouse, France.,ToNIC, Toulouse NeuroImaging Center, Inserm U1214, Toulouse, France
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Mossine AV, Tanzey SS, Brooks AF, Makaravage KJ, Ichiishi N, Miller JM, Henderson BD, Skaddan MB, Sanford MS, Scott PJH. One-pot synthesis of high molar activity 6-[ 18F]fluoro-l-DOPA by Cu-mediated fluorination of a BPin precursor. Org Biomol Chem 2019; 17:8701-8705. [PMID: 31536095 PMCID: PMC6812483 DOI: 10.1039/c9ob01758e] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A one-pot two-step synthesis of 6-[18F]fluoro-l-DOPA ([18F]FDOPA) has been developed involving Cu-mediated radiofluorination of a pinacol boronate ester precursor. The method is fully automated, provides [18F]FDOPA in good activity yield (104 ± 16 mCi, 6 ± 1%), excellent radiochemical purity (>99%) and high molar activity (3799 ± 2087 Ci mmol-1), n = 3, and has been validated to produce the radiotracer for human use.
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Affiliation(s)
- Andrew V Mossine
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Sean S Tanzey
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA. and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Allen F Brooks
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
| | | | - Naoko Ichiishi
- Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Jason M Miller
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA. and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Marc B Skaddan
- AbbVie Translational Imaging, North Chicago, IL 60030, USA
| | - Melanie S Sanford
- Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Peter J H Scott
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA. and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
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D'Ambrosio E, Dahoun T, Pardiñas AF, Veronese M, Bloomfield MAP, Jauhar S, Bonoldi I, Rogdaki M, Froudist-Walsh S, Walters JTR, Howes OD. The effect of a genetic variant at the schizophrenia associated AS3MT/BORCS7 locus on striatal dopamine function: A PET imaging study. Psychiatry Res Neuroimaging 2019; 291:34-41. [PMID: 31386983 PMCID: PMC7099976 DOI: 10.1016/j.pscychresns.2019.07.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 05/28/2019] [Accepted: 07/18/2019] [Indexed: 11/21/2022]
Abstract
One of the most statistically significant loci to result from large-scale GWAS of schizophrenia is 10q24.32. However, it is still unclear how this locus is involved in the pathoaetiology of schizophrenia. The hypothesis that presynaptic dopamine dysfunction underlies schizophrenia is one of the leading theories of the pathophysiology of the disorder. Supporting this, molecular imaging studies show evidence for elevated dopamine synthesis and release capacity. Thus, altered dopamine function could be a potential mechanism by which this genetic variant acts to increase the risk of schizophrenia. We therefore tested the hypothesis that the 10q24.32 region confers genetic risk for schizophrenia through an effect on striatal dopamine function. To this aim we investigated the in vivo relationship between a GWAS schizophrenia-associated SNP within this locus and dopamine synthesis capacity measured using [18F]-DOPA PET in healthy controls. 92 healthy volunteers underwent [18F]-DOPA PET scans to measure striatal dopamine synthesis capacity (indexed as Kicer) and were genotyped for the SNP rs7085104. We found a significant association between rs7085104 genotype and striatal Kicer. Our findings indicate that the mechanism mediating the 10q24.32 risk locus for schizophrenia could involve altered dopaminergic function. Future studies are needed to clarify the neurobiological pathway implicated in this association.
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Affiliation(s)
- Enrico D'Ambrosio
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; Psychiatric Neuroscience Group, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy
| | - Tarik Dahoun
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX37 JX, UK
| | - Antonio F Pardiñas
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - Mattia Veronese
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK
| | - Michael A P Bloomfield
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK; Translational Psychiatry, Research Department of Mental Health Neuroscience, Division of Psychiatry, University College London, Maple House, 149 Tottenham Court Road, London W1T 7NF, UK; Clinical Psychopharmacology Unit, Research Department of Clinical, Educational & Health Psychology, University College London, 1-19 Torrington Place, London WC1E 7HB, UK; NIHR University College London Hospitals Biomedical Research Centre, Maple House, 149 Tottenham Court Road, London W1T 7DN, UK
| | - Sameer Jauhar
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; South London and Maudsley NHS Trust, London, UK
| | - Ilaria Bonoldi
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; South London and Maudsley NHS Trust, London, UK
| | - Maria Rogdaki
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK
| | | | - James T R Walters
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - Oliver D Howes
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK; South London and Maudsley NHS Trust, London, UK.
