Publications by authors named "Makoto Higuchi"

245 Publications

PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, C-GW2580, and C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey.

J Cereb Blood Flow Metab 2021 Mar 24:271678X211004146. Epub 2021 Mar 24.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R, C-GW2580, and compared it to a reported CSF1R tracer, C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic C-GW2580- and C-CPPC-PET images were quantified by reference tissue-based models and standardized uptake value ratio. Both tracers exhibited increased uptake in the lesioned striata of lipopolysaccharide-injected mice and in the forebrains of -knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover, C-GW2580 captured changes in CSF1R availability more sensitively than C-CPPC, with a larger dynamic range and a smaller inter-individual variability, in these model animals. PET imaging of CSF1R in a rhesus monkey displayed moderate-to-high tracer retention in the brain at baseline. Homologous blocker (i. e. unlabeled tracer) treatment reduced the uptake of C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of C-CPPC. In summary, our results demonstrated that C-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.
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http://dx.doi.org/10.1177/0271678X211004146DOI Listing
March 2021

Neuroprotective effect of mitochondrial translocator protein ligand in a mouse model of tauopathy.

J Neuroinflammation 2021 Mar 19;18(1):76. Epub 2021 Mar 19.

Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, 308232, Singapore.

Background: The translocator protein (TSPO) has been identified as a positron emission tomography (PET)-visible biomarker of inflammation and promising immunotherapeutic target for the treatment of Alzheimer's disease (AD). While TSPO ligands have been shown to reduce the accumulation of the toxic Alzheimer's beta-amyloid peptide, their effect on tau pathology has not yet been investigated. To address this, we analyzed the effects of TSPO ligand, Ro5-4864, on the progression of neuropathology in rTg4510 tau transgenic mice (TauTg).

Methods: Brain atrophy, tau accumulation, and neuroinflammation were assessed longitudinally using volumetric magnetic resonance imaging, tau-PET, and TSPO-PET, respectively. In vivo neuroimaging results were confirmed by immunohistochemistry for markers of neuronal survival (NeuN), tauopathy (AT8), and inflammation (TSPO, ionized calcium-binding adaptor molecule 1 or IBA-1, and complement component 1q or C1q) in brain sections from scanned mice.

Results: TSPO ligand treatment attenuated brain atrophy and hippocampal neuronal loss in the absence of any detected effect on tau depositions. Atrophy and neuronal loss were strongly associated with in vivo inflammatory signals measured by TSPO-PET, IBA-1, and levels of C1q, a regulator of the complement cascade. In vitro studies confirmed that the TSPO ligand Ro5-4864 reduces C1q expression in a microglial cell line in response to inflammation, reduction of which has been shown in previous studies to protect synapses and neurons in models of tauopathy.

Conclusions: These findings support a protective role for TSPO ligands in tauopathy, reducing neuroinflammation, neurodegeneration, and brain atrophy.
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http://dx.doi.org/10.1186/s12974-021-02122-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980620PMC
March 2021

Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607.

Acta Neuropathol 2021 Mar 16. Epub 2021 Mar 16.

MRC Laboratory of Molecular Biology, Cambridge, UK.

Tau and Aβ assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.
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http://dx.doi.org/10.1007/s00401-021-02294-3DOI Listing
March 2021

Synthesis and preclinical evaluation of [C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain.

Eur J Nucl Med Mol Imaging 2021 Mar 5. Epub 2021 Mar 5.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.

Purpose: Phosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.

Methods: [C]MTP38 was radiosynthesized by C-cyanation of a bromo precursor with [C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (V). The non-displaceable binding potential (BP) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BP.

Results: [C]MTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated V values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm, respectively. The cerebellar V value was unchanged by pretreatment with unlabeled MTP38. Striatal BP was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill's sigmoidal function.

Conclusion: We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.
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http://dx.doi.org/10.1007/s00259-021-05269-4DOI Listing
March 2021

Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor.

