PET Imaging in ALS

Amyotrophic lateral sclerosis is a neurodegenerative disorder that primarily affects the motor system, but extramotor involvement is common. Progressive muscle weakness and wasting, including bulbar and respiratory muscles, limit survival to 2–5 years after disease onset in most patients. The diagnosis is made on clinical grounds and is based on the presence of signs of upper and lower motor neuron loss in different body regions in the absence of other pathologies that can explain the symptoms and signs of the patient. Making an accurate diagnosis can be difficult in early disease stages. ALS is a heterogeneous disorder with variability in age at onset, in phenotypic presentation, in the extent of frontotemporal involvement and in the disease progression rate. There is a high unmet medical need for objective markers that aid in early diagnosis and in predicting disease outcome. In this chapter, the current knowledge about the diagnostic and prognostic value of 18F 2-fluoro-2-deoxy-D-glucose-PET in ALS is discussed. The potential of other targets and PET tracers to visualize different aspects of ALS disease pathology is described

Highlights lecture EANM 2014: “Gimme gimme gimme those nuclear Super Troupers”

The EANM Congress 2014 took place in Gothenburg, Sweden, from 18 to 22 October under the presidency of Prof. Wim Oyen, chair of the EANM Scientific Committee. Prof. Peter Gjertsson chaired the Local Organizing Committee, according to the standardized EANM congress structure. The meeting was a highlight for the multidisciplinary community that forms the heart and soul of nuclear medicine; attendance was exceptionally high. In total almost 5,300 participants came to Gothenburg, and 1,397 colleagues participated via the EANM LIVE sessions (http://eanmlive.eanm.org/index.php). Participants from all continents were presented with an excellent programme consisting of symposia, scientific and featured sessions, CME sessions, and plenary lectures. These lectures were devoted to nuclear medicine therapy, hybrid imaging and molecular life sciences. Two tracks were included in the main programme, clustering multi-committee involvement: the 5th International Symposium on Targeted Radionuclide-therapy and Dosimetry (ISTARD) and the first Molecules to Man (M2M) track, an initiative of the EANM Committees for Translational Molecular Imaging, Radiopharmacy and Drug Development. The industry made a substantial contribution to the success of the congress demonstrating the latest technology and innovations in the field. During the closing Highlights Lecture, a selection of the best-rated abstracts was presented including diverse areas of nuclear medicine: physics and instrumentation, radiopharmacy, preclinical imaging, oncology (with a focus on the clinical application of newly developed tracers) and radionuclide therapy, cardiology and neurosciences. This Highlights Lecture could only be a brief summary of the large amount of data presented and discussed during the meeting, which can be found in much greater detail in the congress proceedings book, published as Volume 41, Supplement 2 of the European Journal of Nuclear Medicine and Molecular Imaging in October 2014

Synthesis, Biodistribution and In vitro Evaluation of Brain Permeable High Affinity Type 2 Cannabinoid Receptor Agonists [11C]MA2 and [18F]MA3

Abstract The type 2 cannabinoid receptor (CB2) is a member of the endocannabinoid system and is known for its important role in (neuro)inflammation. A PET-imaging agent that allows in vivo visualization of CB2 expression may thus allow quantification of neuroinflammation. In this paper, we report the synthesis, radiosynthesis, biodistribution and in vitro evaluation of a carbon-11 ([11C]MA2) and a fluorine-18 ([18F]MA3) labeled analogue of a highly potent N-arylamide oxadiazole CB2 agonist (EC50 = 0.015 nM). MA2 and MA3 behaved as potent CB2 agonist (EC50: 3 nM and 0.1 nM, respectively) and their in vitro binding affinity for hCB2 was found to be 87 nM and 0.8 nM, respectively. Also MA3 (substituted with a fluoro ethyl group) was found to have higher binding affinity and EC50 values when compared to the originally reported trifluoromethyl analogue 12. [11C]MA2 and [18F]MA3 were successfully synthesized with good radiochemical yield, high radiochemical purity and high specific activity. In mice, both tracers were efficiently cleared from blood and all major organs by the hepatobiliary pathway and importantly these compounds showed high brain uptake. In conclusion, [11C]MA2 and [18F]MA3 are shown to be high potent CB2 agonists with good brain uptake, these favorable characteristics makes them potential PET probes for in vivo imaging of brain CB2 receptors. However in view of its higher affinity and selectivity, further detailed evaluation of MA3 as a PET tracer for CB2 is warranted

