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2. Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model

Author

Leuzy, Antoine, Raket, Lars Lau, Villemagne, Victor L, Klein, Gregory, Tonietto, Matteo, Olafson, Emily, Baker, Suzanne, Saad, Ziad S, Bullich, Santiago, Lopresti, Brian, Bohorquez, Sandra Sanabria, Boada, Mercè, Betthauser, Tobey J, Charil, Arnaud, Collins, Emily C, Collins, Jessica A, Cullen, Nicholas, Gunn, Roger N, Higuchi, Makoto, Hostetler, Eric, Hutchison, R Matthew, Iaccarino, Leonardo, Insel, Philip S, Irizarry, Michael C, Jack, Clifford R, Jagust, William J, Johnson, Keith A, Johnson, Sterling C, Karten, Yashmin, Marquié, Marta, Mathotaarachchi, Sulantha, Mintun, Mark A, Ossenkoppele, Rik, Pappas, Ioannis, Petersen, Ronald C, Rabinovici, Gil D, Rosa‐Neto, Pedro, Schwarz, Christopher G, Smith, Ruben, Stephens, Andrew W, Whittington, Alex, Carrillo, Maria C, Pontecorvo, Michael J, Haeberlein, Samantha Budd, Dunn, Billy, Kolb, Hartmuth C, Sivakumaran, Sudhir, Rowe, Christopher C, Hansson, Oskar, and Doré, Vincent

Subjects
Biological Psychology, Psychology, Biomedical Imaging, Neurodegenerative, Alzheimer's Disease, Brain Disorders, Dementia, Neurosciences, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Bioengineering, Aging, Neurological, Alzheimer Disease, Humans, Positron-Emission Tomography, tau Proteins, Brain, Male, Female, Aged, Cohort Studies, Radiopharmaceuticals, Models, Statistical, [F-18]Flortaucipir, [F-18]RO948, [F-18]MK-6240, [F-18]GTP1, [F-18]PI-2620, Alzheimer's disease, C-Path, CenTauR, Centiloid, CPAD, head-to-head, Imaging, PET, standardization, tau, C‐Path, [18F]Flortaucipir, [18F]GTP1, [18F]MK‐6240, [18F]PI‐2620, [18F]RO948, head‐to‐head, Clinical Sciences, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionTau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis.MethodsUsing head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale.ResultsA strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach.DiscussionPreliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification.HighlightsTested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

Published
2024

6. PET Parametric Imaging: Past, Present, and Future

Author

Wang, Guobao, Rahmim, Arman, and Gunn, Roger N

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Bioengineering, Biomedical Imaging, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Dynamic imaging, image reconstruction, kinetic modeling, parametric imaging, positron emission tomography, PET, dynamic imaging
Abstract

Positron emission tomography (PET) is actively used in a diverse range of applications in oncology, cardiology, and neurology. The use of PET in the clinical setting focuses on static (single time frame) imaging at a specific time-point post radiotracer injection and is typically considered as semi-quantitative; e.g. standardized uptake value (SUV) measures. In contrast, dynamic PET imaging requires increased acquisition times but has the advantage that it measures the full spatiotemporal distribution of a radiotracer and, in combination with tracer kinetic modeling, enables the generation of multiparametric images that more directly quantify underlying biological parameters of interest, such as blood flow, glucose metabolism, and receptor binding. Parametric images have the potential for improved detection and for more accurate and earlier therapeutic response assessment. Parametric imaging with dynamic PET has witnessed extensive research in the past four decades. In this paper, we provide an overview of past and present activities and discuss emerging opportunities in the field of parametric imaging for the future.

Published
2020

7. Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge

Author

Erritzoe, David, Godlewska, Beata R., Rizzo, Gaia, Searle, Graham E., Agnorelli, Claudio, Lewis, Yvonne, Ashok, Abhishekh H., Colasanti, Alessandro, Boura, Iro, Farrell, Chloe, Parfitt, Hollie, Howes, Oliver, Passchier, Jan, Gunn, Roger N., Politis, Marios, Nutt, David J., Cowen, Philip J., Knudsen, Gitte M., and Rabiner, Eugenii A.

Published
2023
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10. Relationship between astrocyte reactivity, using novel 11C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals

Author

Livingston, Nicholas R., Calsolaro, Valeria, Hinz, Rainer, Nowell, Joseph, Raza, Sanara, Gentleman, Steve, Tyacke, Robin J., Myers, Jim, Venkataraman, Ashwin V., Perneczky, Robert, Gunn, Roger N., Rabiner, Eugenii A., Parker, Christine A., Murphy, Philip S., Wren, Paul B., Nutt, David J., Matthews, Paul M., and Edison, Paul

Published
2022
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13. Discovery and clinical translation of ceperognastat, an O‐GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease.

