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[PMID]: 29524637
[Au] Autor:Zhang S; An Q; Wang T; Gao S; Zhou G
[Ad] Address:Department of Medical Genetics and Cell Biology, Shenzhen Key Laboratory of Anti-aging and Regenerative Medicine, Health Sciences Center, Shenzhen University, Shenzhen, 518060, China.
[Ti] Title:Autophagy- and MMP-2/9-mediated Reduction and Redistribution of ZO-1 Contribute to Hyperglycemia-increased Blood-Brain Barrier Permeability during Early Reperfusion in Stroke.
[So] Source:Neuroscience;, 2018 Mar 07.
[Is] ISSN:1873-7544
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Post-stroke hyperglycemia during early reperfusion increases blood-brain barrier (BBB) permeability and subsequently aggravates brain injury and clinical prognosis. The decreased level of tight junction proteins (TJPs) has been reported but the underlying mechanism remains largely elusive. Herein we designed to investigate the detailed molecular events in brain microvascular endothelial cells (BMECs) ex and in vivo. After oxygen-glucose deprivation (OGD) for 90 min and reperfusion with 8 or 16 mM glucose for 30 min, glucose at 16 mM caused significant decrease of the TJP expression and particularly ZO-1 redistribution from membrane to cytoplasm of BMECs. High glucose also markedly promoted the secretion of MMP-2/9 and oxidative/nitrosative stress, enhanced autophagy and increased the Caveolin-1 and LAMP-2 expression. Moreover, in vivo experiments demonstrated that rapamycin-enhanced autophagy further caused ZO-1 reduction and the increased BBB permeability. Therefore, high glucose exposure in the early reperfusion causes the BBB disruption, with MMP-2/9-mediated extracellular degradation, caveolin-1-mediated intracellular translocation and autophagy-lysosome-mediated degradation of ZO-1 protein all together involved in the process. The role of MMP-2/-9 and autophagy in the modulation of paracellular permeability was confirmed by pharmacological inhibition. Therefore, our findings may provide new insights into targeting ZO-1 regulation for the purpose of significantly improving the clinical prognosis of ischemic stroke.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

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[PMID]: 29524538
[Au] Autor:Ruzza P; Vitale RM; Hussain R; Montini A; Honisch C; Pozzebon A; Hughes CS; Biondi B; Amodeo P; Sechi G; Siligardi G
[Ad] Address:Institute of Biomolecular Chemistry of CNR, Padua Unit, Padua, Italy. Electronic address: paolo.ruzza@unipd.it.
[Ti] Title:Chaperone-like effect of ceftriaxone on HEWL aggregation: A spectroscopic and computational study.
[So] Source:Biochim Biophys Acta;, 2018 Mar 07.
[Is] ISSN:0006-3002
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:BACKGROUND: Lysozyme is a widely distributed enzyme present in a variety of tissue and body fluids. Human and hen egg white lysozyme are used as validated model to study protein folding and stability and to understand protein misfolding and aggregation. We recently found that ceftriaxone, a ß-lactam antibiotic able to overcome the blood-brain barrier, successfully eliminated the cellular toxic effects of misfolded proteins as Glial Fibrillary Acidic Protein and α-synuclein. To further understand the anti-amyloidogenic properties of ceftriaxone, we studied its activity towards lysozyme aggregation with the aim to investigate a possible chaperone-like activity of this molecule. METHODS: Here we present the results obtained from fluorescence and synchrotron radiation circular dichroism spectroscopies and from molecular docking and molecular dynamics about the lysozyme-ceftriaxone interaction at neutral and acidic pH values. RESULTS: We found that ceftriaxone exhibits comparable affinity constants to lysozyme in both experimental pH conditions and that its addition enhanced lysozyme stability reducing its aggregation propensity in acidic conditions. Computational methods allowed the identification of the putative binding site of ceftriaxone, thus rationalizing the spectroscopic results. CONCLUSIONS: Spectroscopy data and molecular dynamics indicated a protective effect of ceftriaxone on pathological aggregation phenomena suggesting a chaperone-like effect of this molecule on protein folding. General significance These results, in addition to our previous studies on α-synuclein and GFAP, confirm the property of ceftriaxone to inhibit the pathological protein aggregation of lysozyme also by a chaperone-like mechanism, extending the potential therapeutic application of this molecule to some forms of human hereditary systemic amyloidosis.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  3 / 37466 MEDLINE  
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[PMID]: 29486328
[Au] Autor:Mendes M; Miranda A; Cova T; Gonçalves L; Almeida AJ; Sousa JJ; do Vale MLC; Marques EF; Pais A; Vitorino C
[Ad] Address:Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Centre for Neurosciences and Cell Biology (CNC), University of Coimbra, Rua Larga, Faculty of Medicine, Pólo I, 1st floor, 3004-504 Coimbra, Portugal.