Brain Commun 2021 29;3(1):fcab011. Epub 2021 Jan 29.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Microglia are the resident phagocytes of the central nervous system, and microglial activation is considered to play an important role in the pathogenesis of neurodegenerative diseases. Recent studies with single-cell RNA analysis of CNS cells in Alzheimer's disease and diverse other neurodegenerative conditions revealed that the transition from homeostatic microglia to disease-associated microglia was defined by changes of gene expression levels, including down-regulation of the P2Y12 receptor gene (). However, it is yet to be clarified in Alzheimer's disease brains whether and when this down-regulation occurs in response to amyloid-β and tau depositions, which are core pathological processes in the disease etiology. To further evaluate the significance of P2Y12 receptor alterations in the neurodegenerative pathway of Alzheimer's disease and allied disorders, we generated an anti-P2Y12 receptor antibody and examined P2Y12 receptor expressions in the brains of humans and model mice bearing amyloid-β and tau pathologies. We observed that the brains of both Alzheimer's disease and non-Alzheimer's disease tauopathy patients and tauopathy model mice (rTg4510 and PS19 mouse lines) displayed declined microglial P2Y12 receptor levels in regions enriched with tau inclusions, despite an increase in the total microglial population. Notably, diminution of microglial immunoreactivity with P2Y12 receptor was noticeable prior to massive accumulations of phosphorylated tau aggregates and neurodegeneration in rTg4510 mouse brains, despite a progressive increase of total microglial population. On the other hand, Iba1-positive microglia encompassing compact and dense-cored amyloid-β plaques expressed P2Y12 receptor at varying levels in amyloid precursor protein (APP) mouse models (APP23 and mice). By contrast, neuritic plaques in Alzheimer's disease brains were associated with P2Y12 receptor-negative microglia. These data suggest that the down-regulation of microglia P2Y12 receptor, which is characteristic of disease-associated microglia, is intimately associated with tau rather than amyloid-β pathologies from an early stage and could be a sensitive index for neuroinflammatory responses to Alzheimer's disease-related neurodegenerative processes.
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http://dx.doi.org/10.1093/braincomms/fcab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901060PMC
January 2021

Design, Synthesis, and Biological Evaluation of Novel Fluorescent Probes Targeting the 18-kDa Translocator Protein.

ChemMedChem 2021 Feb 25. Epub 2021 Feb 25.

School of Chemistry and Molecular Bioscience, and Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia.

A series of fluorescent probes from the 6-chloro-2-phenylimidazo[1,2-a]pyridine-3-yl acetamides ligands featuring the 7-nitro-2-oxa-1,3-diazol-4-yl (NBD) moiety has been synthesized and biologically evaluated for their fluorescence properties and for their binding affinity to the 18-kDa translocator protein (TSPO). Spectroscopic studies including UV/Vis absorption and fluorescence measurements showed that the synthesized fluorescent probes exhibit favorable spectroscopic properties, especially in nonpolar environments. In vitro fluorescence staining in brain sections from lipopolysaccharide (LPS)-injected mice revealed partial colocalization of the probes with the TSPO. The TSPO binding affinity of the probes was measured on crude mitochondrial fractions separated from rat brain homogenates in a [ C]PK11195 radioligand binding assay. All the new fluorescent probes demonstrated moderate to high binding affinity to the TSPO, with affinity (K ) values ranging from 0.58 nM to 3.28 μM. Taking these data together, we propose that the new fluorescent probes could be used to visualize the TSPO.
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http://dx.doi.org/10.1002/cmdc.202000984DOI Listing
February 2021

Nasal vaccine delivery attenuates brain pathology and cognitive impairment in tauopathy model mice.

NPJ Vaccines 2020 Mar 25;5(1):28. Epub 2020 Mar 25.

Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto, Kyoto, 606-8507, Japan.

Pathological aggregates of tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-tau). Although immunotherapies of these disorders against tau are emerging, it is unknown whether nasal delivery, which offers many benefits over traditional approaches to vaccine administration, is effective or not for tauopathy. Here, we developed vaccination against a secreted form of pathological tau linked to FTLD-tau using a Sendai virus (SeV) vector infectious to host nasal mucosa, a key part of the immune system. Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production and ameliorated cognitive impairment in FTLD-tau model mice. In vivo imaging and postmortem neuropathological assays demonstrated the suppression of phosphorylated tau accumulation, neurotoxic gliosis, and neuronal loss in the hippocampus of immunized mice. These findings suggest that nasal vaccine delivery may provide a therapeutic opportunity for a broad range of populations with human tauopathy.
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http://dx.doi.org/10.1038/s41541-020-0172-yDOI Listing
March 2020

A first-in-human study of C-MTP38, a novel PET ligand for phosphodiesterase 7.

Eur J Nucl Med Mol Imaging 2021 Feb 10. Epub 2021 Feb 10.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.

Purpose: Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains.

Methods: Seven healthy males underwent a 90-min PET scan after injection of C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (Vs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTM) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference.

Results: PET images with C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. V values were robustly estimated by two-tissue compartment model analysis (mean V = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTM and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTM and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of C-MTP38-PET.

