144 results on '"Zatcepin, A."'
Search Results
2. Enhancing predictability of IDH mutation status in glioma patients at initial diagnosis: a comparative analysis of radiomics from MRI, [18F]FET PET, and TSPO PET
- Author
-
Kaiser, Lena, Quach, S., Zounek, A. J., Wiestler, B., Zatcepin, A., Holzgreve, A., Bollenbacher, A., Bartos, L. M., Ruf, V. C., Böning, G., Thon, N., Herms, J., Riemenschneider, M. J., Stöcklein, S., Brendel, M., Rupprecht, R., Tonn, J. C., Bartenstein, P., von Baumgarten, L., Ziegler, S., and Albert, N. L.
- Published
- 2024
- Full Text
- View/download PDF
3. Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease
- Author
-
Artem Zatcepin, Johannes Gnörich, Boris-Stephan Rauchmann, Laura M. Bartos, Stephan Wagner, Nicolai Franzmeier, Maura Malpetti, Xianyuan Xiang, Yuan Shi, Samira Parhizkar, Maximilian Grosch, Karin Wind-Mark, Sebastian T. Kunte, Leonie Beyer, Carolin Meyer, Desirée Brösamle, Ann-Christin Wendeln, Collins Osei-Sarpong, Steffanie Heindl, Arthur Liesz, Sophia Stoecklein, Gloria Biechele, Anika Finze, Florian Eckenweber, Simon Lindner, Axel Rominger, Peter Bartenstein, Michael Willem, Sabina Tahirovic, Jochen Herms, Katharina Buerger, Mikael Simons, Christian Haass, Rainer Rupprecht, Markus J. Riemenschneider, Nathalie L. Albert, Marc Beyer, Jonas J. Neher, Lars Paeger, Johannes Levin, Günter U. Höglinger, Robert Perneczky, Sibylle I. Ziegler, and Matthias Brendel
- Subjects
Alzheimer’s disease ,Dementia ,Microglia ,Neuroinflammation ,TSPO ,PET ,Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. Methods To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Results Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Conclusion Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.
- Published
- 2024
- Full Text
- View/download PDF
4. Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease
- Author
-
Zatcepin, Artem, Gnörich, Johannes, Rauchmann, Boris-Stephan, Bartos, Laura M., Wagner, Stephan, Franzmeier, Nicolai, Malpetti, Maura, Xiang, Xianyuan, Shi, Yuan, Parhizkar, Samira, Grosch, Maximilian, Wind-Mark, Karin, Kunte, Sebastian T., Beyer, Leonie, Meyer, Carolin, Brösamle, Desirée, Wendeln, Ann-Christin, Osei-Sarpong, Collins, Heindl, Steffanie, Liesz, Arthur, Stoecklein, Sophia, Biechele, Gloria, Finze, Anika, Eckenweber, Florian, Lindner, Simon, Rominger, Axel, Bartenstein, Peter, Willem, Michael, Tahirovic, Sabina, Herms, Jochen, Buerger, Katharina, Simons, Mikael, Haass, Christian, Rupprecht, Rainer, Riemenschneider, Markus J., Albert, Nathalie L., Beyer, Marc, Neher, Jonas J., Paeger, Lars, Levin, Johannes, Höglinger, Günter U., Perneczky, Robert, Ziegler, Sibylle I., and Brendel, Matthias
- Published
- 2024
- Full Text
- View/download PDF
5. Machine learning-based approach reveals essential features for simplified TSPO PET quantification in ischemic stroke patients
- Author
-
Artem Zatcepin, Anna Kopczak, Adrien Holzgreve, Sandra Hein, Andreas Schindler, Marco Duering, Lena Kaiser, Simon Lindner, Martin Schidlowski, Peter Bartenstein, Nathalie Albert, Matthias Brendel, and Sibylle I. Ziegler
- Subjects
Quantitative PET ,TSPO ,Ischemic stroke ,GE180 ,Image-derived input function ,Machine learning ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Introduction: Neuroinflammation evaluation after acute ischemic stroke is a promising option for selecting an appropriate post-stroke treatment strategy. To assess neuroinflammation in vivo, translocator protein PET (TSPO PET) can be used. However, the gold standard TSPO PET quantification method includes a 90 min scan and continuous arterial blood sampling, which is challenging to perform on a routine basis. In this work, we determine what information is required for a simplified quantification approach using a machine learning algorithm. Materials and Methods: We analyzed data from 18 patients with ischemic stroke who received 0–90 min [18F]GE-180 PET as well as T1-weigted (T1w), FLAIR, and arterial spin labeling (ASL) MRI scans. During PET scans, five manual venous blood samples at 5, 15, 30, 60, and 85 min post injection (p.i.) were drawn, and plasma activity concentration was measured. Total distribution volume (VT) was calculated using Logan plot with the full dynamic PET and an image-derived input function (IDIF) from the carotid arteries. IDIF was scaled by a calibration factor derived from all the measured plasma activity concentrations. The calculated VT values were used for training a random forest regressor. As input features for the model, we used three late PET frames (60–70, 70–80, and 80–90 min p.i.), the ASL image reflecting perfusion, the voxel coordinates, the lesion mask, and the five plasma activity concentrations. The algorithm was validated with the leave-one-out approach. To estimate the impact of the individual features on the algorithm’s performance, we used Shapley Additive Explanations (SHAP). Having determined that the three late PET frames and the plasma activity concentrations were the most important features, we tested a simplified quantification approach consisting of dividing a late PET frame by a plasma activity concentration. All the combinations of frames/samples were compared by means of concordance correlation coefficient and Bland-Altman plots. Results: When using all the input features, the algorithm predicted VT values with high accuracy (87.8 ± 8.3%) for both lesion and non-lesion voxels. The SHAP values demonstrated high impact of the late PET frames (60–70, 70–80, and 80–90 min p.i.) and plasma activity concentrations on the VT prediction, while the influence of the ASL-derived perfusion, voxel coordinates, and the lesion mask was low. Among all the combinations of the late PET frames and plasma activity concentrations, the 70–80 min p.i. frame divided by the 30 min p.i. plasma sample produced the closest VT estimate in the ischemic lesion. Conclusion: Reliable TSPO PET quantification is achievable by using a single late PET frame divided by a late blood sample activity concentration.
- Published
- 2024
- Full Text
- View/download PDF
6. Astroglial glucose uptake determines brain FDG-PET alterations and metabolic connectivity during healthy aging in mice
- Author
-
Laura M. Bartos, Sebastian T. Kunte, Stephan Wagner, Philipp Beumers, Rebecca Schaefer, Artem Zatcepin, Yunlei Li, Maria Griessl, Leonie Hoermann, Karin Wind-Mark, Peter Bartenstein, Sabina Tahirovic, Sibylle Ziegler, Matthias Brendel, and Johannes Gnörich
- Subjects
FDG-PET ,Aging ,Astroglia ,Metabolic connectivity ,Scradiotracing ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Purpose: 2-Fluorodeoxyglucose-PET (FDG-PET) is a powerful tool to study glucose metabolism in mammalian brains, but cellular sources of glucose uptake and metabolic connectivity during aging are not yet understood. Methods: Healthy wild-type mice of both sexes (2–21 months of age) received FDG-PET and cell sorting after in vivo tracer injection (scRadiotracing). FDG uptake per cell was quantified in isolated microglia, astrocytes and neurons. Cerebral FDG uptake and metabolic connectivity were determined by PET. A subset of mice received measurement of blood glucose levels to study associations with cellular FDG uptake during aging. Results: Cerebral FDG-PET signals in healthy mice increased linearly with age. Cellular FDG uptake of neurons increased between 2 and 12 months of age, followed by a strong decrease towards late ages. Contrarily, FDG uptake in microglia and astrocytes exhibited a U-shaped function with respect to age, comprising the predominant cellular source of higher cerebral FDG uptake in the later stages. Metabolic connectivity was closely associated with the ratio of glucose uptake in astroglial cells relative to neurons. Cellular FDG uptake was not associated with blood glucose levels and increasing FDG brain uptake as a function of age was still observed after adjusting for blood glucose levels. Conclusion: Trajectories of astroglial glucose uptake drive brain FDG-PET alterations and metabolic connectivity during aging.
