2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Disease-Models--Animal

Multiple sclerosis (MS) is a neuroinflammatory disease with expanding axonal and neuronal degeneration and demyelination in the central nervous system, leading to motor dysfunctions, psychical disability, and cognitive impairment during MS progression. Positron emission tomography (PET) is an imaging technique able to quantify in vivo cellular and molecular alterations. Radiotracers with affinity to intact myelin can be used for in vivo imaging of myelin content changes over time. It is possible to detect either an increase or decrease in myelin content, what means this imaging technique can detect demyelination and remyelination processes of the central nervous system. In this protocol we demonstrate how to use PET imaging to detect myelin changes in the lysolecithin rat model, which is a model of focal demyelination lesion (induced by stereotactic injection) (i.e., a model of multiple sclerosis disease).

Topics: Aniline Compounds; Animals; Disease Models, Animal; Image Processing, Computer-Assisted; Lysophosphatidylcholines; Magnetic Resonance Imaging; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Sheath; Positron-Emission Tomography; Rats; Stereotaxic Techniques; Thiazoles

The observation that amyloid radiotracers developed for Alzheimer's disease bind to cerebral white matter paved the road to nuclear imaging of myelin in multiple sclerosis. The lysolecithin (lysophosphatidylcholine (LPC)) rat model of demyelination proved useful in evaluating and comparing candidate radiotracers to target myelin. Focal demyelination following stereotaxic LPC injection is larger than lesions observed in experimental autoimmune encephalitis models and is followed by spontaneous progressive remyelination. Moreover, the contralateral hemisphere may serve as an internal control in a given animal. However, demyelination can be accompanied by concurrent focal necrosis and/or adjacent ventricle dilation. The influence of these side effects on imaging findings has never been carefully assessed. The present study describes an optimization of the LPC model and highlights the use of MRI for controlling the variability and pitfalls of the model. The prototypical amyloid radiotracer [

Topics: Aniline Compounds; Animals; Autoradiography; Brain Edema; Carbon Radioisotopes; Cerebral Ventricles; Corpus Callosum; Corpus Striatum; Demyelinating Diseases; Dilatation, Pathologic; Disease Models, Animal; Ethylene Glycols; False Positive Reactions; Fluorine Radioisotopes; Image Processing, Computer-Assisted; Injections; Lysophosphatidylcholines; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Myelin Sheath; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques; Thiazoles

Neuroinflammation has been associated with various neurologic diseases, including Alzheimer disease (AD). In AD, the translocator protein 18 kDa (TSPO) is overexpressed in the activated microglia that surround the β-amyloid plaques. In the current longitudinal study using a mouse model of AD, we evaluated the association between β-amyloid deposition and neuroinflammation in AD.

Topics: Alzheimer Disease; Aniline Compounds; Animals; Benzothiazoles; Brain; Carbazoles; Disease Models, Animal; Female; Inflammation; Longitudinal Studies; Mice; Positron-Emission Tomography; Thiazoles

The underlying mechanism of brain glucose hypometabolism, an invariant neurodegenerative feature that tightly correlates with cognitive impairment and disease progression of Alzheimer's disease (AD), remains elusive.. Positron emission tomography with 2-[. FDG SUVRs in frontal, temporal, and parietal cortices of patients with AD were closely correlated with the levels of blood thiamine diphosphate (TDP) and cognitive abilities, but not with brain Aβ deposition. Mice on a thiamine-deprived diet manifested a significant decline of FDG SUVRs in multiple brain regions as compared with those in control mice, with magnitudes highly correlating with both brain and blood TDP levels. There were no significant differences in the changes of FDG SUVRs in observed brain regions between amyloid precursor protein/presenilin-1 and wild-type mice following thiamine deficiency.. We demonstrate, for the first time to our knowledge, in vivo that TDP reduction strongly correlates with brain glucose hypometabolism, whereas amyloid deposition does not. Our study provides new insight into the pathogenesis and therapeutic strategy for AD.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Brain; Disease Models, Animal; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Positron-Emission Tomography; Presenilin-1; Psychiatric Status Rating Scales; Thiamine; Thiamine Pyrophosphate; Thiazoles

Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive impairment. Physical exercise has long been proven to be beneficial in the disorder. The present study was designed to examine the effect of voluntary exercise on spatial memory, imaging, and pathological abnormalities. Particular focus has been given to the role of heme oxygenase-1 (HO-1)-an important cellular cytoprotectant in preserving mental acuity-using an aging rat model of dementia. Male and female Wistar rats were segregated into six groups-namely, (i) aged sedentary (control) females (ASF,

Topics: Aging; Amyloid; Aniline Compounds; Animals; Brain; Cerebral Amyloid Angiopathy; Cognitive Dysfunction; Dementia; Disease Models, Animal; Female; Heme Oxygenase-1; Male; Maze Learning; Physical Conditioning, Animal; Positron-Emission Tomography; Rats, Wistar; Spatial Memory; Thiazoles

Early diagnosis of Alzheimer's disease (AD) remains challenging even with the assistance of imaging. Radiation exposure limits the application of positron emission tomography (PET) for amyloid imaging. Magnetic resonance imaging (MRI) offers superior spatial resolution without the disadvantage of radiation exposure. We developed Mn

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Brain; Cell Line; Disease Models, Animal; Dogs; Early Diagnosis; Female; Humans; Immunohistochemistry; Madin Darby Canine Kidney Cells; Magnetic Resonance Imaging; Magnetite Nanoparticles; Male; Mice; Mice, Transgenic; Plaque, Amyloid; Positron-Emission Tomography; Surface-Active Agents; Thiazoles

In this study, we evaluated the anti-amyloid effect of functionalized nanoliposomes (mApoE-PA-LIP) in a mouse model of Alzheimer's disease with use of positron emission tomography and β-amyloid (Aβ)-targeted tracer [

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Carbon Radioisotopes; Disease Models, Animal; Female; Follow-Up Studies; Humans; Liposomes; Male; Mice, Transgenic; Nanoparticles; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Amyloid-β (Aβ) aggregation in the brain plays a central and initiatory role in pathogenesis and/or progression of Alzheimer's disease (AD). Inhibiting Aβ aggregation is a potential strategy in the prevention of AD. A scavenger peptide, V24P(10-40), designed to decrease Aβ accumulation in the brain, was conjugated to polyethylenimine (PEI) and tested as a preventive/therapeutic strategy for AD in this study. This PEI-conjugated V24P(10-40) peptide was delivered intranasally, as nasal drops, to four-month-old APP/PS1 double transgenic mice for four or eight months. Compared with control values, peptide treatment for four months significantly reduced the amount of GdnHCl-extracted Aβ40 and Aβ42 in the mice's hippocampus and cortex. After treatment for eight months, amyloid load, as quantified by Pittsburgh compound B microPET imaging, was significantly decreased in the mice's hippocampus, cortex, amygdala, and olfactory bulb. Our data suggest that this intranasally delivered scavenger peptide is effective in decreasing Aβ accumulation in the brain of AD transgenic mice. Nasal application of peptide drops is easy to use and could be further developed to prevent and treat AD.

Topics: Administration, Intranasal; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Benzothiazoles; Cell Line, Tumor; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Mutation; Neuroblastoma; Peptide Fragments; Polyethyleneimine; Positron-Emission Tomography; Presenilin-1; Thiazoles

The aim of this study was to compare [(11)C]Pittsburgh compound B ([(11)C]PiB) and [(18)F]florbetaben ([(18)F]FBB) for preclinical investigations of amyloid-β pathology.. We investigated two aged animal models of cerebral amyloidosis with contrasting levels of amyloid-β relating to "high" (APPPS1-21 n = 6, wild type (WT) n = 7) and "low" (BRI1-42 n = 6, WT n = 6) target states, respectively.. APPPS1-21 mice (high target state) demonstrated extensive fibrillar amyloid-β deposition that translated to significantly increased retention of [(11)C]PiB and [(18)F]FBB in comparison to their wild type. The retention pattern of [(11)C]PiB and [(18)F]FBB in this cohort displayed a significant correlation. However, the relative difference in tracer uptake between diseased and healthy mice was substantially higher for [(11)C]PiB than for [(18)F]FBB. Although immunohistochemistry confirmed the high plaque load in APPPS1-21 mice, correlation between tracer uptake and ex vivo quantification of amyloid-β was poor for both tracers. BRI1-42 mice (low target state) did not demonstrate increased tracer uptake.. In cases of high fibrillar amyloid-β burden, both tracers detected significant differences between diseased and healthy mice, with [(11)C]PiB showing a larger dynamic range.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Disease Models, Animal; Immunohistochemistry; Mice; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; Thiazoles

