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https://www.readbyqxmd.com/read/29413519/imaging-translocator-protein-as-a-biomarker-of-neuroinflammation-in-dementia
#1
William C Kreisl, Ioline D Henter, Robert B Innis
Neuroinflammation has long been considered a potential contributor to neurodegenerative disorders that result in dementia. Accumulation of abnormal protein aggregates in Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies is associated with the activation of microglia and astrocytes into proinflammatory states, and chronic low-level activation of glial cells likely contributes to the pathological changes observed in these and other neurodegenerative diseases. The 18kDa translocator protein (TSPO) is a key biomarker for measuring inflammation in the brain via positron emission tomography (PET)...
2018: Advances in Pharmacology
https://www.readbyqxmd.com/read/29315754/tspo-regulation-in-reactive-gliotic-diseases
#2
REVIEW
Adam M McNeela, Charles Bernick, Rochelle M Hines, Dustin J Hines
The brain is the most metabolically active organ in the body. This high metabolic demand is apparent in that 60% of the brain is comprised of mitochondria-enriched cells. A disruption of the brain's ability to meet this immense metabolic demand is central to the pathogenesis of a multitude of neurological disorders, which range from depression to Alzheimer's disease. Central to these pathologies are glial signaling and energy metabolism cascades regulating apoptosis and inflammation. Thus, diseases causing inflammation and disruption of metabolism can be correlated with glial reactivity...
January 6, 2018: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/29242722/recent-progress-in-the-development-of-tspo-pet-ligands-for-neuroinflammation-imaging-in-neurological-diseases
#3
REVIEW
Md Maqusood Alam, Jihye Lee, Sang-Yoon Lee
Neuroinflammation is heavily associated with various neurological diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke. It is strongly characterized by the activation of microglia which can be visualized using position emission tomography (PET). Traditionally, translocator protein 18 kDa (TSPO) has been the preferred target for imaging the inflammatory progression of the microglial component. TSPO is expressed in the outer mitochondrial membrane and present in very low concentrations in the healthy human brain, but is markedly upregulated in response to brain injury and inflammation...
December 2017: Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/29203457/non-invasive-estimation-of-11c-pbr28-binding-potential
#4
Martin Schain, Francesca Zanderigo, R Todd Ogden, William C Kreisl
[11C]PBR28 is a PET radioligand used to estimate densities of the 18 kDa translocator protein (TSPO) in vivo. Since there is no suitable reference region, arterial blood samples are required for full quantification. Here, we evaluate a methodology for full quantification of [11C]PBR28 PET data that does not require either a reference region or blood samples. Simultaneous estimation (SIME) uses time-activity curves from several brain regions to estimate binding potential (BPND), a theoretically more sensitive outcome measure than total distribution volume...
December 1, 2017: NeuroImage
https://www.readbyqxmd.com/read/29135331/imaging-microglial-activation-and-amyloid-burden-in-amnestic-mild-cognitive-impairment
#5
Dunja Knezevic, Nicolaas Paul Lg Verhoeff, Sina Hafizi, Antonio P Strafella, Ariel Graff-Guerrero, Tarek Rajji, Bruce G Pollock, Sylvain Houle, Pablo M Rusjan, Romina Mizrahi
Amnestic mild cognitive impairment (aMCI) is defined as a transitional state between normal aging and Alzheimer's disease (AD). Given the replicated finding of increased microglial activation in AD, we sought to investigate whether microglial activation is also elevated in aMCI and whether it is related to amyloid beta (Aβ) burden in-vivo . Eleven aMCI participants and 14 healthy volunteers completed positron emission tomography (PET) scans with [(18)F]-FEPPA and [(11)C]-PIB. Given the known sensitivity in affinity of second-generation TSPO radioligands, participants were genotyped for the TSPO polymorphism and only high-affinity binders were included...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/29031071/discovery-of-thienopyrrolotriazine-derivatives-to-protect-mitochondrial-function-against-a%C3%AE-induced-neurotoxicity
#6
TaeHun Kim, Woo Seung Son, Mohammad Neaz Morshed, Ashwini M Londhe, Seo Yun Jung, Jong-Hyun Park, Woo-Kyu Park, Sang Min Lim, Ki Duk Park, Sung Jin Cho, Kyu-Sung Jeong, Jiyoun Lee, Ae Nim Pae
Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine group...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28988133/coupling-between-physiological-tspo-expression-in-brain-and-myocardium-allows-stabilization-of-late-phase-cerebral-18-f-ge180-pet-quantification
#7
Maximilian Deussing, Tanja Blume, Lena Vomacka, Christoph Mahler, Carola Focke, Andrei Todica, Marcus Unterrainer, Nathalie L Albert, Simon Lindner, Barbara von Ungern-Sternberg, Karlheinz Baumann, Andreas Zwergal, Peter Bartenstein, Jochen Herms, Axel Rominger, Matthias Brendel
OBJECTIVES: PET imaging of the 18 kDa translocator protein (TSPO), a biomarker of microglial activity, receives growing interest in clinical and preclinical applications of neuroinflammatory and neurodegenerative brain diseases. In globally affected brains, intra-cerebral pseudo reference regions are not feasible. Consequently, many brain-independent approaches have been attempted, including SUV analysis and normalization to muscle- or heart uptake, aiming to stabilize quantitative analysis...
