Publications by authors named "Tetsuya Suhara"

337 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

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

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

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

Pharmacological and Genetic Inhibition of Translocator Protein 18 kDa Ameliorated Neuroinflammation in Murine Endotoxemia Model.

Shock 2020 Dec 4. Epub 2020 Dec 4.

*Department of Emergency and Critical Care Medicine, Graduate School of Biomedical and Health Science, Hiroshima University †National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan ‡Discovery Research Laboratories I, ONO Pharmaceutical Co., Ltd §Department of Neurobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University ||Brain, Mind and KANSEI Sciences Research Center, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 Japan.

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction associated with sepsis. The development of an effective strategy for early diagnosis and therapeutic intervention is essential for the prevention of poor prognosis of SAE. Translocator protein 18 kDa (TSPO) is a mitochondrial protein implicated in steroidogenesis and inflammatory responses. Despite accumulating evidence that implicates TSPO in the neuroinflammatory response of the central nervous system, the possible role of TSPO in SAE remains unclear. Aim of this study is to address a role of TSPO in neuroinflammation using mice 24 h after systemic injection of lipopolysaccharide (LPS), which consistently demonstrated microglial activation and behavioral inhibition. Quantitative polymerase chain reaction analysis revealed that hippocampal TSPO expression was induced following the systemic LPS injection, associated with an increase in pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. Interestingly, pretreatment with the TSPO antagonist, ONO-2952, or germ-line deletion of the TSPO gene exhibited an anti-inflammatory effect with significant suppression of LPS-induced production of those cytokines. These effects demonstrated by the ONO-2952 or TSPO knockout were associated with significant recovery from behavioral inhibition, as shown by improved locomotor activity in the open field analysis. Histological analysis revealed that ONO-2952 pretreatment suppressed the LPS-induced activation of TSPO-expressing microglia in the hippocampus of mice. Collectively, these results suggest that TSPO plays a critical role in the SAE mouse model. Based on this finding, monitoring TSPO activity, as well as the progress of endotoxemia and its sequelae in the animal model, would deepen our understanding of the underlying molecular mechanism of SAE.
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http://dx.doi.org/10.1097/SHK.0000000000001703DOI Listing
December 2020

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

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

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

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

Enhancing Multi-Center Generalization of Machine Learning-Based Depression Diagnosis From Resting-State fMRI.

Front Psychiatry 2020 28;11:400. Epub 2020 May 28.

Division of Information Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Japan.

Resting-state fMRI has the potential to help doctors detect abnormal behavior in brain activity and to diagnose patients with depression. However, resting-state fMRI has a bias depending on the scanner site, which makes it difficult to diagnose depression at a new site. In this paper, we propose methods to improve the performance of the diagnosis of major depressive disorder (MDD) at an independent site by reducing the site bias effects using regression. For this, we used a subgroup of healthy subjects of the independent site to regress out site bias. We further improved the classification performance of patients with depression by focusing on melancholic depressive disorder. Our proposed methods would be useful to apply depression classifiers to subjects at completely new sites.
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http://dx.doi.org/10.3389/fpsyt.2020.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270328PMC
May 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

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

Primary functional brain connections associated with melancholic major depressive disorder and modulation by antidepressants.

Sci Rep 2020 02 26;10(1):3542. Epub 2020 Feb 26.

Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

The limited efficacy of available antidepressant therapies may be due to how they affect the underlying brain network. The purpose of this study was to develop a melancholic MDD biomarker to identify critically important functional connections (FCs), and explore their association to treatments. Resting state fMRI data of 130 individuals (65 melancholic major depressive disorder (MDD) patients, 65 healthy controls) were included to build a melancholic MDD classifier, and 10 FCs were selected by our sparse machine learning algorithm. This biomarker generalized to a drug-free independent cohort of melancholic MDD, and did not generalize to other MDD subtypes or other psychiatric disorders. Moreover, we found that antidepressants had a heterogeneous effect on the identified FCs of 25 melancholic MDDs. In particular, it did impact the FC between left dorsolateral prefrontal cortex (DLPFC)/inferior frontal gyrus (IFG) and posterior cingulate cortex (PCC)/precuneus, ranked as the second 'most important' FC based on the biomarker weights, whilst other eight FCs were normalized. Given that left DLPFC has been proposed as an explicit target of depression treatments, this suggest that the limited efficacy of antidepressants might be compensated by combining therapies with targeted treatment as an optimized approach in the future.
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http://dx.doi.org/10.1038/s41598-020-60527-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044159PMC
February 2020

Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.