The dynamics of β-amyloid deposition and related second-order physiological effects, such as regional cerebral blood flow (rCBF), are key factors for a deeper understanding of Alzheimer's disease (AD). We present longitudinal in vivo data on the dynamics of β-amyloid deposition and the decline of rCBF in two different amyloid precursor protein (APP) transgenic mouse models of AD. Using a multiparametric positron emission tomography and magnetic resonance imaging approach, we demonstrate that in the presence of cerebral β-amyloid angiopathy (CAA), β-amyloid deposition is accompanied by a decline of rCBF. Loss of perfusion correlates with the growth of β-amyloid plaque burden but is not related to the number of CAA-induced microhemorrhages. However, in a mouse model of parenchymal β-amyloidosis and negligible CAA, rCBF is unchanged. Because synaptically driven spontaneous network activity is similar in both transgenic mouse strains, we conclude that the disease-related decline of rCBF is caused by CAA.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Benzothiazoles; Brain; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Cerebrovascular Circulation; Disease Models, Animal; Female; Longitudinal Studies; Magnetic Resonance Imaging; Mice; Mice, Transgenic; Multimodal Imaging; Perfusion Imaging; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

The purpose of this study is to validate the feasibility of a voxel-based analysis of in vivo amyloid-β positron emission tomography (PET) imaging studies in transgenic mouse models of Alzheimer's disease.. We performed [(11)C]PiB PET imaging in 20 APP/PS1 mice and 16 age-matched controls, and histologically determined the individual amyloid-β plaque load. Using SPM software, we performed a voxel-based group comparison plus a regression analysis between PiB retention and actual plaque load, both thresholded at p FWE < 0.05. In addition, we carried out an individual ROI analysis in every animal.. The automated voxel-based group comparison allowed us to identify voxels with significantly increased PiB retention in the cortical and hippocampal regions in transgenic animals compared to controls. The voxel-based regression analysis revealed a significant association between this signal increase and the actual cerebral plaque load. The validity of these results was corroborated by the individual ROI-based analysis.. Voxel-based analysis of in vivo amyloid-β PET imaging studies in mouse models of Alzheimer's disease is feasible and allows studying the PiB retention patterns in whole brain maps. Furthermore, the selected approach in our study also allowed us to establish a quantitative relation between tracer retention and actual plaque pathology in the brain in a voxel-wise manner.

Topics: Alzheimer Disease; Amyloid; Aniline Compounds; Animals; Benzothiazoles; Carbon Radioisotopes; Disease Models, Animal; Female; Male; Mice; Mice, Transgenic; Plaque, Amyloid; Positron-Emission Tomography; Regression Analysis; Signal Processing, Computer-Assisted; Thiazoles