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Tai LC, Liaw TS, Lin Y, Nyein HYY, Bariya M, Ji W, Hettick M, Zhao C, Zhao J, Hou L, Yuan Z, Fan Z, Javey A. Wearable Sweat Band for Noninvasive Levodopa Monitoring. NANO LETTERS 2019; 19:6346-6351. [PMID: 31381353 DOI: 10.1021/acs.nanolett.9b02478] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Levodopa is the standard medication clinically prescribed to patients afflicted with Parkinson's disease. In particular, the monitoring and optimization of levodopa dosage are critical to mitigate the onset of undesired fluctuations in the patients' physical and emotional conditions such as speech function, motor behavior, and mood stability. The traditional approach to optimize levodopa dosage involves evaluating the subjects' motor function, which has many shortcomings due to its subjective and limited quantifiable nature. Here, we present a wearable sweat band on a nanodendritic platform that quantitatively monitors levodopa dynamics in the body. Both stationary iontophoretic induction and physical exercise are utilized as our methods of sweat extraction. The sweat band measures real-time pharmacokinetic profiles of levodopa to track the dynamic response of the drug metabolism. We demonstrated the sweat band's functionalities on multiple subjects with implications toward the systematic administering of levodopa and routine management of Parkinson's disease.
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Affiliation(s)
- Li-Chia Tai
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
| | - Tiffany S Liaw
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
| | - Yuanjing Lin
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
- Department of Electronic and Computer Engineering , Hong Kong University of Science and Technology , Clear Water Bay, Kowloon , Hong Kong SAR , China
| | - Hnin Y Y Nyein
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
| | - Mallika Bariya
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
| | - Wenbo Ji
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
| | - Mark Hettick
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
| | - Chunsong Zhao
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
| | - Jiangqi Zhao
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
| | - Lei Hou
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
| | - Zhen Yuan
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
| | - Zhiyong Fan
- Department of Electronic and Computer Engineering , Hong Kong University of Science and Technology , Clear Water Bay, Kowloon , Hong Kong SAR , China
| | - Ali Javey
- Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States
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Electrochemical biosensors for the detection and study of α-synuclein related to Parkinson's disease - A review. Anal Chim Acta 2019; 1089:32-39. [PMID: 31627816 DOI: 10.1016/j.aca.2019.09.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 09/01/2019] [Accepted: 09/04/2019] [Indexed: 12/11/2022]
Abstract
Parkinson's disease (PD) is a long-term degenerative disorder that affects predominately dopaminergic neurons in the substantia nigra, which mainly control movement. Alpha-synuclein (α-syn) is a major constituent of Lewy bodies that are reported to be the most important toxic species in the brain of PD patients. In this critical review, we highlight novel electrochemical biosensors that have been recently developed utilizing aptamers and antibodies in connection with various nanomaterials to study biomarkers related to PD such as α-syn. We also review several research articles that have utilized electrochemical biosensors to study the interaction of α-syn with biometals as well as small molecules such as clioquinol, (-)-epigallocatechin-3-gallate (EGCG) and baicalein. Due to the significant advances in nanomaterials in the past decade, electrochemical biosensors capable of detecting multiple biomarkers in clinically relevant samples in real-time have been achieved. This may facilitate the path towards commercialization of electrochemical biosensors for clinical applications and high-throughput screening of small molecules for structure-activity relationship (SAR) studies.
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Huang YY, Poniger S, Tsai CL, Tochon-Danguy HJ, Ackermann U, Yen RF. Three-step two-pot automated production of NCA [ 18F]FDOPA with FlexLab module. Appl Radiat Isot 2019; 158:108871. [PMID: 32113705 DOI: 10.1016/j.apradiso.2019.108871] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 08/05/2019] [Accepted: 08/21/2019] [Indexed: 01/12/2023]
Abstract
Automated three-step two-pot production of no-carrier-added (NCA) [18F]FDOPA was first implemented in the iPHASE FlexLab module. Decay-corrected radiochemical yield (RCY) of [18F]FDOPA synthesized by this method was 10~14% (n = 7) with a synthesis time of ~110 min [18F]FDOPA was obtained in > 95% of radiochemical purity with a molar activity of ~431 GBq/μmol. With the method successfully implementing on the commercial FlexLab module and its built-in step-by-step activity monitoring, further processes optimization would be achieved.