J Cereb Blood Flow Metab 2020 08 16;40(8):1576-1585. Epub 2020 Feb 16.

Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, USA.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.
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http://dx.doi.org/10.1177/0271678X20905433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370374PMC
August 2020

Correction of head movement by frame-to-frame image realignment for receptor imaging in positron emission tomography studies with [C]raclopride and [C]FLB 457.

Ann Nucl Med 2019 Dec 11;33(12):916-929. Epub 2019 Oct 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.

Objective: Positron emission tomography (PET) scans of imaging receptors require 60-90-min dynamic acquisition for quantitative analysis. Head movement is often observed during scanning, which hampers the reliable estimation of quantitative parameters. This study evaluated image-based motion correction by frame-to-frame realignment for PET studies with [C]raclopride and [C]FLB 457 acquired by an Eminence SET-3000GCT/X and investigated the effect of this correction on the quantitative outcomes.

Methods: First, an optimal method for estimating motion parameters was evaluated by computer simulation. Simulated emission sinograms were reconstructed to the PET images with or without attenuation correction using a µ-map of the transmission scan. Six motion parameters were estimated frame-by-frame by registering each frame of the PET images to several types of reference images and the reliability of registration was compared. Next, in [C]raclopride and [C]FLB 457 studies in normal volunteers, six motion parameters for each frame were estimated by the registration method determined from the simulation results. Head movement was corrected by realigning the PET images reconstructed with a motion-included µ-map in which a mismatch between the transmission and emission scans was corrected. After this correction, time-activity curves (TAC) for the striatum or cerebral cortex were obtained and the binding potentials of the receptors (BP) were estimated using the simplified reference tissue model.

Results: In the simulations, the motion parameters could be reliably estimated by registering each frame of the non-attenuation-corrected PET images to their early-phase frame. The motion parameters in the human studies were also obtained using the same method. After correction, a discontinuity of TACs in the striatum and cerebral cortex was remarkably improved and the BP values in these regions increased. Compared to the motion-corrected PET images reconstructed using the measured µ-map, the images reconstructed using the motion-included µ-map did not result in a remarkable improvement of BP in the striatum of [C]raclopride studies, while the BP in the cerebral cortex changed in some [C]FLB 457 studies in which large head movement was observed.

Conclusions: In PET receptor imaging, head movement during dynamic scans can be corrected by frame-to-frame realignment. This method is easily applicable to clinical studies and provides reliable TACs and BP.
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http://dx.doi.org/10.1007/s12149-019-01405-1DOI Listing
December 2019

Differentiation Between Dementia With Lewy Bodies And Alzheimer's Disease Using Voxel-Based Morphometry Of Structural MRI: A Multicenter Study.

Neuropsychiatr Dis Treat 2019 19;15:2715-2722. Epub 2019 Sep 19.

2nd Group, 2nd Planning Department, 1st Integrated Communication Division, Communication and Information Center, Information Innovation Operations, Dai Nippon Printing Co., Ltd., Tokyo, Japan.

Background: The differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is particularly important because DLB patients respond better to cholinesterase inhibitors but sometimes exhibit sensitivity to neuroleptics, which may cause worsening of clinical status. Antemortem voxel-based morphometry (VBM) using structural MRI has previously revealed that patients with DLB have normal hippocampal volume, but atrophy in the dorsal mesopontine area.

Objectives: The aim of this multicenter study was to determine whether VBM of the brain stem in addition to that of medial temporal lobe structures improves the differential diagnosis of AD and DLB.

Methods: We retrospectively chose 624 patients who were clinically diagnosed with either DLB (239 patients) or AD (385 patients) from 10 institutes using different MR scanners with different magnetic field strengths. In all cases, VBM was performed on 3D T1-weighted images. The degree of local atrophy was calculated using Z-score by comparison with a database of normal volumes of interest (VOIs) in medial temporal lobe (MTL) and the dorsal brain stem (DBS). The discrimination of DLB and AD was evaluated using Z-score values in these two VOIs. MRI data from 414 patients were used as the training data set to determine the classification criteria, with the MRI data from the remaining 210 patients used as the test data set.

