Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Corticobasal syndrome (CBS) is a neurodegenerative disease diagnosed based on clinical manifestations such as asymmetrical parkinsonism, limb apraxia, and speech and language impairment. The background pathology of CBS is commonly a variety of proteinopathies, but association with cerebrovascular disease has also been reported. Foix-Chavany-Marie syndrome (FCMS) is a rare neurological disorder characterized by facio-pharyngo-glossal diplegia with automatic-voluntary movement dissociation presenting with bilateral paresis of the facial, lingual, pharyngeal and masticatory muscles. FCMS is commonly attributable to stroke. Transactive response DNA binding protein of 43 kD (TDP-43) proteinopathy is also known as the pathological background of FCMS, while the pathological background of the majority of CBS cases consists of diverse tauopathies instead of TDP-43 proteinopathy. In this report, we describe a case mimicking FCMS that was finally diagnosed as CBS with suggested 4-repeat tauopathy. CASE PRESENTATION: A 68-year-old female started experiencing difficulty speaking followed by difficulty writing, and especially texting, several years before her visit. Her impairment had been gradually worsening, and she came to our hospital. On neurological examination, she demonstrated the facial apraxia, frontal lobe dysfunction, and upper motor neuron signs. She presented some characteristics suggestive of FCMS. Her symptoms exhibited rapid progression and myoclonus, parkinsonism, and left-side dominant cortical sensory deficit occurred, resulting in the fulfillment of diagnostic criteria for CBS after 9 months. Tau PET imaging displayed notable ligand uptake in the brainstem, subthalamic nuclei, basal ganglia, and bilateral subcortical frontal lobe, suggesting that her pathological background was 4-repeat tauopathy. As a result of her progressive dysphagia, she became unable to eat and passed away after 12 months. CONCLUSION: We hereby present an atypical case of CBS showing clinical features mimicking FCMS at first presentation. TDP-43 proteinopathy was suspected based on the clinical symptoms in the early stages of the disease; however, the clinical course and imaging findings including tau PET suggested that her pathological background was 4-repeat tauopathy.

DOI： 10.1186/s12877-023-04564-z

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Language：Japanese   Publisher：(一社)日本認知症学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本認知症学会  

J-GLOBAL

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Publisher：Cold Spring Harbor Laboratory  

Abstract

Several blood-based assays for phosphorylated tau (p-tau) have been developed to detect brain tau pathologies in Alzheimer’s disease (AD). However, plasma p-tau measured by currently available assays is influenced by brain amyloid and, therefore, could not accurately reflect brain tau deposits. Here, we devised a novel immunoassay that can quantify N- and C-terminally truncated p-tau fragments (mid-p-tau181) in human plasma. We measured plasma p-tau181 levels in 164 participants who underwent both amyloid and tau positron emission tomography (PET) scans using mid-p-tau181 and conventional p-tau181 assays. The mid-p-tau181 assay displayed stronger correlations with tau PET accumulation than the conventional assay in the AD continuum and accurately distinguished between tau PET-positive and -negative cases. Furthermore, the mid-p-tau181 assay demonstrated a trajectory similar to tau PET alongside cognitive decline. Consequently, our mid-p-tau181 assay could be useful in evaluating the extent of brain tau burden in AD.

DOI： 10.1101/2023.09.15.23295595

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OBJECTIVE: Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD. METHODS: The study included 30 AD and 30 cognitively unimpaired participants. For AD participants, amyloid and tau depositions were confirmed by positron emission tomography using [11 C]PiB and [18 F]florzolotau, respectively. Myo-inositol, an astroglial marker, and lactate in the posterior cingulate cortex were quantified by magnetic resonance spectroscopy. These magnetic resonance spectroscopy metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker, and amyloid and tau positron emission tomography. RESULTS: Myo-inositol and lactate levels were higher in AD patients than in cognitively unimpaired participants (p < 0.05). Myo-inositol levels correlated with lactate levels (r = 0.272, p = 0.047). Myo-inositol and lactate levels were positively associated with the Clinical Dementia Rating sum-of-boxes scores (p < 0.05). Significant correlations were noted between myo-inositol levels and plasma glial fibrillary acidic protein, tau phosphorylated at threonine 181 levels, and amyloid and tau positron emission tomography accumulation in the posterior cingulate cortex (p < 0.05). INTERPRETATION: We found high myo-inositol levels accompanied by increased lactate levels in the posterior cingulate cortex in AD patients, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo-inositol and plasma glial fibrillary acidic protein may reflect similar astrocytic changes as biomarkers of AD. ANN NEUROL 2023.

DOI： 10.1002/ana.26797

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Increased excitatory neuronal tones have been implicated in autism, but its mechanism remains elusive. The amplified glutamate signals may arise from enhanced glutamatergic circuits, which can be affected by astrocyte activation and suppressive signaling of dopamine neurotransmission. We tested this hypothesis using magnetic resonance spectroscopy and positron emission tomography scan with ¹¹C-SCH23390 for dopamine D1 receptors in the anterior cingulate cortex (ACC). We enrolled 18 male adults with high-functioning autism and 20 typically developed (TD) male subjects. The autism group showed elevated glutamate, glutamine, and myo-inositol (mI) levels compared with the TD group (p = 0.045, p = 0.044, p = 0.030, respectively) and a positive correlation between glutamine and mI levels in the ACC (r = 0.54, p = 0.020). In autism and TD groups, ACC D1 receptor radioligand binding was negatively correlated with ACC glutamine levels (r =  − 0.55, p = 0.022; r =  − 0.58, p = 0.008, respectively). The enhanced glutamate-glutamine metabolism might be due to astroglial activation and the consequent reinforcement of glutamine synthesis in autistic brains. Glutamine synthesis could underly the physiological inhibitory control of dopaminergic D1 receptor signals. Our findings suggest a high neuron excitation-inhibition ratio with astrocytic activation in the etiology of autism.

DOI： 10.1038/s41598-023-38306-3

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Other Link： https://www.nature.com/articles/s41598-023-38306-3

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Background: Heterogeneity in Alzheimer's disease (AD) has been reported on the basis of clinical, neuropathological, and neuroimaging data. However, most of the indices, including cerebral atrophy evaluated using magnetic resonance imaging and amyloid b (Ab) accumulation detected using positron emission tomography (PET), lack sensitivity, and specificity for categorization. Aim: Herein, we used a novel PET ligand for tau to estimate the differential distribution of tau in the subtypes of AD. Methods: Patients with posterior cortical atrophy (PCA; n = 3), frontal variant of AD (FAD; n = 1), logopenic variant primary progressive aphasia (LPPA; n = 2), typical AD (TAD; n = 6), and healthy controls (HC; n = 12) were studied. Ab and tau accumulation were evaluated using [C-11]PiB and [C-11]PBB3, respectively. Results: Amyloid b accumulation was confirmed in all PCA, FAD, LPPA, and TAD cases. Tau accumulation was dominantly high in the occipital lobes in the PCA, strikingly high in the frontal lobes in the FAD, and moderately high in the angular gyrus of the dominant hemisphere in the LPPA. Tau accumulation in TAD cases was significantly higher than age-dependent tau accumulation in HC in these subtype-specific regions as well as in AD signature regions. Glucose utilization was reversely correlated with PBB3 accumulation in the subtype-specific regions. Conclusions: Tau accumulates differently in the four subtypes of AD, suggesting that tau pathology may be closely associated with unique clinical features.

DOI： 10.1111/ncn3.12715

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Central serotonin (5-hydroxytryptamine, 5-HT) neurotransmission has been implicated in the etiology of depression. Most antidepressants ameliorate depressive symptoms by increasing 5-HT at synaptic clefts but their effect on 5-HT receptors has yet to be clarified. 11C-WAY-100635 and 18F-MPPF are positron emission tomography (PET) radioligands for 5-HT1A receptors. While binding of both ligands reflects 5-HT1A receptor density, 18F-MPPF biding may also be affected by extracellular 5-HT concentrations. This dual-tracer PET study explored the neurochemical substrates underlying antidepressant effects in patients with depression. Eleven patients with depression, including nine treated with antidepressants, and sixteen age- and sex-matched healthy subjects underwent PET scans with 11C-WAY-100635 and 18F-MPPF. Radioligand binding was determined by calculating the non-displaceable binding potential (BPND). Patients treated with antidepressants showed significantly lower 18F-MPPF BPND in neocortical regions and raphe nuclei but not in limbic regions than controls. No significant group differences in 11C-WAY-100635 BPND were found in any of the regions. Significant correlations of BPND between 11C-WAY-100635 and 18F-MPPF were observed in limbic regions and raphe nuclei of healthy controls, but no such associations were found in antidepressant-treated patients. Moreover, 18F-MPPF BPND in limbic regions was significantly correlated with the severity of depressive symptoms. These results suggest a diversity of antidepressant-induced extracellular 5-HT elevations in the limbic system among depressive patients, which is associated with the individual variability of clinical symptoms following the treatment.