- Published
- 2024
- Full Text
- View/download PDF
7. Towards multicenter β-amyloid PET imaging in mouse models: A triple scanner head-to-head comparison
- Author
-
Johannes Gnörich, Mara Koehler, Karin Wind-Mark, Carolin Klaus, Artem Zatcepin, Giovanna Palumbo, Manvir Lalia, Laura Sebastian Monasor, Leonie Beyer, Florian Eckenweber, Maximilian Scheifele, Franz-Josef Gildehaus, Barbara von Ungern-Sternberg, Henryk Barthel, Osama Sabri, Peter Bartenstein, Jochen Herms, Sabina Tahirovic, Nicolai Franzmeier, Sibylle Ziegler, and Matthias Brendel
- Subjects
None ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Aim: β-amyloid (Aβ) small animal PET facilitates quantification of fibrillar amyloidosis in Alzheimer's disease (AD) mouse models. Thus, the methodology is receiving growing interest as a monitoring tool in preclinical drug trials. In this regard, harmonization of data from different scanners at multiple sites would allow the establishment large collaborative cohorts and may facilitate efficacy comparison of different treatments. Therefore, we objected to determine the level of agreement of Aβ-PET quantification by a head-to-head comparison of three different state-of-the-art small animal PET scanners, which could help pave the way for future multicenter studies. Methods: Within a timeframe of 5 ± 2 weeks, transgenic APPPS1 (n = 9) and wild-type (WT) (n = 8) mice (age range: 13–16 months) were examined three times by Aβ-PET ([18F]florbetaben) using a Siemens Inveon DPET, a MedisonanoScan PET/MR, and a MedisonanoScan PET/CT with harmonized reconstruction protocols. Cortex-to-white-matter 30–60 min p.i. standardized uptake value ratios (SUVRCTX/WM) were calculated to compare binding differences, effect sizes (Cohen's d) and z-score values of APPPS1 relative to WT mice. Correlation coefficients (Pearson's r) were calculated for the agreement of individual SUVR between different scanners. Voxel-wise analysis was used to determine the agreement of spatial pathology patterns. For validation of PET imaging against the histological gold standard, individual SUVR values were subject to a correlation analysis with area occupancy of methoxy‑X04 staining. Results: All three small animal PET scanners yielded comparable group differences between APPPS1 and WT mice (∆PET=20.4 % ± 2.9 %, ∆PET/MR=18.4 % ± 4.5 %, ∆PET/CT=18.1 % ± 3.3 %). Voxel-wise analysis confirmed a high degree of congruency of the spatial pattern (Dice coefficient (DC)PETvs.PET/MR=83.0 %, DCPETvs.PET/CT=69.3 %, DCPET/MRvs.PET/CT=81.9 %). Differences in the group level variance of the three scanners resulted in divergent z-scores (zPET=11.5 ± 1.6; zPET/MR=5.3 ± 1.3; zPET/CT=3.4 ± 0.6) and effect sizes (dPET=8.5, dPET/MR=4.5, dPET/CT=4.1). However, correlations at the individual mouse level were still strong between scanners (rPETvs.PET/MR=0.96, rPETvs.PET/CT=0.91, rPET/MRvs.PET/CT=0.87; all p ≤ 0.0001). Methoxy-X04 staining exhibited a significant correlation across all three PET machines combined (r = 0.76, p < 0.0001) but also at individual level (PET: r = 0.81, p = 0.026; PET/MR: r = 0.89, p = 0.0074; PET/CT: r = 0.93, p = 0.0028). Conclusions: Our comparison of standardized small animal Aβ-PET acquired by three different scanners substantiates the possibility of moving towards a multicentric approach in preclinical AD research. The alignment of image acquisition and analysis methods achieved good overall comparability between data sets. Nevertheless, differences in variance of sensitivity and specificity of different scanners may limit data interpretation at the individual mouse level and deserves methodological optimization.
- Published
- 2024
- Full Text
- View/download PDF
8. Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia
- Author
-
Xia, Dan, Lianoglou, Steve, Sandmann, Thomas, Calvert, Meredith, Suh, Jung H, Thomsen, Elliot, Dugas, Jason, Pizzo, Michelle E, DeVos, Sarah L, Earr, Timothy K, Lin, Chia-Ching, Davis, Sonnet, Ha, Connie, Leung, Amy Wing-Sze, Nguyen, Hoang, Chau, Roni, Yulyaningsih, Ernie, Lopez, Isabel, Solanoy, Hilda, Masoud, Shababa T, Liang, Chun-chi, Lin, Karin, Astarita, Giuseppe, Khoury, Nathalie, Zuchero, Joy Yu, Thorne, Robert G, Shen, Kevin, Miller, Stephanie, Palop, Jorge J, Garceau, Dylan, Sasner, Michael, Whitesell, Jennifer D, Harris, Julie A, Hummel, Selina, Gnörich, Johannes, Wind, Karin, Kunze, Lea, Zatcepin, Artem, Brendel, Matthias, Willem, Michael, Haass, Christian, Barnett, Daniel, Zimmer, Till S, Orr, Anna G, Scearce-Levie, Kimberly, Lewcock, Joseph W, Di Paolo, Gilbert, and Sanchez, Pascal E
- Subjects
Neurosciences ,Aging ,Acquired Cognitive Impairment ,Alzheimer's Disease ,Biotechnology ,Genetics ,Neurodegenerative ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Alzheimer Disease ,Amyloid beta-Peptides ,Amyloid beta-Protein Precursor ,Amyloidosis ,Animals ,Brain ,Disease Models ,Animal ,Mice ,Mice ,Transgenic ,Microglia ,Plaque ,Amyloid ,Receptors ,GABA ,Neuritic plaques ,Vascular amyloid ,Neurodegeneration ,Astrogliosis ,Phagocytic microglia ,Lipid dyshomeostasis ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
BackgroundGenetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain.MethodsWe engineered a novel App knock-in mouse model (AppSAA) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous AppSAA mice at different ages in brain and/ or biofluids. Wild type littermate mice were used as experimental controls. We used in situ imaging technologies to define the whole-brain distribution of amyloid plaques and compare it to other AD mouse models and human brain pathology. To further explore the microglial response to AD relevant pathology, we isolated microglia with fibrillar Aβ content from the brain and performed transcriptomics and metabolomics analyses and in vivo brain imaging to measure energy metabolism and microglial response. Finally, we also characterized the mice in various behavioral assays.ResultsLeveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The AppSAA knock-in mouse model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of CSF markers of neurodegeneration. Those observations were associated with increased TSPO and FDG-PET brain signals and a hyperactivity phenotype as the animals aged.DiscussionOur findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology.
- Published
- 2022
9. Astroglial glucose uptake determines brain FDG-PET alterations and metabolic connectivity during healthy aging in mice
- Author
-
Bartos, Laura M., Kunte, Sebastian T., Wagner, Stephan, Beumers, Philipp, Schaefer, Rebecca, Zatcepin, Artem, Li, Yunlei, Griessl, Maria, Hoermann, Leonie, Wind-Mark, Karin, Bartenstein, Peter, Tahirovic, Sabina, Ziegler, Sibylle, Brendel, Matthias, and Gnörich, Johannes
- Published
- 2024
- Full Text
- View/download PDF
10. Towards multicenter β-amyloid PET imaging in mouse models: A triple scanner head-to-head comparison
- Author
-
Gnörich, Johannes, Koehler, Mara, Wind-Mark, Karin, Klaus, Carolin, Zatcepin, Artem, Palumbo, Giovanna, Lalia, Manvir, Monasor, Laura Sebastian, Beyer, Leonie, Eckenweber, Florian, Scheifele, Maximilian, Gildehaus, Franz-Josef, von Ungern-Sternberg, Barbara, Barthel, Henryk, Sabri, Osama, Bartenstein, Peter, Herms, Jochen, Tahirovic, Sabina, Franzmeier, Nicolai, Ziegler, Sibylle, and Brendel, Matthias
- Published
- 2024
- Full Text
- View/download PDF
11. Machine learning-based approach reveals essential features for simplified TSPO PET quantification in ischemic stroke patients
- Author
-
Zatcepin, Artem, Kopczak, Anna, Holzgreve, Adrien, Hein, Sandra, Schindler, Andreas, Duering, Marco, Kaiser, Lena, Lindner, Simon, Schidlowski, Martin, Bartenstein, Peter, Albert, Nathalie, Brendel, Matthias, and Ziegler, Sibylle I.
- Published
- 2024
- Full Text
- View/download PDF
12. Depletion and activation of microglia impact metabolic connectivity of the mouse brain
- Author
-
Gnörich, Johannes, Reifschneider, Anika, Wind, Karin, Zatcepin, Artem, Kunte, Sebastian T., Beumers, Philipp, Bartos, Laura M., Wiedemann, Thomas, Grosch, Maximilian, Xiang, Xianyuan, Fard, Maryam K., Ruch, Francois, Werner, Georg, Koehler, Mara, Slemann, Luna, Hummel, Selina, Briel, Nils, Blume, Tanja, Shi, Yuan, Biechele, Gloria, Beyer, Leonie, Eckenweber, Florian, Scheifele, Maximilian, Bartenstein, Peter, Albert, Nathalie L., Herms, Jochen, Tahirovic, Sabina, Haass, Christian, Capell, Anja, Ziegler, Sibylle, and Brendel, Matthias
- Published
- 2023
- Full Text
- View/download PDF
13. [18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data
- Author
-
Ballweg, Anna, Klaus, Carolin, Vogler, Letizia, Katzdobler, Sabrina, Wind, Karin, Zatcepin, Artem, Ziegler, Sibylle I., Secgin, Birkan, Eckenweber, Florian, Bohr, Bernd, Bernhardt, Alexander, Fietzek, Urban, Rauchmann, Boris-Stephan, Stoecklein, Sophia, Quach, Stefanie, Beyer, Leonie, Scheifele, Maximilian, Simmet, Marcel, Joseph, Emanuel, Lindner, Simon, Berg, Isabella, Koglin, Norman, Mueller, Andre, Stephens, Andrew W., Bartenstein, Peter, Tonn, Joerg C., Albert, Nathalie L., Kümpfel, Tania, Kerschensteiner, Martin, Perneczky, Robert, Levin, Johannes, Paeger, Lars, Herms, Jochen, and Brendel, Matthias
- Published
- 2023
- Full Text
- View/download PDF
14. Validity and value of metabolic connectivity in mouse models of β-amyloid and tauopathy
- Author
-
François Ruch, Johannes Gnörich, Karin Wind, Mara Köhler, Artem Zatcepin, Thomas Wiedemann, Franz-Joseph Gildehaus, Simon Lindner, Guido Boening, Barbara von Ungern-Sternberg, Leonie Beyer, Jochen Herms, Peter Bartenstein, Matthias Brendel, and Florian Eckenweber
- Subjects
Alzheimer's disease ,Metabolic connectivity ,Amyloidosis ,Tauopathy ,Small-animal PET ,Morris water maze ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Among functional imaging methods, metabolic connectivity (MC) is increasingly used for investigation of regional network changes to examine the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) or movement disorders. Hitherto, MC was mostly used in clinical studies, but only a few studies demonstrated the usefulness of MC in the rodent brain. The goal of the current work was to analyze and validate metabolic regional network alterations in three different mouse models of neurodegenerative diseases (β-amyloid and tau) by use of 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) imaging. We compared the results of FDG-µPET MC with conventional VOI-based analysis and behavioral assessment in the Morris water maze (MWM). The impact of awake versus anesthesia conditions on MC read-outs was studied and the robustness of MC data deriving from different scanners was tested. MC proved to be an accurate and robust indicator of functional connectivity loss when sample sizes ≥12 were considered. MC readouts were robust across scanners and in awake/ anesthesia conditions. MC loss was observed throughout all brain regions in tauopathy mice, whereas β-amyloid indicated MC loss mainly in spatial learning areas and subcortical networks. This study established a methodological basis for the utilization of MC in different β-amyloid and tau mouse models. MC has the potential to serve as a read-out of pathological changes within neuronal networks in these models.