Author

Kielbasa, William, Goldsmith, Paul, Donnelly, Kevin B., Nuthall, Hugh N., Shcherbinin, Sergey, Fleisher, Adam S., Hendle, Jörg, DuBois, Susan L., Lowe, Stephen L., Zhang, Feiyu Fred, Woerly, Eric M., Dreyfus, Nicolas J.‐F., Evans, David, Gilmore, Jeremy, Mancini, Michele, Constantinescu, Cristian C., Gunn, Roger N., Russell, David S., Collins, Emily C., and Brys, Miroslaw

Subjects
ALZHEIMER'S disease, TAUOPATHIES, CENTRAL nervous system, DRUG design, THERAPEUTICS, TAU proteins
Abstract

INTRODUCTION: The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O‐GlcNAcylation, an important post‐translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O‐GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O‐GlcNAcase (OGA) catalyzes the removal of O‐GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD. METHODS: A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure‐based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O‐GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy. RESULTS: Ceperognastat is a potent, central nervous system (CNS)‐penetrant, low‐dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat. DISCUSSION: Ceperognastat is an orally available, highly potent, CNS‐penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O‐GlcNAc‐tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program. Highlights: Ceperognastat is a highly potent, CNS‐penetrant OGA inhibitor.Ceperognastat is both orally available and CNS‐penetrant even when given at low doses.Ceperognastat can achieve > 95% OGA enzyme occupancy in the animal and human brain.Ceperognastat had an acceptable safety profile in Phase 1 clinical studies. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study

Author

Wilson, Heather, Dervenoulas, George, Pagano, Gennaro, Koros, Christos, Yousaf, Tayyabah, Picillo, Marina, Polychronis, Sotirios, Simitsi, Athina, Giordano, Beniamino, Chappell, Zachary, Corcoran, Benjamin, Stamelou, Maria, Gunn, Roger N, Pellecchia, Maria Teresa, Rabiner, Eugenii A, Barone, Paolo, Stefanis, Leonidas, and Politis, Marios

Published
2019
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19. The relationship between SV2A levels, neural activity, and cognitive function in healthy humans: A [11C]UCB-J PET and fMRI study

Author

Shatalina, Ekaterina, primary, Onwordi, Ellis Chika, additional, Whitehurst, Thomas, additional, Whittington, Alexander, additional, Mansur, Ayla, additional, Arumuham, Atheeshaan, additional, Statton, Ben, additional, Berry, Alaine, additional, Marques, Tiago Reis, additional, Gunn, Roger N., additional, Natesan, Sridhar, additional, Nour, Matthew M., additional, Rabiner, Eugenii A., additional, Wall, Matthew B., additional, and Howes, Oliver D., additional

Published
2024
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20. The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study

Author

Onwordi, Ellis Chika, Whitehurst, Thomas, Mansur, Ayla, Statton, Ben, Berry, Alaine, Quinlan, Marina, O’Regan, Declan P., Rogdaki, Maria, Marques, Tiago Reis, Rabiner, Eugenii A., Gunn, Roger N., Vernon, Anthony C., Natesan, Sridhar, and Howes, Oliver D.

Published
2021
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24. Estimating Braak stage from [18F]MK6240 PET scans

Author

Whittington, Alex, primary, Porat, Lily, additional, Christian, Bradley T., additional, Devanand, Devanand P., additional, Hostetler, Eric D., additional, Johnson, Keith A., additional, Johnson, Sterling C, additional, Klunk, William E, additional, Lao, Patrick J., additional, Rowe, Christopher C, additional, Devanarayan, Viswanath, additional, Reilhac, Anthonin, additional, Reyderman, Larisa, additional, Irizarry, Michael C., additional, Charil, Arnaud, additional, and Gunn, Roger N, additional

Published
2023
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26. Evaluation of Intraperitoneal [ 18 F]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity.