DOI： 10.1093/ijnp/pyad026

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BACKGROUND: Deterioration of the oral environment is one of the risk factors for dementia. A previous study of an Alzheimer's disease (AD) model mouse suggests that tooth loss induces denervation of the mesencephalic trigeminal nucleus and neuroinflammation, possibly leading to accelerated tau dissemination from the nearby locus coeruleus (LC). OBJECTIVE: To elucidate the relevance of oral conditions and amyloid-β (Aβ) and tau pathologies in human participants. METHODS: We examined the number of remaining teeth and the biofilm-gingival interface index in 24 AD-spectrum patients and 19 age-matched healthy controls (HCs). They also underwent positron emission tomography (PET) imaging of Aβ and tau with specific radiotracers, 11C-PiB and 18F-PM-PBB3, respectively. All AD-spectrum patients were Aβ-positive, and all HCs were Aβ-negative. We analyzed the correlation between the oral parameters and radiotracer retention. RESULTS: No differences were found in oral conditions between the AD and HC groups. 11C-PiB retentions did not correlate with the oral indices in either group. In AD-spectrum patients, brain-wide, voxel-based image analysis highlighted several regions, including the LC and associated brainstem substructures, as areas where 18F-PM-PBB3 retentions negatively correlated with the remaining teeth and revealed the correlation of tau deposits in the LC (r = -0.479, p = 0.018) primarily with the hippocampal and neighboring areas. The tau deposition in none of the brain regions was associated with the periodontal status. CONCLUSIONS: Our findings with previous preclinical evidence imply that tooth loss may enhance AD tau pathogenesis, promoting tau spreading from LC to the hippocampal formation.

DOI： 10.3233/JAD-230581

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We report a 63-year-old female patient with progressive supranuclear palsy (PSP). She presented predominant postural instability and "saccadic ping-pong gaze" (SPPG). She had unprovoked falls recurrently within a year from the onset of gait disturbance. She tended to fall backward with eye closure but had no freezing of gait on examination. She showed no signs of nuchal dystonia, limb tremor, rigidity, spasticity, or ataxia. The dopaminergic response was negative. On the initial examination, her vertical eye movements were normal, but frequent macro square wave jerks and SPPG were observed. SPPG consisted of short-cycle, horizontal conjugate irregular pendular oscillations of the eye position from the midpoint with superimposed small saccades. SPPG was observed usually in the dark, not in the daylight, and with eye closure by using electrooculogram and infrared charge-coupled device imaging. One and a half years after the first examination, she was diagnosed as probable PSP with vertical supranuclear gaze palsy. SPPG was first described in patients who are unconscious by Johkura in 1998 as a "saccadic" variant of "ping-pong gaze (PPG)." PPG, short-cycle periodic alternating gaze, has been described in comatose patients since 1967. On the other hand, abnormal eye movement, which looks the same as SPPG in coma, has been described in conscious patients with PSP or spinocerebellar degeneration (SCD) in Japanese literature since 1975. However, it has been called "transient alternating saccades (TAS)." Nowadays, we believe it is more appropriate to call this abnormal eye movement "SPPG" instead of TAS. Here, we propose that PSP, a neuro-degenerative disease, should be added as one of the etiologies of SPPG. We discuss the differences between PPG/SPPG in coma and SPPG in PSP and the possible pathophysiological mechanism of SPPG in relation to cerebellar oculomotor dysfunctions.

DOI： 10.3389/fneur.2023.1100931

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INTRODUCTION: Recently, an increasing number of tau tracers have become available. There is a need to standardize quantitative tau measures across tracers, supporting a universal scale. We developed several cortical tau masks and applied them to generate a tau imaging universal scale. METHOD: One thousand forty-five participants underwent tau scans with either 18F-flortaucipir, 18F-MK6240, 18F-PI2620, 18F-PM-PBB3, 18F-GTP1, or 18F-RO948. The universal mask was generated from cognitively unimpaired amyloid beta (Aβ)- subjects and Alzheimer's disease (AD) patients with Aβ+. Four additional regional cortical masks were defined within the constraints of the universal mask. A universal scale, the CenTauRz, was constructed. RESULTS: None of the regions known to display off-target signal were included in the masks. The CenTauRz allows robust discrimination between low and high levels of tau deposits. DISCUSSION: We constructed several tau-specific cortical masks for the AD continuum and a universal standard scale designed to capture the location and degree of abnormality that can be applied across tracers and across centers. The masks are freely available at https://www.gaain.org/centaur-project.

DOI： 10.1002/dad2.12454

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Patients with progressive supranuclear palsy (PSP) frequently exhibit apathy but the neuropathological processes leading to this phenotype remain elusive. We aimed to examine the involvement of tau protein depositions, oxidative stress (OS), and neuronal loss in the apathetic manifestation of PSP. Twenty patients with PSP and twenty-three healthy controls were enrolled. Tau depositions and brain volumes were evaluated via positron-emission tomography (PET) using a specific probe, 18F-PM-PBB3, and magnetic resonance imaging, respectively. Glutathione (GSH) levels in the anterior and posterior cingulate cortices were quantified by magnetic resonance spectroscopy. Tau pathologies were observed in the subcortical and cortical structures of the patient brains. The angular gyrus exhibited a positive correlation between tau accumulations and apathy scale (AS). Although PSP cases did not show GSH level alterations compared with healthy controls, GSH levels in posterior cingulate cortex were correlated with AS and tau depositions in the angular gyrus. Marked atrophy was observed in subcortical areas, and gray matter volumes in the inferior frontal gyrus and anterior cingulate cortex were positively correlated with AS but showed no correlation with tau depositions and GSH levels. Path analysis highlighted synergistic contributions of tau pathologies and GSH reductions in the posterior cortex to AS, in parallel with associations of gray matter atrophy in the anterior cortex with AS. Apathetic phenotypes may arise from PET-visible tau aggregation and OS compromising the neural circuit resilience in the posterior cortex, along with neuronal loss, with neither PET-detectable tau pathologies nor OS in the anterior cortex.

DOI： 10.1016/j.jns.2022.120514

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Positron emission tomography (PET) with 18F-PM-PBB3 (18F-APN-1607, 18F-Florzolotau) enables high-contrast detection of tau depositions in various neurodegenerative dementias, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). A simplified method for quantifying radioligand binding in target regions is to employ the cerebellum as a reference (CB-ref) on the assumption that the cerebellum has minimal tau pathologies. This procedure is typically valid in AD, while FTLD disorders exemplified by progressive supranuclear palsy (PSP) are characterized by occasional tau accumulations in the cerebellum, hampering the application of CB-ref. The present study aimed to establish an optimal method for defining reference tissues on 18F-PM-PBB3-PET images of AD and non-AD tauopathy brains. We developed a new algorithm to extract reference voxels with a low likelihood of containing tau deposits from gray matter (GM-ref) or white matter (WM-ref) by a bimodal fit to an individual, voxel-wise histogram of the radioligand retentions and applied it to 18F-PM-PBB3-PET data obtained from age-matched 40 healthy controls (HCs) and 23 CE, 40 PSP, and five other tau-positive FTLD patients. PET images acquired at 90-110 min after injection were averaged and co-registered to corresponding magnetic resonance imaging space. Subsequently, we generated standardized uptake value ratio (SUVR) images estimated by CB-ref, GM-ref and WM-ref, respectively, and then compared the diagnostic performances. GM-ref and WM-ref covered a broad area in HCs and were free of voxels located in regions known to bear high tau burdens in AD and PSP patients. However, radioligand retentions in WM-ref exhibited age-related declines. GM-ref was unaffected by aging and provided SUVR images with higher contrast than CB-ref in FTLD patients with suspected and confirmed corticobasal degeneration. The methodology for determining reference tissues as optimized here improves the accuracy of 18F-PM-PBB3-PET measurements of tau burdens in a wide range of neurodegenerative illnesses.