Automated quantitative gait analysis in animal models of movement disorders

<p>Abstract</p> <p>Background</p> <p>Accurate and reproducible behavioral tests in animal models are of major importance in the development and evaluation of new therapies for central nervous system disease. In this study we investigated for the first time gait parameters of rat models for Parkinson's disease (PD), Huntington's disease (HD) and stroke using the Catwalk method, a novel automated gait analysis test. Static and dynamic gait parameters were measured in all animal models, and these data were compared to readouts of established behavioral tests, such as the cylinder test in the PD and stroke rats and the rotarod tests for the HD group.</p> <p>Results</p> <p>Hemiparkinsonian rats were generated by unilateral injection of the neurotoxin 6-hydroxydopamine in the striatum or in the medial forebrain bundle. For Huntington's disease, a transgenic rat model expressing a truncated huntingtin fragment with multiple CAG repeats was used. Thirdly, a stroke model was generated by a photothrombotic induced infarct in the right sensorimotor cortex. We found that multiple gait parameters were significantly altered in all three disease models compared to their respective controls. Behavioural deficits could be efficiently measured using the cylinder test in the PD and stroke animals, and in the case of the PD model, the deficits in gait essentially confirmed results obtained by the cylinder test. However, in the HD model and the stroke model the Catwalk analysis proved more sensitive than the rotarod test and also added new and more detailed information on specific gait parameters.</p> <p>Conclusion</p> <p>The automated quantitative gait analysis test may be a useful tool to study both motor impairment and recovery associated with various neurological motor disorders.</p

Neuroinflammation as potential precursor of leukoencephalopathy in early-stage breast cancer patients:A cross-sectional PET-MRI study

BACKGROUND: Although chemotherapy-induced leukoencephalopathy has been described in case and cohort studies, literature remains inconclusive about its prevalence and mechanisms. Therefore, we investigated the presence of leukoencephalopathy after multiagent chemotherapy in women treated for breast cancer and potential underlying neuroinflammatory processes. METHODS: In this exploratory study, 15 chemotherapy-treated and 15 age-matched chemotherapy-naïve patients with early-stage breast cancer, as well as 15 healthy controls underwent simultaneous PET-MR neuroimaging, including T1-weighted MPRAGE, T2-weighted FLAIR and dynamic PET with the 18-kDA translocator protein (TSPO) radioligand [(18)F]DPA-714. Total and regional (juxtacortical, periventricular, deep white matter and infratentorial) lesion burden were compared between the groups with one-way ANOVA. With paired t-tests, [(18)F]DPA-714 volume of distribution [V(T), including partial volume correction (PVC)] in lesioned and normal appearing white matter (NAWM) were compared within subjects, to investigate inflammation. Finally, two general linear models were used to examine the predictive values of neurofilament light-chain (NfL) serum levels on (1) total lesion burden or (2) PVC [(18)F]DPA-714 V(T) of lesions showing elevated inflammation. RESULTS: No significant differences were found in total or localized lesion burden. However, significantly higher (20–45%) TSPO uptake was observed in juxtacortical lesions (p ≤ 0.008, t ≥ 3.90) compared to NAWM in both cancer groups, but only persisted for chemotherapy-treated patients after PVC (p = 0.005, t = 4.30). NfL serum levels were not associated with total lesion volume or tracer uptake in juxtacortical lesions. CONCLUSION: This multimodal neuroimaging study suggests that neuroinflammatory processes could be involved in the development of juxtacortical, but not periventricular or deep white matter, leukoencephalopathy shortly after chemotherapy for early-stage breast cancer

August 21, 2018

status: publishe

Regional accuracy of ZTE-based attenuation correction in static and dynamic brain PET/MR

Accurate MR-based attenuation correction (MRAC) is essential for quantitative PET/MR imaging of the brain. In this study, we analyze the regional bias caused by MRAC based on Zero-Echo-Time MR images (ZTEAC) compared to CT-based AC (CTAC) in static and dynamic PET imaging. In addition the results are compared to the performance of the current default Atlas-based AC (AtlasAC) implemented in the GE SIGNA PET/MR. Methods: Thirty static [18F]FDG and 11 dynamic [18}F]PE2I acquisitions from a GE SIGNA PET/MR were reconstructed using ZTEAC (using a research tool, GE Healthcare), single-subject AtlasAC (the current default AC in GE's SIGNA PET/MR) and CTAC (from a PET/CT acquisition of the same day). In the 30 static [18F]FDG reconstructions, the bias caused by ZTEAC and AtlasAC in the mean uptake of 85 anatomical volumes of interest (VOIs) of the Hammers' atlas was analyzed in PMOD. For the 11 dynamic [18}F]PE2I reconstructions, the bias caused by ZTEAC and AtlasAC in the non displaceable binding potential BPnd in the striatum was calculated with cerebellum as the reference region and a simplified reference tissue model. Results: The regional bias caused by ZTEAC in the static [18F]FDG reconstructions ranged from -8.0% to +7.7% (mean 0.1%, SD 2.0%). For AtlasAC this bias ranged from -31.6% to +16.6% (mean -0.4%, SD 4.3%). The bias caused by AtlasAC showed a clear gradient in the cranio-caudal direction (-4.2% in the cerebellum, +6.6% in the left superior frontal gyrus). The bias in the striatal BPnd for the [18F]PE2I reconstructions ranged from -0.8% to +4.8% (mean 1.5%, SD 1.4%) using ZTEAC and from -0.6% to +9.4% using AtlasAC (mean 4.2%, SD 2.6%). Conclusion: ZTEAC provides excellent quantitative accuracy for static and dynamic brain PET/MR, comparable to CTAC, and is clearly superior to the default AtlasAC currently implemented in the GE SIGNA PET/MR.Comment: 23 pages in total, 7 figures, 1 table, 3 supplementary figures, 5 supplementary table

