Article
Immunology
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 Kuempfel, Martin Kerschensteiner, Robert Perneczky, Johannes Levin, Lars Paeger, Jochen Herms, Matthias Brendel
Summary: This study investigates the capability of a novel MAO-B PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer's disease (AD) and in patients with neurological diseases. The results demonstrate that [F-18]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.
JOURNAL OF NEUROINFLAMMATION
(2023)
Article
Neurosciences
Konstantinos Chiotis, Charlotte Johansson, Elena Rodriguez-Vieitez, Nicholas J. Ashton, Kaj Blennow, Henrik Zetterberg, Caroline Graff, Agneta Nordberg
Summary: Plasma GFAP concentration and astrocyte 11C-DED brain binding levels showed a negative correlation in both sporadic and Autosomal Dominant Alzheimer's disease. It suggests that they may reflect different states or subtypes of astrogliosis. Increased 11C-DED brain binding appears to occur earlier in the progression of Alzheimer's disease than increased plasma GFAP concentration.
MOLECULAR NEURODEGENERATION
(2023)
Review
Geriatrics & Gerontology
Kenji Ishibashi
Summary: MAO-B PET can be used as a clinical marker for neurodegeneration, neuroinflammation, and brain tumors. By imaging MAO-B levels and astrogliosis, it can identify degenerative lesions, inflammatory lesions, and astrocytic gliomas.
GERIATRICS & GERONTOLOGY INTERNATIONAL
(2023)
Article
Radiology, Nuclear Medicine & Medical Imaging
Victor L. Villemagne, Ryuichi Harada, Vincent Dore, Shozo Furumoto, Rachel Mulligan, Yukitsuka Kudo, Samantha Burnham, Natasha Krishnadas, Svetlana Bozinovski, Kun Huang, Brian J. Lopresti, Kazuhiko Yanai, Christopher C. Rowe, Nobuyuki Okamura
Summary: The study found that 18F-SMBT-1 is a highly selective and low nonspecific binding MAO-B tracer, which can potentially be used as a surrogate marker of reactive astrogliosis.
JOURNAL OF NUCLEAR MEDICINE
(2022)
Article
Clinical Neurology
Yuko Koshimori, Michael D. Cusimano, Erica L. Vieira, Pablo M. Rusjan, Stephen J. Kish, Neil Vasdev, Sho Moriguchi, Isabelle Boileau, Thomas Chao, Zahra Nasser, M. Ishrat Husain, Khunsa Faiz, Joeffre Braga, Jeffrey H. Meyer
Summary: Traumatic brain injury (TBI) is common, but the reason behind persisting symptoms in some patients is unknown. Astrogliosis, a response to brain injury, may be a potential therapeutic target, but its presence in TBI patients with persistent symptoms has not been confirmed.
Review
Biochemistry & Molecular Biology
Amit Kumar, Igor C. Fontana, Agneta Nordberg
Summary: Astrocytes play a crucial role in brain functioning and are involved in the pathophysiology of Alzheimer's disease and other neurodegenerative disorders through reactive astrogliosis.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Immunology
Corinne A. Auger, Valentina Perosa, Steven M. Greenberg, Susanne J. van Veluw, Mariel G. Kozberg
Summary: This study found a strong relationship between iron deposition and reactive astrogliosis on the surface of the cortex.
JOURNAL OF NEUROINFLAMMATION
(2023)
Review
Biochemistry & Molecular Biology
Marta Valenza, Roberta Facchinetti, Giorgia Menegoni, Luca Steardo, Caterina Scuderi
Summary: Alzheimer's disease treatments are not curative, new approaches are needed. Astrocytes are targeted as a specific method. Studies suggest that palmitoylethanolamide may have a potential therapeutic effect by modulating astrocytes.
Review
Cell Biology
Igor C. Fontana, Miriam Scarpa, Mona-Lisa Malarte, Filipa M. Rocha, Sira Auselle-Bosch, Marina Bluma, Marco Bucci, Konstantinos Chiotis, Amit Kumar, Agneta Nordberg
Summary: Reactive astrogliosis, occurring before the deposition of A beta plaques, tau pathology, and neurodegeneration, is an early event in Alzheimer's disease (AD). Advances in PET imaging have provided ways to assess reactive astrogliosis in the living brain. The heterogeneity of reactive astrogliosis in AD suggests that astrocytic body fluid biomarkers might have different trajectories than astrocytic PET imaging, and further research on innovative astrocytic PET radiotracers and fluid biomarkers may improve the detection of AD in its early stages.