- Published
- 2024
- Full Text
- View/download PDF
15. Validity and value of metabolic connectivity in mouse models of β-amyloid and tauopathy
- Author
-
Ruch, François, Gnörich, Johannes, Wind, Karin, Köhler, Mara, Zatcepin, Artem, Wiedemann, Thomas, Gildehaus, Franz-Joseph, Lindner, Simon, Boening, Guido, von Ungern-Sternberg, Barbara, Beyer, Leonie, Herms, Jochen, Bartenstein, Peter, Brendel, Matthias, and Eckenweber, Florian
- Published
- 2024
- Full Text
- View/download PDF
16. [18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data
- Author
-
Anna Ballweg, Carolin Klaus, Letizia Vogler, Sabrina Katzdobler, Karin Wind, Artem Zatcepin, Sibylle I. Ziegler, Birkan Secgin, Florian Eckenweber, Bernd Bohr, Alexander Bernhardt, Urban Fietzek, Boris-Stephan Rauchmann, Sophia Stoecklein, Stefanie Quach, Leonie Beyer, Maximilian Scheifele, Marcel Simmet, Emanuel Joseph, Simon Lindner, Isabella Berg, Norman Koglin, Andre Mueller, Andrew W. Stephens, Peter Bartenstein, Joerg C. Tonn, Nathalie L. Albert, Tania Kümpfel, Martin Kerschensteiner, Robert Perneczky, Johannes Levin, Lars Paeger, Jochen Herms, and Matthias Brendel
- Subjects
MAO-B ,PET ,Astrocytes ,Deprenyl ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objectives Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. Methods A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3–21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and β-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer’s disease continuum (AD, n = 2), Parkinson’s disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. Results We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p
- Published
- 2023
- Full Text
- View/download PDF
17. Detectors in positron emission tomography
- Author
-
Artem Zatcepin and Sibylle I. Ziegler
- Subjects
Positron emission tomography (PET) ,PET detectors ,Avalanche photodiode ,Silicon photomultiplier ,Photomultiplier tubes ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Positron emission tomography is a highly sensitive molecular imaging modality, based on the coincident detection of annihilation photons after positron decay. The most used detector is based on dense, fast, and luminous scintillators read out by light sensors. This review covers the various detector concepts for clinical and preclinical systems.
- Published
- 2023
- Full Text
- View/download PDF
18. Depletion and activation of microglia impact metabolic connectivity of the mouse brain
- Author
-
Johannes Gnörich, Anika Reifschneider, Karin Wind, Artem Zatcepin, Sebastian T. Kunte, Philipp Beumers, Laura M. Bartos, Thomas Wiedemann, Maximilian Grosch, Xianyuan Xiang, Maryam K. Fard, Francois Ruch, Georg Werner, Mara Koehler, Luna Slemann, Selina Hummel, Nils Briel, Tanja Blume, Yuan Shi, Gloria Biechele, Leonie Beyer, Florian Eckenweber, Maximilian Scheifele, Peter Bartenstein, Nathalie L. Albert, Jochen Herms, Sabina Tahirovic, Christian Haass, Anja Capell, Sibylle Ziegler, and Matthias Brendel
- Subjects
FDG–PET ,Neurodegeneration ,Microglia ,Metabolic connectivity ,scRadiotracing ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Highlights Microglial activation influences metabolic connectivity. Microglial depletion results in distinct decreases of metabolic connectivity. Metabolic connectivity increases in progranulin deficient mice. Cellular FDG allocation in progranulin deficient mice is shifted to microglia.
- Published
- 2023
- Full Text
- View/download PDF
19. Distinct molecular profiles of skull bone marrow in health and neurological disorders
- Author
-
Kolabas, Zeynep Ilgin, Kuemmerle, Louis B., Perneczky, Robert, Förstera, Benjamin, Ulukaya, Selin, Ali, Mayar, Kapoor, Saketh, Bartos, Laura M., Büttner, Maren, Caliskan, Ozum Sehnaz, Rong, Zhouyi, Mai, Hongcheng, Höher, Luciano, Jeridi, Denise, Molbay, Muge, Khalin, Igor, Deligiannis, Ioannis K., Negwer, Moritz, Roberts, Kenny, Simats, Alba, Carofiglio, Olga, Todorov, Mihail I., Horvath, Izabela, Ozturk, Furkan, Hummel, Selina, Biechele, Gloria, Zatcepin, Artem, Unterrainer, Marcus, Gnörich, Johannes, Roodselaar, Jay, Shrouder, Joshua, Khosravani, Pardis, Tast, Benjamin, Richter, Lisa, Díaz-Marugán, Laura, Kaltenecker, Doris, Lux, Laurin, Chen, Ying, Zhao, Shan, Rauchmann, Boris-Stephan, Sterr, Michael, Kunze, Ines, Stanic, Karen, Kan, Vanessa W.Y., Besson-Girard, Simon, Katzdobler, Sabrina, Palleis, Carla, Schädler, Julia, Paetzold, Johannes C., Liebscher, Sabine, Hauser, Anja E., Gokce, Ozgun, Lickert, Heiko, Steinke, Hanno, Benakis, Corinne, Braun, Christian, Martinez-Jimenez, Celia P., Buerger, Katharina, Albert, Nathalie L., Höglinger, Günter, Levin, Johannes, Haass, Christian, Kopczak, Anna, Dichgans, Martin, Havla, Joachim, Kümpfel, Tania, Kerschensteiner, Martin, Schifferer, Martina, Simons, Mikael, Liesz, Arthur, Krahmer, Natalie, Bayraktar, Omer A., Franzmeier, Nicolai, Plesnila, Nikolaus, Erener, Suheda, Puelles, Victor G., Delbridge, Claire, Bhatia, Harsharan Singh, Hellal, Farida, Elsner, Markus, Bechmann, Ingo, Ondruschka, Benjamin, Brendel, Matthias, Theis, Fabian J., and Erturk, Ali
- Published
- 2023
- Full Text
- View/download PDF
20. Detectors in positron emission tomography
- Author
-
Zatcepin, Artem and Ziegler, Sibylle I.
- Published
- 2023
- Full Text
- View/download PDF
21. Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia
- Author
-
Dan Xia, Steve Lianoglou, Thomas Sandmann, Meredith Calvert, Jung H. Suh, Elliot Thomsen, Jason Dugas, Michelle E. Pizzo, Sarah L. DeVos, Timothy K. Earr, Chia-Ching Lin, Sonnet Davis, Connie Ha, Amy Wing-Sze Leung, Hoang Nguyen, Roni Chau, Ernie Yulyaningsih, Isabel Lopez, Hilda Solanoy, Shababa T. Masoud, Chun-chi Liang, Karin Lin, Giuseppe Astarita, Nathalie Khoury, Joy Yu Zuchero, Robert G. Thorne, Kevin Shen, Stephanie Miller, Jorge J. Palop, Dylan Garceau, Michael Sasner, Jennifer D. Whitesell, Julie A. Harris, Selina Hummel, Johannes Gnörich, Karin Wind, Lea Kunze, Artem Zatcepin, Matthias Brendel, Michael Willem, Christian Haass, Daniel Barnett, Till S. Zimmer, Anna G. Orr, Kimberly Scearce-Levie, Joseph W. Lewcock, Gilbert Di Paolo, and Pascal E. Sanchez
- Subjects
Neuritic plaques ,Vascular amyloid ,Neurodegeneration ,Astrogliosis ,Phagocytic microglia ,Lipid dyshomeostasis ,Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background Genetic mutations underlying familial Alzheimer’s disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain. Methods We engineered a novel App knock-in mouse model (App SAA) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous App SAA mice at different ages in brain and/ or biofluids. Wild type littermate mice were used as experimental controls. We used in situ imaging technologies to define the whole-brain distribution of amyloid plaques and compare it to other AD mouse models and human brain pathology. To further explore the microglial response to AD relevant pathology, we isolated microglia with fibrillar Aβ content from the brain and performed transcriptomics and metabolomics analyses and in vivo brain imaging to measure energy metabolism and microglial response. Finally, we also characterized the mice in various behavioral assays. Results Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The App SAA knock-in mouse model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of CSF markers of neurodegeneration. Those observations were associated with increased TSPO and FDG-PET brain signals and a hyperactivity phenotype as the animals aged. Discussion Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology.