Conclusion: We have provided the first demonstration of PET visualization of PDE7 in human brains. C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.
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http://dx.doi.org/10.1007/s00259-021-05235-0DOI Listing
February 2021

Detection of Alzheimer's disease-related neuroinflammation by a PET ligand selective for glial versus vascular translocator protein.

J Cereb Blood Flow Metab 2021 Feb 8:271678X21992457. Epub 2021 Feb 8.

Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

A substantial and constitutive expression of translocator protein (TSPO) in cerebral blood vessels hampers the sensitive detection of neuroinflammation characterized by greatly induced TSPO expression in activated glia. Here, we conducted in vivo positron emission tomography (PET) and in vitro autoradiographic imaging of normal and TSPO-deficient mouse brains to compare the binding properties of F-FEBMP, a relatively novel TSPO radioligand developed for human studies based on its insensitivity to a common polymorphism, with C-PK11195, as well as other commonly used TSPO radioligands including C-PBR28, C-Ac5216 and F-FEDAA1106. TSPO in cerebral vessels of normal mice was found to provide a major binding site for C-PK11195, C-PBR28 and F-FEDAA1106, in contrast to no overt specific binding of F-FEBMP and C-Ac5216 to this vascular component. In addition, F-FEBMP yielded PET images of microglial TSPO with a higher contrast than C-PK11195 in a tau transgenic mouse modeling Alzheimer's disease (AD) and allied neurodegenerative tauopathies. Moreover, TSPO expression examined by immunoblotting was significantly increased in AD brains compared with healthy controls, and was well correlated with the autoradiographic binding of F-FEBMP but not C-PK11195. Our findings support the potential advantage of comparatively glial TSPO-selective radioligands such as F-FEBMP for PET imaging of inflammatory glial cells.
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http://dx.doi.org/10.1177/0271678X21992457DOI Listing
February 2021

Comparison of MRI-based and PET-based image pre-processing for quantification of C-PBB3 uptake in human brain.

Z Med Phys 2021 Feb 14;31(1):37-47. Epub 2021 Jan 14.

Medical Radiation Physics, Department of Nuclear Medicine, Ulm University, Ulm, Germany; Department of Nuclear Medicine, Ulm University, Ulm, Germany.

Purpose: Quantification of tau load using C-PBB3-PET has the potential to improve diagnosis of neurodegenerative diseases. Although MRI-based pre-processing is used as a reference method, not all patients have MRI. The feasibility of a PET-based pre-processing for the quantification of C-PBB3 tracer was evaluated and compared with the MRI-based method.

Materials And Methods: Fourteen patients with decreased recent memory were examined with C-PBB3-PET and MRI. The PET scans were visually assessed and rated as either PBB3(+) or PBB3(-). The image processing based on the PET-based method was validated against the MRI-based approach. The regional uptakes were quantified using the Mesial-temporal/Temporoparietal/Rest of neocortex (MeTeR) regions. SUVR values were calculated by normalizing to the cerebellar reference region to compare both methods within the patient groups.

Results: Significant correlations were observed between the SUVRs of the MRI-based and the PET-based methods in the MeTeR regions (r=0.91; r=0.98; r=0.96; p<0.0001). However, the Bland-Altman plot showed a significant bias between both methods in the subcortical Me region (bias: -0.041; 95% CI: -0.061 to -0.024; p=0.003). As in the MRI-based method, the C-PBB3 uptake obtained with the PET-based method was higher for the PBB3(+) group in each of the cortical regions and for the whole brain than for the PBB3(-) group (PET-based: 1.11 vs. 0.96; Cliff's Delta (d)=0.68; p=0.04; MRI-based: 1.11 vs. 0.97; d=0.70; p=0.03). To differentiate between positive and negative scans, Youden's index estimated the best cut-off of 0.99 from the ROC curve with good accuracy (AUC: 0.88±0.10; 95% CI: 0.67-1.00) and the same sensitivity (83%) and specificity (88%) for both methods.

Conclusion: The PET-based pre-processing method developed to quantify the tau burden with C-PBB3 provided comparable SUVR values and effect sizes as the MRI-based reference method. Furthermore, both methods have a comparable discrimination accuracy between PBB3(+) and PBB3(-) groups as assessed by visual rating. Therefore, the presented PET-based method can be used for clinical diagnosis if no MRI image is available.
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http://dx.doi.org/10.1016/j.zemedi.2020.12.002DOI Listing
February 2021

Biodistribution and radiation dosimetry of the positron emission tomography probe for AMPA receptor, [C]K-2, in healthy human subjects.

Sci Rep 2021 Jan 15;11(1):1598. Epub 2021 Jan 15.

Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

[C]K-2, a radiotracer exhibiting high affinity and selectivity for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), is suitable for the quantification of AMPARs in living human brains and potentially useful in the identification of epileptogenic foci in patients. This study aimed to estimate the radiation doses of [C]K-2 in various organs and calculate the effective dose after injection of [C]K-2 in healthy human subjects. Twelve healthy male subjects were registered and divided into two groups (370 or 555 MBq of [C]K-2), followed by 2 h whole-body scans. We estimated the radiation dose of each organ and then calculated the effective dose for each subject. The highest uptake of [C]K-2 was observed in the liver, while the brain also showed relatively high uptake. The urinary bladder exhibited the highest radiation dose. The kidneys and liver also showed high radiation doses after [C]K-2 injections. The effective dose of [C]K-2 ranged from 5.0 to 5.2 μSv/MBq. Our findings suggest that [C]K-2 is safe in terms of the radiation dose and adverse effects. The injection of 370-555 MBq (10 to 15 mCi) for PET studies using this radiotracer is applicable in healthy human subjects and enables serial PET scans in a single subject.
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http://dx.doi.org/10.1038/s41598-021-81002-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810729PMC
January 2021

Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease.

Acta Neuropathol Commun 2021 01 5;9(1). Epub 2021 Jan 5.

Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Aichi, 464-8601, Japan.

Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, App with amyloid pathology, rTg4510 with tauopathy, and SOD1 with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1 microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.
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http://dx.doi.org/10.1186/s40478-020-01099-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786928PMC
January 2021

Pick's Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling.

Int J Mol Sci 2020 Dec 31;22(1). Epub 2020 Dec 31.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer's disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick's disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick's disease (Tau). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore Tau binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with Tau. The probes bind to Tau at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of Tau specific PET tracers.
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http://dx.doi.org/10.3390/ijms22010349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796283PMC
December 2020

multimodal imaging of adenosine A receptors in neuroinflammation after experimental stroke.

Theranostics 2021 1;11(1):410-425. Epub 2021 Jan 1.

Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain.

Adenosine A receptors (AARs) are promising imaging biomarkers and targets for the treatment of stroke. Nevertheless, the role of AARs on ischemic damage and its subsequent neuroinflammatory response has been scarcely explored so far. In this study, the expression of AARs after transient middle cerebral artery occlusion (MCAO) was evaluated by positron emission tomography (PET) with [F]CPFPX and immunohistochemistry (IHC). In addition, the role of AARs on stroke inflammation using pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [F]DPA-714 (TSPO) and [F]FLT (cellular proliferation), as well as IHC and neurofunctional studies. In the ischemic territory, [F]CPFPX signal and IHC showed the overexpression of AARs in microglia and infiltrated leukocytes after cerebral ischemia. Ischemic rats treated with the AAR agonist ENBA showed a significant decrease in both [F]DPA-714 and [F]FLT signal intensities at day 7 after cerebral ischemia, a feature that was confirmed by IHC results. Besides, the activation of AARs promoted the reduction of the brain lesion, as measured with TW-MRI, and the improvement of neurological outcome including motor, sensory and reflex responses. These results show for the first time the PET imaging of AARs expression after cerebral ischemia in rats and the application of [F]FLT to evaluate glial proliferation in response to treatment. Notably, these data provide evidence for AARs playing a key role in the control of both the activation of resident glia and the proliferation of microglia and macrophages after experimental stroke in rats.
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http://dx.doi.org/10.7150/thno.51046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681082PMC
January 2021

Differential associations of dopamine synthesis capacity with the dopamine transporter and D2 receptor availability as assessed by PET in the living human brain.

Neuroimage 2021 02 11;226:117543. Epub 2020 Nov 11.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa Inage-ku, Chiba 263-8555, Japan.

Background: The dopamine (DA) neurotransmission has been implicated in fundamental brain functions, exemplified by movement controls, reward-seeking, motivation, and cognition. Although dysregulation of DA neurotransmission in the striatum is known to be involved in diverse neuropsychiatric disorders, it is yet to be clarified whether components of the DA transmission, such as synthesis, receptors, and reuptake are coupled with each other to homeostatically maintain the DA neurotransmission. The purpose of this study was to investigate associations of the DA synthesis capacity with the availabilities of DA transporters and D2 receptors in the striatum of healthy subjects.

Methods: First, we examined correlations between the DA synthesis capacity and DA transporter availability in the caudate and putamen using PET data with L-[β-C]DOPA and [F]FE-PE2I, respectively, acquired from our past dual-tracer studies. Next, we investigated relationships between the DA synthesis capacity and D2 receptor availability employing PET data with L-[β-C]DOPA and [C]raclopride, respectively, obtained from other previous dual-tracer assays.

