Neuroinflammation Extends Brain Tissue at Risk to Vital Peri-Infarct Tissue: A Double Tracer [<sup>11</sup>C]PK11195- and [<sup>18</sup>F]FDG-PET Study

Schroeter, Michael; Dennin, Maria Adele; Walberer, Maureen; Backes, Heiko; Neumaier, Bernd; Fink, Gereon R.; Graf, Rudolf

doi:10.1038/jcbfm.2009.36

Cited by 113 publications

(101 citation statements)

References 45 publications

(69 reference statements)

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“…It was suggesting that 18 F-BCPP-EF could be useful to detect ischemic neuronal damage at the subacute phase 7 days after ischemic insult (Day-7), 7 at which time unexpectedly higher 18 F-fluoro-2-deoxy-Dglucose (FDG) uptake was observed in the damaged area than in the contralateral intact area. 9,10 The FDG-PET is a well-established technique for quantitative imaging of the regional cerebral metabolic rate of glucose (rCMRglc) in living brain, which is based on the assumption that rCMRglc reflects energy metabolism via oxidative phosphorylation. However, the unexpectedly high uptake of 18 F-FDG in ischemia-damaged areas suggested that 18 F-FDG was taken up into not only normal tissues but also inflammatory regions with microglial activation.…”

Section: Introductionmentioning

confidence: 99%

“…However, the unexpectedly high uptake of 18 F-FDG in ischemia-damaged areas suggested that 18 F-FDG was taken up into not only normal tissues but also inflammatory regions with microglial activation. 9,10 Since recent PET research has indicated that neurodegenerative disorders showed neuroinflammation with microglial activation, 11 PET probes to image MC-I activity would be favorable for more accurate assessment of neurodegenerative damage using PET.…”

Section: Introductionmentioning

confidence: 99%

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PET Imaging of Ischemia-Induced Impairment of Mitochondrial Complex I Function in Monkey Brain

Tsukada

Ohba

Nishiyama

et al. 2014

J Cereb Blood Flow Metab

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To assess the capability of 18 F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ( 18 F-BCPP-EF), a novel positron emission tomography (PET) probe for mitochondrial complex I (MC-I) activity, as a specific marker of ischemia-induced neuronal death without being disturbed by inflammation, translational research was conducted using an animal PET in ischemic brains of Cynomolgus monkeys (Macaca fascicularis). Focal ischemia was induced by the right middle cerebral artery occlusion for 3 hours, then PET scans were conducted at Day-7 with 15 O-gases for regional cerebral blood flow (rCBF) and regional cerebral metabolism of oxygen (rCMRO 2 ), and 18 F-BCPP-EF for MC-I with arterial blood sampling. On Day-8, the additional PET scans conducted with 11 C-flumazenil ( 11 C-FMZ) for central-type benzodiazepine receptors, 11 C-PBR28 for translocator protein, and 18 F-fluoro-2-deoxy-D-glucose ( 18 F-FDG) for regional cerebral metabolic rate of glucose (rCMRglc). The total distribution volume (V T ) values of 18 F-BCPP-EF showed the significant reduction in MC-I activity in the damaged area at Day-7. When correlated with rCBF and rCMRO 2 , the V T values of 18 F-BCPP-EF provided better correlation with rCMRO 2 than with rCBF. In the inflammatory regions (region of interest, ROI PBR ) of the ischemic hemisphere detected with 11 C-PBR28, higher 18 F-FDG uptake and lower V T of 18 F-BCPP-EF, 11 C-FMZ, and rCMRO 2 than those in normal contralateral hemisphere were observed. These results strongly suggested that 18 F-BCPP-EF could discriminate the neuronal damaged areas with neuroinflammation, where 18 F-FDG could not owing to its high uptake into the activated microglia.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PET Imaging of Ischemia-Induced Impairment of Mitochondrial Complex I Function in Monkey Brain

Tsukada

Ohba

Nishiyama

et al. 2014

J Cereb Blood Flow Metab

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“…11 C]PK11195 fulfils this requirement by selectively binding to the translocator protein-18 kDa expressed on inflammatory cells, specifically visualizing post-ischemic cellular neuroinflammatory processes [96] . Since [ 11 C]PK11195 is radiolabeled with the isotope 11-C with a half-life of -20 min, sequential PETimaging with [ 18 F]FLT is possible by waiting for -5 half-lives or 100 min between scans.…”