[Ti] Title:Modeling of ultra-small lipid nanoparticle surface charge for targeting glioblastoma.
[So] Source:Eur J Pharm Sci;117:255-269, 2018 Feb 24.
[Is] ISSN:1879-0720
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Surface modification of ultra-small nanostructured lipid carriers (usNLC) via introduction of a positive charge is hypothesized to prompt site-specific drug delivery for glioblastoma multiforme (GBM) treatment. A more effective interaction with negatively charged lipid bilayers, including the blood-brain barrier (BBB), will facilitate the nanoparticle access to the brain. For this purpose, usNLC with a particle size of 43.82 ±â€¯0.03 nm and a polydispersity index of 0.224 were developed following a Quality by Design approach. Monomeric and gemini surfactants, either with conventional headgroups or serine-based ones, were tested for the surface modification, and the respective safety and efficacy to target GBM evaluated. A comprehensive in silico-in vitro approach is also provided based on molecular dynamics simulations and cytotoxicity studies. Overall, monomeric serine-derived surfactants displayed the best performance, considering altogether particle size, zeta potential, cytotoxic profile and cell uptake. Although conventional surfactants were able to produce usNLC with suitable physicochemical properties and cell uptake, their use is discouraged due to their high cytotoxicity. This study suggests that monomeric serine-derived surfactants are promising agents for developing nanosystems aiming at brain drug delivery.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

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[PMID]: 29458086
[Au] Autor:Rosas-Hernandez H; Cuevas E; Escudero-Lourdes C; Lantz SM; Sturdivant NM; Imam SZ; Sarkar S; Slikker W; Paule MG; Balachandran K; Ali SF
[Ad] Address:Division of Neurotoxicology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR, 72079, USA.
[Ti] Title:Characterization of uniaxial high-speed stretch as an in vitro model of mild traumatic brain injury on the blood-brain barrier.
[So] Source:Neurosci Lett;672:123-129, 2018 Feb 16.
[Is] ISSN:1872-7972
[Cp] Country of publication:Ireland
[La] Language:eng
[Ab] Abstract:Traumatic brain injury (TBI) occurs when external mechanical forces induce brain damage as result of impact, penetration or rapid acceleration/deceleration that causes deformation of brain tissue. Depending on its severity, TBI can be classified as mild, moderate or severe and can lead to blood-brain barrier (BBB) dysfunction. In the present study, we evaluated the effects of uniaxial high-speed stretch (HSS) at 0, 5, 10 and 15% on a pure culture of primary rat brain endothelial cells as an in vitro model of TBI to the BBB. LDH release, viability and apoptosis analysis, expression of tight junction proteins and endothelial permeability were evaluated 24 h after a single stretch episode. HSS slightly increased cell death and apoptosis at 10 and 15%, while LDH release was increased only at 15% stretch. Occludin expression was increased at 10% stretch, while claudin-5 expression was increased at 5% stretch, which also decreased the endothelial permeability. In summary, 15% HSS induced low levels of cell death, consistent with mild TBI and very low percentages of HSS (5%) enhanced the BBB properties, promoting the formation of a stronger barrier. These data support the use of 15% HSS as valuable tool in the study of mild TBI to the BBB in vitro.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
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[PMID]: 29428540
[Au] Autor:Bicker J; Alves G; Fortuna A; Soares-da-Silva P; Falcão A
[Ad] Address:Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
[Ti] Title:In vitro assessment of the interactions of dopamine ß-hydroxylase inhibitors with human P-glycoprotein and Breast Cancer Resistance Protein.
[So] Source:Eur J Pharm Sci;117:35-40, 2018 Feb 08.