DOI： 10.1016/j.neuroimage.2022.119763

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DOI： 10.1002/mds.29186

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BACKGROUND: We recently developed a positron emission tomography (PET) probe, [18 F]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed. OBJECTIVE: We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities. METHODS: Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others. RESULTS: The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively. CONCLUSIONS: These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

DOI： 10.1002/mds.29173

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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The authors regret that the title that appears in the original article is incorrect. Methods of the assessment of radiometabolites in plasma by high-performance liquid chromatography (HPLC) in the supplementary should also be corrected. The author wrote “An aliquot of the supernatant was analyzed by radio-HPLC (Analytical column: Waters XBridge OST C18 (10 × 50 mm; particle size, 2.5 μm), acetonitrile (90%; A) and ammonium acetate (0.02 M; B) were used as mobile phases (40/60 A/B) at a flow rate of 5.0 mL/min.”. This was incorrect. The correct description is “An aliquot of the supernatant was analyzed by radio-HPLC with a C18 column (Main column: Waters Atlantis T3 OBD Prep, 10 × 150 mm; particle size, 5 μm; guard column: Waters Atlantis T3, 10 × 10 mm; particle size, 5 μm), and the mixture of acetonitrile (A) and water (B) were used as mobile phases (A/B, 40/60) at a flow rate of 4.5 mL/min.” The original article has been corrected.

DOI： 10.1007/s00259-022-05795-9

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INTRODUCTION: Corticobasal degeneration (CBD) is the most common neuropathological substrate for clinically diagnosed corticobasal syndrome (CBS), while identifying CBD pathology in living individuals has been challenging. This study aimed to examine the capability of positron emission tomography (PET) to detect CBD-type tau depositions and neuropathological classification of CBS. METHODS: Sixteen CBS cases diagnosed by Cambridge's criteria and 12 cognitively healthy controls (HCs) underwent PET scans with 11C-PiB, 11C-PBB3, and 18F-FDG, along with T1-weighted magnetic resonance imaging. Amyloid positivity was assessed by visual inspection of 11C-PiB retentions. Tau positivity was judged by quantitative comparisons of 11C-PBB3 binding to HCs. RESULTS: Sixteen CBS cases consisted of two cases (13%) with amyloid and tau positivities indicative of Alzheimer's disease (AD) pathologies, 11 cases (69%) with amyloid negativity and tau positivity, and three cases (19%) with amyloid and tau negativities. Amyloid(-), tau(+) CBS cases showed increased retentions of 11C-PBB3 in the frontoparietal areas, basal ganglia, and midbrain, and reduced metabolism in the precentral gyrus and thalamus relative to HCs. The enhanced tau probe retentions in the frontal gray and white matters partially overlapped with metabolic deficits and atrophy and correlated with Clinical Dementia Rating scores. CONCLUSIONS: PET-based classification of CBS was in accordance with previous neuropathological reports on the prevalences of AD, non-AD tauopathies, and others in CBS. The current work suggests that 11C-PBB3-PET may assist the biological classification of CBS and understanding of links between CBD-type tau depositions and neuronal deteriorations leading to cognitive declines.

DOI： 10.1016/j.parkreldis.2022.04.015

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00259-021-05671-y

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Other Link： https://link.springer.com/article/10.1007/s00259-021-05671-y/fulltext.html

Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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 11C-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 11C-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 (VTs) 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 (MRTMO) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference. RESULTS: PET images with 11C-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. VT values were robustly estimated by two-tissue compartment model analysis (mean VT = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTMO and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTMO and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11C-MTP38-PET. CONCLUSION: We have provided the first demonstration of PET visualization of PDE7 in human brains. 11C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.

DOI： 10.1007/s00259-021-05235-0

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Fluctuations of neuronal activities in the brain may underlie relatively slow components of neurofunctional alterations, which can be modulated by food intake and related systemic metabolic statuses. Glutamatergic neurotransmission plays a major role in the regulation of excitatory tones in the central nervous system, although just how dietary elements contribute to the tuning of this system remains elusive. Here, we provide the first demonstration by bimodal positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) that metabotropic glutamate receptor subtype 5 (mGluR5) ligand binding and glutamate levels in human brains are dynamically altered in a manner dependent on food intake and consequent changes in plasma glucose levels. The brain-wide modulations of central mGluR5 ligand binding and glutamate levels and profound neuronal activations following systemic glucose administration were further proven by PET, MRS, and intravital two-photon microscopy, respectively, in living rodents. The present findings consistently support the notion that food-associated glucose intake is mechanistically linked to glutamatergic tones in the brain, which are translationally accessible in vivo by bimodal PET and MRS measurements in both clinical and non-clinical settings.

DOI： 10.1177/0271678X211004150

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Language：Japanese   Publisher：金原出版(株)  

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

バイオマーカーに求められる役割は、診断、経過の把握、予後や治療反応の予測など多岐にわたる。認知症の実臨床においては、治療可能な認知症の除外と大まかな背景病理に対応する状態を評価することが現状であり、具体的な背景病理の確認にはまだ限界がある。疾患修飾薬の開発ならびにこれを用いた先制治療においては、発症前を含む超早期診断と治療反応評価に寄与するバイオマーカーが重要となり、アミロイドPETは前者に、タウPETは前者および後者に寄与するものと期待される。Aβを標的とした診断・治療が現実のものとなりつつあるが、より簡便で低侵襲かつ安価なバイオマーカーの開発が期待される。(著者抄録)

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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 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of 18F-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 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.

DOI： 10.1016/j.neuron.2020.09.042

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), frequently observed in the Kii peninsula of Japan, is pathologically characterized by widespread tau pathology in the cerebrum and brainstem. Here, we report a case of Kii ALS/PDC predominantly presenting progressive parkinsonism. Tau positron emission tomography (PET) imaging with F-18-PM-PBB3 suggested tau deposition in the substantia nigra of the midbrain and subcortical areas, but not in the cerebral cortex, which was similar to progressive supranuclear palsy (PSP), suggesting that parkinsonism-predominant type of Kii ALS/PDC may have a similar area of tau deposition to PSP.

DOI： 10.1111/ncn3.12463

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Language：Japanese   Publisher：(一社)日本核医学会  

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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.

DOI： 10.1093/cercor/bhaa211

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：English   Publisher：日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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, [11C]PBB3, and an Aβ radioligand, [11C]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 [11C]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.

DOI： 10.1038/s41380-020-0766-9

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Language：English  

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.

DOI： 10.3390/ijms21124443

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

アミロイドPETやタウPETなどの神経病理イメージングは、アルツハイマー病などの変性性認知症において病理学的知見に基づいた生前診断を可能とする分子イメージング技術である。アミロイドPETは脳内局所における一定密度以上のアミロイドβ蓄積を可視化できる。タウPETは脳内のタウたんぱく病変を可視化し、集積の分布や程度は、臨床症状や重症度と関連する。疾患によりタウたんぱく病変は性状が異なり、トレーサーごとに可視化できるタウたんぱく病変の種類が異なる。神経病理イメージング技術は、神経変性疾患の疾患修飾薬開発を行う上で基盤的な技術となりつつある。(著者抄録)

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An 86-year-old man, who had undergone a lumboperitoneal shunt for idiopathic normal pressure hydrocephalus (iNPH) implanted 4 years earlier showed progressive parkinsonism for the past year. His clinical symptoms, including resting tremor and rapid eye movement sleep behavior disorder, responsiveness to levodopa, and abnormal findings on ¹²³I-meta-iodobenzylguanidine myocardial scintigraphy and dopamine transporter imaging, indicated that his pathological background of parkinsonism included concomitant synucleinopathy, such as Parkinson's disease or dementia with Lewy bodies, in addition to iNPH. Clinicians should consider the possibility of concomitant proteinopathies and their treatments when clinical symptoms become evident after shunt operations in patients with iNPH.

