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TSPO alzheimer

Gernot Kleinberger, Matthias Brendel, Eva Mracsko, Benedikt Wefers, Linda Groeneweg, Xianyuan Xiang, Carola Focke, Maximilian Deußing, Marc Suárez-Calvet, Fargol Mazaheri, Samira Parhizkar, Nadine Pettkus, Wolfgang Wurst, Regina Feederle, Peter Bartenstein, Thomas Mueggler, Thomas Arzberger, Irene Knuesel, Axel Rominger, Christian Haass
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation. Consistent with a loss-of-function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p...
July 3, 2017: EMBO Journal
Rostom Mabrouk, Antonio P Strafella, Dunja Knezevic, Christine Ghadery, Romina Mizrahi, Avideh Gharehgazlou, Yuko Koshimori, Sylvain Houle, Pablo Rusjan
PURPOSE: The input function (IF) is a core element in the quantification of Translocator protein 18 kDa with positron emission tomography (PET), as no suitable reference region with negligible binding has been identified. Arterial blood sampling is indeed needed to create the IF (ASIF). In the present manuscript we study individualization of a population based input function (PBIF) with a single arterial manual sample to estimate total distribution volume (VT) for [18F]FEPPA and to replicate previously published clinical studies in which the ASIF was used...
2017: PloS One
Dunja Knezevic, Romina Mizrahi
Neuroinflammatory changes have been demonstrated to be an important feature of Alzheimer's disease (AD); however, the exact role of neuroinflammation and its progression during disease is still not well understood. One of the main drivers of the neuroinflammatory process are microglial cells. Positron Emission Tomography allows for the quantification of microglial activation by labelling the Translocator Protein 18kDa (TSPO), which becomes overexpressed upon activation of microglial cells. Several radioligands have been designed to target TSPO and have been studied in-vivo in AD populations...
May 19, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
Lu Wang, Ran Cheng, Masayuki Fujinaga, Jian Yang, Yiding Zhang, Akiko Hatori, Katsushi Kumata, Jing Yang, Neil Vasdev, Yunfei Du, Chongzhao Ran, Ming-Rong Zhang, Steven H Liang
A suitable TSPO PET ligand may visualize and quantify neuroinflammation in a living brain. Herein we report a (18)F-ligand, [(18)F]2 ([(18)F]FDPA), is radiolabeled in high yield and high specific activity based on our spirocyclic iodonium ylide (SCIDY) strategy. [(18)F]2 demonstrated saturable specific binding to TSPO, substantially elevated brain uptake, and slow washout of bound PET signal in the preclinical models of brain neuroinflammation (cerebral ischemia and Alzheimer's disease).
June 22, 2017: Journal of Medicinal Chemistry
Michelle L James, Nadia P Belichenko, Adam J Shuhendler, Aileen Hoehne, Lauren E Andrews, Christina Condon, Thuy-Vi V Nguyen, Vladimer Reiser, Paul Jones, William Trigg, Jianghong Rao, Sanjiv S Gambhir, Frank M Longo
Microglial activation is a key pathological feature of Alzheimer's disease (AD). PET imaging of translocator protein 18 kDa (TSPO) is a strategy to detect microglial activation in vivo. Here we assessed flutriciclamide ([(18)F]GE-180), a new second-generation TSPO-PET radiotracer, for its ability to monitor response to LM11A-31, a novel AD therapeutic in clinical trials. AD mice displaying pathology were treated orally with LM11A-31 for 3 months. Subsequent [(18)F]GE-180-PET imaging revealed significantly lower signal in cortex and hippocampus of LM11A-31-treated AD mice compared to those treated with vehicle, corresponding with decreased levels of TSPO immunostaining and microglial Iba1 immunostaining...
2017: Theranostics
Julien Lagarde, Marie Sarazin, Michel Bottlaender
Increasing evidence suggests that neuroinflammation contributes to the pathophysiology of many neurodegenerative diseases, especially Alzheimer's disease (AD). Molecular imaging by PET may be a useful tool to assess neuroinflammation in vivo, thus helping to decipher the complex role of inflammatory processes in the pathophysiology of neurodegenerative diseases and providing a potential means of monitoring the effect of new therapeutic approaches. For this objective, the main target of PET studies is the 18 kDa translocator protein (TSPO), as it is overexpressed by activated microglia...
May 17, 2017: Journal of Neural Transmission
Sushil Sharma, Walter Lipincott
Alzheimer disease (AD) is an age-related neurodegenerative disorder, characterized by loss of memory and cognitive function. It is the common cause of dementia in elderly and is a global health concern as the population of people aged 85 and older, is growing alarmingly. Although pharmacotherapy for the treatment of AD has improved, lot of work remains to treat this devastating disease. AD pathology begins even before the onset of clinical symptoms. Because therapies could be more effective if implemented early in the disease progression, it is highly prudent to discover reliable biomarkers, to detect its exact pathophysiology during pre-symptomatic stage...