[Is] ISSN:1879-0720
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Inhibition of the biosynthesis of noradrenaline is a currently explored strategy for the treatment of hypertension, congestive heart failure and pulmonary arterial hypertension. While some dopamine ß-hydroxylase (DBH) inhibitors cross the blood-brain barrier (BBB) and cause central as well as peripheral effects (nepicastat), others have limited access to the brain (etamicastat, zamicastat). In this context, peripheral selectivity is clinically advantageous, in order to prevent alterations of noradrenaline levels in the CNS and the occurrence of adverse central effects. A limited brain exposure results from the combination of several factors, such as a reduced passive permeability or affinity for efflux transporters, but efflux liabilities may also lead to unwanted drug-drug interactions (DDIs) in the presence of co-administered substrates or inhibitors. Thus, the purpose of the study herein presented was to explore the interaction of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), the two major efflux transporters of the BBB that hamper the entry of several drugs to the brain, with the DBH inhibitors, etamicastat, nepicastat and zamicastat. Madin-Darby canine kidney cells (MDCK II) and transfected lines with human MDR1 (MDCK-MDR1) and ABCG2 (MDCK-BCRP) genes were used as a BBB surrogate model. P-gp and BCRP substrates and/or inhibitors were identified through intracellular accumulation and bidirectional permeability assays. The obtained data revealed that zamicastat is a concentration-dependent dual P-gp and BCRP inhibitor with IC values of 73.8 ±â€¯7.2 µM and 17.0 ±â€¯2.7 µM, while etamicastat and nepicastat inhibited BCRP to greater extent than P-gp, with IC values of 47.7 ±â€¯1.8 µM and 59.2 ±â€¯9.4 µM, respectively. Additionally, etamicastat was identified as P-gp and BCRP dual substrate, as demonstrated by net flux ratios of 5.84 and 3.87 and decreased >50% by verapamil and Ko143. Conversely, nepicastat revealed to be a P-gp-only substrate, with a net flux ratio of 2.01, reduced to 0.92 in the presence of verapamil. Furthermore, nepicastat displayed a consistently higher apparent permeability (>8.49 × 10 cm s ) than etamicastat (<0.58 × 10 cm s ). The identification of etamicastat as a dual efflux substrate suggests that P-gp and BCRP may be partially responsible for the limited central exposure of this compound, in association with its low passive permeability. Moreover, the weak efflux inhibitory potencies of etamicastat and nepicastat revealed a low DDI risk, while the dual P-gp/BCRP inhibition of zamicastat could be studied in the future with synergically effluxed compounds, for which BBB penetration is severely impaired.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

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[PMID]: 29427702
[Au] Autor:Taccola C; Cartot-Cotton S; Valente D; Barneoud P; Aubert C; Boutet V; Gallen F; Lochus M; Nicolic S; Dodacki A; Smirnova M; Cisternino S; Declèves X; Bourasset F
[Ad] Address:Pharmacokinetics, Dynamics and Metabolism, Translational Medicine & Early Development, Sanofi, France; Variabilité de Réponse aux Psychotropes, Inserm, U1144, Paris F-75006, France; Faculté de Pharmacie de Paris, Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Did
[Ti] Title:High brain distribution of a new central nervous system drug candidate despite its P-glycoprotein-mediated efflux at the mouse blood-brain barrier.
[So] Source:Eur J Pharm Sci;117:68-79, 2018 Feb 07.
[Is] ISSN:1879-0720
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Efficacy of drugs aimed at treating central nervous system (CNS) disorders rely partly on their ability to cross the cerebral endothelium, also called the blood-brain barrier (BBB), which constitutes the main interface modulating exchanges of compounds between the brain and blood. In this work, we used both, conventional pharmacokinetics (PK) approach and in situ brain perfusion technique to study the blood and brain PK of PKRinh, an inhibitor of the double-stranded RNA-dependent protein kinase (PKR) activation, in mice. PKRinh showed a supra dose-proportional blood exposure that was not observed in the brain, and a brain to blood AUC ratio of unbound drug smaller than 1 at all tested doses. These data suggested the implication of an active efflux at the BBB. Using in situ brain perfusion technique, we showed that PKRinh has a very high brain uptake clearance which saturates with increasing concentrations. Fitting the data to a Michaelis-Menten