DOI： 10.2169/internalmedicine.4553-20

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Language：Japanese   Publisher：千葉医学会  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：千葉医学会  

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Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：(株)ワールドプランニング  

ポジトロン放出断層撮影(PET)はもとより研究用ツールとして開発され発展してきた経緯をもつが、[18F]fluorodeoxyglucose-PET(FDG-PET)などで得られた知見は今日の認知症診断に利用され、他の臨床検査にも応用されている。また近年では、アミロイドやタウといった異常蓄積タンパク質を可視化する神経病理イメージングが隆盛を迎え、さまざまなPET診断薬が開発されている。神経病理イメージングはアルツハイマー病(AD)の発症前診断を可能とする一方で、根本的治療薬のない現在、画像診断のもたらす心理的影響についても配慮する必要がある。本稿では、ADを対象とするPETを中心とした技術の発展について概説した。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J02464&link_issn=&doc_id=20200420130002&doc_link_id=%2Faj2rsizd%2F2020%2F003103%2F003%2F0227-0232%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faj2rsizd%2F2020%2F003103%2F003%2F0227-0232%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(有)科学評論社  

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Publishing type：Research paper (scientific journal)   Publisher：Open Access Text Pvt, Ltd.  

DOI： 10.15761/npc.1000211

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Neuropsychological tests, structural neuroimaging, and functional neuroimaging are employed as diagnostic and monitoring biomarkers of patients with Alzheimer's disease (AD)Objective:We aimed to elucidate the similarities and differences in neuropsychological tests and neuroimaging with the use of the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog), structural magnetic resonance image (MRI), and perfusion single photon emission computed tomography (SPECT), and parametric image analyses to understand its role in AD. METHODS: Clinically-diagnosed AD patients (n = 155) were scanned with three-dimensional T1-weighted MRI and N-isopropyl-p-[123I] iodoamphetamine SPECT. Statistical parametric mapping 12 was used for preprocessing images, statistical analyses, and voxel-based morphometry for gray matter volume analyses. Group comparison (AD versus healthy controls), multiple regression analyses with MMSE, ADAS-cog total score, and ADAS-cog subscores as variables, were performed. RESULTS: The AD group showed bilateral hippocampal volume reduction and hypoperfusion in the bilateral temporo-parietal lobe and posterior midline structures. Worse MMSE and ADAS-cog total score were associated with bilateral temporo-parietal volume loss and hypoperfusion. MMSE, but not ADAS-cog, was associated with the posterior midline structures. The ADAS-cog subscores were associated with the temporal volume, while perfusion analyses were linked to the left temporo-parietal region with the language function and right analogous region with the constructional praxis subscore. CONCLUSION: MMSE and ADAS-cog are associated with temporo-parietal regions, both in volume and perfusion. The MMSE score is associated with posterior midline structures and linked to an abnormal diagnostic AD pattern. Perfusion image analyses better represents the cognitive function in AD patients.

DOI： 10.3233/JAD-200676

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press ({OUP})  

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.

DOI： 10.1093/brain/awz238

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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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.

DOI： 10.2147/ndt.s222966

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Language：Japanese   Publisher：(株)日本医事新報社  

＜Point＞▼陽電子放射線断層撮影(PET)を用いてアミロイドやタウなどを可視化する神経病理イメージングは、アルツハイマー病などの変性性認知症において病理学的知見に基づいた生前診断を可能とする分子イメージング技術である▼アミロイドPETは脳内局所における一定密度以上のアミロイドβ蓄積を可視化できる▼タウPETは脳内のタウ蛋白病変を可視化し、集積の分布や程度は、臨床症状や重症度と関連する▼疾患によりタウ蛋白病変は性状が異なり、プローブごとに可視化できるタウ蛋白病変の種類が異なる▼神経病理イメージング技術は、神経変性疾患の疾患修飾薬開発を行う上で基盤的な技術となりつつある(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

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 [11C]PBB3 and [11C]DPA713. METHODS: Twenty patients with early AD and 20 age-matched normal control (NC) subjects underwent a series of PET measurements with [11C]PBB3 for tau aggregation and [11C]DPA713 for microglial activation (neuroinflammation). Inter- and intrasubject comparisons were performed regarding the levels of [11C]PBB3 binding potential (BPND) and [11C]DPA713 BPND in the light of cognitive functions using statistical parametric mapping (SPM) and regions of interest (ROIs) method. RESULTS: The [11C]PBB3 BPND was greater in the temporo-parietal regions of AD patents than NC subjects, and a similar increasing pattern of [11C]DPA713 BPND was observed in the same patients. Correlation analyses within the AD group showed a positive direct correlation between [11C]PBB3 BPND and [11C]DPA713 BPND in the parahippocampus. Pass analysis revealed that cognitive impairment was more likely linked to the level of the parahippocampal [11C]PBB3 BPND than that of [11C]DPA713 BPND. 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.

DOI： 10.1007/s00415-019-09400-2

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Language：Japanese   Publisher：医歯薬出版(株)  

タウ蛋白の異常凝集体からなるタウ病変は、Alzheimer病(AD)に代表されるさまざまな認知症患者の脳内に認められ、病態への深い関与が推察されている。近年、脳内タウ病変を生体内で可視化する実用的なタウPETイメージング技術が登場したことで、認知症病態の解明が急速に進みつつある。タウPETで評価をしたタウ病変は病気の症状に関連する脳領域に認められ、患者の死後脳を用いた研究で確認されているタウ病変の分布と一致している。さらに、タウPETの集積程度は認知機能障害や運動機能障害などの臨床的重症度とも相関を認めている。このことはタウPETが認知症の診断のみならず、客観的な重症度評価を行う検査としても有用である可能性を示唆している。タウPETの登場により、脳病態の理解は深化しつつある。さらに、今後登場が期待されるタウを標的とした疾患修飾薬の臨床試験においても、診断およびモニタリングバイオマーカーとして基盤的技術となることが期待される。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2019&ichushi_jid=J00060&link_issn=&doc_id=20190830020009&doc_link_id=%2Faa7ayuma%2F2019%2F027009%2F010%2F0732-0738%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2019%2F027009%2F010%2F0732-0738%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：千葉医学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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 [11 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 [11 C]PBB3 binding in widespread regions from an early disease stage. CONCLUSIONS: [11 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.

DOI： 10.1002/mds.27623

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Language：Japanese   Publisher：千葉医学会  

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<h4>Background</h4>[¹¹ 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.<h4>Objectives</h4>To explore the usefulness of [¹¹ 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.<h4>Methods</h4>We assessed 13 PSP patients and 13 age-matched healthy control subjects. Individuals negative for amyloid β PET with [¹¹ C]Pittsburgh compound B underwent clinical scoring, MR scans, and [¹¹ C]pyridinyl-butadienyl-benzothiazole 3/PET.<h4>Results</h4>There were significant differences in binding potential for [¹¹ 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. [¹¹ 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 [¹¹ 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.<h4>Conclusions</h4>Our findings support the in vivo detectability of tau fibrils characteristic of PSP by [¹¹ C]pyridinyl-butadienyl-benzothiazole 3/PET, and imply distinct and synergistic contributions of gray matter and white matte tau pathologies to clinical symptoms. [¹¹ 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.

DOI： 10.1002/mds.27643

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DOI： 10.2174/1874120701913010055

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To characterize the distribution of tau pathology in patients with amyotrophic lateral sclerosis/parkinsonism dementia complex on the Kii Peninsula (Kii ALS/PDC) by tau PET using [11C]PBB3 as ligand. METHODS: This is a cross-sectional study of 5 patients with ALS/PDC and one asymptomatic participant with a dense family history of ALS/PDC from the Kii Peninsula who took part in this study. All were men, and their age was 76 ± 8 (mean ± SD) years. Thirteen healthy men (69 ± 6 years) participated as healthy controls (HCs). Dynamic PET scans were performed following injection of [11C]PBB3, and parametric PET images were generated by voxel-by-voxel calculation of binding potential (BP* ND) using a multilinear reference tissue model. [11C] Pittsburgh compound B (PiB) PET, MRI, and cognitive tests were also performed. RESULTS: A voxel-based comparison of [11C]PBB3 BP* ND illustrated PET-detectable tau deposition in the cerebral cortex and white matter, and pontine basis including the corticospinal tract in Kii ALS/PDC patients compared with HCs (uncorrected p < 0.05). Group-wise volume of interest analysis of [11C]PBB3 BP* ND images showed increased BP* ND in the hippocampus and in frontal and parietal white matters of Kii ALS/PDC patients relative to HCs (p < 0.05, Holm-Sidak multiple comparisons test). BP* ND in frontal, temporal, and parietal gray matters correlated with Mini-Mental State Examination scores in Kii ALS/PDC patients (p < 0.05). All Kii ALS/PDC patients were negative for [11C]PiB (β-amyloid) except one with marginal positivity. CONCLUSION: [11C]PBB3 PET visualized the characteristic topography of tau pathology in Kii ALS/PDC, corresponding to clinical phenotypes of this disease.