February 20, 2017: Current Alzheimer Research
TaeHun Kim, Ha Yun Yang, Beoung Gun Park, Seo Yun Jung, Jong-Hyun Park, Ki Duk Park, Sun-Joon Min, Jinsung Tae, Hyejin Yang, Suengmok Cho, Sung Jin Cho, Hyundong Song, Inhee Mook-Jung, Jiyoun Lee, Ae Nim Pae
In this study, we designed a library of compounds based on the structures of well-known ligands of the 18 kDa translocator protein (TSPO), one of the putative components of the mPTP. We performed diverse mitochondrial functional assays to assess their ability to restore cells from Aβ-induced toxicity in vitro and in vivo. Among tested compounds, compound 25 effectively improved cognitive function in animal models of AD. Given the excellent in vitro and in vivo activity and a favorable pharmacokinetic profile of compound 25, we believe that it can serve as a promising lead compound for a potential treatment option for AD...
January 5, 2017: European Journal of Medicinal Chemistry
Akshay Nair, Mattia Veronese, Xiaohui Xu, Charles Curtis, Federico Turkheimer, Robert Howard, Suzanne Reeves
PURPOSE: In order to maximise the utility of [(11)C]-PBR28 for use in longitudinal studies and clinical trials in Alzheimer's disease (AD), there is a need to develop non-invasive metrics of tracer binding that do not require arterial cannulation. Recent work has suggested that standardised uptake value (SUV)-based methods may be sensitive to changes in translocator protein (TSPO) levels associated with neurodegeneration. However, the test-retest reliability of these approaches in AD over a time period relevant for clinical trials is unknown...
December 2016: EJNMMI Research
Aurélie Doméné, Chelsea Cavanagh, Guylène Page, Sylvie Bodard, Christophe Klein, Cécile Delarasse, Sylvie Chalon, Slavica Krantic
Recent mouse studies of the presymptomatic stage of Alzheimer's disease (AD) have suggested that proinflammatory changes, such as glial activation and cytokine induction, may occur already at this early stage through unknown mechanisms. Because TNFα contributes to increased Aβ production from the Aβ precursor protein (APP), we assessed a putative correlation between APP/Aβ and TNFα during the presymptomatic stage as well as early astrocyte activation in the hippocampus of 3-month-old APPswe/PS1dE9 mice...
2016: International Journal of Alzheimer's Disease
Anna M Barron, Masaki Tokunaga, Ming-Rong Zhang, Bin Ji, Tetsuya Suhara, Makoto Higuchi
BACKGROUND: Obesity has been identified as a risk factor for cognitive decline and Alzheimer's disease (AD). The aim of this study was to investigate the effect of obesity on neuroinflammation and cerebral glucose metabolism using PET in a mouse model of β-amyloidosis and determine the relationship between these PET imaging biomarkers, pathogenic changes, and functional outcomes. METHODS: Three-month-old C57BL/J6 mice were fed either a standard (control group) or high-fat diet (obese group) for 3 months and intracerebroventricularly infused with vehicle or human beta amyloid 1-42 (Aβ42)...
August 31, 2016: Journal of Neuroinflammation
William C Kreisl, Chul Hyoung Lyoo, Jeih-San Liow, Monica Wei, Joseph Snow, Emily Page, Kimberly J Jenko, Cheryl L Morse, Sami S Zoghbi, Victor W Pike, R Scott Turner, Robert B Innis
This longitudinal study sought to determine whether the 18 kDa translocator protein (TSPO), a marker of neuroinflammation, increases over time in Alzheimer's disease. Positron emission tomography imaging with the TSPO radioligand (11)C-PBR28 was performed at baseline and after a median follow-up of 2.7 years in 14 amyloid-positive patients and 8 amyloid-negative controls. Patients had a greater increase in TSPO binding than controls in inferior parietal lobule, precuneus, occipital cortex, hippocampus, entorhinal cortex, and combined middle and inferior temporal cortex...
August 2016: Neurobiology of Aging
Sandeep S V Golla, Ronald Boellaard, Vesa Oikonen, Anja Hoffmann, Bart N M van Berckel, Albert D Windhorst, Jere Virta, Erik T Te Beek, Geert Jan Groeneveld, Merja Haaparanta-Solin, Pauliina Luoto, Nina Savisto, Olof Solin, Ray Valencia, Andrea Thiele, Jonas Eriksson, Robert C Schuit, Adriaan A Lammertsma, Juha O Rinne
(18)F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of (18)F-DPA-714 binding. METHODS: Ninety-minute dynamic (18)F-DPA-714 PET scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer disease (AD) patients were used. Plasma-input-based Logan graphical analysis and spectral analysis were used to generate parametric volume of distribution (VT) images...