Author

Halff, Els F., Natesan, Sridhar, Bonsall, David R., Veronese, Mattia, Garcia-Hidalgo, Anna, Kokkinou, Michelle, Tang, Sac-Pham, Riggall, Laura J., Gunn, Roger N., Irvine, Elaine E., Withers, Dominic J., Wells, Lisa A., Howes, Oliver D., and Vasdev, Neil

Subjects
KETAMINE, DOPAMINE, DOPAMINERGIC neurons, POSITRON emission tomography, INTRACLASS correlation, METHYL aspartate receptors, JUGULAR vein, RADIOACTIVE tracers
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 K i Mod in a within-subject design of both administration routes, (iii) test-retest evaluation of K i Mod in a within-subject design of intraperitoneal radiotracer administration, and (iv) validation of K i 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 K i 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. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Guidelines for the content and format of PET brain data in publications and archives: A consensus paper

Author

Knudsen, Gitte M, Ganz, Melanie, Appelhoff, Stefan, Boellaard, Ronald, Bormans, Guy, Carson, Richard E, Catana, Ciprian, Doudet, Doris, Gee, Antony D, Greve, Douglas N, Gunn, Roger N, Halldin, Christer, Herscovitch, Peter, Huang, Henry, Keller, Sune H, Lammertsma, Adriaan A, Lanzenberger, Rupert, Liow, Jeih-San, Lohith, Talakad G, Lubberink, Mark, Lyoo, Chul H, Mann, J John, Matheson, Granville J, Nichols, Thomas E, Nørgaard, Martin, Ogden, Todd, Parsey, Ramin, Pike, Victor W, Price, Julie, Rizzo, Gaia, Rosa-Neto, Pedro, Schain, Martin, Scott, Peter JH, Searle, Graham, Slifstein, Mark, Suhara, Tetsuya, Talbot, Peter S, Thomas, Adam, Veronese, Mattia, Wong, Dean F, Yaqub, Maqsood, Zanderigo, Francesca, Zoghbi, Sami, and Innis, Robert B

Published
2020
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29. Disease-related patterns of in vivo pathology in Corticobasal syndrome

Author

Niccolini, Flavia, Wilson, Heather, Hirschbichler, Stephanie, Yousaf, Tayyabah, Pagano, Gennaro, Whittington, Alexander, Caminiti, Silvia P., Erro, Roberto, Holton, Janice L., Jaunmuktane, Zane, Esposito, Marcello, Martino, Davide, Abdul, Ali, Passchier, Jan, Rabiner, Eugenii A., Gunn, Roger N., Bhatia, Kailash P., Politis, Marios, and for the Alzheimer’s Disease Neuroimaging Initiative

Published
2018
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34. Brain Serotonin Release Is Reduced in Patients With Depression:A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge

Author

Erritzoe, David, Godlewska, Beata R., Rizzo, Gaia, Searle, Graham E., Agnorelli, Claudio, Lewis, Yvonne, Ashok, Abhishekh H., Colasanti, Alessandro, Boura, Iro, Farrell, Chloe, Parfitt, Hollie, Howes, Oliver, Passchier, Jan, Gunn, Roger N., Politis, Marios, Nutt, David J., Cowen, Philip J., Knudsen, Gitte M., Rabiner, Eugenii A., Erritzoe, David, Godlewska, Beata R., Rizzo, Gaia, Searle, Graham E., Agnorelli, Claudio, Lewis, Yvonne, Ashok, Abhishekh H., Colasanti, Alessandro, Boura, Iro, Farrell, Chloe, Parfitt, Hollie, Howes, Oliver, Passchier, Jan, Gunn, Roger N., Politis, Marios, Nutt, David J., Cowen, Philip J., Knudsen, Gitte M., and Rabiner, Eugenii A.

Published
2023

35. Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of Synaptic Vesicle Glycoprotein 2A

Author

Onwordi, Ellis Chika, primary, Whitehurst, Thomas, additional, Shatalina, Ekaterina, additional, Mansur, Ayla, additional, Arumuham, Atheeshaan, additional, Osugo, Martin, additional, Marques, Tiago Reis, additional, Jauhar, Sameer, additional, Gupta, Susham, additional, Mehrotra, Ravi, additional, Rabiner, Eugenii A., additional, Gunn, Roger N., additional, Natesan, Sridhar, additional, and Howes, Oliver D., additional

Published
2023
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36. Synaptic terminal density early in the course of schizophrenia: an in vivo UCB-J positron emission tomographic imaging study of synaptic vesicle glycoprotein 2A (SV2a)

Author

Onwordi, Ellis Chika, Whitehurst, Thomas, Shatalina, Ekaterina, Mansur, Ayla, Arumuham, Atheeshaan, Osugo, Martin, Reis Marques, Tiago, Jauhar, Sameer, Gupta, Susham, Mehrotra, Ravi, Rabiner, Eugenii A., Gunn, Roger N., Natesan, Sridhar, and Howes, Oliver