Follow-up of β-amyloid (Aβ) deposition in transgenic mouse models of Alzheimer disease (AD) would be a valuable translational tool in the preclinical evaluation of potential antiamyloid therapies. This study aimed to evaluate the ability of the clinically used PET tracer (11)C-Pittsburgh compound B ((11)C-PIB) to detect changes over time in Aβ deposition in the brains of living mice representing the APP23, Tg2576, and APP(swe)-PS1(dE9) transgenic mouse models of AD.. Mice from each transgenic strain were imaged with 60-min dynamic PET scans at 7-9, 12, 15, and 18-22 mo of age. Regional (11)C-PIB retention was quantitated as distribution volume ratios using Logan graphical analysis with cerebellar reference input, as radioactivity uptake ratios between the frontal cortex (FC) and the cerebellum (CB) during the 60-min scan, and as bound-to-free ratios in the late washout phase (40-60 min). Ex vivo autoradiography experiments were performed after the final imaging session to validate (11)C-PIB binding to Aβ deposits. Additionally, the presence of Aβ deposits was evaluated in vitro using staining with thioflavin-S and Aβ1-40, Aβ1-16, and AβN3(pE) immunohistochemistry.. Neocortical (11)C-PIB retention was markedly increased in old APP23 mice with large thioflavin-S-positive Aβ deposits. At 12 mo, the Logan distribution volume ratio for the FC was 1.03 and 0.93 (n = 2), increasing to 1.38 ± 0.03 (n = 3) and 1.34 (n = 1) at 18 and 21 mo of age, respectively. An increase was also observed in bound-to-free ratios for the FC between young (7- to 12-mo-old) and old (15- to 22-mo-old) APP23 mice. Binding of (11)C-PIB to Aβ-rich cortical regions was also evident in ex vivo autoradiograms of APP23 brain sections. In contrast, no increases in (11)C-PIB retention were observed in aging Tg2576 or APP(swe)-PS1(dE9) mice in vivo, although in the latter, extensive Aβ deposition was already observed at 9 mo of age with immunohistochemistry.. The results suggest that (11)C-PIB binding to Aβ deposits in transgenic mouse brain is highly dependent on the AD model and the structure of its Aβ plaques. Longitudinal in vivo (11)C-PIB uptake studies are possible in APP23 mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Autoradiography; Benzothiazoles; Brain; Disease Models, Animal; Female; Longitudinal Studies; Male; Mice; Mice, Transgenic; Positron-Emission Tomography; Thiazoles

Accumulation of intracellular tau fibrils has been the focus of research on the mechanisms of neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Here, we have developed a class of tau ligands, phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums (PBBs), for visualizing diverse tau inclusions in brains of living patients with AD or non-AD tauopathies and animal models of these disorders. In vivo optical and positron emission tomographic (PET) imaging of a transgenic mouse model demonstrated sensitive detection of tau inclusions by PBBs. A pyridinated PBB, [(11)C]PBB3, was next applied in a clinical PET study, and its robust signal in the AD hippocampus wherein tau pathology is enriched contrasted strikingly with that of a senile plaque radioligand, [(11)C]Pittsburgh Compound-B ([(11)C]PIB). [(11)C]PBB3-PET data were also consistent with the spreading of tau pathology with AD progression. Furthermore, increased [(11)C]PBB3 signals were found in a corticobasal syndrome patient negative for [(11)C]PIB-PET.

Topics: Age Factors; Aged; Alzheimer Disease; Aminopyridines; Amyloid beta-Peptides; Aniline Compounds; Animals; Autoradiography; Benzothiazoles; Brain; Brain Mapping; Calcium-Binding Proteins; Carbon Isotopes; Disease Models, Animal; DNA-Binding Proteins; Dose-Response Relationship, Drug; Female; Humans; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Middle Aged; Mutation; Positron-Emission Tomography; Protein Structure, Secondary; tau Proteins; Tauopathies; Thiazoles

The aim of this study was to investigate the potential of [(18)F]flutemetamol as a preclinical PET tracer for imaging β-amyloid (Aβ) deposition by comparing its pharmacokinetics to those of [(11)C]Pittsburgh compound B ([(11)C]PIB) in wild-type Sprague Dawley rats and C57Bl/6N mice. In addition, binding of [(18)F]flutemetamol to Aβ deposits was studied in the Tg2576 transgenic mouse model of Alzheimer's disease.. [(18)F]Flutemetamol biodistribution was evaluated using ex vivo PET methods and in vivo PET imaging in wild-type rats and mice. Metabolism and binding of [(11)C]PIB and [(18)F]flutemetamol to plasma proteins were analysed using thin-layer chromatography and ultrafiltration methods, respectively. Radiation dose estimates were calculated from rat ex vivo biodistribution data. The binding of [(18)F]flutemetamol to Aβ deposits was also studied using ex vivo and in vitro autoradiography. The location of Aβ deposits in the brain was determined with thioflavine S staining and immunohistochemistry.. The pharmacokinetics of [(18)F]flutemetamol resembled that of [(11)C]PIB in rats and mice. In vivo studies showed that both tracers readily entered the brain, and were excreted via the hepatobiliary pathway in both rats and mice. The metabolism of [(18)F]flutemetamol into radioactive metabolites was faster than that of [(11)C]PIB. [(18)F]Flutemetamol cleared more slowly from the brain than [(11)C]PIB, particularly from white matter, in line with its higher lipophilicity. Effective dose estimates for [(11)C]PIB and [(18)F]flutemetamol were 2.28 and 6.65 μSv/MBq, respectively. Autoradiographs showed [(18)F]flutemetamol binding to fibrillar Aβ deposits in the brain of Tg2576 mice.. Based on its pharmacokinetic profile, [(18)F]flutemetamol showed potential as a PET tracer for preclinical imaging. It showed good brain uptake and was bound to Aβ deposits in the brain of Tg2576 mice. However, its high lipophilicity might complicate the analysis of PET data, particularly in small-animal imaging.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Benzothiazoles; Disease Models, Animal; Fluorine Radioisotopes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Thiazoles; Tissue Distribution