October 5, 2017: NeuroImage
https://www.readbyqxmd.com/read/28986511/neuroinflammation-appears-early-and-then-plateaus-in-a-mouse-model-of-alzheimer-s-disease-shown-by-pet-imaging
#8
Francisco R López-Picón, Anniina Snellman, Olli Eskola, Semi Helin, Olof Solin, Merja Haaparanta-Solin, Juha O Rinne
Rationale: Neuroinflammation has been associated with different neurological diseases including Alzheimer's disease (AD). In AD, the translocator protein 18kDa (TSPO) is overexpressed in the activated microglia that surround the β-amyloid plaques. In the current longitudinal study, using a mouse model of AD, we evaluated the association between β-amyloid deposition and neuroinflammation in AD. Methods: To monitor the longitudinal changes in β-amyloid deposition and neuroinflammation, we used in vivo PET imaging and ex vivo autoradiography with (11)C-PIB and a TSPO tracer, (18)F-GE-180, in the APP23 mouse model of AD...
October 6, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28901441/profiling-of-differentially-expressed-genes-in-adipose-tissues-of-multiple-symmetric-lipomatosis
#9
Ke Chen, Linghao Wang, Wenjun Yang, Changfa Wang, Gui Hu, Zhaohui Mo
Multiple symmetric lipomatosis (MSL) is a rare disorder characterized by aberrant multiple and symmetric subcutaneous adipose tissue accumulation in the face, neck, shoulders, back, chest and abdomen, severely affecting the quality of life of patients. At present, precise MSL etiology and pathogenesis remain to be elucidated. The present study first utilized a digital gene expression technique with a next‑generation sequencing platform to profile differentially expressed genes in three cases of MSL vs. normal control tissue...
November 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28559417/the-ftd-like-syndrome-causing-trem2-t66m-mutation-impairs-microglia-function-brain-perfusion-and-glucose-metabolism
#10
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
https://www.readbyqxmd.com/read/28545084/feasibility-study-of-tspo-quantification-with-18f-feppa-using-population-based-input-function
#11
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
https://www.readbyqxmd.com/read/28533150/molecular-imaging-of-neuroinflammation-in-alzheimer-s-disease-and-mild-cognitive-impairment
#12
REVIEW
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
https://www.readbyqxmd.com/read/28530834/a-facile-radiolabeling-of-18f-fdpa-via-spirocyclic-iodonium-ylides-preliminary-pet-imaging-studies-in-preclinical-models-of-neuroinflammation
#13
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 18F-ligand, [18F]2 ([18F]FDPA), is radiolabeled in high yield and high specific activity based on our spirocyclic iodonium ylide (SCIDY) strategy. [18F]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
https://www.readbyqxmd.com/read/28529627/-18-f-ge-180-pet-detects-reduced-microglia-activation-after-lm11a-31-therapy-in-a-mouse-model-of-alzheimer-s-disease
#14
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
https://www.readbyqxmd.com/read/28516240/in-vivo-pet-imaging-of-neuroinflammation-in-alzheimer-s-disease
#15
REVIEW
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
https://www.readbyqxmd.com/read/28219319/biomarkers-in-alzheimer-s-disease-recent-update
#16
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
https://www.readbyqxmd.com/read/27855359/discovery-of-benzimidazole-derivatives-as-modulators-of-mitochondrial-function-a-potential-treatment-for-alzheimer-s-disease
#17
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
https://www.readbyqxmd.com/read/27678494/test-retest-analysis-of-a-non-invasive-method-of-quantifying-11-c-pbr28-binding-in-alzheimer-s-disease
#18
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
https://www.readbyqxmd.com/read/27672476/expression-of-phenotypic-astrocyte-marker-is-increased-in-a-transgenic-mouse-model-of-alzheimer-s-disease-versus-age-matched-controls-a-presymptomatic-stage-study
#19
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
https://www.readbyqxmd.com/read/27578213/assessment-of-neuroinflammation-in-a-mouse-model-of-obesity-and-%C3%AE-amyloidosis-using-pet
#20
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
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