Abstract

BACKGROUND: The synaptic hypothesis is an influential theory of the pathoaetiology of schizophrenia. Supporting this, there is lower uptake of the synaptic terminal density marker UCB-J in patients with chronic schizophrenia compared to controls. However, it is unclear whether these differences are present early in the illness. To address this, we investigated [11C]UCB-J volume of distribution (VT) in antipsychotic-naïve/free patients with schizophrenia (SCZ) recruited from first-episode services compared to healthy volunteers (HV). METHODS: Forty-two volunteers (SCZ n = 21, HV n = 21) underwent [11C]UCB-J positron emission tomography to index [11C]UCB-J VT and distribution volume ratio (DVR) in the anterior cingulate, frontal, and dorsolateral prefrontal cortices, temporal, parietal and occipital lobes, hippocampus, thalamus and amygdala. Symptom severity was assessed in the SCZ group using the Positive and Negative Syndrome Scale (PANSS). RESULTS: We found no significant effects of group on [11C]UCB-J VT or DVR in most regions of interest (effect sizes from d=0.0 to 0.7, p>0.05), other than lower DVR in the temporal lobe (d=0.7, uncorrected p

Published
2023

40. A Generalised Spatio-Temporal Registration Framework for Dynamic PET Data: Application to Neuroreceptor Imaging

Author

Jiao, Jieqing, Schnabel, Julia A., Gunn, Roger N., Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Doug, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Mori, Kensaku, editor, Sakuma, Ichiro, editor, Sato, Yoshinobu, editor, Barillot, Christian, editor, and Navab, Nassir, editor

Published
2013
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41. Spatial-temporal Pharmacokinetic Model Based Registration of 4D Brain PET Data

Author

Jiao, Jieqing, Searle, Graham E., Tziortzi, Andri C., Salinas, Cristian A., Gunn, Roger N., Schnabel, Julia A., Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Doug, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Durrleman, Stanley, editor, Fletcher, Tom, editor, Gerig, Guido, editor, and Niethammer, Marc, editor

Published
2012
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42. A PET-CT study on neuroinflammation in Huntington’s disease patients participating in a randomized trial with laquinimod

Author

Roussakis, Andreas-Antonios, primary, Gennaro, Marta, additional, Gordon, Mark Forrest, additional, Reilmann, Ralf, additional, Borowsky, Beth, additional, Rynkowski, Gail, additional, Lao-Kaim, Nicholas P, additional, Papoutsou, Zoe, additional, Savola, Juha-Matti, additional, Hayden, Michael R, additional, Owen, David R, additional, Kalk, Nicola, additional, Lingford-Hughes, Anne, additional, Gunn, Roger N, additional, Searle, Graham, additional, Tabrizi, Sarah J, additional, and Piccini, Paola, additional

Published
2023
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48. In Vivo Head‐To‐Head Comparison of [ 18 F]GTP1 and [ 18 F]PI2620 in Alzheimer’s Disease

Author

Bohorquez, Sandra Sanabria, primary, Constantinescu, Cristian, additional, Manser, Paul T, additional, Gunn, Roger N, additional, Russell, David S, additional, Tonietto, Matteo, additional, Bullich, Santiago, additional, Stephens, Andrew W, additional, Mueller, Andre, additional, Klein, Gregory, additional, Teng, Edmond, additional, and Pickthorn, Karen, additional

Published
2022
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49. 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

Author

Halff, Els F., primary, Natesan, Sridhar, additional, Bonsall, David R., additional, Veronese, Mattia, additional, Garcia-Hidalgo, Anna, additional, Kokkinou, Michelle, additional, Tang, Sac-Pham, additional, Riggall, Laura J., additional, Gunn, Roger N., additional, Irvine, Elaine E., additional, Withers, Dominic J., additional, Wells, Lisa A., additional, and Howes, Oliver D., additional

Published
2022
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50. Neurons derived from individual early Alzheimer’s disease patients reflect their clinical vulnerability

Author

Ng, Bryan, primary, Rowland, Helen A, additional, Wei, Tina, additional, Arunasalam, Kanisa, additional, Hayes, Emma Mee, additional, Koychev, Ivan, additional, Hedegaard, Anne, additional, Ribe, Elena M, additional, Chan, Dennis, additional, Chessell, Tharani, additional, Ffytche, Dominic, additional, Gunn, Roger N, additional, Kocagoncu, Ece, additional, Lawson, Jennifer, additional, Malhotra, Paresh A, additional, Ridha, Basil H, additional, Rowe, James B, additional, Thomas, Alan J, additional, Zamboni, Giovanna, additional, Buckley, Noel J, additional, Cader, Zameel M, additional, Lovestone, Simon, additional, and Wade-Martins, Richard, additional

Published
2022
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