Quantitative longitudinal imaging of activated microglia as a marker of inflammation in the pilocarpine rat model of epilepsy using [11C]-(R)-PK11195 PET and MRI

Inflammation may play a role in the development of epilepsy after brain insults. [11C]-(R)-PK11195 binds to TSPO, expressed by activated microglia. We quantified [11C]-(R)-PK11195 binding during epileptogenesis after pilocarpine-induced status epilepticus (SE), a model of temporal lobe epilepsy. Nine male rats were studied thrice (D0-1, D0 + 6, D0 + 35, D0 = SE induction). In the same session, 7T T2-weighted images and DTI for mean diffusivity (MD) and fractional anisotropy (FA) maps were acquired, followed by dynamic PET/CT. On D0 + 35, femoral arterial blood was sampled for rat-specific metabolite-corrected arterial plasma input functions (AIFs). In multiple MR-derived ROIs, we assessed four kinetic models (two with AIFs; two using a reference region), standard uptake values (SUVs), and a model with a mean AIF. All models showed large (up to two-fold) and significant TSPO binding increases in regions expected to be affected, and comparatively little change in the brainstem, at D0 + 6. Some individuals showed increases at D0 + 35. AIF models yielded more consistent increases at D0 + 6. FA values were decreased at D0 + 6 and had recovered by D0 + 35. MD was increased at D0 + 6 and more so at D0 + 35. [11C]-(R)-PK11195 PET binding and MR biomarker changes could be detected with only nine rats, highlighting the potential of longitudinal imaging studies.

[1]  P. Deyn,et al.  Brain inflammation in a chronic epilepsy model: Evolving pattern of the translocator protein during epileptogenesis , 2015, Neurobiology of Disease.

[2]  Kimberly J. Jenko,et al.  Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein. , 2015, JAMA neurology.

[3]  M. Hoehn,et al.  In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke , 2015, Neuroscience.

[4]  P. Matthews,et al.  Positron-emission tomography molecular imaging of glia and myelin in drug discovery for multiple sclerosis , 2015, Expert opinion on drug discovery.

[5]  Abraham Z. Snyder,et al.  Quantitative Amyloid Imaging Using Image-Derived Arterial Input Function , 2015, PloS one.

[6]  Richard E. Carson,et al.  11C-PBR28 imaging in multiple sclerosis patients and healthy controls: test-retest reproducibility and focal visualization of active white matter areas , 2015, European Journal of Nuclear Medicine and Molecular Imaging.

[7]  W. Löscher,et al.  Inter-individual variation in the effect of antiepileptic drugs in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice , 2015, Neuropharmacology.

[8]  Amanda M. Brown,et al.  Understanding the MIND phenotype: macrophage/microglia inflammation in neurocognitive disorders related to human immunodeficiency virus infection , 2015, Clinical and Translational Medicine.

[9]  Bruce R. Rosen,et al.  Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: Assessed with [11C]-PBR28 , 2015, NeuroImage: Clinical.

[10]  M. Schwartz,et al.  Glial scar and immune cell involvement in tissue remodeling and repair following acute CNS injuries , 2014, Glia.

[11]  Nicolas Costes,et al.  A Multi-Atlas Based Method for Automated Anatomical Rat Brain MRI Segmentation and Extraction of PET Activity , 2014, PloS one.

[12]  A. Lammertsma,et al.  (R)-[11C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: Evaluation in a rat epilepsy model , 2014, Neuropharmacology.

[13]  U. Dirnagl,et al.  Specific Imaging of Inflammation with the 18kDa Translocator Protein Ligand DPA-714 in Animal Models of Epilepsy and Stroke , 2013, PloS one.

[14]  E. Aronica,et al.  Epilepsy and brain inflammation , 2013, Experimental Neurology.

[15]  David Silbersweig,et al.  Imaging Inflammation in a Patient with Epilepsy Due to Focal Cortical Dysplasia , 2013, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[16]  Stefanie Dedeurwaerdere,et al.  PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy , 2012, EJNMMI Research.