Section: Stem Cell-mediated Regeneration After Focal Cerebral Ischemiamentioning

confidence: 99%

In vivoimaging of endogenous neural stem cells in the adult brain

Rueger

Schroeter

2015

WJSC

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The discovery of endogenous neural stem cells (eNSCs) in the adult mammalian brain with their ability to self-renew and differentiate into functional neurons, astrocytes and oligodendrocytes has raised the hope for novel therapies of neurological diseases. Experimentally, those eNSCs can be mobilized in vivo , enhancing regeneration and accelerating functional recovery after, e.g., focal cerebral ischemia, thus constituting a most promising approach in stem cell research. In order to translate those current experimental approaches into a clinical setting in the future, non-invasive imaging methods are required to monitor eNSC activation in a longitudinal and intraindividual manner. As yet, imaging protocols to assess eNSC mobilization non-invasively in the live brain remain scarce, but considerable progress has been made in this field in recent years. This review summarizes and discusses the current imaging modalities suitable to monitor eNSCs in individual experimental animals over time, including optical imaging, magnetic resonance tomography and-spectroscopy, as well as positron emission tomography (PET). Special emphasis is put on the potential of each imaging method for a possible clinical translation, and on the specificity of the signal obtained. PET-imaging with the radiotracer 3'-deoxy-3'-[18 F]fluoro-L-thymidine in particular constitutes a modality with excellent potential for clinical translation but low specificity; however, concomitant imaging of neuroinflammation is feasible and increases its specificity. The non-invasive imaging strategies presented here allow for the exploitation of novel treatment strategies based upon the regenerative potential of eNSCs, and will help to facilitate a translation into the clinical setting.

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“…A less prominent signal indicating elevated translocator protein 18 kDa expression was observed in the region surrounding the infarct on day 7, which was colocalized with an increased glucose metabolism and accumulated microglias and macrophages. This periinfarct neuroinflammation may contribute to the extension of tissue damage (73).…”

Section: Microglial Activation As An Indicator Of Inflammationmentioning

confidence: 99%

Radionuclide Imaging in Ischemic Stroke

Heiss

2014

J Nucl Med

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Learning Objectives: On successful completion of this activity, participants should be able to describe (1) the physiologic and metabolic variables relevant for brain function and the radionuclides and methods to measure these variables in cerebrovascular disease, especially ischemic stroke; (2) the radionuclide methods to determine the thresholds of flow and metabolism relevant for preservation of function and morphology and the obtained values in their relevance to prognosis and potential treatment; and (3) the applications of radionuclide imaging for identifying pathophysiologic changes responsible for extension of ischemic lesions, for defining the hemodynamic reserve in vascular disease, for detecting remote effects outside the primary lesions, and for locating compensatory activation in disturbed functional networks.Financial Disclosure: Dr. Heiss is supported by the Wolf-Dieter Heiss Foundation within the Max Planck Society. The author of this article has indicated no other relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through November 2017.Ischemic stroke is caused by interruption or significant impairment of blood supply to the brain, which leads to a cascade of metabolic and molecular alterations resulting in functional disturbance and morphologic damage. The changes in regional cerebral blood flow and regional metabolism can be assessed by radionuclide imaging, especially SPECT and PET. SPECT and PET have broadened our understanding of flow and metabolic thresholds critical for maintenance of brain function and morphology: PET was essential in the transfer of the concept of the penumbra to clinical stroke and thereby had a great impact on developing treatment strategies. Receptor ligands can be applied as early markers of irreversible neuronal damage and can predict the size of the final infarcts, which is important for decisions on invasive therapy in large ("malignant") infarction. With SPECT and PET, the reserve capacity of the blood supply can be tested in obstructive arteriosclerosis, which is essential for planning interventions. The effect of a stroke on surrounding and contralateral primarily unaffected tissue can be investigated, helping to understand symptoms caused by disturbance in functional networks. Activation studies are useful to demonstrate alternative pathways to compensate for lesions and to test the effect of rehabilitative therapy. Radioisotope studies help to detect neuroinflammation and its effect on extension of tissue damage. Despite the...

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Neuroinflammation Extends Brain Tissue at Risk to Vital Peri-Infarct Tissue: A Double Tracer [¹¹C]PK11195- and [¹⁸F]FDG-PET Study

Cited by 113 publications

References 45 publications

PET Imaging of Ischemia-Induced Impairment of Mitochondrial Complex I Function in Monkey Brain

PET Imaging of Ischemia-Induced Impairment of Mitochondrial Complex I Function in Monkey Brain

In vivoimaging of endogenous neural stem cells in the adult brain

Radionuclide Imaging in Ischemic Stroke

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Neuroinflammation Extends Brain Tissue at Risk to Vital Peri-Infarct Tissue: A Double Tracer [11C]PK11195- and [18F]FDG-PET Study

Cited by 113 publications

References 45 publications

PET Imaging of Ischemia-Induced Impairment of Mitochondrial Complex I Function in Monkey Brain

PET Imaging of Ischemia-Induced Impairment of Mitochondrial Complex I Function in Monkey Brain

In vivoimaging of endogenous neural stem cells in the adult brain

Radionuclide Imaging in Ischemic Stroke

Contact Info

Product

Resources

About

Neuroinflammation Extends Brain Tissue at Risk to Vital Peri-Infarct Tissue: A Double Tracer [¹¹C]PK11195- and [¹⁸F]FDG-PET Study