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Affiliation(s)
- Ya-Yao Huang
- PET Center, Department of Nuclear Medicine, National Taiwan University Hospital, 7, Chung-Shan S. Road, Taipei, 100, Taiwan.
| | - Stan Poniger
- Department of Molecular Imaging and Therapy, Austin Health, 145 Studley Road, Heidelberg, Victoria, 3084, Australia; iPHASE Technologies, 3 Cypress Ave, Glen Waverley, Victoria, 3150, Australia
| | - Chia-Ling Tsai
- PET Center, Department of Nuclear Medicine, National Taiwan University Hospital, 7, Chung-Shan S. Road, Taipei, 100, Taiwan
| | - Henri J Tochon-Danguy
- Department of Molecular Imaging and Therapy, Austin Health, 145 Studley Road, Heidelberg, Victoria, 3084, Australia; iPHASE Technologies, 3 Cypress Ave, Glen Waverley, Victoria, 3150, Australia
| | - Uwe Ackermann
- Department of Molecular Imaging and Therapy, Austin Health, 145 Studley Road, Heidelberg, Victoria, 3084, Australia
| | - Ruoh-Fang Yen
- PET Center, Department of Nuclear Medicine, National Taiwan University Hospital, 7, Chung-Shan S. Road, Taipei, 100, Taiwan; Molecular Imaging Center, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei, 106, Taiwan
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Arora S, Damle NA, Passah A, Sharma R, Goyal H, Arunraj ST, Gupta P, Jana M. Tracer Accumulation in Relation to Venous Thrombus on 18F-DOPA PET/CT in a Case of Persistent Hyperinsulinemic Hypoglycemia of Infancy. Nucl Med Mol Imaging 2019; 53:148-151. [PMID: 31057687 PMCID: PMC6473011 DOI: 10.1007/s13139-018-00568-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 12/10/2018] [Accepted: 12/26/2018] [Indexed: 10/27/2022] Open
Abstract
18F-DOPA PET/CT is commonly done in patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) to look for any focal lesion in the pancreas. We present the findings in a 20-day-old neonate with PHHI who underwent 18F-DOPA PET/CT. The scan showed diffuse uptake in the pancreas with no focal lesion, physiologic excretion into the genito-urinary system, and interestingly tracer accumulation was seen in the inferior vena cava and ilio-femoral veins which is a non-physiological site for tracer accumulation. The uptake corresponded to a large venous thrombus which was confirmed by a venous Doppler.
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Affiliation(s)
- Saurabh Arora
- Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Nishikant Avinash Damle
- Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Averilicia Passah
- Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Rajni Sharma
- Department of Paediatric Endocrinology, All India Institute of Medical Sciences, New Delhi, 110029 India
| | - Harish Goyal
- Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | | | - Priyanka Gupta
- Department of Paediatric Endocrinology, All India Institute of Medical Sciences, New Delhi, 110029 India
| | - Manisha Jana
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, 110029 India
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Abi-Dargham A. From "bedside" to "bench" and back: A translational approach to studying dopamine dysfunction in schizophrenia. Neurosci Biobehav Rev 2018; 110:174-179. [PMID: 30528375 DOI: 10.1016/j.neubiorev.2018.12.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 11/25/2018] [Accepted: 12/04/2018] [Indexed: 01/07/2023]
Abstract
Despite multiple lines of research, a mechanistic understanding of schizophrenia remains elusive. Neuroimaging studies have yielded observations that can be used in translational studies in animals to attempt to uncover their cellular and circuit basis and their significance for the diseased human brain. Enhanced D2 stimulation in the striatum is a well replicated and established observation in patients with schizophrenia. This "bedside" observation was reproduced "at the bench" level by creating a transgenic mouse overexpressing D2 receptors in dorsal striatum (D2R-OE mouse). The D2R-OE mouse showed multiple behavioral, molecular, electrophysiological and anatomical alterations. Some of these are consistent with findings in patients with schizophrenia, providing construct validity to the model and mechanistic insights for the observations made in humans. Other findings were novel, and provide an opportunity for a reverse translational effort back into the clinic. In this review we will summarize the process of translation and back translation from the D2R-OE mouse and describe the insights into the pathophysiology of the disease gained through this type of translational work.
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Affiliation(s)
- Anissa Abi-Dargham
- Departments of Psychiatry and Radiology, Stony Brook School of Medicine, HSC-T10-087H, 101 Nicolls Road, Stony Brook, NY, 11794-8101, United States.
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