DOI： 10.1212/WNL.0000000000006736

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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.

DOI： 10.3233/JAD-190620

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本難病医療ネットワーク学会  

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Apathy is a common neuropsychological symptom in Alzheimer's disease (AD), and previous studies demonstrated that neuronal loss and network disruption in some brain regions play pivotal roles in the pathogenesis of apathy. However, contributions of tau and amyloid-β (Aβ) depositions, pathological hallmarks of AD, to the manifestation of apathy remain elusive. METHODS: Seventeen patients with AD underwent positron emission tomography (PET) with 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) and 11C-Pittsburgh compound-B (11C-PiB) to estimate tau and Aβ accumulations using standardised uptake value ratio (SUVR) images. 11C-PBB3 and 11C-PiB SUVR were compared between AD patients with high and low Apathy Scale (AS) scores. Additionally, volumetric and diffusion tensor MRI was performed in those areas where any significant difference was observed in PET analyses. Correlation and path analyses among AS and estimated imaging parameters were also conducted. RESULTS: AD patients with high AS scores showed higher 11C-PBB3 SUVR in the orbitofrontal cortex (OFC) than those with low AS scores, while 11C-PiB SUVR in any brain regions did not differ between them. Elevated 11C-PBB3 SUVR in OFC, decreased OFC thickness and decreased fractional anisotropy (FA) in the uncinate fasciculus (UNC), which is structurally connected to OFC, correlated significantly with increased scores of the AS. Path analysis indicated that increased 11C-PBB3 SUVR in OFC affects apathy directly and through reduction of OFC thickness and subsequent decrease of FA in UNC. CONCLUSIONS: The present findings suggested that tau pathology in OFC may provoke focal neurotoxicity in OFC and the following disruption of the OFC-UNC network, leading to the emergence and progression of apathy in AD.

DOI： 10.1136/jnnp-2018-317970

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Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

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© 2018, The Author(s). Purpose: Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (11C-THK5351 and11C-PBB3) in a head-to-head, in vivo, multimodal design. Methods: Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer’s disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer’s disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers11C-THK5351 and11C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer11C-AZD2184, a T1-MRI sequence, and neuropsychological assessment. Results: The load and regional distribution of binding differed between11C-THK5351 and11C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of11C-PBB3, but not that of11C-THK5351, in the temporal lobe resembled that of11C-AZD2184, with strong correlations detected between11C-PBB3 and11C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with11C-THK5351 than with11C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with11C-THK5351 than with11C-PBB3 binding. Conclusion: This research suggests different molecular targets for these tracers; while11C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of11C-THK5351 fitted the expected distribution of tau pathology in Alzheimer’s disease better and was more closely related to downstream disease markers.

DOI： 10.1007/s00259-018-4012-5

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There is no reliable objective indicator for upper motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). To determine the clinical significance and potential utility of magnetic resonance (MR) signals, we investigated the relationship between clinical symptoms and susceptibility changes in the motor cortex measured using susceptibility-weighted MR imaging taken by readily available 3-T MRI in clinical practice. Twenty-four ALS patients and 14 control subjects underwent 3-T MR T1-weighted imaging and susceptibility-weighted MR imaging with the principles of echo-shifting with a train of observations (PRESTO) sequence. We analysed relationships between relative susceptibility changes in the motor cortex assessed using voxel-based analysis (VBA) and clinical scores, including upper motor neuron score, ALS functional rating scale revised score, and Medical Research Council sum score on physical examination. Patients with ALS exhibited significantly lower signal intensity in the precentral gyrus on susceptibility-weighted MR imaging compared with controls. Clinical scores were significantly correlated with susceptibility changes. Importantly, the extent of the susceptibility changes in the bilateral precentral gyri was significantly correlated with upper motor neuron scores. The results of our pilot study using VBA indicated that low signal intensity in motor cortex on susceptibility-weighted MR imaging may correspond to clinical symptoms, particularly upper motor neuron dysfunction. Susceptibility-weighted MR imaging may be a useful diagnostic tool as an objective indicator of upper motor neuron dysfunction.

DOI： 10.1007/s00415-017-8728-0

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© 2018 - IOS Press and the authors. All rights reserved. Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset. Objective: The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age. Methods: 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value <0.05 on cluster-level and cluster extent over 30 voxels. Results: Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart. Conclusion: Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.

DOI： 10.3233/JAD-170749

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BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset. OBJECTIVE: The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age. METHODS: 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value <0.05 on cluster-level and cluster extent over 30 voxels. RESULTS: Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart. CONCLUSION: Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.

DOI： 10.3233/JAD-170749

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IOS PRESS  

Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset.Objective: The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[C-11] methylpiperidinyl-4-acetate ([C-11] MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age.Methods: 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [C-11] MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value < 0.05 on cluster-level and cluster extent over 30 voxels.Results: Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Z(max) = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart.Conclusion: Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.

DOI： 10.3233/JAD-170749

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BACKGROUND: Type 2 diabetes mellitus (DM) has been shown to increase the risk for cognitive decline and dementia, such as Alzheimer disease (AD) and vascular dementia (VaD). In addition to AD and VaD, there may be a dementia subgroup associated with specific DM-related metabolic abnormalities rather than AD pathology or cerebrovascular disease, referred to as diabetes-related dementia (DrD). METHOD: We studied 11C-PiB and 11C-PBB3 positron emission tomography (PET) in 31 subjects with DrD and 5 subjects with AD associated with DM to assess amyloid and tau deposits in the brain. RESULTS: All subjects with AD showed both positive PiB and PBB3. However, only 12 out of 31 subjects (39%) with DrD showed positive PiB, whereas 17 out of 21 subjects (81%) who underwent PBB3 PET showed positive PBB3. Depending on the positivity of PiB and PBB3, we classified 21 subjects into a negative PiB and a positive PBB3 pattern (11 cases, 52%), indicating tauopathy, a positive PiB and a positive PBB3 pattern (6 cases, 29%), indicating AD pathology, or a negative PiB and a negative PBB3 pattern (4 cases, 19%). Among 11 subjects showing a negative PiB and a positive PBB3 pattern, there were 2 PBB3 deposit patterns, including the medial temporal lobe only and extensive neocortex beyond the medial temporal lobe. CONCLUSION: DrD showed variable amyloid and tau accumulation patterns in the brain. DrD may be associated predominantly with tau pathology, in addition to AD pathology and non-amyloid/non-tau neuronal damage due to DM-related metabolic abnormalities.

DOI： 10.2174/1567205015666180709113338

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press ({OUP})  

<h4>Background</h4>The norepinephrine transporter in the brain has been targeted in the treatment of psychiatric disorders. Duloxetine is a serotonin and norepinephrine reuptake inhibitor that has been widely used for the treatment of depression. However, the relationship between dose and plasma concentration of duloxetine and norepinephrine transporter occupancy in the human brain has not been determined. In this study, we examined norepinephrine transporter occupancy by different doses of duloxetine.<h4>Methods</h4>We calculated norepinephrine transporter occupancies from 2 positron emission tomography scans using (S,S)-[18F]FMeNER-D2 before and after a single oral dose of duloxetine (20 mg, n = 3; 40 mg, n = 3; 60 mg, n =2). Positron emission tomography scans were performed from 120 to 180 minutes after an i.v. bolus injection of (S,S)-[18F]FMeNER-D2. Venous blood samples were taken to measure the plasma concentration of duloxetine just before and after the second positron emission tomography scan.<h4>Results</h4>Norepinephrine transporter occupancy by duloxetine was 29.7% at 20 mg, 30.5% at 40 mg, and 40.0% at 60 mg. The estimated dose of duloxetine inducing 50% norepinephrine transporter occupancy was 76.8 mg, and the estimated plasma drug concentration inducing 50% norepinephrine transporter occupancy was 58.0 ng/mL.<h4>Conclusions</h4>Norepinephrine transporter occupancy by clinical doses of duloxetine was approximately 30% to 40% in human brain as estimated using positron emission tomography with (S,S)-[18F]FMeNER-D2.