Alzheimer's disease is defined pathologically by the presence of senile plaques, which consist primarily of extracellular aggregates of fibrillar Abeta peptide, and neurofibrillary tangles, which are abnormal, intracellular bundles of fibrillar tau protein. The advent of amyloid binding agents as diagnostic imaging probes for Alzheimer's disease (AD) has made it imperative to understand at a molecular and disease level what these ligands are reporting. In addition to improving the accuracy of diagnosis, we argue that these selective ligands can serve as probes for molecular polymorphisms that may govern the pathogenicity of abnormal protein aggregates.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Benzothiazoles; Binding Sites; Binding, Competitive; Coloring Agents; Congo Red; Diagnostic Imaging; Disease Models, Animal; Humans; Ligands; Molecular Probes; Pathology, Molecular; Plaque, Amyloid; Predictive Value of Tests; Protein Isoforms; Thiazoles

Microglial overactivation, which is secondary to abnormalities of amyloid-beta peptide (Abeta) and tau proteins in the pathogenic cascade leading to onset of Alzheimer's disease (AD), accelerates tau pathology, according to our recent observations using mouse models of tauopathies, and this positive feedback results in formation of a vicious cycle between upstream and downstream processes, potentially hampering effective suppression of the entire cascade by anti-amyloid treatments. This motivates our present work aimed at dual monitoring of amyloidosis and microgliosis in living animal models of AD, toward therapeutic regulation of these two processes capable of halting the self-perpetuating cycle.. Transgenic mice expressing mutant amyloid precursor protein (APP23 mice) was examined by high-resolution positron emission tomography (PET) after administration of amyloid probe, Pittsburg Compound B (PIB) synthesized with high specific radioactivity (SA). Microglial activation in these mice was also imaged by PET and specific tracer, [(18)F]fluoroethyl-DAA1106.. Progressive amyloidosis in APP23 mice was visualized by PET and high-SA PIB. In vitro assays revealed preferential binding of PIB to N-terminally modified Abeta, Abeta(N3pE). As levels of this Abeta subspecies in model mice are lower than those in AD patients, our findings plausibly explain advantages of high-SA tracers in sensitive detection of mouse amyloid. Near-simultaneous monitoring of amyloid removal and microgliosis in APP23 mice following injection of anti-Abeta antibody demonstrated positive correlation between levels of initially existing amyloid and antibody-induced microglial activation, suggesting the possibility of microglial overactivation in immunotherapy for subjects with abundant amyloid.. The present animal imaging system would substantially facilitate establishment of a safe and effective therapeutic strategy targeting multiple key processes in the AD pathogenesis.

Topics: Acetamides; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Autoradiography; Brain; Brain Mapping; Disease Models, Animal; Humans; Isotopes; Mice; Mice, Transgenic; Microglia; Mutation; Phenyl Ethers; Positron-Emission Tomography; Protein Binding; tau Proteins; Thiazoles