Article
Biochemistry & Molecular Biology
Ryuichi Harada, Yuki Shimizu, Yiqing Du, Yoichi Ishikawa, Ren Iwata, Yukitsuka Kudo, Kazuhiko Yanai, Nobuyuki Okamura, Shozo Furumoto
Summary: In this study, the effect of the chirality of [F-18]SMBT-1 on its performance as a tracer was investigated. (S)-[F-18]6 showed higher binding affinity and selectivity for MAO-B compared to (R)-[F-18]6. Additionally, (S)-[F-18]6 exhibited better pharmacokinetic and metabolic properties. These findings suggest that (S)-[F-18]6 is a promising candidate for in vivo imaging of MAO-B.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Radiology, Nuclear Medicine & Medical Imaging
Victor L. Villemagne, Ryuichi Harada, Vincent Dore, Shozo Furumoto, Rachel Mulligan, Yukitsuka Kudo, Samantha Burnham, Natasha Krishnadas, Pierrick Bourgeat, Ying Xia, Simon Laws, Svetlana Bozinovski, Kun Huang, Milos D. Ikonomovic, Jurgen Fripp, Kazuhiko Yanai, Nobuyuki Okamura, Christopher C. Rowe
Summary: A neuroinflammatory reaction in AD brains involves reactive astrocytes that overexpress MAO-B. The PET tracer 18F-SMBT-1 showed significantly higher binding in A beta+ CN individuals and A beta+ AD patients compared to A beta-CN individuals. These findings suggest that 18F-SMBT-1 binding can be detected at the preclinical stages of A beta accumulation, supporting its use as a surrogate marker of astrogliosis in the AD continuum.
JOURNAL OF NUCLEAR MEDICINE
(2022)
Article
Psychiatry
Pratishtha Chatterjee, Steve Pedrini, Erik Stoops, Kathryn Goozee, Victor L. Villemagne, Prita R. Asih, Inge M. W. Verberk, Preeti Dave, Kevin Taddei, Hamid R. Sohrabi, Henrik Zetterberg, Kaj Blennow, Charlotte E. Teunissen, Hugo M. Vanderstichele, Ralph N. Martins
Summary: The study found that plasma GFAP levels are elevated in cognitively normal older adults at risk of AD, indicating that astrocytic damage or activation may start from the pre-symptomatic stage of the disease and is associated with brain Aβ load. The potential of plasma GFAP to contribute to a diagnostic blood biomarker panel, along with plasma Aβ 1-42/Aβ 1-40 ratios, for cognitively normal older adults at risk of AD was highlighted by the observations from the present study.
TRANSLATIONAL PSYCHIATRY
(2021)
Article
Clinical Neurology
Anniina Snellman, Laura L. Ekblad, Jouni Tuisku, Mikko Koivumaki, Nicholas J. Ashton, Juan Lantero-Rodriguez, Thomas K. Karikari, Semi Helin, Marco Bucci, Eliisa Loyttyniemi, Riitta Parkkola, Mira Karrasch, Michael Scholl, Henrik Zetterberg, Kaj Blennow, Juha O. Rinne
Summary: This study used positron emission tomography (PET) and blood biomarker measurements to examine differences in neuroinflammation and beta-amyloid (Aβ) and their association in cognitively unimpaired individuals. The results showed that only Aβ burden measured by PET differed among cognitively unimpaired elderly with different APOE ε4 gene dose, while the differences in neuroinflammation markers were not significant. However, APOE ε4 gene dose seemed to modulate the association between neuroinflammation and Aβ.
ALZHEIMERS RESEARCH & THERAPY
(2023)
Article
Chemistry, Medicinal
Karar T. Shukur, Tugba Ercetin, Chiara Luise, Wolfgang Sippl, Okan Sirkecioglu, Mert Ulgen, Goknil P. Coskun, Mine Yarim, Mustafa Gazi, Hayrettin O. Gulcan
Summary: A series of urolithin amide derivatives were synthesized and evaluated for their inhibitory potential on cholinesterases and MAO-B. The most potent inhibitors were identified, and docking studies revealed their binding modes with the targets. These compounds showed potential for multitarget ligand design in Alzheimer's disease drug development.