Results: The DLB and AD patients did not differ with respect to mean age or Mini-Mental State Examination scores. Z-index scores showed that there was significantly more atrophy in MTL of AD patients, compared to DLB patients and in DBS of DLB patients, compared to AD patients. The discrimination accuracies of VBM were 63.3% in the test data set and 73.4% in the training data set.

Conclusion: VBM of DBS in addition to that of MTL improves the differentiation of DLB and AD.
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http://dx.doi.org/10.2147/NDT.S222966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757232PMC
September 2019

PET-detectable tau pathology correlates with long-term neuropsychiatric outcomes in patients with traumatic brain injury.

Brain 2019 10;142(10):3265-3279

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

Tau deposits is a core feature of neurodegenerative disorder following traumatic brain injury (TBI). Despite ample evidence from post-mortem studies demonstrating exposure to both mild-repetitive and severe TBIs are linked to tau depositions, associations of topology of tau lesions with late-onset psychiatric symptoms due to TBI have not been explored. To address this issue, we assessed tau deposits in long-term survivors of TBI by PET with 11C-PBB3, and evaluated those associations with late-life neuropsychiatric outcomes. PET data were acquired from 27 subjects in the chronic stage following mild-repetitive or severe TBI and 15 healthy control subjects. Among the TBI patients, 14 were diagnosed as having late-onset symptoms based on the criteria of traumatic encephalopathy syndrome. For quantification of tau burden in TBI brains, we calculated 11C-PBB3 binding capacity (cm3), which is a summed voxel value of binding potentials (BP*ND) multiplied by voxel volume. Main outcomes of the present study were differences in 11C-PBB3 binding capacity between groups, and the association of regional 11C-PBB3 binding capacity with neuropsychiatric symptoms. To confirm 11C-PBB3 binding to tau deposits in TBI brains, we conducted in vitro PBB3 fluorescence and phospho-tau antibody immunofluorescence labelling of brain sections of chronic traumatic encephalopathy obtained from the Brain Bank. Our results showed that patients with TBI had higher 11C-PBB3 binding capacities in the neocortical grey and white matter segments than healthy control subjects. Furthermore, TBI patients with traumatic encephalopathy syndrome showed higher 11C-PBB3 binding capacity in the white matter segment than those without traumatic encephalopathy syndrome, and regional assessments revealed that subgroup difference was also significant in the frontal white matter. 11C-PBB3 binding capacity in the white matter segment correlated with the severity of psychosis. In vitro assays demonstrated PBB3-positive tau inclusions at the depth of neocortical sulci, confirming 11C-PBB3 binding to tau lesions. In conclusion, increased 11C-PBB3 binding capacity is associated with late-onset neuropsychiatric symptoms following TBI, and a close correlation was found between psychosis and 11C-PBB3 binding capacity in the white matter.
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http://dx.doi.org/10.1093/brain/awz238DOI Listing
October 2019

Classification of Clinically Diagnosed Alzheimer's Disease Associated with Diabetes Based on Amyloid and Tau PET Results.

J Alzheimers Dis 2019 ;71(1):261-271

Department of Geriatric Medicine, Tokyo Medical University, Tokyo, Japan.

Background/objective: Although type 2 diabetes mellitus (DM) is a risk factor for the development of dementia, the underlying brain pathologies and mechanisms vary among patients. In this study, we classified patients with clinically diagnosed Alzheimer's disease (AD) associated with DM into subgroups based on their amyloid and tau accumulation patterns on positron emission tomography (PET), and analyzed the differences in clinical features and brain imaging findings between the subgroups.

Methods: Sixty-four patients with probable or possible AD associated with DM were classified using PiB (detects amyloid, A) and PBB3 (detects tau, T) PET studies. Patients were classified into the A+/T+ group (n = 35, AD pathology), the A- /T+ group (n = 19, tauopathy), and the A- /T- group (n = 10, non-amyloid/non-tau neuronal damage).

Results: Compared with the A+/T+ group, the A- /T+ group showed less-well controlled glycemia, longer duration of diabetes, more glucose variability, higher frequency of insulin therapy and biochemical hypoglycemia, and greater impairment of frontal lobe function, slower progression of cognitive decline, fewer APOE4 carriers, less severe medial temporal lobe atrophy, and lower frequency of posterior cerebral hypoperfusion. This subgroup showed different clinical and radiological features from AD.