equation revealed that PKRinh transport through the BBB is composed of a passive unsaturable flux and an active saturable protein-mediated efflux with a k of ≅ 3 µM. We were able to show that the ATP-binding cassette (ABC) transporter P-gp (Abcb1), but not Bcrp (Abcg2), was involved in the brain to blood efflux of PKRinh. At the circulating PKRinh concentrations of this study, the P-gp was not saturated, in accordance with the linear brain PKRinh PK. Finally, PKRinh had high brain uptake clearance (14 µl/g/s) despite it is a good P-gp substrate (P-gp Efflux ratio ≅ 3.6), and reached similar values than the cerebral blood flow reference, diazepam, in P-gp saturation conditions. With its very unique brain transport properties, PKRinh improves our knowledge about P-gp-mediated efflux across the BBB for the development of new CNS directed drugs.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

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[PMID]: 29360998
[Au] Autor:Tagge CA; Fisher AM; Minaeva OV; Gaudreau-Balderrama A; Moncaster JA; Zhang XL; Wojnarowicz MW; Casey N; Lu H; Kokiko-Cochran ON; Saman S; Ericsson M; Onos KD; Veksler R; Senatorov VV; Kondo A; Zhou XZ; Miry O; Vose LR; Gopaul KR; Upreti C; Nowinski CJ; Cantu RC; Alvarez VE; Hildebrandt AM; Franz ES; Konrad J; Hamilton JA; Hua N; Tripodis Y; Anderson AT; Howell GR; Kaufer D; Hall GF; Lu KP; Ransohoff RM; Cleveland RO; Kowall NW; Stein TD; Lamb BT; Huber BR; Moss WC; Friedman A; Stanton PK; McKee AC; Goldstein LE
[Ad] Address:Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, MA 02118, USA.
[Ti] Title:Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.
[So] Source:Brain;141(2):422-458, 2018 Feb 01.
[Is] ISSN:1460-2156
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Data-Review
[do] DOI:10.1093/brain/awx350

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[PMID]: 29294343
[Au] Autor:Singh S; Houng AK; Reed GL
[Ad] Address:Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: satishsingh@email.arizona.edu.
[Ti] Title:Matrix Metalloproteinase-9 Mediates the Deleterious Effects of α2-Antiplasmin on Blood-Brain Barrier Breakdown and Ischemic Brain Injury in Experimental Stroke.
[So] Source:Neuroscience;376:40-47, 2017 Dec 30.
[Is] ISSN:1873-7544
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:During acute brain ischemia, α2-antiplasmin markedly enhances brain injury, blood-brain barrier breakdown and matrix metalloproteinase-9 (MMP-9) expression. Although α2-antiplasmin inhibits fibrin thrombus-degradation, and MMP-9 is a collagen-degrading enzyme altering blood-brain barrier, both have similar deleterious effects on the ischemic brain. We examined the hypothesis that MMP-9 is an essential downstream mediator of α2-antiplasmin's deleterious effects during brain ischemia. Middle cerebral artery thromboembolic stroke was induced in a randomized, blinded fashion in mice with increased blood levels of α2-antiplasmin. There was a robust increase in MMP-9 expression (immunofluorescence) in the ischemic vs. the non-ischemic hemisphere of MMP-9 but not MMP-9 mice, 24 h after stroke. Brain swelling and hemorrhage were significantly increased in the ischemic vs. the non-ischemic hemisphere of MMP-9 mice. By comparison to MMP-9 mice, the ischemic hemispheres of MMP-9 mice showed a ∼6-fold reduction in brain swelling (p < 0.001) and a ∼9-fold reduction in brain hemorrhage. Brain infarction (p < 0.0001) and TUNEL-positive cell death (p < 0.001) were significantly diminished in the ischemic hemisphere of MMP-9 mice vs. MMP-9 mice. Ischemic breakdown of the blood-brain barrier and fibrin deposition were also significantly reduced in MMP-9 mice vs. MMP-9 mice (p < 0.05), as measured by quantitative immunofluorescence. We conclude that MMP-9 deficiency ablates many of the deleterious effects of high α2-antiplasmin levels, significantly reducing blood-brain barrier breakdown, TUNEL-positive cell death, brain hemorrhage, swelling and infarction. This suggests that the two molecules may be in a shared pathway in which MMP-9 is essential downstream for the deleterious effects of α2-antiplasmin in ischemic stroke.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  9 / 37466 MEDLINE  
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[PMID]: 29524138
[Au] Autor:Pyles B; Bailus BJ; O'Geen H; Segal DJ
[Ad] Address:Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA, USA.
[Ti] Title:Purified Protein Delivery to Activate an Epigenetically Silenced Allele in Mouse Brain.
[So] Source:Methods Mol Biol;1767:227-239, 2018.