ARCHIV DER PHARMAZIE
(2021)
Article
Clinical Neurology
Andrea L. Benedet, Wagner S. Brum, Oskar Hansson, Alzheimer's Disease Neuroimaging Initiative, Thomas K. Karikari, Eduardo R. Zimmer, Henrik Zetterberg, Kaj Blennow, Nicholas J. Ashton
Summary: Plasma A beta 42/40, quantified by IP-MS, demonstrates high performance in detecting A beta positivity at all stages of AD continuum, with GFAP and p-tau181 contributing further in cognitive impaired stage. However, variations between assays greatly affect the performance of A beta 42/40 but not of GFAP and p-tau181. Plasma GFAP and p-tau181 should be considered for more robust determination of A beta burden in cognitively unimpaired and cognitively impaired participants when dealing with between-assay CVs exceeding 5%.
ALZHEIMERS RESEARCH & THERAPY
(2022)
Article
Radiology, Nuclear Medicine & Medical Imaging
Silvio R. Meier, Dag Sehlin, Sahar Roshanbin, Victoria Lim Falk, Takashi Saito, Takaomi C. Saido, Ulf Neumann, Johanna Rokka, Jonas Eriksson, Stina Syvanen
Summary: This study compared an antibody-based PET ligand with C-11-PiB for the detection of nonfibrillar A beta in Alzheimer disease mouse models. The results showed that the antibody-based ligand could detect changes in brain A beta levels after anti-A beta therapy, while C-11-PiB was unable to quantify the decreased A beta levels.
JOURNAL OF NUCLEAR MEDICINE
(2022)
Article
Neurosciences
Rebecca Faresjo, Gillian Bonvicini, Xiaotian T. Fang, Ximena Aguilar, Dag Sehlin, Stina Syvanen
Summary: This study compared the brain pharmacokinetics of two BBB-penetrating bispecific antibodies of different sizes and found that the smaller non-IgG antibody di-scFv3D6-8D3 exhibited faster elimination from blood, lower brain C-max, higher parenchymal-to-capillary concentration ratio, and earlier brain elimination compared to the larger IgG-based bispecific antibody mAb3D6-scFv8D3. The study also indicated that di-scFv3D6-8D3 had lower avidity towards TfR1, potentially contributing to its faster brain delivery.
FLUIDS AND BARRIERS OF THE CNS
(2021)
Article
Neurosciences
Sahar Roshanbin, Mengfei Xiong, Greta Hultqvist, Linda Soderberg, Olof Zachrisson, Silvio Meier, Sara Ekmark-Lewen, Joakim Bergstrom, Martin Ingelsson, Dag Sehlin, Stina Syvanen
Summary: By utilizing bispecific antibodies for PET imaging, alpha SYN was successfully visualized in the mouse brain, showing potential application in synucleinopathies. However, challenges remain in imaging intracellular alpha SYN inclusions.
Article
Radiology, Nuclear Medicine & Medical Imaging
Silvio R. Meier, Dag Sehlin, Stina Syvanen
Summary: The study investigated the brain delivery of the nanobody VHH-E9, which binds to GFAP expressed by reactive astrocytes, through TfR-mediated transcytosis. The results showed that VHH-E9 fused to TfR displayed higher brain concentrations, but there was no difference in brain uptake and retention over time between wild-type and transgenic mice.
NUCLEAR MEDICINE AND BIOLOGY
(2022)
Review
Chemistry, Multidisciplinary
Stina Syvanen, Silvio R. Meier, Sahar Roshanbin, Mengfei Xiong, Rebecca Faresjo, Tobias Gustavsson, Gillian Bonvicini, Eva Schlein, Ximena Aguilar, Ulrika Julku, Jonas Eriksson, Dag Sehlin
Summary: Positron emission tomography (PET) is a medical imaging technique that has become important in clinical trials of drugs against Alzheimer's disease (AD). PET data contributed to the approval of aducanumab, an antibody targeting amyloid-beta (A beta) aggregates, by showing a dose-dependent reduction in brain amyloid. PET is also useful in preclinical studies with animal models of A beta pathology. It allows for longitudinal studies and has high translatability between species.
