Glial Cell–Mediated Deterioration and Repair of the Nervous System after Traumatic Brain Injury in a Rat Model as Assessed by Positron Emission Tomography

Yu, In Kyu; Inaji, Motoki; Maeda, Jun; Okauchi, Takashi; Nariai, Tadashi; Ohno, Kikuo; Higuchi, Makoto; Suhara, Tetsuya

doi:10.1089/neu.2009.1196

Cited by 78 publications

(50 citation statements)

References 41 publications

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“…As the most dominant PET imaging tracer, [ 18 F]FDG has also been used to evaluate the cerebral glucose metabolism in rodent CNS disease models [13, 22, 23]. Consistent with these studies, we found a low-uptake area in the early phase after damage due to disturbance of blood circulation and normal brain function.…”

Section: Discussionsupporting

confidence: 88%

PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714

Wang

Yue

Kiesewetter

et al. 2014

Eur J Nucl Med Mol Imaging

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Purpose Inflammatory response in injured brain parenchyma after traumatic brain injury (TBI) is crucial to its pathologic process. In order to follow the microglia activation and neuroinflammation after TBI, herein, we performed PET imaging in a rat TBI model using 18F-labeled DPA-714, a ligand of 18 KDa translocator protein (TSPO). Methods TBI was induced in male SD rats by controlled cortical impact (CCI). The success of the TBI model was confirmed by magnetic resonance imaging (MRI). Automated synthesis of [18F]DPA-714 was carried out using a slightly modified TRACERLab FX-FN module. In vivo PET imaging was performed at different time points after surgery by an Inveon small animal PET scanner. The specificity of [18F]DPA-714 was confirmed by displacement study with an unlabeled competitive TSPO ligand, PK11195. Ex vivo autoradiography as well as immunofluorescence staining was carried out to confirm the in vivo PET results. Results Both in vivo T2-weighted MR images and ex vivo TTC staining results revealed successful establishment of the TBI model. Compared with the sham group, [18F]DPA-714 uptake was significantly higher in the injured brain area on PET images. Increased lesion-to-normal brain ratio of [18F]DPA-714 in TBI rats was observed at day 2 after surgery, peaked around day 6 (2.65 ± 0.36) and then decreased gradually to nearly normal level at day 28. Displacement study using PK11195 confirmed the specific binding of [18F]DPA-714 to TSPO. Ex vivo autoradiography was consistent with in vivo PET results. The immunofluorescence staining showed a time course of TSPO expression after TBI and the temporal and spatial distribution of microglia in damaged brain area. Conclusion TSPO targeted PET using [18F]DPA-714 as the imaging probe can be used to dynamically monitor inflammatory response after TBI in a non-invasive manner. This method will not only facilitate a better understanding of inflammation process after traumatic brain injury, but also provide a useful in vivo monitoring strategy for anti-inflammation therapy of TBI.

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Section: Discussionsupporting

confidence: 88%

PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714

Wang

Yue

Kiesewetter

et al. 2014

Eur J Nucl Med Mol Imaging

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“…On the contrary, astrocyte activation has been shown to be correlated with 18 FDG changes after TBI and other models of neuronal damage, 50,51 and our data show a significant correlation between GFAP quantitation and 18 FDG uptake at 24 h post-injury. Several TBI studies have shown a pronounced upregulation of astrocyte markers of activation after injury, including GFAP and vimentin, with a time course that strongly parallels the recovery in glucose uptake observed in our current study.…”

Section: Discussioncontrasting

confidence: 49%

Mild Traumatic Brain Injury Results in Depressed Cerebral Glucose Uptake: An ¹⁸FDG PET Study

Selwyn

Hockenbury²,

Jaiswal³

et al. 2013

Journal of Neurotrauma

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Moderate to severe traumatic brain injury (TBI) in humans and rats induces measurable metabolic changes, including a sustained depression in cerebral glucose uptake. However, the effect of a mild TBI on brain glucose uptake is unclear, particularly in rodent models. This study aimed to determine the glucose uptake pattern in the brain after a mild lateral fluid percussion (LFP) TBI. Briefly, adult male rats were subjected to a mild LFP and positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)FDG), which was performed prior to injury and at 3 and 24 h and 5, 9, and 16 days post-injury. Locomotor function was assessed prior to injury and at 1, 3, 7, 14, and 21 days after injury using modified beam walk tasks to confirm injury severity. Histology was performed at either 10 or 21 days post-injury. Analysis of function revealed a transient impairment in locomotor ability, which corresponds to a mild TBI. Using reference region normalization, PET imaging revealed that mild LFP-induced TBI depresses glucose uptake in both the ipsilateral and contralateral hemispheres in comparison with sham-injured and naïve controls from 3 h to 5 days post-injury. Further, areas of depressed glucose uptake were associated with regions of glial activation and axonal damage, but no measurable change in neuronal loss or gross tissue damage was observed. In conclusion, we show that mild TBI, which is characterized by transient impairments in function, axonal damage, and glial activation, results in an observable depression in overall brain glucose uptake using (18)FDG-PET.