Results: We found a significant positive correlation between the DA synthesis capacity and DA transporter availability in the putamen, while no significant correlations between the DA synthesis capacity and D2 receptor availability in the striatum.

Conclusion: The intimate association of the DA synthesis rate with the presynaptic reuptake of DA indicates homeostatic maintenance of the baseline synaptic DA concentration. In contrast, the total abundance of D2 receptors, which consist of presynaptic autoreceptors and postsynaptic modulatory receptors, may not have an immediate relationship to this regulatory mechanism.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117543DOI Listing
February 2021

High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies.

Neuron 2021 01 29;109(1):42-58.e8. Epub 2020 Oct 29.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer's disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick's disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.
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http://dx.doi.org/10.1016/j.neuron.2020.09.042DOI Listing
January 2021

Radiosynthesis and quality control testing of the tau imaging positron emission tomography tracer [ F]PM-PBB3 for clinical applications.

J Labelled Comp Radiopharm 2021 Mar 7;64(3):109-119. Epub 2020 Nov 7.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Recently, we produced C-labeled 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ([ C]PBB3) as a clinically useful positron emission tomography (PET) tracer for in vivo imaging of tau pathologies in the human brain. To overcome the limitations (i.e., rapid in vivo metabolism and short half-life) of [ C]PBB3, we further synthesized F-labeled 1-fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol ([ F]PM-PBB3). [ F]PM-PBB3 is also a useful tau PET tracer for imaging tau pathologies. In this study, we developed a routine radiosynthesis and quality control testing of [ F]PM-PBB3 for clinical applications. [ F]PM-PBB3 was synthesized by direct F-fluorination of the tosylated derivative, followed by removal of the protecting group. [ F]PM-PBB3 was obtained with sufficient radioactivity (25 ± 6.0% of the nondecay-corrected radiochemical yield at the end of synthesis, EOS), radiochemical purity (98 ± 0.6%), and molar activity (350 ± 94 GBq/μmol at EOS; n = 53). Moreover, [ F]PM-PBB3 consistently retained >95% of radiochemical purity for 60 min without undergoing photoisomerization using a new UV-cutoff light (yellow light) fixed in the hot cell to monitor the synthesis. All the results of the quality control testing for the [ F]PM-PBB3 injection complied with our in-house quality control and quality assurance specifications. We have accomplished >200 production runs of [ F]PM-PBB3 in our facility for various research purposes.
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http://dx.doi.org/10.1002/jlcr.3890DOI Listing
March 2021

Regulation of Anxiety and Depression by Mitochondrial Translocator Protein-Mediated Steroidogenesis: the Role of Neurons.

Mol Neurobiol 2021 Feb 29;58(2):550-563. Epub 2020 Sep 29.

Department of Functional Brain Imaging Research, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Pharmacological studies have implicated the translocator protein (TSPO) in the regulation of complex behaviors including anxiety and depression, effects thought to be mediated by increased synthesis of neuroactive steroid hormones. However, TSPO function in the brain remains to be corroborated in vivo via genetic studies. To address this, we developed global TSPO knockout (TSPO-KO) and neuronal TSPO transgenic (TSPO-Tg) mouse models to investigate TSPO function in the regulation of anxiety- and depression-related behaviors using elevated plus maze and forced swim test paradigms. Neuroactive steroid hormones were measured in the brain by mass spectrometry. In vivo TSPO ligand pharmacokinetics was investigated using competitive PET with F-FE-DAA1106. Genetic TSPO deficiency increased anxiety-related behavior and impaired brain steroidogenesis but did not affect depressive behaviors. Using the TSPO-KO model, we then demonstrated the specificity of Ac-5216, also known as XBD-173 or Emapunil, as an anxiolytic targeting TSPO at doses optimized by competitive PET for high cortical occupancy. Neuronal TSPO overexpression decreased depressive behaviors, an effect that was dependent on steroidogenesis, and partially reversed anxiogenic behavior in TSPO-KO mice. These findings demonstrate that TSPO is critical for brain steroidogenesis and modulates anxiety- and depression-related behaviors. However, we demonstrate that key differences in the contribution of neuronal TSPO to the modulation of these complex behaviors, illustrating the tissue- and cell-specific importance of TSPO. The TSPO-KO and TSPO-Tg mice provide the tools and rationale for the development of therapeutic approaches targeting TSPO in the brain for treatment of neuropsychiatric conditions.
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http://dx.doi.org/10.1007/s12035-020-02136-5DOI Listing
February 2021

Identification and in vitro characterization of C05-01, a PBB3 derivative with improved affinity for alpha-synuclein.