PHARMACEUTICAL RESEARCH
(2022)
Article
Cell Biology
Joshua Spurrier, LaShae Nicholson, Xiaotian T. Fang, Austin J. Stoner, Takuya Toyonaga, Daniel Holden, Timothy R. Siegert, William Laird, Mary Alice Allnutt, Marius Chiasseu, A. Harrison Brody, Hideyuki Takahashi, Sarah Helena Nies, Azucena Perez Canamas, Pragalath Sadasivam, Supum Lee, Songye Li, Le Zhang, Yiyun H. Huang, Richard E. Carson, Zhengxin Cai, Stephen M. Strittmatter
Summary: Selective modulation of mGluR5 can protect synapses from damage caused by microglial mediators, restoring synaptic density and reducing Tau protein accumulation. The therapeutic effect persists in aged mouse AD models, and also prevents the synaptic localization and engulfment of complement component C1Q.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Pharmacology & Pharmacy
Sahar Roshanbin, Ulrika Julku, Mengfei Xiong, Jonas Eriksson, Eliezer Masliah, Greta Hultqvist, Joakim Bergstrom, Martin Ingelsson, Stina Syvanen, Dag Sehlin
Summary: This study investigated a modified bispecific antibody for improved brain uptake in the treatment of Parkinson's disease. The results showed that the antibody could efficiently and quickly penetrate the brain and reduce the aggregation of alpha SYN.
Article
Medicine, Research & Experimental
Eva Schlein, Stina Syvanen, Johanna Rokka, Tobias Gustavsson, Raffaella Rossin, Marc Robillard, Jonas Eriksson, Dag Sehlin
Summary: Small molecule imaging agents have limitations in detecting certain types of amyloid-beta pathology. This study explores alternative strategies using bispecific and monospecific antibodies to enhance imaging contrast by increasing antibody clearance from blood. The results show that these strategies can significantly shorten the circulation time of the antibody and improve imaging contrast. This has the potential to enable imaging at earlier time points and combine antibodies with short-lived radionuclides.
MOLECULAR PHARMACEUTICS
(2022)
Article
Chemistry, Medicinal
Sara Lopes van den Broek, Vladimir Shalgunov, Rocio Garcia Vazquez, Natalie Beschorner, Natasha S. R. Bidesi, Maiken Nedergaard, Gitte M. Knudsen, Dag Sehlin, Stina Syvanen, Matthias M. Herth
Summary: Pretargeting is a nuclear imaging technique that utilizes bioorthogonal chemistry to achieve efficient imaging with antibodies, particularly in the field of neurodegenerative diseases. Research suggests that uptake of large molecule antibodies in the brain can be enhanced through ligand-mediated transport, potentially enabling pretargeted imaging beyond the BBB.
Article
Neurosciences
Gillian Bonvicini, Stina Syvanen, Ken G. G. Andersson, Merja Haaparanta-Solin, Francisco Lopez-Picon, Dag Sehlin
Summary: This study investigates the efficacy of using transferrin receptor (TfR) as a targeting strategy to transport amyloid-beta (Aβ) immunoPET ligands across the blood-brain barrier (BBB). The results indicate that the affinity to TfR affects the efficiency of crossing the BBB, and this method shows potential for imaging Aβ pathology in rats.
TRANSLATIONAL NEURODEGENERATION
(2022)
Article
Cell Biology
Emma Brolin, Martin Ingelsson, Joakim Bergstrom, Anna Erlandsson
Summary: Growing evidence suggests that pathological alpha-synuclein aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) begins at the synapses. This study examined the effect of monomers and preformed fibrils (PFFs) of alpha-synuclein on the distribution of SNARE proteins in primary cortical neurons. Short-term exposure to monomers or PFFs led to altered co-localization of VAMP-2 and syntaxin-1, and SNAP-25 and syntaxin-1, indicating a direct influence on SNARE protein distribution. Long-term exposure to PFFs resulted in reduced co-localization of VAMP-2 and SNAP-25. Similarly, extracellular vesicles from astrocytes treated with PFFs also affected the co-localization of VAMP-2 and SNAP-25. These findings demonstrate that different forms of alpha-synuclein can impact the distribution of SNARE proteins at the synapse.
CELLULAR AND MOLECULAR NEUROBIOLOGY
(2023)
Article
Neurosciences
Tobias Mothes, Benjamin Portal, Evangelos Konstantinidis, Khalid Eltom, Sylwia Libard, Linn Streubel-Gallasch, Martin Ingelsson, Jinar Rostami, Maria Lindskog, Anna Erlandsson
Summary: Tau deposits in astrocytes are observed in Alzheimer's disease and other tauopathies, and their origin and relevance for disease progression remain unknown. This study shows that human astrocytes facilitate the spreading of pathological tau from cell to cell. Astrocytes engulf and process tau from dead neurons and AD brain tissue, and then spread the pathogenic tau to nearby cells via secretion and tunneling nanotube mediated transfer. Co-culture experiments also demonstrate that tau-containing astrocytes induce tau pathology in healthy human neurons. The findings suggest that astrocytes play a central role in mediating tau pathology and may serve as potential treatment targets for Alzheimer's disease and other tauopathies.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2023)