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“…Similarly, a prior study found increased [ 11 C]DAA1106 binding in participants with AD compared with control subjects across many regions, including dorsal and medial prefrontal cortex, lateral temporal cortex, parietal cortex, occipital cortex, anterior cingulate cortex, striatum, and cerebellum [12]. [(3)H]DAA1106 binding was also found to be elevated in a rat model of traumatic brain injury [13, 14]. Additionally, in a recent study, researchers found no significant difference between [ 11 C]DAA1106 binding in cortical regions of patients with schizophrenia compared to normal controls [15].…”

Section: Introductionmentioning

confidence: 84%

Radiation dosimetry and biodistribution of the translocator protein radiotracer [11C]DAA1106 determined with PET/CT in healthy human volunteers

Brody¹,

Okita²,

Shieh³

et al. 2014

Nuclear Medicine and Biology

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Introduction When microglia become activated (an integral part of neuroinflammation), cellular morphology changes and expression of translocator protein (TSPO) 18 kDa is increased. Over the past several years, [11C]DAA1106 has emerged as a reliable radiotracer for labeling TSPO with high affinity during positron emission tomography (PET) scanning. While [11C]DAA1106 PET scanning has been used in several research studies, a radiation dosimetry study of this radiotracer in humans has not yet been published. Methods Twelve healthy participants underwent full body dynamic [11C]DAA1106 PET scanning, with 8 sequential whole body scans (approximately 12 bed positions each), following a single injection. Regions of interest were drawn manually and time activity curves (TACs) were obtained for 15 organs. OLINDA/EXM 1.1 was used to compute radiation absorbed doses to the target organs, as well as effective dose (ED) and effective dose equivalent (EDE). Results The ED and EDE were 4.06 ± 0.58 μSv/MBq and 5.89 ± 0.83 μSv/MBq, respectively. The highest absorbed doses were to the heart wall, kidney, liver, pancreas, and spleen. TACs revealed that peak dose rates are during the first scan (at 6 min) for all organs other than the urinary bladder wall, which had its peak dose rate during the fourth scan (at 30 min). Conclusions The recently developed radiotracer [11C]DAA1106 has its EDE and target-organ absorbed dose such that, for a single administration, its radiation dosimetry is well within the U.S. FDA guidelines for basic research studies in adults. This dose level implies that the dosimetry for multiple [11C]DAA1106 scans within a given year also falls within FDA guidelines, and this favorable property makes this radiotracer suitable for examining microglial activation repeatedly over time, which may in the future be useful for longitudinal tracking of disease progression and monitoring of therapy response in conditions marked by neuroinflammation (e.g., head trauma and multiple sclerosis).

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Glial Cell–Mediated Deterioration and Repair of the Nervous System after Traumatic Brain Injury in a Rat Model as Assessed by Positron Emission Tomography

Cited by 78 publications

References 41 publications

PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714

PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714

Mild Traumatic Brain Injury Results in Depressed Cerebral Glucose Uptake: An ¹⁸FDG PET Study

Radiation dosimetry and biodistribution of the translocator protein radiotracer [11C]DAA1106 determined with PET/CT in healthy human volunteers

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Glial Cell–Mediated Deterioration and Repair of the Nervous System after Traumatic Brain Injury in a Rat Model as Assessed by Positron Emission Tomography

Cited by 78 publications

References 41 publications

PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714

PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714

Mild Traumatic Brain Injury Results in Depressed Cerebral Glucose Uptake: An 18FDG PET Study

Radiation dosimetry and biodistribution of the translocator protein radiotracer [11C]DAA1106 determined with PET/CT in healthy human volunteers

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Mild Traumatic Brain Injury Results in Depressed Cerebral Glucose Uptake: An ¹⁸FDG PET Study