- Published
- 2022
- Full Text
- View/download PDF
22. Assessment of [18F]PI-2620 Tau-PET Quantification via Non-Invasive Automatized Image Derived Input Function.
- Author
-
Meindl, Maria, Zatcepin, Artem, Gnörich, Johannes, Scheifele, Maximilian, Zaganjori, Mirlind, Groß, Mattes, Lindner, Simon, Schaefer, Rebecca, Simmet, Marcel, Roemer, Sebastian, Katzdobler, Sabrina, Levin, Johannes, Höglinger, Günter, Bischof, Ann-Cathrin, Barthel, Henryk, Sabri, Osama, Bartenstein, Peter, Saller, Thomas, Franzmeier, Nicolai, and Ziegler, Sibylle
- Subjects
- *
PROGRESSIVE supranuclear palsy , *POSITRON emission tomography , *ALZHEIMER'S disease , *GLOBUS pallidus , *CAROTID artery - Abstract
Purpose: [18F]PI-2620 positron emission tomography (PET) detects misfolded tau in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). We questioned the feasibility and value of absolute [18F]PI-2620 PET quantification for assessing tau by regional distribution volumes (VT). Here, arterial input functions (AIF) represent the gold standard, but cannot be applied in routine clinical practice, whereas image-derived input functions (IDIF) represent a non-invasive alternative. We aimed to validate IDIF against AIF and we evaluated the potential to discriminate patients with PSP and AD from healthy controls by non-invasive quantification of [18F] PET. Methods: In the first part of the study, we validated AIF derived from radial artery whole blood against IDIF by investigating 20 subjects (ten controls and ten patients). IDIF were generated by manual extraction of the carotid artery using the average and the five highest (max5) voxel intensity values and by automated extraction of the carotid artery using the average and the maximum voxel intensity value. In the second part of the study, IDIF quantification using the IDIF with the closest match to the AIF was transferred to group comparison of a large independent cohort of 40 subjects (15 healthy controls, 15 PSP patients and 10 AD patients). We compared VT and VT ratios, both calculated by Logan plots, with distribution volume (DV) ratios using simplified reference tissue modelling and standardized uptake value (SUV) ratios. Results: AIF and IDIF showed highly correlated input curves for all applied IDIF extraction methods (0.78 < r < 0.83, all p < 0.0001; area under the curves (AUC): 0.73 < r ≤ 0.82, all p ≤ 0.0003). Regarding the VT values, correlations were mainly found between those generated by the AIF and by the IDIF methods using the maximum voxel intensity values. Lowest relative differences (RD) were observed by applying the manual method using the five highest voxel intensity values (max5) (AIF vs. IDIF manual, avg: RD = -82%; AIF vs. IDIF automated, avg: RD = -86%; AIF vs. IDIF manual, max5: RD = -6%; AIF vs. IDIF automated, max: RD = -26%). Regional VT values revealed considerable variance at group level, which was strongly reduced upon scaling by the inferior cerebellum. The resulting VT ratio values were adequate to detect group differences between patients with PSP or AD and healthy controls (HC) (PSP target region (globus pallidus): HC vs. PSP vs. AD: 1.18 vs. 1.32 vs. 1.16; AD target region (Braak region I): HC vs. PSP vs. AD: 1.00 vs. 1.00 vs. 1.22). VT ratios and DV ratios outperformed SUV ratios and VT in detecting differences between PSP and healthy controls, whereas all quantification approaches performed similarly in comparing AD and healthy controls. Conclusion: Blood-free IDIF is a promising approach for quantification of [18F]PI-2620 PET, serving as correlating surrogate for invasive continuous arterial blood sampling. Regional [18F]PI-2620 VT show large variance, in contrast to regional [18F]PI-2620 VT ratios scaled with the inferior cerebellum, which are appropriate for discriminating PSP, AD and healthy controls. DV ratios obtained by simplified reference tissue modeling are similarly suitable for this purpose. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
23. 18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model
- Author
-
Laura M. Bartos, Sabrina V. Kirchleitner, Jens Blobner, Karin Wind, Lea H. Kunze, Adrien Holzgreve, Lukas Gold, Artem Zatcepin, Zeynep Ilgin Kolabas, Selin Ulukaya, Lorraine Weidner, Stefanie Quach, Denise Messerer, Peter Bartenstein, Joerg C. Tonn, Markus J. Riemenschneider, Sibylle Ziegler, Louisa von Baumgarten, Nathalie L. Albert, and Matthias Brendel
- Subjects
TSPO ,PET ,glioblastoma ,mouse model ,SB28 ,Medicine (General) ,R5-920 - Abstract
IntroductionThe 18 kDa translocator protein (TSPO) receives growing interest as a biomarker in glioblastoma. Mouse models can serve as an important tool for the investigation of biomarkers in glioblastoma, but several glioblastoma models indicated only low TSPO-PET signals in contrast to high TSPO-PET signals of human glioblastoma. Thus, we aimed to investigate TSPO-PET imaging in the syngeneic immunocompetent SB28 mouse model, which is thought to closely represent the tumor microenvironment (TME) of human glioblastoma.MethodsDynamic TSPO-PET/CT imaging was performed for 60 min after injection of 13.6 ± 4.2 MBq [18F]GE-180. Contrast enhanced CT (ceCT) was acquired prior to PET and served for assessment of tumor volumes and attenuation correction. SB28 and sham mice were imaged at an early (week-1; n = 6 SB28, n = 6 sham) and a late time-point (week-3; n = 8 SB28, n = 9 sham) after inoculation. Standard of truth ex vivo tumor volumes were obtained for SB28 mice at the late time-point. Tracer kinetics were analyzed for the lesion site and the carotid arteries to establish an image derived input function (IDIF). TSPO-PET and ceCT lesion volumes were compared with ex vivo volumes by calculation of root-mean-square-errors (RMSE). Volumes of distribution (VTmax/mean) in the lesion were calculated using carotid IDIF and standardized uptake values (SUVmax/mean) were obtained for a 40–60 min time frame.ResultsHigher uptake rate constants (K1) were observed for week-1 SB28 tumor lesions when compared to week-3 SB28 tumor lesions. Highest agreement between TSPO-PET lesion volumes and ex vivo tumor volumes was achieved with a 50% maximum threshold (RMSE-VT: 39.7%; RMSE-SUV: 34.4%), similar to the agreement of ceCT tumor volumes (RMSE: 30.1%). Lesions of SB28 mice had higher PET signal when compared to sham mice at week-1 (VTmax 6.6 ± 2.9 vs. 3.9 ± 0.8, p = 0.035; SUVmax 2.3 ± 0.5 vs. 1.2 ± 0.1, p < 0.001) and PET signals remained at a similar level at week-3 (VTmax 5.0 ± 1.6 vs. 2.7 ± 0.8, p = 0.029; SUVmax 1.9 ± 0.5 vs. 1.2 ± 0.2, p = 0.0012). VTmax correlated with SUVmax (R2 = 0.532, p < 0.001).ConclusionTSPO-PET imaging of immunocompetent SB28 mice facilitates early detection of tumor signals over sham lesions. SB28 tumors mirror high TSPO-PET signals of human glioblastoma and could serve as a valuable translational model to study TSPO as an imaging biomarker.
- Published
- 2022
- Full Text
- View/download PDF
24. Enhancing predictability of IDH mutation status in glioma patients at initial diagnosis: a comparative analysis of radiomics from MRI, [18F]FET PET, and TSPO PET.
- Author
-
Kaiser, Lena, Quach, S., Zounek, A. J., Wiestler, B., Zatcepin, A., Holzgreve, A., Bollenbacher, A., Bartos, L. M., Ruf, V. C., Böning, G., Thon, N., Herms, J., Riemenschneider, M. J., Stöcklein, S., Brendel, M., Rupprecht, R., Tonn, J. C., Bartenstein, P., von Baumgarten, L., and Ziegler, S.
- Subjects
POSITRON emission tomography ,RADIOMICS ,CENTRAL nervous system tumors ,RECEIVER operating characteristic curves ,MAGNETIC resonance imaging ,FEATURE extraction - Abstract
Purpose: According to the World Health Organization classification for tumors of the central nervous system, mutation status of the isocitrate dehydrogenase (IDH) genes has become a major diagnostic discriminator for gliomas. Therefore, imaging-based prediction of IDH mutation status is of high interest for individual patient management. We compared and evaluated the diagnostic value of radiomics derived from dual positron emission tomography (PET) and magnetic resonance imaging (MRI) data to predict the IDH mutation status non-invasively. Methods: Eighty-seven glioma patients at initial diagnosis who underwent PET targeting the translocator protein (TSPO) using [
18 F]GE-180, dynamic amino acid PET using [18 F]FET, and T1-/T2-weighted MRI scans were examined. In addition to calculating tumor-to-background ratio (TBR) images for all modalities, parametric images quantifying dynamic [18 F]FET PET information were generated. Radiomic features were extracted from TBR and parametric images. The area under the receiver operating characteristic curve (AUC) was employed to assess the performance of logistic regression (LR) classifiers. To report robust estimates, nested cross-validation with five folds and 50 repeats was applied. Results: TBRGE-180 features extracted from TSPO-positive volumes had the highest predictive power among TBR images (AUC 0.88, with age as co-factor 0.94). Dynamic [18 F]FET PET reached a similarly high performance (0.94, with age 0.96). The highest LR coefficients in multimodal analyses included TBRGE-180 features, parameters from kinetic and early static [18 F]FET PET images, age, and the features from TBRT2 images such as the kurtosis (0.97). Conclusion: The findings suggest that incorporating TBRGE-180 features along with kinetic information from dynamic [18 F]FET PET, kurtosis from TBRT2 , and age can yield very high predictability of IDH mutation status, thus potentially improving early patient management. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
25. Reduced Acquisition Time [18F]GE-180 PET Scanning Protocol Replaces Gold-Standard Dynamic Acquisition in a Mouse Ischemic Stroke Model
- Author
-
Artem Zatcepin, Steffanie Heindl, Ulrike Schillinger, Lena Kaiser, Simon Lindner, Peter Bartenstein, Anna Kopczak, Arthur Liesz, Matthias Brendel, and Sibylle I. Ziegler
- Subjects
positron emission tomography (PET) ,GE-180 imaging ,microglia ,stroke ,neuroinflammation ,image-derived blood input function (IDIF) ,Medicine (General) ,R5-920 - Abstract
AimUnderstanding neuroinflammation after acute ischemic stroke is a crucial step on the way to an individualized post-stroke treatment. Microglia activation, an essential part of neuroinflammation, can be assessed using [18F]GE-180 18 kDa translocator protein positron emission tomography (TSPO-PET). However, the commonly used 60–90 min post-injection (p.i.) time window was not yet proven to be suitable for post-stroke neuroinflammation assessment. In this study, we compare semi-quantitative estimates derived from late time frames to quantitative estimates calculated using a full 0–90 min dynamic scan in a mouse photothrombotic stroke (PT) model.Materials and MethodsSix mice after PT and six sham mice were included in the study. For a half of the mice, we acquired four serial 0–90 min scans per mouse (analysis cohort) and calculated standardized uptake value ratios (SUVRs; cerebellar reference) for the PT volume of interest (VOI) in five late 10 min time frames as well as distribution volume ratios (DVRs) for the same VOI. We compared late static 10 min SUVRs and the 60–90 min time frame of the analysis cohort to the corresponding DVRs by linear fitting. The other half of the animals received a static 60–90 min scan and was used as a validation cohort. We extrapolated DVRs by using the static 60–90 min p.i. time window, which were compared to the DVRs of the analysis cohort.ResultsWe found high linear correlations between SUVRs and DVRs in the analysis cohort for all studied 10 min time frames, while the fits of the 60–70, 70–80, and 80–90 min p.i. time frames were the ones closest to the line of identity. For the 60–90 min time window, we observed an excellent linear correlation between SUVR and DVR regardless of the phenotype (PT vs. sham). The extrapolated DVRs of the validation cohort were not significantly different from the DVRs of the analysis group.ConclusionSimplified quantification by a reference tissue ratio of the late 60–90 min p.i. [18F]GE-180 PET image can replace full quantification of a dynamic scan for assessment of microglial activation in the mouse PT model.