DOI： 10.1093/ijnp/pyx069

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) is an endemic disease observed in the Kii peninsula, Guam, and Papua. We report a case of a 76-year old man with ALS/PDC of the Kii peninsula of Japan (Kii ALS/PDC). The patient was born and grew up in the Kii peninsula. He moved out at age three, and developed symptoms 73 years later. He showed pyramidal sign, parkinsonian symptoms, and mildly impaired cognitive function. I-131-metaiodobenzylguanidine myocardial scintigraphy showed decreased cardiac sympathetic nerve function, and dopamine transporter single photon emission computed tomography imaging showed decreased I-123-N-omega-fluoropropy1-2 beta-carbomethoxy3 beta-(4-iodo phenyl) nortropane accumulation. Cerebral blood flow showed hypoperfusion. Positron emission tomography showed widespread tau deposition in his brain. This is a migration case of Kii ALS/PDC with the shortest stay in the endemic area and the longest delay to develop the disease, indicating a genetic factor for the disease development in a considerable degree. (C) 2017 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jocn.2017.08.057

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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The central dopaminergic system is of major importance in the pathophysiology of Parkinson's disease, schizophrenia, and other neuropsychiatric disorders. In the present study, the normative data of dopaminergic neurotransmission functions in the midbrain, consisting of neuromelanin, dopamine synthesis, dopamine transporters and dopamine D₂ receptors, were constructed using magnetic resonance (MR) imaging and positron emission tomography (PET). PET studies with L-[β-¹¹C]DOPA, [¹⁸F]FE-PE2I and [¹¹C]FLB457 and MRI studies were performed on healthy young men. Neuromelanin accumulation measured by MRI was compared with dopaminergic functions, dopamine synthesis capacity, dopamine transporter binding and dopamine D₂ receptor binding measured by PET in the substantia nigra. Although neuromelanin is synthesized from DOPA and dopamine in dopaminergic neurons, neuromelanin accumulation did not correlate with dopamine synthesis capacity in young healthy subjects. The role of dopamine transporters in the substantia nigra is considered to be the transport of dopamine into neurons, and therefore dopamine transporter binding might be related to neuromelanin accumulation; however, no significant correlation was observed between them. A positive correlation between dopamine D₂ receptor binding and neuromelanin accumulation was observed, indicating a feedback mechanism by dopaminergic autoreceptors. Discrepancies in regional distribution between neuromelanin accumulation and dopamine synthesis capacity, dopamine transporter binding or dopamine D₂ receptor binding were observed in the substantia nigra.

DOI： 10.1016/j.neuroimage.2017.06.066

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Language：English   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.biopsych.2017.02.676

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Language：English   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.biopsych.2017.02.796

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc  

Introduction Amyloid-β (Aβ) and tau accumulations may occur independently and concurrently as exemplified by primary age-related tauopathy and Alzheimer's disease (AD), respectively. Interactions between Aβ and tau accumulations and their influence on clinical features, however, are still unclear. Methods Associations among clinical symptoms, gray-matter volume, regional tau, and Aβ deposition assessed by positron emission tomography with [11C]pyridinyl-butadienyl-benzothiazole 3 (PBB3) and [11C]Pittsburgh compound-B (PiB), were evaluated in 17 AD, 9 mild cognitive impairment due to AD, and 28 PiB(−)-cognitive healthy controls (HCs). Results High tau burden was associated with aging and low-level education in PiB(−)-HC and AD-spectrum groups, and with high Aβ burden and low-level education in all subjects. It was not Aβ but tau accumulation that showed significant associations with cognitive performance even in PiB(−)-HC. Discussion The present study indicated aging and low-level education after Aβ would be enhancers for tau pathology, associated with neurodegeneration and cognitive impairment in healthy and diseased elderly individuals.

DOI： 10.1016/j.dadm.2016.12.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

High non-specific uptake of [C-11]Pittsburgh compound B ([C-11]PiB) in white matter and signal spillover from white matter, due to partial volume effects, confound radioactivity measured in positron emission tomography (PET) with [C-11]PiB. We aimed to reveal the partial volume effect in absolute values of kinetic parameters for [C-11]PiB, in terms of spillover from white matter. Dynamic data acquired in [C-11]PiB PET scans with five healthy volunteers and eight patients with Alzheimer's disease were corrected with region-based and voxel-based partial volume corrections. Binding potential (BPND) was estimated using the two-tissue compartment model analysis with a plasma input function. Partial volume corrections significantly decreased cortical BPND values. The degree of decrease in healthy volunteers (-52.7 +/- 5.8%) was larger than that in Alzheimer's disease patients (-11.9 +/- 4.2%). The simulation demonstrated that white matter spillover signals due to the partial volume effect resulted in an overestimation of cortical BPND, with a greater degree of overestimation for lower BPND values. Thus, an overestimation due to partial volume effects is more severe in healthy volunteers than in Alzheimer's disease patients. Partial volume corrections may be useful for accurately quantifying A beta deposition in cortical regions. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license.

DOI： 10.1016/j.neuroimage.2016.09.028

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1002/gps.4385

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

The loss of dopaminergic (DA) neurons in the substantia nigra (SN) is a major pathophysiological feature of patients with Parkinson's disease (PD). As nigral DA neurons contain both neuromelanin (NM) and dopamine transporter (DAT), decreased intensities in both NM-sensitive MRI and DAT PET reflect decreased DA neuronal density. This study demonstrates that a more specific metric for the nigral DA neuronal density can be derived with multimodal MRI and PET. Participants were 11 clinically diagnosed PD patients and 10 age and gender matched healthy controls (HCs). Two quantities, the NM-related index (R-NM) and the binding potential of the radiotracer [F-18] FE-PE2I to DAT (BPND) in SN, were measured for each subject using MRI and PET, respectively. Principal component analysis (PCA) was applied to the multimodal data set to estimate principal components. One of the components, PCP, corresponds to a basis vector oriented in a direction where both BPND and R-NM increase. The ability of BPND, R-NM and PCP to discriminate between HC and PD groups was compared. Correlation analyses between the motor score of the unified Parkinson's disease rating scale and each metric were also performed. PCP, BPND and R-NM for PD patients were significantly lower than those for HCs (F = 16.26, P&lt;0.001; F = 6.05, P = 0.008; F = 7.31, P = 0.034, respectively). The differential diagnostic performance between the HC and PD groups as assessed by the area under the receiver-operating characteristic curve was best for PCP (0.94, 95% CI: 0.66-1.00). A significant negative correlation was found between the motor severity score and PCp (R = -0.70, P&lt;0.001) and R-NM (R = -0.52, P = 0.015), but not for BPND (R = -0.36, P = 0.110). PCA of multimodal NM-sensitive MRI and DAT PET data provides a metric for nigral DA neuronal density that will help illuminate the pathophysiology of PD in SN. Further studies are required to explore whether PCA is useful for other parkinsonian syndromes.

DOI： 10.1371/journal.pone.0151191

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER HEIDELBERG  

Background: Quantitative in vivo imaging of tau pathologies potentially improves diagnostic accuracy of neurodegenerative tauopathies and would facilitate evaluation of disease-modifying drugs targeting tau lesions in these diseases. Tau pathology can be quantified by reference tissue models without arterial blood sampling when reference tissue devoid of target binding sites is available. The cerebellar cortex has been used as a reference region in analyses of tau positron emission tomography (PET) data in Alzheimer's disease (AD). However, in a significant subset of tauopathies such as progressive supranuclear palsy and corticobasal degeneration, tau accumulation may occur in diverse brain regions including the cerebellar cortex. This hampers selection of a distinctive reference region lacking binding sites for a tau PET ligand. The purpose of this study was to develop a new method to quantify specific binding of a PET radioligand, C-11-PBB3, to tau deposits using reference voxels extracted from cortical gray matter, which have a low likelihood of containing tau accumulations.
Methods: We reanalyzed C-11-PBB3 PET data of seven mild AD patients (ADs) and seven elderly healthy control subjects (HCs) acquired in a previous study. As a standard method, parametric images of binding potential (BPND*) were initially generated using reference tissue manually defined on the cerebellar cortex. We then constructed a frequency histogram of BPND* values in these parametric images and selected cortical gray matter voxels contained in a certain range of the histogram with a low likelihood of having C-11-PBB3 binding sites. Finally, these reference voxels were used for generating new BPND* parametric images.
Results: Reference tissue voxels defined by the histogram analysis spread throughout the cortical gray matter of AD and HC brains. The BPND* values determined by our new method correlated very well with those estimated by the standard method (r(2) = 0.94), although the binding estimates by the current method were slightly higher by similar to 0.14 than those by the standard method.
Conclusions: We developed and validated a new method enabling quantification of tau lesions that can accumulate in the cerebellum and other extensive brain areas. This method may be applicable to all tauopathy subtypes and various tau PET ligands besides C-11-PBB3.