[17]  M. Avoli,et al.  Jasper's basic mechanisms of the epilepsies , 2012 .

[18]  E. Aronica,et al.  Glia–Neuron Interactions in Ictogenesis and Epileptogenesis , 2012 .

[19]  J. Hirvonen,et al.  Increased In Vivo Expression of an Inflammatory Marker in Temporal Lobe Epilepsy , 2012, The Journal of Nuclear Medicine.

[20]  M. Avoli,et al.  Glia-neuronal interactions in ictogenesis and epileptogenesis: role of inflammatory mediators -- Jasper's Basic Mechanisms of the Epilepsies , 2012 .

[21]  E. Aronica,et al.  Glia-neuronal interactions in ictogenesis and epileptogenesis: role of inflammatory mediators , 2012 .

[22]  R. Köhling,et al.  Seizure frequency in pilocarpine‐treated rats is independent of circadian rhythm , 2011, Epilepsia.

[23]  D. Sharp,et al.  Inflammation after trauma: Microglial activation and traumatic brain injury , 2011, Annals of neurology.

[24]  Annamaria Vezzani,et al.  Inflammation and prevention of epileptogenesis , 2011, Neuroscience Letters.

[25]  Eleonora Aronica,et al.  Inflammation in epilepsy: Clinical observations , 2011, Epilepsia.

[26]  Roger N Gunn,et al.  Two Binding Sites for [3H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[27]  Sébastien Ourselin,et al.  Fast free-form deformation using graphics processing units , 2010, Comput. Methods Programs Biomed..

[28]  Daniel Rueckert,et al.  Improving intersubject image registration using tissue-class information benefits robustness and accuracy of multi-atlas based anatomical segmentation , 2010, NeuroImage.

[29]  F. Yasuno,et al.  Increased Binding of Peripheral Benzodiazepine Receptor in Alzheimer's Disease Measured by Positron Emission Tomography with [11C]DAA1106 , 2008, Biological Psychiatry.

[30]  Eleonora Aronica,et al.  Innate and adaptive immunity during epileptogenesis and spontaneous seizures: Evidence from experimental models and human temporal lobe epilepsy , 2008, Neurobiology of Disease.

[31]  P. Ryvlin,et al.  Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus , 2007, Neurobiology of Disease.

[32]  F. Turkheimer,et al.  Reference and target region modeling of [11C]-(R)-PK11195 brain studies. , 2007, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[33]  B. Lopresti,et al.  The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: From pathology to imaging , 2006, Progress in Neurobiology.

[34]  Daniel Rueckert,et al.  Automatic anatomical brain MRI segmentation combining label propagation and decision fusion , 2006, NeuroImage.

[35]  B. Weissman,et al.  Peripheral benzodiazepine receptors: on mice and human brain imaging , 2003, Journal of neurochemistry.

[36]  R B Banati,et al.  The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. , 2000, Brain : a journal of neurology.

[37]  R B Banati,et al.  Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK11195 , 2000, Neurology.

[38]  F E Turkheimer,et al.  [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis , 1999, Neurology.

[39]  A. Lammertsma,et al.  Simplified Reference Tissue Model for PET Receptor Studies , 1996, NeuroImage.

[40]  N. Volkow,et al.  Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[41]  Prognosis.  Guidelines for Epidemiologic Studies on Epilepsy , 1993, Epilepsia.

[42]  David J. Schlyer,et al.  Graphical Analysis of Reversible Radioligand Binding from Time—Activity Measurements Applied to [N-11C-Methyl]-(−)-Cocaine PET Studies in Human Subjects , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[43]  D. Duverger,et al.  The quantification of brain lesions with anω 3 site ligand: a critical analysis of animal models of cerebral ischaemia and neurodegeneration , 1990, Brain Research.

[44]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. 3. Mechanisms. , 1972, Electroencephalography and clinical neurophysiology.

[45]  R. Racine.  Modification of seizure activity by electrical stimulation. I. After-discharge threshold. , 1972, Electroencephalography and clinical neurophysiology.

[46]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. II. Motor seizure. , 1972, Electroencephalography and clinical neurophysiology.