- Published
- 2022
- Full Text
- View/download PDF
26. Feasibility analysis of a droppable igniter for in-situ combustion
- Author
-
Jiang, Haiyan, Zatcepin, Vladislav, Liu, Wenqiang, Yuan, Shibao, Zhao, Liming, and Wang, Boyi
- Published
- 2019
- Full Text
- View/download PDF
27. Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution
- Author
-
Bartos, Laura M., primary, Kirchleitner, Sabrina V., additional, Kolabas, Zeynep Ilgin, additional, Quach, Stefanie, additional, Beck, Alexander, additional, Lorenz, Julia, additional, Blobner, Jens, additional, Mueller, Stephan A., additional, Ulukaya, Selin, additional, Hoeher, Luciano, additional, Horvath, Izabela, additional, Wind-Mark, Karin, additional, Holzgreve, Adrien, additional, Ruf, Viktoria C., additional, Gold, Lukas, additional, Kunze, Lea H., additional, Kunte, Sebastian T., additional, Beumers, Philipp, additional, Park, Ha Eun, additional, Antons, Melissa, additional, Zatcepin, Artem, additional, Briel, Nils, additional, Hoermann, Leonie, additional, Schaefer, Rebecca, additional, Messerer, Denise, additional, Bartenstein, Peter, additional, Riemenschneider, Markus J., additional, Lindner, Simon, additional, Ziegler, Sibylle, additional, Herms, Jochen, additional, Lichtenthaler, Stefan F., additional, Ertürk, Ali, additional, Tonn, Joerg C., additional, von Baumgarten, Louisa, additional, Albert, Nathalie L., additional, and Brendel, Matthias, additional
- Published
- 2023
- Full Text
- View/download PDF
28. Multimodale Radiomicsanalysen zur Prädiktion des IDH-Mutationsstatus bei erstdiagnostizierten Gliomen
- Author
-
Kaiser, L., additional, Quach, S., additional, Zounek, A. J., additional, Zatcepin, A., additional, Holzgreve, A., additional, Bollenbacher, A., additional, Bartos, L., additional, Ruf, V., additional, Böning, G., additional, von Baumgarten, L., additional, Thon, N., additional, Herms, J., additional, Riemenschneider, M. J., additional, Stöcklein, S., additional, Brendel, M., additional, Rupprecht, R., additional, Tonn, J. C., additional, Bartenstein, P., additional, Ziegler, S., additional, and Albert, N. L., additional
- Published
- 2023
- Full Text
- View/download PDF
29. Depletion and activation of microglia alter metabolic connectivity of the mouse brain
- Author
-
Gnörich, J., additional, Reifschneider, A., additional, Wind, K., additional, Zatcepin, A., additional, Kunte, S., additional, Beumers, P., additional, Bartos, L., additional, Wiedemann, T., additional, Grosch, M., additional, Xiang, X., additional, Khojasteh-Fard, M., additional, Ruch, F., additional, Werner, G., additional, Koehler, M., additional, Slemann, L., additional, Hummel, S., additional, Haass, C., additional, Capell, A., additional, Ziegler, S., additional, and Brendel, M., additional
- Published
- 2023
- Full Text
- View/download PDF
30. Depletion and activation of microglia alter metabolic connectivity of the mouse brain
- Author
-
J. Gnörich, A. Reifschneider, K. Wind, A. Zatcepin, S. Kunte, P. Beumers, L. Bartos, T. Wiedemann, M. Grosch, X. Xiang, M. Khojasteh-Fard, F. Ruch, G. Werner, M. Koehler, L. Slemann, S. Hummel, C. Haass, A. Capell, S. Ziegler, and M. Brendel
- Published
- 2023
31. Multimodale Radiomicsanalysen zur Prädiktion des IDH-Mutationsstatus bei erstdiagnostizierten Gliomen
- Author
-
L. Kaiser, S. Quach, A. J. Zounek, A. Zatcepin, A. Holzgreve, A. Bollenbacher, L. Bartos, V. Ruf, G. Böning, L. von Baumgarten, N. Thon, J. Herms, M. J. Riemenschneider, S. Stöcklein, M. Brendel, R. Rupprecht, J. C. Tonn, P. Bartenstein, S. Ziegler, and N. L. Albert
- Published
- 2023
32. Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution
- Author
-
Bartos, Laura M, primary, Kirchleitner, Sabrina V, additional, Kolabas, Zeynep Ilgin, additional, Quach, Stefanie, additional, Blobner, Jens, additional, Mueller, Stephan A, additional, Ulukaya, Selin, additional, Hoeher, Luciano, additional, Horvath, Izabela, additional, Wind-Mark, Karin, additional, Holzgreve, Adrien, additional, Ruf, Viktoria C, additional, Gold, Lukas, additional, Kunze, Lea H, additional, Kunte, Sebastian T, additional, Beumers, Philipp, additional, Antons, Melissa, additional, Zatcepin, Artem, additional, Briel, Nils, additional, Hoermann, Leonie, additional, Messerer, Denise, additional, Bartenstein, Peter, additional, Riemenschneider, Markus J, additional, Lindner, Simon, additional, Ziegler, Sibylle, additional, Herms, Jochen, additional, Lichtenthaler, Stefan F, additional, Ertürk, Ali, additional, Tonn, Joerg C, additional, Baumgarten, Louisa von, additional, Albert, Nathalie L, additional, and Brendel, Matthias, additional
- Published
- 2023
- Full Text
- View/download PDF
33. Machine learning-based approach reveals essential features for simplified TSPO PET quantification in ischemic stroke patients
- Author
-
Zatcepin, Artem, primary, Kopczak, Anna, additional, Holzgreve, Adrien, additional, Hein, Sandra, additional, Schindler, Andreas, additional, Duering, Marco, additional, Kaiser, Lena, additional, Lindner, Simon, additional, Schidlowski, Martin, additional, Bartenstein, Peter, additional, Albert, Nathalie, additional, Brendel, Matthias, additional, and Ziegler, Sibylle I., additional
- Published
- 2023
- Full Text
- View/download PDF
34. [18F]DED PET Imaging of Reactive Astrogliosis in Neurodegenerative Diseases: Preclinical Proof of Concept and First-in-Human Data
- Author
-
Ballweg, Anna, primary, Klaus, Carolin, additional, Vogler, Letizia, additional, Katzdobler, Sabrina, additional, Wind, Karin, additional, Zatcepin, Artem, additional, Ziegler, Sibylle, additional, Secgin, Birkan, additional, Eckenweber, Florian, additional, Bohr, Bernd, additional, Bernhardt, Alexander, additional, Fietzek, Urban, additional, Rauchmann, Boris-Stephan, additional, Stoecklein, Sophia, additional, Quach, Stefanie, additional, Beyer, Leonie, additional, Scheifele, Maximilian, additional, Simmet, Marcel, additional, Joseph, Emanuel, additional, Lindner, Simon, additional, Berg, Isabella, additional, Koglin, Norman, additional, Mueller, Andre, additional, Stephens, Andrew, additional, Bartenstein, Peter, additional, Tonn, Joerg-Christian, additional, Albert, Nathalie, additional, Kümpfel, Tanja, additional, Kerschensteiner, Martin, additional, Perneczky, Robert, additional, Levin, Johannes, additional, Paeger, Lars, additional, Herms, Jochen, additional, and Brendel, Matthias, additional
- Published
- 2022
- Full Text
- View/download PDF
35. Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution
- Author
-
Laura M Bartos, Sabrina V Kirchleitner, Zeynep Ilgin Kolabas, Stefanie Quach, Jens Blobner, Stephan A Mueller, Selin Ulukaya, Luciano Hoeher, Izabela Horvath, Karin Wind-Mark, Adrien Holzgreve, Viktoria C Ruf, Lukas Gold, Lea H Kunze, Sebastian T Kunte, Philipp Beumers, Melissa Antons, Artem Zatcepin, Nils Briel, Leonie Hoermann, Denise Messerer, Peter Bartenstein, Markus J Riemenschneider, Simon Lindner, Sibylle Ziegler, Jochen Herms, Stefan F Lichtenthaler, Ali Ertürk, Joerg C Tonn, Louisa von Baumgarten, Nathalie L Albert, and Matthias Brendel
- Abstract
Various cellular sources hamper interpretation of positron-emission-tomography (PET) biomarkers in the tumor microenvironment (TME). We developed immunomagnetic cell sorting afterin vivoradiotracer injection (scRadiotracing) in combination with 3D-histology via tissue clearing to dissect the cellular allocation of PET signals in the TME. In SB28 glioblastoma mice, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs). Cellular radiotracer uptake was validated by proteomics and confirmed forin vitrosamples of patients with glioblastoma. Regional agreement between PET signals and single cell tracer uptake predicted the individual cell distribution in 3D-histology. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma, however proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D-histology facilitates precise allocation of complex PET signal sources and will serve to validate novel TAM-specific radioligands.