DOI： 10.1186/s13550-016-0182-y

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Language：Japanese   Publisher：The Japanese Society of Medical Imaging Technology  

On the clinical management of neurodegenerative dementia including Alzheimer's disease (AD), molecular imaging using positron emission topography (PET), which makes it possible to detect in vivo pathological modification in the brain, have been developed. While amyloid PET imaging implies an important role for diagnosis of AD, tau PET imaging also would be useful as a biomarker to diagnose tauopathies including non-AD dementia as well as to evaluate disease severity.

DOI： 10.11409/mit.34.22

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Other Link： http://search.jamas.or.jp/link/ui/2016310922

Language：Japanese   Publisher：(一社)日本神経学会  

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Copyright © 2015 John Wiley & Sons, Ltd. Objective To investigate the diagnostic performance of brain acetylcholinesterase (AChE) activity measurement using N-[11C]-methyl-4-piperidyl acetate (MP4A) and PET in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Methods Participants were 14 DLB patients, 25 AD patients and 18 age-matched healthy controls (HC). All subjects underwent PET scans and MP4A to measure regional brain AChE activity. We performed anatomical standardization of each brain image, and k3 values, an index of AChE activity, in each voxel were estimated by nonlinear least squares analysis. Volumes of interest (VOIs) were identified on parametric k3 images in frontal, temporal, parietal and occipital cortices, and in anterior and posterior cingulate gyri (ACG and PCG). In each VOI, the differential diagnostic performance between AD and DLB of k3 values was assessed by area under the curve (AUC) of the receiver-operating characteristic. Voxel-based statistical analyses were also performed. Results Mean cortical AChE activities in AD patients (-8.2% compared with normal mean) and DLB patients (-27.8%) were lower than HCs (p-<-0.05, p-<-0.001, respectively). There was a significant difference in mean cortical AChE activities between AD and DLB patients (p-<-0.001). All regional brain AChE activities of defined VOIs except ACG were able to well discriminate DLB from AD, and notably performance was the most significant in PCG (AUC-=-0.989, 95% CI: 0.965-1.000). Conclusions Brain cholinergic deficit is consistently prominent in DLB compared with AD. PET measurement of brain AChE activity may be useful for the differential diagnosis between DLB and AD.

DOI： 10.1002/gps.4338

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Language：Japanese   Publisher：(株)中外医学社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NUCLEAR MEDICINE INC  

Tau accumulation in the brain is a pathologic hallmark of Alzheimer disease and other tauopathies. Quantitative visualization of tau pathology in humans can be a powerful method as a diagnostic aid and for monitoring potential therapeutic interventions. We established methods of PET quantification of tau pathology with C-11-PBB3 (2-((1E,3E)-4-(6-(C-11-methylamino)pyridin-3-yl)buta-1,3-dienyl) benzo[d]thiazol-6-ol), considering its radiometabolite entering the brain. Methods: Seven Alzheimer disease patients and 7 healthy subjects underwent dynamic 11C-PBB3 PET scanning. Arterial blood was sampled to obtain the parent and metabolite input functions. Quantification of C-11-PBB3 binding was performed using dual-input models that take the brain metabolite activity into consideration, traditional single-input models without such considerations, and the reference tissue model (MRTMO) and standardized uptake value ratio (SUVR). The cerebellar cortex was used as the reference tissue for all methods. Results: The dual-input graphical models estimated binding parameter (BPND*) stably (similar to 0.36 in high-binding regions). The MRTMO BPND* matched the corresponding BPND* by the dual-input graphical model (r(2) = 1.00). SUVR minus 1 correlated well with MRTMO BPND* (r(2) &gt; 0.97). However, BPND by the single-input models did not correlate with BPND* by the dual-input graphical model (r(2) = 0.04). Conclusion: The dual-input graphical model BPND* is consistent with the reference tissue BPND* and SUVR-1, suggesting that these parameters can accurately quantify binding of C-11-PBB3 despite the entry of its radiometabolites into the brain.

DOI： 10.2967/jnumed.115.160127

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Other Link： http://orcid.org/0000-0002-7927-9483

Language：Japanese   Publisher：(一社)日本核医学会  

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<h4>Unlabelled</h4>Alzheimer disease is the cause of up to one-third of cases of primary progressive aphasia or corticobasal syndrome. The primary objective of this study was to determine the accuracy of 18F-FDG PET metabolic imaging for the detection of Alzheimer disease in patients with primary progressive aphasia or corticobasal syndrome.<h4>Methods</h4>A cohort of patients (n=94), including those with an expert clinical diagnosis of logopenic (n=19), nonfluent (n=16), or semantic (n=13) variants of primary progressive aphasia, corticobasal syndrome (n=14), or Alzheimer disease (n=24), underwent 18F-FDG metabolic and 11C-labeled Pittsburgh compound B (11C-PiB) amyloid PET brain imaging. 18F-FDG PET scans interpreted with Neurostat and 3D-SSP displays were classified as revealing Alzheimer disease or "other" by interpreters who were unaware of the clinical assessments and 11C-PiB PET results. 11C-PiB PET imaging was considered to be the diagnostic reference standard, with a threshold standardized uptake value ratio of 1.5 being indicative of Alzheimer disease pathology. To address possible bias from subgroup selection for the Alzheimer disease binary classifier, we calculated both conventional and balanced accuracies.<h4>Results</h4>Diagnoses of Alzheimer disease based on 18F-FDG PET resulted in 84% accuracy (both conventional and balanced). In comparison, diagnoses based on clinical assessments resulted in 65% conventional accuracy and 67% balanced accuracy.<h4>Conclusion</h4>Brain 18F-FDG PET scans interpreted with Neurostat and 3D-SSP displays accurately detected Alzheimer disease in patients with primary progressive aphasia or corticobasal syndrome as focal-onset dementias. In such diagnostically challenging cohorts, (18)F-FDG PET imaging can provide more accurate diagnoses, enabling more appropriate therapy.

DOI： 10.2967/jnumed.115.161067

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publishing type：Research paper (scientific journal)  

To study distribution and patterns of nerve hypertrophy in chronic inflammatory demyelinating polyneuropathy (CIDP), magnetic resonance neurography with 3-dimensional reconstruction of short tau inversion recovery images was performed in 33 patients. This technique clearly showed longitudinal morphological changes from the cervical roots to the nerve trunks in the proximal arm. Nerve enlargement was detected in 88% of the patients. According to the clinical subtype of CIDP, typical CIDP patients showed symmetric and root-dominant hypertrophy, whereas Lewis-Sumner syndrome patients had multifocal fusiform hypertrophy in the nerve trunks. The patterns of nerve hypertrophy presumably reflect the different pathophysiology of each CIDP subtype.

DOI： 10.1002/ana.24314

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BENTHAM SCIENCE PUBL LTD  

C-11-Pittsburgh compound B (PiB) uptake in PET images is frequently used to analyze beta amyloid (A beta) deposition in living individuals, but its correlation with histologically determined A beta has not been examined. Six individuals with dementia underwent PiB-PET imaging, and their brains were analyzed neuropathologically (mean interval between imaging and death: 816 days; PiB positive: negative, 3: 3; male: female, 3: 3; mean age: 84.0 years). PiB uptake (reported as standardized uptake value ratio [SUVR]) was analyzed in 11 cortical regions and 10 subcortical grey matter areas and compared with the A beta load (% area [the percentage of total area positive for A beta] and number of neuritic plaques) seen with immunohistochemical staining with an anti-A beta 11-28 antibody. Two PiB-positive subjects had abundant neuritic plaques and were diagnosed with Alzheimer's disease (AD). SUVR and % area were strongly correlated in the cortical regions of these subjects (subject 1: r = 0.65, p = 0.03; subject 2: r = 0.80, p = 0.003). The other PiB-positive subject (subject 3) showed focal PiB uptake. In subject 3 and the 3 PiB-negative subjects (subjects 4-6), there was no correlation between regional SUVR and % area or neuritic plaques. PiB uptake was not correlated with A beta deposition in subcortical regions. High PiB positivity in the cerebral cortex suggests the presence of substantial A beta deposition and neuritic plaques associated with the pathologic changes of AD. Our results suggest that high cortical SUVR is a reliable marker of AD. Subcortical PiB positivity must be interpreted more carefully.