Conclusion: Among patients with clinically diagnosed AD with DM, there are subgroups with neuronal damage independent of AD pathology. A subgroup of dementia patients suspected of having tauopathy is strongly associated with DM-related metabolic abnormalities. This study highlights the identification of a novel dementia subgroup (diabetes-related dementia), which is important for considering appropriate therapies and care in clinical practice.
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http://dx.doi.org/10.3233/JAD-190620DOI Listing
October 2020

Association between Brain and Plasma Glutamine Levels in Healthy Young Subjects Investigated by MRS and LC/MS.

Nutrients 2019 Jul 19;11(7). Epub 2019 Jul 19.

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

Both glutamine (Gln) and glutamate (Glu) are known to exist in plasma and brain. However, despite the assumed relationship between brain and plasma, no studies have clarified the association between them. Proton magnetic resonance spectroscopy (MRS) was sequentially performed twice, with a 60-min interval, on 10 males and 10 females using a 3T scanner. Blood samples for liquid chromatography-mass spectrometry (LC/MS) to measure Gln and Glu concentrations in plasma were collected during the time interval between the two MRS sessions. MRS voxels of interest were localized at the posterior cingulate cortex (PCC) and cerebellum (Cbll) and measured by the SPECIAL sequence. Spearman's correlation coefficient was used to examine the association between brain and plasma metabolites. The Gln concentrations in PCC (mean of two measurements) were positively correlated with Gln concentrations in plasma ( < 0.01, = 0.72). However, the Glu concentrations in the two regions were not correlated with those in plasma. Consideration of the different dynamics of Gln and Glu between plasma and brain is crucial when addressing the pathomechanism and therapeutic strategies for brain disorders such as Alzheimer's disease and hepatic encephalopathy.
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http://dx.doi.org/10.3390/nu11071649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682979PMC
July 2019

In vivo direct relation of tau pathology with neuroinflammation in early Alzheimer's disease.

J Neurol 2019 Sep 28;266(9):2186-2196. Epub 2019 May 28.

Department of Biofunctional Imaging, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama Higashi-ku, Hamamatsu, 431-3192, Japan.

Objective: Neuronal damage and neuroinflammation are important events occurring in the brain of Alzheimer's disease (AD). The purpose of this study was to clarify in vivo mutual relationships among abnormal tau deposition, neuroinflammation and cognitive impairment in patients with early AD using positron emission tomography (PET) with [C]PBB3 and [C]DPA713.

Methods: Twenty patients with early AD and 20 age-matched normal control (NC) subjects underwent a series of PET measurements with [C]PBB3 for tau aggregation and [C]DPA713 for microglial activation (neuroinflammation). Inter- and intrasubject comparisons were performed regarding the levels of [C]PBB3 binding potential (BP) and [C]DPA713 BP in the light of cognitive functions using statistical parametric mapping (SPM) and regions of interest (ROIs) method.

Results: The [C]PBB3 BP was greater in the temporo-parietal regions of AD patents than NC subjects, and a similar increasing pattern of [C]DPA713 BP was observed in the same patients. Correlation analyses within the AD group showed a positive direct correlation between [C]PBB3 BP and [C]DPA713 BP in the parahippocampus. Pass analysis revealed that cognitive impairment was more likely linked to the level of the parahippocampal [C]PBB3 BP than that of [C]DPA713 BP.

Conclusions: The pattern of abnormal tau deposition was very similar to that of neuroinflammation in patients with early-stage AD. Specifically, the direct positive correlation of tau pathology with neuroinflammation in the parahippocampus suggests that neuronal damage in this region is closely associated with microglial activation. Consistently, tau aggregation in this region matters more than neuroinflammation regarding the cognitive deterioration in AD.
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http://dx.doi.org/10.1007/s00415-019-09400-2DOI Listing
September 2019

Abnormal axon guidance signals and reduced interhemispheric connection via anterior commissure in neonates of marmoset ASD model.

Neuroimage 2019 07 3;195:243-251. Epub 2019 Apr 3.

Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan; Ichinohe Group, Laboratory for Molecular Analysis of Higher Brain Function, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. Electronic address:

In autism spectrum disorder (ASD), disrupted functional and structural connectivity in the social brain has been suggested as the core biological mechanism underlying the social recognition deficits of this neurodevelopmental disorder. In this study, we aimed to identify genetic and neurostructural abnormalities at birth in a non-human primate model of ASD, the common marmoset with maternal exposure to valproic acid (VPA), which has been reported to display social recognition deficit in adulthood. Using a comprehensive gene expression analysis, we found that 20 genes were significantly downregulated in VPA-exposed neonates. Of these, Frizzled3 (FZD3) and PIK3CA were identified in an axon guidance signaling pathway. FZD3 is essential for the normal development of the anterior commissure (AC) and corpus callosum (CC); hence, we performed diffusion tensor magnetic resonance imaging with a 7-Tesla scanner to measure the midsagittal sizes of these structures. We found that the AC size in VPA-exposed neonates was significantly smaller than that in age-matched controls, while the CC size did not differ. These results suggest that downregulation of the genes related to axon guidance and decreased AC size in neonatal primates may be linked to social brain dysfunctions that can happen later in life.
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http://dx.doi.org/10.1016/j.neuroimage.2019.04.006DOI Listing
July 2019

In vivo binding of a tau imaging probe, [ C]PBB3, in patients with progressive supranuclear palsy.

Mov Disord 2019 05 20;34(5):744-754. Epub 2019 Mar 20.

Department of Functional Brain Imaging Research (DOFI), Clinical Research Cluster, National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Chiba, Japan.

Background: [ C]pyridinyl-butadienyl-benzothiazole 3 is a PET imaging agent designed for capturing pathological tau aggregates in diverse neurodegenerative disorders, and would be of clinical utility for neuropathological investigations of PSP.

Objectives: To explore the usefulness of [ C]pyridinyl-butadienyl-benzothiazole 3/PET in assessing characteristic distributions of tau pathologies and their association with clinical symptoms in the brains of living PSP patients.

Methods: We assessed 13 PSP patients and 13 age-matched healthy control subjects. Individuals negative for amyloid β PET with [ C]Pittsburgh compound B underwent clinical scoring, MR scans, and [ C]pyridinyl-butadienyl-benzothiazole 3/PET.

Results: There were significant differences in binding potential for [ C]pyridinyl-butadienyl-benzothiazole 3 between PSP patients and healthy control subjects (P = 0.02). PSP patients exhibited greater radioligand retention than healthy control subjects in multiple brain regions, including frontoparietal white matter, parietal gray matter, globus pallidus, STN, red nucleus, and cerebellar dentate nucleus. [ C]pyridinyl-butadienyl-benzothiazole 3 deposition in frontoparietal white matter, but not gray matter, was correlated with general severity of parkinsonian and PSP symptoms, whereas both gray matter and white matter [ C]pyridinyl-butadienyl-benzothiazole 3 accumulations in the frontoparietal cortices were associated with nonverbal cognitive impairments. Autoradiographic and fluorescence labeling with pyridinyl-butadienyl-benzothiazole 3 was observed in gray matter and white matter of PSP motor cortex tissues.

Conclusions: Our findings support the in vivo detectability of tau fibrils characteristic of PSP by [ C]pyridinyl-butadienyl-benzothiazole 3/PET, and imply distinct and synergistic contributions of gray matter and white matte tau pathologies to clinical symptoms. [ C]pyridinyl-butadienyl-benzothiazole 3/PET potentially provides a neuroimaging-based index for the evolution of PSP tau pathologies promoting the deterioration of motor and cognitive functions. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593859PMC
May 2019

Clinical heterogeneity of frontotemporal dementia and Parkinsonism linked to chromosome 17 caused by MAPT N279K mutation in relation to tau positron emission tomography features.

Mov Disord 2019 04 17;34(4):568-574. Epub 2019 Feb 17.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

Background: While mechanistic links between tau abnormalities and neurodegeneration have been proven in frontotemporal dementia and parkinsonism linked to chromosome 17 caused by MAPT mutations, variability of the tau pathogenesis and its relation to clinical progressions in the same MAPT mutation carriers are yet to be clarified.

Objectives: The present study aimed to analyze clinical profiles, tau accumulations, and their correlations in 3 kindreds with frontotemporal dementia and parkinsonism linked to chromosome 17 attributed to the MAPT N279K mutation.

Methods: Four patients with N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT underwent [ C]PBB3-PET to estimate regional tau loads.

Results: Haplotype assays revealed that these kindreds originated from a single founder. Despite homogeneity of the disease-causing MAPT allele, clinical progression was more rapid in 2 kindreds than in the other. The kindred with slow progression showed mild tau depositions, mostly confined to the midbrain and medial temporal areas. In contrast, kindreds with rapid progression showed profoundly increased [ C]PBB3 binding in widespread regions from an early disease stage.