- Published
- 2023
36. Microglia-PET imaging as a surrogate marker for post-stroke neuroinflammation in preclinical mouse models and clinical cases: quantitative PET data analysis using biokinetic modeling and machine learning including information from multiparametric MRI scans
- Author
-
Zatcepin, Artem
- Subjects
positron emission tomography, kinetic modeling, machine learning, microglia, stroke ,FOS: Medical and Health Sciences - Abstract
Background Ischemic stroke is the second leading cause of death and the third main cause of long-term disability worldwide, which explains the need for novel therapies to improve neurological recovery. Microglia, brain resident immune cells, are a suitable target for such a therapy. These cells express 18 kDa translocator protein (TSPO) when activated, which enables neuroinflammation monitoring using positron emission tomography (PET) with TSPO tracers, such as [18F]GE-180. However, the signal in PET images originates not only from specific binding of the tracer to the receptor of interest; it is contaminated by non-specific binding and free tracer in both tissue and blood. Gold-standard quantification of [18F]GE-180 specific binding is currently performed using pharmacokinetic modeling, which requires a longer scanning time and continuous arterial blood sampling. This is not only burdensome for the hospital staff, but also associated with additional risks and discomfort for the patient. Aim The aim of this work was to establish a simplified [18F]GE-180 PET scanning protocol for a mouse ischemic stroke model and translate it into human PET by integrating additional potentially relevant information using machine learning (ML) and taking a well-established pharmacokinetic modeling method as the ground truth. Materials and Methods Mouse study: Six mice after photothrombotic stroke (PT) and six sham mice were included in the study and scanned using a dedicated small-animal PET/MR scanner. For a half of the mice, we acquired four serial 0–90 min post injection (p.i.) scans per mouse (analysis cohort) and calculated quantitative TSPO binding estimates (distribution volume ratio, DVR) as well as semi-quantitative estimates (standardized uptake volume ratio, SUVR) for five late 10 min time frames. We compared how well the obtained SUVRs approximated DVR by means of linear fitting and Pearson correlation coefficient. The other half of the mice received 60-90 min p.i. [18F]GE-180 PET and was used as a validation cohort. Human study: 18 subjects after acute ischemic stroke received 0-90 min p.i. [18F]GE-180 PET along with a number of MRI sequences. Five manual venous blood samples were drawn during the PET scan and their activity concentration was measured. Based on dynamic PET data, a quantitative TSPO binding estimate was calculated voxelwise. We trained an ML algorithm using these estimates as the ground truth and three late 10 min PET frames, the ASL image, voxel co-ordinates, the lesion mask, and the five plasma activity concentrations as input features. Using Shapley Additive Explanations, we determined that the three late PET frames and the plasma activity concentrations had the highest impact on the model’s performance. We then tested a simplified quantification approach consisting of dividing a late PET frame by a plasma activity concentration. All the combinations of frames/samples were compared by means of concordance correlation coefficient and Bland-Altman plots. Results The mouse study showed that the 60–70, 70–80, and 80–90 min p.i. frames produce the closest approximation for 90 min scan-based DVR in both sham and PT mice. The human study demonstrated on an individual voxel basis an additional value of the late plasma activity concentration in approximating the quantitative 90 min scan-based TSPO estimate. The 70-80 min p.i. frame divided by the 30 min p.i. plasma sample produced the closest semi-quantitative estimate in the ischemic lesion. Conclusion Reliable simplified TSPO quantification in patients after acute ischemic stroke is achievable by using a short late PET frame divided by a late plasma activity concentration and can thus replace full quantification based on a 90 min dynamic scan. The ML-based procedure of estimating feature importance used in this work can be applied for other conditions and other tracers in the future., Hintergrund Der ischämische Schlaganfall ist weltweit die zweithäufigste Todesursache und die dritthäufigste Ursache für Langzeitbehinderungen, was den Bedarf an neuartigen Therapien zur Verbesserung der neurologischen Erholung erklärt. Mikroglia, Immunzellen im Gehirn, sind ein geeignetes Ziel für eine solche Therapie. Diese Zellen exprimieren das 18 kDa-Translokatorprotein (TSPO), wenn sie aktiviert sind, was die Messung von Neuroinflammation mittels Positronen-Emissions-Tomographie (PET) mit TSPO-Tracern wie [18F]GE-180 ermöglicht. Das Signal in den PET-Bildern stammt jedoch nicht nur von der spezifischen Bindung des Tracers an den betreffenden Rezeptor, sondern wird auch durch unspezifische Bindungen und freien Tracer im Gewebe und im Blut kontaminiert. Die Goldstandard-Quantifizierung der spezifischen Bindung von [18F]GE-180 wird derzeit mit Hilfe pharmakokinetischer Modelle durchgeführt, was eine längere Messzeit und eine kontinuierliche arterielle Blutentnahme erfordert. Dies ist nicht nur für das Krankenhauspersonal belastend, sondern auch mit zusätzlichen Risiken und Unannehmlichkeiten für die Patienten verbunden. Zielsetzung Ziel dieser Arbeit war es, ein vereinfachtes [18F]GE-180-PET-Scanprotokoll für ein ischämisches Schlaganfallmodell bei Mäusen zu erstellen und es auf die PET-Untersuchung bei Menschen zu übertragen, indem zusätzliche potenziell relevante Informationen mit Hilfe von maschinellem Lernen (ML) integriert werden und eine wohl etablierte pharmakokinetische Modellierungsmethode als Grundwahrheit verwendet wird. Material und Methoden Mausstudie: Sechs Mäuse nach photothrombotischem Schlaganfall (PT) und sechs Mäuse nach identischer Versuchsdurchführung, jedoch ohne Schlaganfall (sham), wurden in die Studie aufgenommen und mit einem dedizierten Kleintier-PET/MR-Scanner untersucht. Für die Hälfte der Mäuse wurden vier serielle Messungen 0-90 Minuten nach der Injektion (p.i.) pro Maus (Analysekohorte) durchgeführt und die TSPO_Bindung quantitativ geschätzt (Distribution Volume Ratio, DVR). Zusätzlich wurden semi-quantitative Schätzungen (Standardized Uptake Volume Ratio, SUVR) für fünf späte 10 min Zeitfenster berechnet. Wir verglichen die Eignung der SUVRs als Näherung für die DVR mittels linearer Anpassung und Pearson-Korrelationskoeffizient. Die andere Hälfte der Mäuse erhielt 60-90 min p.i. [18F]GE-180-PET und wurde als Validierungskohorte verwendet. Humanstudie: 18 Probanden erhielten nach einem akuten ischämischen Schlaganfall 0-90 min p.i. [18F]GE-180-PET zusammen mit einer Reihe von MRT-Sequenzen. Fünf manuelle venöse Blutproben wurden während des PET-Scans entnommen und ihre Aktivitätskonzentration gemessen. Auf der Grundlage der dynamischen PET-Daten wurde eine quantitative Schätzung der TSPO-Bindung voxelweise berechnet. Wir trainierten einen ML-Algorithmus, der diese Schätzungen als Grundwahrheit und drei späte 10 min PET-Bilder, das ASL-Bild, Voxelkoordinaten, die Läsionsmaske und die fünf Plasmaaktivitätskonzentrationen als Eingangsmerkmale verwendete. Unter Verwendung von Shapley Additive Explanations stellten wir fest, dass die drei späten PET-Bilder und die Plasmaaktivitätskonzentrationen den größten Einfluss auf die Qualität des Modells hatten. Anschließend testeten wir eine vereinfachte Quantifizierungsmethode, die darin bestand, ein spätes PET-Bild durch eine Plasmaaktivitätskonzentration zu dividieren. Alle Kombinationen von Bildern/Proben wurden anhand von Konkordanz-Korrelationskoeffizienten und Bland-Altman-Diagrammen verglichen. Ergebnisse Die Mausstudie zeigte, dass die 60-70, 70-80 und 80-90 min p.i. Zeitfenster die beste Näherung an die 90 min Scan basierte DVR sowohl bei den Sham- als auch bei den PT-Mäusen produzieren. Die Humanstudie zeigte auf der Basis individueller Voxel einen zusätzlichen Wert der späten Plasmaaktivitätskonzentration für die Näherung an die quantitative 90-min Scan-basierten TSPO-Schätzung. Die Division der Werte im 70-80 min p.i. Zeitfenster mit dem Messwert der 30 min p.i. Plasmaprobe ergab die genaueste semi-quantitative Schätzung in der ischämischen Läsion. Schlussfolgerung Eine zuverlässige vereinfachte TSPO-Quantifizierung bei Patienten nach einem akuten ischämischen Schlaganfall ist durch die Verwendung eines kurzen späten PET-Zeitfensters geteilt durch eine späte Plasmaaktivitätskonzentration möglich und kann somit eine vollständige Quantifizierung auf der Grundlage eines 90 min dynamischen Scans ersetzen. Das in dieser Arbeit verwendete ML-basierte Verfahren zur Schätzung der Relevanz verschiedener Merkmale kann in Zukunft auch für andere Erkrankungen und Tracer angewendet werden.