October 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Masamichi Yokokura, Tatsuhiro Terada, Tomoyasu Bunai, Kyoko Nakaizumi, Kiyokazu Takebayashi, Yasuhide Iwata, Etsuji Yoshikawa, Masami Futatsubashi, Katsuaki Suzuki, Norio Mori, Yasuomi Ouchi
The presence of activated microglia in the brains of healthy elderly people is a matter of debate. We aimed to clarify the degree of microglial activation in aging and dementia as revealed by different tracers by comparing the binding potential (BPND) in various brain regions using a first-generation translocator protein (TSPO) tracer [(11)C]( R)PK11195 and a second-generation tracer [(11)C]DPA713. The BPND levels, estimated using simplified reference tissue models, were compared among healthy young and elderly individuals and patients with Alzheimer's disease (AD) and were correlated with clinical scores...
March 2017: Journal of Cerebral Blood Flow and Metabolism
Fei Li, Jian Liu, Nan Liu, Leslie A Kuhn, R Michael Garavito, Shelagh Ferguson-Miller
Translocator protein 18 kDa (TSPO) was previously known as the peripheral benzodiazepine receptor (PBR) in eukaryotes, where it is mainly localized to the mitochondrial outer membrane. Considerable evidence indicates that it plays regulatory roles in steroidogenesis and apoptosis and is involved in various human diseases, such as metastatic cancer, Alzheimer's and Parkinson's disease, inflammation, and anxiety disorders. Ligands of TSPO are widely used as diagnostic tools and treatment options, despite there being no clear understanding of the function of TSPO...
May 24, 2016: Biochemistry
Nazanin Mirzaei, Sac Pham Tang, Sharon Ashworth, Christopher Coello, Christophe Plisson, Jan Passchier, Vimal Selvaraj, Robin J Tyacke, David J Nutt, Magdalena Sastre
Microglial activation has been linked with deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulated in reactive microglia. Accurate visualization and quantification of microglial density by PET imaging using the TSPO tracer [(11)C]-R-PK11195 has been challenging due to the limitations of the ligand. In this study, it was aimed to evaluate the new TSPO tracer [(11)C]PBR28 as a marker for microglial activation in the 5XFAD transgenic mouse model of AD...
June 2016: Glia
Matthias Brendel, Federico Probst, Anna Jaworska, Felix Overhoff, Viktoria Korzhova, Nathalie L Albert, Roswitha Beck, Simon Lindner, Franz-Josef Gildehaus, Karlheinz Baumann, Peter Bartenstein, Gernot Kleinberger, Christian Haass, Jochen Herms, Axel Rominger
UNLABELLED: Amyloid imaging by small-animal PET in models of Alzheimer disease (AD) offers the possibility to track amyloidogenesis and brain energy metabolism. Because microglial activation is thought to contribute to AD pathology, we undertook a triple-tracer small-animal PET study to assess microglial activation and glucose metabolism in association with amyloid plaque load in a transgenic AD mouse model. METHODS: Groups of PS2APP and C57BL/6 wild-type mice of various ages were examined by small-animal PET...
June 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Li Ma, Hui Zhang, Na Liu, Pei-qi Wang, Wen-zhi Guo, Qiang Fu, Lin-bo Jiao, Ya-qun Ma, Wei-Dong Mi
Translocator protein 18 kDa (TSPO) is now an attractive drug target for controlling neuroinflammation. Studies applying TSPO ligands to neurodegenerative diseases, especially Alzheimer's disease (AD), were rare. Our study was aimed to evaluate the effect of PK11195, a specific TSPO ligand, in an animal model of neuroinflammation caused by systemic LPS administration. C57/BL6 mice were treated with lipopolysaccharide (LPS, 500 μg/kg, i.p.) three days after PK11195 administration (3mg/kg, i.p.). The drugs were not discontinued until the mice were sacrificed...
March 2016: Brain Research Bulletin
Daniel Felsky, Philip L De Jager, Julie A Schneider, Konstantinos Arfanakis, Debra A Fleischman, Zoe Arvanitakis, William G Honer, Jennie G Pouget, Romina Mizrahi, Bruce G Pollock, James L Kennedy, David A Bennett, Aristotle N Voineskos
The translocator protein, a microglial-expressed marker of neuroinflammation, has been implicated in Alzheimer's disease, which is characterized by alterations in vascular and inflammatory states. ATSPOvariant, rs6971, determines binding affinity of exogenous radioligandsin vivo; however, the effect of these altered binding characteristics on inflammatory and cerebrovascular biomarkers has not been assessed. In 2345 living subjects (Alzheimer's Disease Neuroimaging Initiative, n = 1330) and postmortem brain samples (Religious Orders Study and Memory and Aging Project, n = 1015), we analyzed effects of rs6971 on white matter hyperintensisites, cerebral infarcts, circulating inflammatory biomarkers, amyloid angiopathy, and microglial activation...
April 2016: Journal of Cerebral Blood Flow and Metabolism
P Porcu, A M Barron, C A Frye, A A Walf, S-Y Yang, X-Y He, A L Morrow, G C Panzica, R C Melcangi
Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the GABAA receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases...
February 2016: Journal of Neuroendocrinology
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