Brain Res 2020 12 18;1749:147131. Epub 2020 Sep 18.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.

The neuropathological hallmark of Parkinsońs disease, multiple system atrophy and dementia with Lewy bodies is the accumulation of α-synuclein. The development of an imaging biomarker for α-synuclein is an unmet need. To date, no selective α-synuclein imaging agent has been identified, though initial studies suggest that the tau tracer [C]PBB3 displays some degree of binding to α-synuclein. In this study, a series of compounds derived from the PBB3 scaffold were examined using fluorescence imaging and tissue microarrays (TMAs) derived from brain samples with different proteinopathies. One compound, C05-01, was selected based on its higher fluorescence signal associated with Lewy body aggregates compared with other PBB3 analogues. In vitro binding assays using human brain homogenates and recombinant fibrils indicated that C05-01 had higher affinity for α-synuclein (K/Ki 25 nM for fibrils, Ki 3.5 nM for brain homogenates) as compared with PBB3 (K 58 nM). In autoradiography (ARG) studies using fresh frozen human tissue and TMAs, [H]C05-01 displayed specific binding in cases with α-synuclein pathology. C05-01 is the first PBB3 analogue developed as a potential compound targeting α-synuclein. Despite improved affinity for α-synuclein, C05-01 showed specific binding in AD tissue with Amyloid β and tau pathology, as well as relatively high non-specific and off-target binding. Additional efforts are needed to optimize the pharmacological and physicochemical properties of this series of compounds as ligands for α-synuclein. This study also showed that the construction of TMAs from different proteinopathies provides a tool for evaluation of fluorescent or radiolabelled compounds binding to misfolded proteins.
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http://dx.doi.org/10.1016/j.brainres.2020.147131DOI Listing
December 2020

Binding of Dopamine D1 Receptor and Noradrenaline Transporter in Individuals with Autism Spectrum Disorder: A PET Study.

Cereb Cortex 2020 Nov;30(12):6458-6468

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Chiba 263-8555, Japan.

Although previous studies have suggested the involvement of dopamine (DA) and noradrenaline (NA) neurotransmissions in the autism spectrum disorder (ASD) pathophysiology, few studies have examined these neurotransmissions in individuals with ASD in vivo. Here, we investigated DA D1 receptor (D1R) and noradrenaline transporter (NAT) binding in adults with ASD (n = 18) and neurotypical controls (n = 20) by utilizing two different PET radioligands, [11C]SCH23390 and (S,S)-[18F]FMeNER-D2, respectively. We found no significant group differences in DA D1R (striatum, anterior cingulate cortex, and temporal cortex) or NAT (thalamus and pons) binding. However, in the ASD group, there were significant negative correlations between DA D1R binding (striatum, anterior cingulate cortex and temporal cortex) and the "attention to detail" subscale score of the Autism Spectrum Quotient. Further, there was a significant positive correlation between DA D1R binding (temporal cortex) and emotion perception ability assessed by the neurocognitive battery. Associations of NAT binding with empathic abilities and executive function were found in controls, but were absent in the ASD group. Although a lack of significant group differences in binding might be partly due to the heterogeneity of ASD, our results indicate that central DA and NA function might play certain roles in the clinical characteristics of ASD.
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http://dx.doi.org/10.1093/cercor/bhaa211DOI Listing
November 2020

The Imaging Features and Clinical Associations of a Novel Tau PET Tracer-18F-APN1607 in Alzheimer Disease.

Clin Nucl Med 2020 Oct;45(10):747-756

APRINOIA Therapeutics, Taipei, Taiwan.

Purpose Of The Report: In vivo tau PET imaging could help clarify the spatial distribution of tau deposition in Alzheimer disease (AD) and aid in the differential diagnosis of tauopathies. To date, there have been no in vivo F-APN1607 tau PET studies in patients with AD.

Methods: We applied tau tracer in 12 normal controls (NCs) and 10 patients in the mild to moderate stage of probable AD. Detailed clinical information, cognitive measurements, and disease severity were documented. Regional SUV ratios (SUVRs) from F-AV-45 (florbetapir), F-APN1607 PET images, and regional gray matter (GM) atrophic ratios were calculated for further analysis.