- Published
- 2023
- Full Text
- View/download PDF
37. Machine learning-based approach reveals essential features for simplified TSPO PET quantification in ischemic stroke patients
- Author
-
Artem Zatcepin, Anna Kopczak, Adrien Holzgreve, Sandra Hein, Andreas Schindler, Marco Duering, Lena Kaiser, Simon Lindner, Martin Schidlowski, Peter Bartenstein, Nathalie Albert, Matthias Brendel, and Sibylle I. Ziegler
- Subjects
Quantitative PET ,Ischemic stroke ,Radiological and Ultrasound Technology ,GE180 ,Machine learning ,Biophysics ,Image-derived input function ,Radiology, Nuclear Medicine and imaging ,ddc:610 ,TSPO - Abstract
Neuroinflammation evaluation after acute ischemic stroke is a promising option for selecting an appropriate post-stroke treatment strategy. To assess neuroinflammation in vivo, translocator protein PET (TSPO PET) can be used. However, the gold standard TSPO PET quantification method includes a 90 min scan and continuous arterial blood sampling, which is challenging to perform on a routine basis. In this work, we determine what information is required for a simplified quantification approach using a machine learning algorithm.We analyzed data from 18 patients with ischemic stroke who received 0-90 min [18F]GE-180 PET as well as T1-weigted (T1w), FLAIR, and arterial spin labeling (ASL) MRI scans. During PET scans, five manual venous blood samples at 5, 15, 30, 60, and 85 min post injection (p.i.) were drawn, and plasma activity concentration was measured. Total distribution volume (VT) was calculated using Logan plot with the full dynamic PET and an image-derived input function (IDIF) from the carotid arteries. IDIF was scaled by a calibration factor derived from all the measured plasma activity concentrations. The calculated VT values were used for training a random forest regressor. As input features for the model, we used three late PET frames (60-70, 70-80, and 80-90 min p.i.), the ASL image reflecting perfusion, the voxel coordinates, the lesion mask, and the five plasma activity concentrations. The algorithm was validated with the leave-one-out approach. To estimate the impact of the individual features on the algorithm's performance, we used Shapley Additive Explanations (SHAP). Having determined that the three late PET frames and the plasma activity concentrations were the most important features, we tested a simplified quantification approach consisting of dividing a late PET frame by a plasma activity concentration. All the combinations of frames/samples were compared by means of concordance correlation coefficient and Bland-Altman plots.When using all the input features, the algorithm predicted VT values with high accuracy (87.8 ± 8.3%) for both lesion and non-lesion voxels. The SHAP values demonstrated high impact of the late PET frames (60-70, 70-80, and 80-90 min p.i.) and plasma activity concentrations on the VT prediction, while the influence of the ASL-derived perfusion, voxel coordinates, and the lesion mask was low. Among all the combinations of the late PET frames and plasma activity concentrations, the 70-80 min p.i. frame divided by the 30 min p.i. plasma sample produced the closest VT estimate in the ischemic lesion.Reliable TSPO PET quantification is achievable by using a single late PET frame divided by a late blood sample activity concentration.
- Published
- 2023
38. [18F]DED PET Imaging of Reactive Astrogliosis in Neurodegenerative Diseases: Preclinical Proof of Concept and First-in-Human Data
- Author
-
Anna Ballweg, Carolin Klaus, Letizia Vogler, Sabrina Katzdobler, Karin Wind, Artem Zatcepin, Sibylle Ziegler, Birkan Secgin, Florian Eckenweber, Bernd Bohr, Alexander Bernhardt, Urban Fietzek, Boris-Stephan Rauchmann, Sophia Stoecklein, Stefanie Quach, Leonie Beyer, Maximilian Scheifele, Marcel Simmet, Emanuel Joseph, Simon Lindner, Isabella Berg, Norman Koglin, Andre Mueller, Andrew Stephens, Peter Bartenstein, Joerg-Christian Tonn, Nathalie Albert, Tanja Kümpfel, Martin Kerschensteiner, Robert Perneczky, Johannes Levin, Lars Paeger, Jochen Herms, and Matthias Brendel
- Abstract
Objective Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. Methods A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3–21.0 months) underwent 60 min dynamic [18F]D2-deprenyl ([18F]DED), static 18kDa translocator protein (TSPO, [18F]GE-180) and β-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients with Alzheimer’s disease (AD, n = 2), Parkinson’s disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1) and oligodendroglioma (n = 1) underwent 60 min dynamic [18F]DED PET and the data were analyzed using equivalent quantification strategies. Results We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]DED DVR when compared to age-matched WT mice at 5 months (thalamus: +4.3%; p = 0.048), 13 months (hippocampus: +7.6%, p = 0.022) and 19 months (hippocampus: +12.3%, p 18F]DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and β-amyloid PET and [18F]DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p 18F]DED VT patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (AD, PD, MSA) and neuroinflammatory conditions, whereas the oligodendroglioma lesion indicated no altered [18F]DED binding. Conclusion [18F]DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.
- Published
- 2022
39. 18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model
- Author
-
Bartos, Laura M., primary, Kirchleitner, Sabrina V., additional, Blobner, Jens, additional, Wind, Karin, additional, Kunze, Lea H., additional, Holzgreve, Adrien, additional, Gold, Lukas, additional, Zatcepin, Artem, additional, Kolabas, Zeynep Ilgin, additional, Ulukaya, Selin, additional, Weidner, Lorraine, additional, Quach, Stefanie, additional, Messerer, Denise, additional, Bartenstein, Peter, additional, Tonn, Joerg C., additional, Riemenschneider, Markus J., additional, Ziegler, Sibylle, additional, von Baumgarten, Louisa, additional, Albert, Nathalie L., additional, and Brendel, Matthias, additional
- Published
- 2022
- Full Text
- View/download PDF
40. Engineering of a System for the Production of Mutant Human Alpha-Fetoprotein in the Methylotrophic Yeast Pichia pastoris
- Author
-
Morozkina, E. V., Vavilova, E. A., Zatcepin, S. S., Klyachko, E. V., Yagudin, T. A., Chulkin, A. M., Dudich, I. V., Semenkova, L. N., Churilova, I. V., and Benevolensky, S. V.
- Published
- 2016
- Full Text
- View/download PDF
41. Improving depth-of-interaction resolution in pixellated PET detectors using neural networks
- Author
-
Zatcepin, A, Pizzichemi, M, Polesel, A, Paganoni, M, Auffray, E, Ziegler, S, Omidvari, N, Zatcepin A., Pizzichemi M., Polesel A., Paganoni M., Auffray E., Ziegler S. I., Omidvari N., Zatcepin, A, Pizzichemi, M, Polesel, A, Paganoni, M, Auffray, E, Ziegler, S, Omidvari, N, Zatcepin A., Pizzichemi M., Polesel A., Paganoni M., Auffray E., Ziegler S. I., and Omidvari N.
- Abstract
Parallax error is a common issue in high-resolution preclinical positron emission tomography (PET) scanners as well as in clinical scanners that have a long axial field of view (FOV), which increases estimation uncertainty of the annihilation position and therefore degrades the spatial resolution. A way to address this issue is depth-of-interaction (DOI) estimation. In this work we propose two machine learning-based algorithms, a dense and a convolutional neural network (NN), as well as a multiple linear regression (MLR)-based method to estimate DOI in depolished PET detector arrays with single-sided readout. The algorithms were tested on an 8× 8 array of 1.53× 1.53× 15 mm3 crystals and a 4× 4 array of 3.1× 3.1× 15 mm3 crystals, both made of Ce:LYSO scintillators and coupled to a 4× 4 array of 3× 3 mm3 silicon photomultipliers (SiPMs). Using the conventional linear DOI estimation method resulted in an average DOI resolution of 3.76 mm and 3.51 mm FWHM for the 8× 8 and the 4× 4 arrays, respectively. Application of MLR outperformed the conventional method with average DOI resolutions of 3.25 mm and 3.33 mm FWHM, respectively. Using the machine learning approaches further improved the DOI resolution, to an average DOI resolution of 2.99 mm and 3.14 mm FWHM, respectively, and additionally improved the uniformity of the DOI resolution in both arrays. Lastly, preliminary results obtained by using only a section of the crystal array for training showed that the NN-based methods could be used to reduce the number of calibration steps required for each detector array.
- Published
- 2020
42. Desynchronization of microglial activity is closely associated with cognitive decline in Alzheimer’s disease
- Author
-
A. Zatcepin, X. Xiang, S. Parhizkar, J. Gnörich, M. Grosch, K. Wind, Y. Shi, L. Beyer, G. Biechele, F. Eckenweber, T. Wiedemann, S. Lindner, A. Rominger, P. Bartenstein, M. Willem, S. Tahirovic, J. Herms, C. Haass, S. Ziegler, and M. Brendel
- Published
- 2022
43. [18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data.