Conclusions: [ C]PBB3-PET can capture four-repeat tau pathologies characteristic of N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT. Our findings indicate that, in addition to the mutated MAPT allele, genetic and/or epigenetic modifiers of tau pathologies lead to heterogeneous clinicopathological features. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593784PMC
April 2019

First prototyping of a dedicated PET system with the hemisphere detector arrangement.

Phys Med Biol 2019 03 8;64(6):065004. Epub 2019 Mar 8.

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

A strong demand is expected for high-sensitivity, high-resolution and low-cost brain positron emission tomography (PET) imaging for early diagnosis of dementia, as well as for general neuroscience studies. Therefore, we have proposed novel geometries of a hemisphere detector arrangement for high-sensitivity brain imaging, in which an add-on detector at the chin position or neck position helps in sensitivity uniformity improvement. In this study, we developed the first prototype system for proof-of-concept using four-layer depth-of-interaction detectors, each of which consisted of 16  ×  16  ×  4 Zr-doped GSO crystals with dimensions of 2.8  ×  2.8  ×  7.5 mm and a high-sensitivity 64-channel flat-panel photomultiplier tube. We used 47 detectors to form a hemisphere detector with a hemisphere shape of 25 cm inner diameter and 50 cm outer diameter, and we used seven detectors for each of the add-on detectors. The total detector number of 54 was about one-fourth that of a typical whole-body PET scanner. The hemisphere detector for the prototype system was realized by multiple rings having different numbers of detectors and a cross-shaped top detector unit covering the top. Performance evaluation showed uniform spatial resolutions of 3-4 mm by the filtered back-projection method. Imaging tests of a hot-rod phantom done with an iterative method were able to resolve 2.2 mm rods. Peak sensitivity was measured as more than 10% at a region near the top of the head, which was achieved with the help of the top detector unit. In addition, using the prototype system, we performed the first FDG clinical test with a healthy volunteer. The results showed that the proposed geometries had high potential for realizing high-sensitivity, high-resolution, and low-cost brain PET imaging. As for the add-on detector position, it was shown that the neck position resulted in higher sensitivity and wider field of view (FOV) than the chin position because the add-on detector at the neck position can be placed continuously to the hemisphere detector and close to the FOV.
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http://dx.doi.org/10.1088/1361-6560/ab012cDOI Listing
March 2019

Signaling Incentive and Drive in the Primate Ventral Pallidum for Motivational Control of Goal-Directed Action.

J Neurosci 2019 03 9;39(10):1793-1804. Epub 2019 Jan 9.

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

Processing incentive and drive is essential for control of goal-directed behavior. The limbic part of the basal ganglia has been emphasized in these processes, yet the exact neuronal mechanism has remained elusive. In this study, we examined the neuronal activity of the ventral pallidum (VP) and its upstream area, the rostromedial caudate (rmCD), while two male macaque monkeys performed an instrumental lever release task in which a visual cue indicated the forthcoming reward size. We found that the activity of some neurons in VP and rmCD reflected the expected reward size transiently following the cue. Reward size coding appeared earlier and stronger in VP than in rmCD. We also found that the activity in these areas was modulated by the satiation level of monkeys, which also occurred more frequently in VP than in rmCD. The information regarding reward size and satiation level was independently signaled in the neuronal populations of these areas. The data thus highlighted the neuronal coding of key variables for goal-directed behavior in VP. Furthermore, pharmacological inactivation of VP induced more severe deficit of goal-directed behavior than inactivation of rmCD, which was indicated by abnormal error repetition and diminished satiation effect on the performance. These results suggest that VP encodes incentive value and internal drive and plays a pivotal role in the control of motivation to promote goal-directed behavior. The limbic part of the basal ganglia has been implicated in the motivational control of goal-directed action. Here, we investigated how the ventral pallidum (VP) and the rostromedial caudate (rmCD) encode incentive value and internal drive and control goal-directed behavior. Neuronal recording and subsequent pharmacological inactivation revealed that VP had stronger coding of reward size and satiation level than rmCD. Reward size and satiation level were independently encoded in the neuronal population of these areas. Furthermore, VP inactivation impaired goal-directed behavior more severely than rmCD inactivation. These results highlight the central role of VP in the motivational control of goal-directed action.
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http://dx.doi.org/10.1523/JNEUROSCI.2399-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407294PMC
March 2019