Results: Quantitative analyses showed significantly elevated SUVRs in the frontal, temporal, parietal, occipital lobes, anterior and posterior cingulate gyri, precuneus, and parahippocampal region (all P's < 0.01) with medium to large effect sizes (0.44-0.75). The SUVRs from F-APN1607 PET imaging showed significant correlations with the Alzheimer's Disease Assessment Scale (ADAS-cog) scores (all P's < 0.01) and strong correlation coefficients (R ranged from 0.54 to 0.68), even adjusted for age and sex effects. Finally, the SUVRs from F-APN1607 PET imaging of the parahippocampal region showed rapid saturation as the ADAS-cog scores increased, and the SUVRs of the posterior cingulate gyrus and the temporal, frontal, parietal, and occipital regions slowly increased. The combined SUVRs from amyloid, tau PET, and regional GM atrophic ratio showed regional specific patterns as the ADAS-cog scores increased.

Conclusions: Our findings suggest that the F-APN1607 tau tracer correlated well with cognitive changes and demonstrated the spatial pattern of amyloid, tau deposition, and GM atrophy in the progression of AD.
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http://dx.doi.org/10.1097/RLU.0000000000003164DOI Listing
October 2020

Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys.

Nat Neurosci 2020 09 6;23(9):1157-1167. Epub 2020 Jul 6.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.
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http://dx.doi.org/10.1038/s41593-020-0661-3DOI Listing
September 2020

In vivo positron emission tomography imaging of mitochondrial abnormalities in a mouse model of tauopathy.

Neurobiol Aging 2020 10 19;94:140-148. Epub 2020 May 19.

Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan. Electronic address:

Damaged mitochondria may be one of the earliest manifestations of Alzheimer's disease. Because oxidative phosphorylation is a primary source of neuronal energy, unlike glycolysis-dependent energy production in inflamed glia, mitochondrial respiration could provide a selective biomarker of neuronal deterioration in Alzheimer's disease. Here we used a recently developed positron emission tomography (PET) probe targeting mitochondrial complex I (MC-I), F-BCPP-EF, to non-invasively visualize mitochondrial abnormalities in the brains of tau transgenic mice (rTg4510). Tauopathy and neuroinflammation were visualized by PET using a tau probe C-PBB3 and a translocator protein probe, F-FEBMP, respectively. A marked reduction in F-BCPP-EF uptake was observed in hippocampal and forebrain regions of tau transgenic mice, colocalizing with regions of tauopathy, neuronal damage, and neuroinflammation. MC-I signals were highly correlated with atrophy assayed by magnetic resonance imaging, but negatively associated with inflammatory signals, indicating that neuronal metabolic signals measured by MC-I PET were robust to inflammatory interference. MC-I may be a useful imaging biomarker to detect neuronal damage and metabolic changes with minimal interference from concomitant glial hypermetabolism.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.05.003DOI Listing
October 2020

Excess tau PET ligand retention in elderly patients with major depressive disorder.

Mol Psychiatry 2020 Jul 1. Epub 2020 Jul 1.

Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Depression is one of the common psychiatric disorders in old age. Major depressive disorder (MDD) has been identified as a risk factor or prodrome for neurodegenerative dementias, suggesting neuropathological overlaps and a continuum between MDD and neurodegenerative disorders. In this study, we examined tau and amyloid-β (Aβ) accumulations in the brains of MDD and healthy controls using positron emission tomography (PET) to explore pathological substrates of this illness. Twenty MDD and twenty age-matched, healthy controls were examined by PET with a tau radioligand, [C]PBB3, and an Aβ radioligand, [C]PiB. Radioligand retentions were quantified as a standardized uptake value ratio (SUVR). We also assessed clinical manifestations of the patients using the 17-item Hamilton Depression Scale, the Geriatric Depression Scale, and psychotic symptoms. Mean cortical [C]PBB3 SUVRs in MDD patients were significantly higher than those of healthy controls. These values were higher in MDD patients with psychotic symptoms than in those without any. The present findings indicate that tau depositions may underlie MDD, and especially in patients with psychotic symptoms. PET detection of tau accumulations may provide mechanistic insights into neuronal dysfunctions in these cases and could serve as predictions of their clinical consequences.
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http://dx.doi.org/10.1038/s41380-020-0766-9DOI Listing
July 2020

Heavy Tau Burden with Subtle Amyloid β Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer's Disease with APP Osaka Mutation.

Int J Mol Sci 2020 Jun 22;21(12). Epub 2020 Jun 22.

Department of Neurology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.

We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer's disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aβ, tau and neurodegeneration, we performed tau and Aβ PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer's disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aβ accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aβ can induce tau accumulation and neuronal degeneration without forming senile plaques.
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http://dx.doi.org/10.3390/ijms21124443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352205PMC
June 2020

Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model.