[Is] ISSN:1940-6029
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The ability to activate or repress specific genes in the brain could have a tremendous impact for understanding and treating neurological disorders. Artificial transcription factors based on zinc finger, TALE, and CRISPR/Cas9 programmable DNA-binding platforms have been widely used to regulate the expression of specific genes in cultured cells, but their delivery into the brain represents a critical challenge to apply such tools in live animals. In previous work, we developed a purified, zinc finger-based artificial transcription factor that could be injected systemically, cross the blood-brain barrier, and alter expression of a specific gene in the brain of an adult mouse model of Angelman syndrome. Importantly, our mode of delivery produced widespread distribution throughout the brain. Here we describe our most current methods for the production and purification of the factor, dosage optimization, and use of live animal fluorescence imaging to visualize the kinetics of distribution.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:In-Data-Review
[do] DOI:10.1007/978-1-4939-7774-1_12

  10 / 37466 MEDLINE  
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[PMID]: 29523925
[Au] Autor:Unterrainer M; Mahler C; Vomacka L; Lindner S; Havla J; Brendel M; Böning G; Ertl-Wagner B; Kümpfel T; Milenkovic VM; Rupprecht R; Kerschensteiner M; Bartenstein P; Albert NL
[Ad] Address:Department of Nuclear Medicine, University Hospital, Ludwig-Maximilians University Munich, Marchioninistr. 15, 81377, Munich, Germany.
[Ti] Title:TSPO PET with [ F]GE-180 sensitively detects focal neuroinflammation in patients with relapsing-remitting multiple sclerosis.
[So] Source:Eur J Nucl Med Mol Imaging;, 2018 Mar 09.
[Is] ISSN:1619-7089
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:PURPOSE: Expression of the translocator protein (TSPO) is upregulated in activated macrophages/microglia and is considered to be a marker of neuroinflammation. We investigated the novel TSPO ligand [ F]GE-180 in patients with relapsing-remitting multiple sclerosis (RRMS) to determine the feasibility of [ F]GE-180 PET imaging in RRMS patients and to assess its ability to detect active inflammatory lesions in comparison with the current gold standard, contrast-enhanced magnetic resonance imaging (MRI). METHODS: Nineteen RRMS patients were prospectively included in this study. All patients underwent TSPO genotyping and were classified as high-affinity, medium-affinity or low-affinity binders (HAB/MAB/LAB). PET scans were performed after administration of 189 ± 12 MBq [ F]GE-180, and 60-90 min summation images were used for visual analysis and assessment of standardized uptake values (SUV). The frontal nonaffected cortex served as a pseudoreference region (PRR) for evaluation of SUV ratios (SUVR). PET data were correlated with MRI signal abnormalities, i.e. T2 hyperintensity or contrast enhancement (CE). When available, previous MRI data were used to follow the temporal evolution of individual lesions. RESULTS: Focal lesions were identified as hot spots by visual inspection. Such lesions were detected in 17 of the 19 patients and overall 89 [ F]GE-180-positive lesions were found. TSPO genotyping revealed 11 patients with HAB status, 5 with MAB status and 3 with LAB status. There were no associations between underlying binding status (HAB, MAB and LAB) and the signal intensity in either lesions (SUVR 1.87 ± 0.43, 1.95 ± 0.48 and 1.86 ± 0.80, respectively; p = 0.280) or the PRR (SUV 0.36 ± 0.03, 0.40 ± 0.06 and 0.37 ± 0.03, respectively; p = 0.990). Of the 89 [ F]GE-180-positive lesions, 70 showed CE on MRI, while the remainder presented as T2 lesions without CE. SUVR were significantly higher in lesions with CE than in those without (2.00 ± 0.53 vs. 1.60 ± 0.15; p = 0.001). Notably, of 19 [ F]GE-180-positive lesions without CE, 8 previously showed CE, indicating that [ F]GE-180 imaging may be able to detect lesional activity that is sustained beyond the blood-brain barrier breakdown. CONCLUSION: [ F]GE-180 PET can detect areas of focal macrophage/microglia activation in patients with RRMS in lesions with and without CE on MRI. Therefore, [ F]GE-180 PET imaging is a sensitive and quantitative approach to the detection of active MS lesions. It may provide information beyond contrast-enhanced MRI and is readily applicable to all patients. [ F]GE-180 PET imaging is therefore a promising new tool for the assessment of focal inflammatory activity in MS.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher
[do] DOI:10.1007/s00259-018-3974-7


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