- Author
-
Ballweg, Anna, Klaus, Carolin, Vogler, Letizia, Katzdobler, Sabrina, Wind, Karin, Zatcepin, Artem, Ziegler, Sibylle I., Secgin, Birkan, Eckenweber, Florian, Bohr, Bernd, Bernhardt, Alexander, Fietzek, Urban, Rauchmann, Boris-Stephan, Stoecklein, Sophia, Quach, Stefanie, Beyer, Leonie, Scheifele, Maximilian, Simmet, Marcel, Joseph, Emanuel, and Lindner, Simon
- Subjects
POSITRON emission tomography ,GLIAL fibrillary acidic protein ,NEURODEGENERATION ,GLIOSIS ,ALZHEIMER'S disease - Abstract
Objectives: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer's disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. Methods: A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3–21.0 months) underwent 60 min dynamic [
18 F]fluorodeprenyl-D2 ([18 F]F-DED), static 18 kDa translocator protein (TSPO, [18 F]GE-180) and β-amyloid ([18 F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer's disease continuum (AD, n = 2), Parkinson's disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18 F]F-DED PET and the data were analyzed using equivalent quantification strategies. Results: We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18 F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001; thalamus: + 15.2%, p < 0.0001). Specific [18 F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and β-amyloid PET and [18 F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001; thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [18 F]F-DED VT and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [18 F]F-DED binding following the known physiological MAO-B expression in brain. Conclusions: [18 F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF
44. Desynchronization of microglial activity is closely associated with cognitive decline in Alzheimer’s disease
- Author
-
Zatcepin, A., additional, Xiang, X., additional, Parhizkar, S., additional, Gnörich, J., additional, Grosch, M., additional, Wind, K., additional, Shi, Y., additional, Beyer, L., additional, Biechele, G., additional, Eckenweber, F., additional, Wiedemann, T., additional, Lindner, S., additional, Rominger, A., additional, Bartenstein, P., additional, Willem, M., additional, Tahirovic, S., additional, Herms, J., additional, Haass, C., additional, Ziegler, S., additional, and Brendel, M., additional
- Published
- 2022
- Full Text
- View/download PDF
45. Reduced Acquisition Time [18F]GE-180 PET Scanning Protocol Replaces Gold-Standard Dynamic Acquisition in a Mouse Ischemic Stroke Model
- Author
-
Zatcepin, Artem, primary, Heindl, Steffanie, additional, Schillinger, Ulrike, additional, Kaiser, Lena, additional, Lindner, Simon, additional, Bartenstein, Peter, additional, Kopczak, Anna, additional, Liesz, Arthur, additional, Brendel, Matthias, additional, and Ziegler, Sibylle I., additional
- Published
- 2022
- Full Text
- View/download PDF
46. Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency
- Author
-
Anika Reifschneider, Sophie Robinson, Bettina van Lengerich, Johannes Gnörich, Todd Logan, Steffanie Heindl, Miriam A Vogt, Endy Weidinger, Lina Riedl, Karin Wind, Artem Zatcepin, Ida Pesämaa, Sophie Haberl, Brigitte Nuscher, Gernot Kleinberger, Julien Klimmt, Julia K Götzl, Arthur Liesz, Katharina Bürger, Matthias Brendel, Johannes Levin, Janine Diehl‐Schmid, Jung Suh, Gilbert Di Paolo, Joseph W Lewcock, Kathryn M Monroe, Dominik Paquet, Anja Capell, and Christian Haass
- Subjects
Male ,pharmacology [Antibodies] ,microglia ,physiopathology [Brain] ,SYK protein, human ,drug effects [Microglia] ,Monocytes ,metabolism [Lysosomes] ,immunology [Antibodies] ,Progranulins ,genetics [Membrane Glycoproteins] ,genetics [Receptors, Immunologic] ,Receptors, Immunologic ,Mice, Knockout ,Membrane Glycoproteins ,General Neuroscience ,neurodegeneration ,Brain ,metabolism [Receptors, Immunologic] ,metabolism [Syk Kinase] ,drug effects [Monocytes] ,Grn protein, mouse ,frontotemporal lobar degeneration ,Female ,Microglia ,immunology [Membrane Glycoproteins] ,deficiency [Progranulins] ,General Biochemistry, Genetics and Molecular Biology ,Antibodies ,lysosomes ,Trem2 protein, mouse ,ddc:570 ,progranulin ,Animals ,Humans ,Syk Kinase ,Molecular Biology ,diagnostic imaging [Brain] ,immunology [Receptors, Immunologic] ,General Immunology and Microbiology ,TREM2 protein, human ,pathology [Frontotemporal Lobar Degeneration] ,metabolism [Frontotemporal Lobar Degeneration] ,physiology [Microglia] ,Mice, Inbred C57BL ,Disease Models, Animal ,Frontotemporal Lobar Degeneration ,Lysosomes ,metabolism [Membrane Glycoproteins] ,pathology [Lysosomes] ,metabolism [Monocytes] - Abstract
Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody-treated PGRN-deficient microglia derived from human-induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light-chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2-dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection.
- Published
- 2022
47. Additional file 10 of Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia
- Author
-
Xia, Dan, Lianoglou, Steve, Sandmann, Thomas, Calvert, Meredith, Suh, Jung H., Thomsen, Elliot, Dugas, Jason, Pizzo, Michelle E., DeVos, Sarah L., Earr, Timothy K., Lin, Chia-Ching, Davis, Sonnet, Ha, Connie, Leung, Amy Wing-Sze, Nguyen, Hoang, Chau, Roni, Yulyaningsih, Ernie, Lopez, Isabel, Solanoy, Hilda, Masoud, Shababa T., Liang, Chun-chi, Lin, Karin, Astarita, Giuseppe, Khoury, Nathalie, Zuchero, Joy Yu, Thorne, Robert G., Shen, Kevin, Miller, Stephanie, Palop, Jorge J., Garceau, Dylan, Sasner, Michael, Whitesell, Jennifer D., Harris, Julie A., Hummel, Selina, Gnörich, Johannes, Wind, Karin, Kunze, Lea, Zatcepin, Artem, Brendel, Matthias, Willem, Michael, Haass, Christian, Barnett, Daniel, Zimmer, Till S., Orr, Anna G., Scearce-Levie, Kimberly, Lewcock, Joseph W., Di Paolo, Gilbert, and Sanchez, Pascal E.
- Abstract
Additional file 10: Table s2. Mouse Cohorts.
- Published
- 2022
- Full Text
- View/download PDF
48. Additional file 9 of Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia
- Author
-
Xia, Dan, Lianoglou, Steve, Sandmann, Thomas, Calvert, Meredith, Suh, Jung H., Thomsen, Elliot, Dugas, Jason, Pizzo, Michelle E., DeVos, Sarah L., Earr, Timothy K., Lin, Chia-Ching, Davis, Sonnet, Ha, Connie, Leung, Amy Wing-Sze, Nguyen, Hoang, Chau, Roni, Yulyaningsih, Ernie, Lopez, Isabel, Solanoy, Hilda, Masoud, Shababa T., Liang, Chun-chi, Lin, Karin, Astarita, Giuseppe, Khoury, Nathalie, Zuchero, Joy Yu, Thorne, Robert G., Shen, Kevin, Miller, Stephanie, Palop, Jorge J., Garceau, Dylan, Sasner, Michael, Whitesell, Jennifer D., Harris, Julie A., Hummel, Selina, Gnörich, Johannes, Wind, Karin, Kunze, Lea, Zatcepin, Artem, Brendel, Matthias, Willem, Michael, Haass, Christian, Barnett, Daniel, Zimmer, Till S., Orr, Anna G., Scearce-Levie, Kimberly, Lewcock, Joseph W., Di Paolo, Gilbert, and Sanchez, Pascal E.
- Abstract
Additional file 9: Table s1. Primers.
- Published
- 2022
- Full Text
- View/download PDF
49. Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in neuroinflammation
- Author
-
Zeynep Ilgin Kolabas, Louis B. Kuemmerle, Robert Perneczky, Benjamin Förstera, Maren Büttner, Ozum Sehnaz Caliskan, Mayar Ali, Zhouyi Rong, Hongcheng Mai, Selina Hummel, Laura M. Bartos, Gloria Biechele, Artem Zatcepin, Natalie L. Albert, Marcus Unterrainer, Johannes Gnörich, Shan Zhao, Igor Khalin, Boris-Stephan Rauchmann, Muge Molbay, Michael Sterr, Ines Kunze, Karen Stanic, Simon Besson-Girard, Anna Kopczak, Sabrina Katzdobler, Carla Palleis, Ozgun Gokce, Heiko Lickert, Hanno Steinke, Ingo Bechmann, Katharina Buerger, Johannes Levin, Christian Haass, Martin Dichgans, Joachim Havla, Tania Kümpfel, Martin Kerschensteiner, Mikael Simons, Nikolaus Plesnila, Natalie Krahmer, Harsharan Singh Bhatia, Suheda Erener, Farida Hellal, Matthias Brendel, Fabian J. Theis, and Ali Erturk
- Subjects
musculoskeletal diseases - Abstract
SUMMARYThe meninges of the brain are an important component of neuroinflammatory response. Diverse immune cells move from the calvaria marrow into the dura mater via recently discovered skull-meninges connections (SMCs). However, how the calvaria bone marrow is different from the other bones and whether and how it contributes to human diseases remain unknown. Using multi-omics approaches and whole mouse transparency we reveal that bone marrow cells are highly heterogeneous across the mouse body. The calvaria harbors the most distinct molecular signature with hundreds of differentially expressed genes and proteins. Acute brain injury induces skull-specific alterations including increased calvaria cell numbers. Moreover, TSPO-positron-emission-tomography imaging of stroke, multiple sclerosis and neurodegenerative disease patients demonstrate disease-associated uptake patterns in the human skull, mirroring the underlying brain inflammation. Our study indicates that the calvaria is more than a physical barrier, and its immune cells may present new ways to control brain pathologies.Graphical AbstractHighlightsBone marrow across the mouse body display heterogeneity in their molecular profileCalvaria cells have a distinct profile that is relevant to brain pathologiesBrain native proteins are identified in calvaria in pathological statesTSPO-PET imaging of the human skull can be a proxy of neuroinflammation in the brainSupplementary Videos can be seen at: http://discotechnologies.org/Calvaria/
- Published
- 2021
50. Reduced Acquisition Time [
- Author
-
Artem, Zatcepin, Steffanie, Heindl, Ulrike, Schillinger, Lena, Kaiser, Simon, Lindner, Peter, Bartenstein, Anna, Kopczak, Arthur, Liesz, Matthias, Brendel, and Sibylle I, Ziegler
- Abstract
Understanding neuroinflammation after acute ischemic stroke is a crucial step on the way to an individualized post-stroke treatment. Microglia activation, an essential part of neuroinflammation, can be assessed using [Six mice after PT and six sham mice were included in the study. For a half of the mice, we acquired four serial 0-90 min scans per mouse (analysis cohort) and calculated standardized uptake value ratios (SUVRs; cerebellar reference) for the PT volume of interest (VOI) in five late 10 min time frames as well as distribution volume ratios (DVRs) for the same VOI. We compared late static 10 min SUVRs and the 60-90 min time frame of the analysis cohort to the corresponding DVRs by linear fitting. The other half of the animals received a static 60-90 min scan and was used as a validation cohort. We extrapolated DVRs by using the static 60-90 min p.i. time window, which were compared to the DVRs of the analysis cohort.We found high linear correlations between SUVRs and DVRs in the analysis cohort for all studied 10 min time frames, while the fits of the 60-70, 70-80, and 80-90 min p.i. time frames were the ones closest to the line of identity. For the 60-90 min time window, we observed an excellent linear correlation between SUVR and DVR regardless of the phenotype (PTSimplified quantification by a reference tissue ratio of the late 60-90 min p.i. [
- Published
- 2021
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.