J Neurosci 2020 04 7;40(17):3491-3501. Epub 2020 Apr 7.

Department of Functional Brain Imaging

Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies. In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[C]ABP688 and [C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.
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http://dx.doi.org/10.1523/JNEUROSCI.2880-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178904PMC
April 2020

Protein Deficiency-Induced Behavioral Abnormalities and Neurotransmitter Loss in Aged Mice Are Ameliorated by Essential Amino Acids.

Front Nutr 2020 11;7:23. Epub 2020 Mar 11.

Ajinomoto Co., Inc., Kawasaki, Japan.

Nutritional epidemiology shows that insufficient protein intake is related to senile dementia. The levels of protein intake in aged people are positively associated with memory function, and elderly people with high protein intake have a low risk of mild cognitive impairment. Although the beneficial roles of protein nutrition in maintaining brain function in aged people are well demonstrated, little is known about the mechanism by which dietary intake of protein affects memory and brain conditions. We fed aged mice a low protein diet (LPD) for 2 months, which caused behavioral abnormalities, and examined the nutritional effect of essential amino acid administration under LPD conditions. The passive avoidance test revealed that LPD mice demonstrated learning and memory impairment. Similarly, the LPD mice showed agitation and hyperactive behavior in the elevated plus maze test. Moreover, LPD mice exhibited decreased concentrations of gamma-aminobutyric acid (GABA), glutamate, glycine, dopamine, norepinephrine, serotonin and aspartate in the brain. Interestingly, oral administration of seven essential amino acids (EAAs; valine, leucine, isoleucine, lysine, phenylalanine, histidine, and tryptophan) to LPD mice, which can be a source of neurotransmitters, reversed those behavioral changes. The oral administration of EAAs restored the brain concentration of glutamate, which is involved in learning and memory ability and may be associated with the observed behavioral changes. Although the details of the link between decreased amino acid and neurotransmitter concentrations and behavioral abnormalities must be examined in future studies, these findings suggest the importance of dietary protein and essential amino acids for maintaining brain function.
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http://dx.doi.org/10.3389/fnut.2020.00023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079559PMC
March 2020

Nasal vaccine delivery attenuates brain pathology and cognitive impairment in tauopathy model mice.

NPJ Vaccines 2020 24;5:28. Epub 2020 Mar 24.

1Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto, Kyoto, 606-8507 Japan.

Pathological aggregates of tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-tau). Although immunotherapies of these disorders against tau are emerging, it is unknown whether nasal delivery, which offers many benefits over traditional approaches to vaccine administration, is effective or not for tauopathy. Here, we developed vaccination against a secreted form of pathological tau linked to FTLD-tau using a Sendai virus (SeV) vector infectious to host nasal mucosa, a key part of the immune system. Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production and ameliorated cognitive impairment in FTLD-tau model mice. In vivo imaging and postmortem neuropathological assays demonstrated the suppression of phosphorylated tau accumulation, neurotoxic gliosis, and neuronal loss in the hippocampus of immunized mice. These findings suggest that nasal vaccine delivery may provide a therapeutic opportunity for a broad range of populations with human tauopathy.
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http://dx.doi.org/10.1038/s41541-020-0172-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096417PMC
March 2020

Tau PET Imaging.

Authors:
Makoto Higuchi

Adv Exp Med Biol 2019 ;1184:217-230

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

The deposition of fibrillar tau aggregates has been implicated in Alzheimer's disease (AD) and allied neurodegenerative disorders collectively referred to as tauopathies. Growing non-clinical and clinical evidence has supported intimate links between tau fibrillogenesis and neuronal deteriorations, rationalizing the development of imaging agents for tau fibrils to gain etiological insights into tauopathies and to facilitate diagnostic and therapeutic approaches to these diseases. Radiochemicals derived from three major chemotypes were initially applied to positron emission tomography (PET) studies of human subjects, demonstrating their utility for capturing AD-type tau deposits with reasonably high contrast. Meanwhile, these tracers suffered substantial off-target binding in the brain and did not offer sensitive detection of tau lesions in a large proportion of non-AD tauopathies. To overcome such drawbacks, 'second-generation' tau PET probes have been generated and examined in clinical settings. These tracers have enabled specific assays of AD tau pathologies, and a novel radiocompound developed by our research group has been shown to produce high contrasts for AD and non-AD tau aggregates, potentially allowing diagnostic evaluations of diverse tauopathies on an individual basis.
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http://dx.doi.org/10.1007/978-981-32-9358-8_18DOI Listing
April 2020