To evaluate whether the newly-synthesized positron emission tomography (PET) tracer, [18F]2-(4'-(methylamino)phenyl)-6-fluoroethoxy- benzothiazole ([18F] O-FEt-PIB), could bind to beta-amyloid aggregates in a rat model of Alzheimer's disease (AD) using micro-PET.. [18F]O-FEt-PIB was synthesized and purified by radio HPLC. PET imaging was performed with a R4 rodent model scanner in 3 model and 3 control rats. Dynamic PET scans were performed for 40 min in each rat following an injection of approximately 37 MBq of [18F]O-FEt-PIB. Static scans were also performed for 15 min in each rat. PET data were reconstructed by a maximum posteriori probability algorithm. On the coronal PET images, regions of interest were respectively placed on the cortex, hemicerebrum [including the hippocampus and thalamus (HT)], and were guided by a 3-D digital map of the rat brain or the brain images of [18F]2-Deoxy-2-fluoro-D-glucose ([18F]FDG) in normal rats. Time-activity curves (TAC) were obtained for the cerebrum and cerebellum. The activity difference value (ADV) between 2 hemicerebrums was also calculated.. The TAC for [18F]O-FEt-PIB in the cerebrum or cerebellum peaked early (at approximately 2 min), but washed out a little slowly. In the dynamic and static micro-PET images, increased radioactivity was found in the area of the right HT in the model rats where infused with beta-amyloid (1-40). No distinct difference of radioactivity was found between the right and left HT areas in the control rats. The ADV(HT) was approximately 14.6% in the AD model rats and approximately 4 times greater than that of the control rats (3.9%).. To our knowledge, this study is the first to evaluate a small molecular PET probe for the beta-amyloid deposits in vivo using micro-PET imaging in an AD-injected rat model. The suitable biological characters showed that the tracer had potential to be developed as a probe for detecting beta-amyloid plaques in AD.

Topics: Algorithms; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Brain; Diagnostic Imaging; Disease Models, Animal; Fluorodeoxyglucose F18; Hippocampus; Male; Peptide Fragments; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Thalamus; Thiazoles; Tissue Distribution

We provide the first evidence for the capability of a high-resolution positron emission tomographic (PET) imaging system in quantitatively mapping amyloid accumulation in living amyloid precursor protein transgenic (Tg) mice. After the intravenous administration of N-[11C]methyl-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [11C]PIB for "Pittsburgh Compound-B") with high-specific radioactivity, the Tg mice exhibited high-level retention of radioactivity in amyloid-rich regions. PET investigation for Tg mice over an extended range of ages, including longitudinal assessments, demonstrated age-dependent increase in radioligand binding consistent with progressive amyloid accumulation. Reduction in amyloid levels in the hippocampus of Tg mice was also successfully monitored by multiple PET scans along the time course of anti-amyloid treatment using an antibody against amyloid beta peptide (Abeta). Moreover, PET scans with [18F]fluoroethyl-DAA1106, a radiotracer for activated glia, were conducted for these individuals parallel to amyloid imaging, revealing treatment-induced neuroinflammatory responses, the magnitude of which intimately correlated with the levels of pre-existing amyloid estimated by [11C]PIB. It is also noteworthy that the localization and abundance of [11C]PIB autoradiographic signals were closely associated with those of N-terminally truncated and modified Abeta, AbetaN3-pyroglutamate, in Alzheimer's disease (AD) and Tg mouse brains, implying that the detectability of amyloid by [11C]PIB positron emission tomography is dependent on the accumulation of specific Abeta subtypes. Our results support the usefulness of the small animal-dedicated PET system in conjunction with high-specific radioactivity probes and appropriate Tg models not only for clarifying the mechanistic properties of amyloidogenesis in mouse models but also for preclinical tests of emerging diagnostic and therapeutic approaches to AD.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Antibodies; Disease Models, Animal; Female; Inflammation; Longitudinal Studies; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurofibrillary Tangles; Positron-Emission Tomography; Thiazoles

The purpose of this study was to evaluate the capacity of [11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify beta-amyloid (Abeta) plaques in the Tg2576 mouse model of Alzheimer's disease (AD).. PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0+/-1.8 months; 23.6+/-2.6 g) overexpressing a mutated form of human beta-amyloid precursor protein (APP) known to result in the production of Abeta plaques, and in six elderly wild-type litter mates (age 21.8+/-1.6 months; 29.5+/-4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S.. TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06+/-0.04 vs 0.98+/-0.07, p=0.04; 1.06+/-0.09 vs 0.93+/-0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Abeta plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice.. Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Abeta plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Abeta plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Abeta plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Brain; Disease Models, Animal; Feasibility Studies; Female; Metabolic Clearance Rate; Mice; Mice, Transgenic; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles; Tissue Distribution