PET imaging of TSPO in a rat model of local neuroinflammation induced by intracerebral injection of lipopolysaccharide.

OBJECTIVE: The goal of this study was to measure functional and structural aspects of local neuroinflammation induced by intracerebral injection of lipopolysaccharide (LPS) in rats using TSPO microPET imaging with [(18)F]DPA-714, magnetic resonance imaging (MRI), in vitro autoradiography and immunohistochemistry (IHC) in order to characterize a small animal model for screening of new PET tracers targeting neuroinflammation. METHODS: Rats were injected stereotactically with LPS (50 μg) in the right striatum and with saline in the left striatum. [(18)F]DPA-714 microPET, MRI, in vitro autoradiography and IHC studies were performed at different time points after LPS injection for 1 month. RESULTS: Analysis of the microPET data demonstrated high uptake of the tracer in the LPS injected site with an affected-to-non-affected side-binding potential ratio (BPright-to-left) of 3.0 at 3 days after LPS injection. This BP ratio decreased gradually over time to 0.9 at 30 days after LPS injection. In vitro autoradiography ([(18)F]DPA-714) and IHC (CD68, GFAP and TSPO) confirmed local neuroinflammation in this model. Dynamic contrast enhanced (DCE) MRI demonstrated BBB breakdown near the LPS injection site at day 1, which gradually resolved over time and was absent at 1 month after LPS injection. CONCLUSION: The LPS model is useful for first screening of newly developed tracers because of the easy design and the robust, unilateral inflammatory reaction allowing the use of the contralateral region as control. Additionally, this model can be used to test and follow up the benefits of anti-inflammatory therapies by non-invasive imaging

Bioluminescence imaging of stroke-induced endogenous neural stem cell response

Brain injury following stroke affects neurogenesis in the adult mammalian brain. However, a complete under¬standing of the origin and fate of the endogenous neural stem cells (eNSCs) in vivo is missing. Tools and technol¬ogy that allow non-invasive imaging and tracking of eNSCs in living animals will help to overcome this hurdle. In this study, we aimed to monitor eNSCs in a photothrombotic (PT) stroke model using in vivo bioluminescence imaging (BLI). In a first strategy, inducible transgenic mice expressing firefly luciferase (Fluc) in the eNSCs were generated. In animals that received stroke, an increased BLI signal originating from the infarct region was ob¬served. However, due to histological limitations, the identity and exact origin of cells contributing to the in¬creased BLI signal could not be revealed. To overcome this limitation, we developed an alternative strategy employing stereotactic injection of conditional lentiviral vectors (Cre-Flex LVs) encoding Fluc and eGFP in the subventricular zone (SVZ) of Nestin-Cre transgenic mice, thereby specifically labeling the eNSCs. Upon induction of stroke, increased eNSC proliferation resulted in a significant increase in BLI signal between 2 days and 2 weeks after stroke, decreasing after 3 months. Additionally, the BLI signal relocalized from the SVZ towards the infarct region during the 2 weeks following stroke. Histological analysis at 90 days post stroke showed that in the peri-infarct area, 36% of labeled eNSC progeny differentiated into astrocytes, while 21% differentiated into mature neu¬rons. In conclusion, we developed and validated a novel imaging technique that unequivocally demonstrates that nestin+ eNSCs originating from the SVZ respond to stroke injury by increased proliferation, migration towards the infarct region and differentiation into both astrocytes and neurons. In addition, this new approach allows non-invasive and specific monitoring of eNSCs overtime, opening perspectives for preclinical evaluation of can¬didate stroke therapeutics