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(株)インナービジョン  

精神疾患においては、統合失調症や気分変調症などで、それぞれ脳内でのドーパミン、セロトニンなどの神経伝達の変調がその病態にかかわる可能性が示されてきており、その解明や治療薬の開発、治療薬の調節方法が進んでいる。一方、神経変性疾患では、病態に密接に関与する異常蓄積タンパクの解明が進み、家族性に発症する変性疾患においては、例えばアルツハイマー病(以下、AD)ではアミロイドβタンパク(amiroidβ:Aβ)の異常凝集が老人斑として病態に関与しているが、その前駆体であるβアミロイド前駆体タンパク(amyloid precursor protein:APP)をコードする遺伝子の異常など、原因遺伝子レベルまで解明が進んでいる。経時的に異常タンパク蓄積の分布、程度、影響を見ていくことは、病態の解明、さらには治療法の開発、治療効果判定などに重要であるが、特に中枢神経系では存命時の病理学的な検索は侵襲性が高く、死後脳などの検索が主となるため客観的評価が難しい。分子イメージングにより、神経伝達物質の受容体やトランスポーターの分布・密度・動的な推移を評価することと、異常タンパクの蓄積を画像化することで、さらなる病態解明や治療ターゲットの選定が可能となりうる。前者は、受容体へ結合した治療薬の受容体占有率などを評価することで、個人ごとに薬効を認め、かつ副作用のない至適投与量を決めるテーラーメイド医療の実現にも寄与する可能性がある。後者は、臨床症状の発現に先行する異常タンパクの蓄積を評価することで超早期診断を実現し、さらには近年開発が進められている、異常タンパク蓄積を抑える治療薬などの治療効果判定にも重要な役割を担うことが期待される。本稿では、精神・神経疾患における分子イメージング研究の現状と、今後期待される臨床への展開について述べる。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NUCLEAR MEDICINE INC  

Characteristic neuropathologic changes in Alzheimer disease (AD) are amyloid-p deposits and neurofibrillary tangles. Recently, a new radioligand for amyloid senile plaques, C-11-labeled 5-(6-{[tertbutyl(dimethyl)sily]oxy}-1,3-benzothiazol-2-yl)pyridin-2-amine (C-11-AZD2184), was developed, and it was reported to show rapid brain uptake followed by rapid washout. In this study, C-11-AZD2184 binding in control subjects and AD patients was examined in more detail by compartment model analysis using a metabolite-corrected arterial input function. The accuracy of simplified quantitative methods using a reference brain region was also evaluated. Methods: After intravenous bolus injection of C-11-AZD2184, a dynamic PET scan was obtained for 90 min in 6 control subjects and 8 AD patients. To obtain the arterial input function, arterial blood sampling and high-performance liquid chromatography analysis were performed. Results: Time activity curves in all brain regions could be described using the standard 2-tissue-compartment model. The total distribution volume ratios to reference region (DVR) in cerebral cortical regions were significantly higher in AD patients than in control subjects. Although there was no conspicuous accumulation of radioactivity in white matter as compared with other amyloid radioligands, DVR values in the centrum semiovale were more than 1 for both control subjects and AD patients, suggesting binding to myelin. The standardized uptake value ratio calculated from integrated time activity curves in brain regions and the reference region was statistically in good agreement with DVR. Conclusion: Although the white matter binding of C-11-AZD2184 may have some effect on cortical measurement, it can be concluded that the kinetic behavior of C-11-AZD2184 is suitable for quantitative analysis. The standardized uptake value ratio can be used as a validated measure of C-11-AZD2184 binding in clinical examinations without arterial input function.

DOI： 10.2967/jnumed.113.133793

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Other Link： http://orcid.org/0000-0002-7927-9483

Language：English   Publishing type：Research paper (scientific journal)  

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Characteristic neuropathologic changes in Alzheimer disease (AD) are amyloid-β deposits and neurofibrillary tangles. Recently, a new radioligand for amyloid senile plaques, (11)C-labeled 5-(6-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzothiazol-2-yl)pyridin-2-amine ((11)C-AZD2184), was developed, and it was reported to show rapid brain uptake followed by rapid washout. In this study, (11)C-AZD2184 binding in control subjects and AD patients was examined in more detail by compartment model analysis using a metabolite-corrected arterial input function. The accuracy of simplified quantitative methods using a reference brain region was also evaluated.After intravenous bolus injection of (11)C-AZD2184, a dynamic PET scan was obtained for 90 min in 6 control subjects and 8 AD patients. To obtain the arterial input function, arterial blood sampling and high-performance liquid chromatography analysis were performed.Time-activity curves in all brain regions could be described using the standard 2-tissue-compartment model. The total distribution volume ratios to reference region (DVR) in cerebral cortical regions were significantly higher in AD patients than in control subjects. Although there

DOI： 10.2967/jnumed.113.133793

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Purpose The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The F-18-labeled amyloid tracer, [F-18]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1,3-benzoxazol-6-yl)oxy]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [C-11]Pittsburgh compound B (PIB) and [F-18]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared.
Methods Two PET scans, one of each with [C-11]PIB and [F-18]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation.
Results No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [F-18]FACT studies without partial volume correction, while significant differences were observed in [C-11]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [F-18]FACT studies as well as [C-11]PIB. Relatively lower uptakes of [C-11]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [F-18]FACT. Relatively higher uptake of [C-11]PIB in distribution was observed in the frontal and parietal cortices.
Conclusion Since [F-18]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [C-11]PIB and [F-18]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic and histochemical assays of postmortem AD brain sections.

DOI： 10.1007/s00259-013-2620-7

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OBJECTIVE: Neuropsychiatric symptoms affect many patients with Alzheimer's disease (AD). ((11)C)Pittsburgh Compound-B (PIB) positron emission tomography (PET) has enabled the in vivo visualisation of brain amyloid-β (Aβ) deposition. This study exploratively investigated the correlation between brain Aβ deposition measured by ((11)C)PIB PET and neuropsychiatric symptoms in AD. METHODS: Participants were 28 patients (15 women, 13 men) with PIB-positive AD. Clinical assessments included Mini-Mental State Examination, Clinical Dementia Rating scale, neuropsychiatry inventory (NPI) and frontal assessment battery. All patients underwent three-dimensional T1-weighted MRI and ((11)C)PIB PET. The distribution volume ratio (DVR), an index of ((11)C)PIB retention and, thus, Aβ deposition, was estimated voxel by voxel from ((11)C)PIB PET data with partial volume correction. Voxel-based correlation analysis was performed to assess the relationships between DVR and each NPI subscale. Additionally, voxel-based analysis of covariance (ANCOVA) of the DVR images was performed between Patients with AD with and without each neuropsychiatric symptom. Voxel-based morphometry analysis of MRI was also performed. RESULTS: Apathy subscale was correlated with ((11)C)PIB retention in the bilateral frontal and right anterior cingulate. ((11)C)PIB retention was greater in the bilateral frontal cortex of patients with AD with apathy than those of without apathy. Overlapping areas between the two analyses were the bilateral orbitofrontal gyrus and left superior frontal gyrus. Other NPI subscales were not correlated with ((11)C)PIB retention. Voxel-based morphometry analysis of MRI showed no significant cluster of correlation between grey matter volume and NPI subscales. CONCLUSIONS: This study revealed that prefrontal Aβ deposition correlates with apathy.

DOI： 10.1136/jnnp-2013-306110

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Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹⁸F]FMeNER-D₂ to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED₅₀) and concentration (EC₅₀) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

DOI： 10.1017/S1461145713001521

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Nowadays, abnormally aggregated proteins which have pivotal role in the pathology of neurodegenerative dementia, such as amyloid β, hyperphosphorylated tau, α-synuclein and so on, have been become major targets of molecular neuroimaging as well as disease modifying treatment for dementia. All the amyloid-targeted agents have so far ended with disappointing results and have failed to bring about any delay in the disease progression; however, it has been shown that amyloid imaging demonstrates strong concordant with histopathology for brain amyloid β, and is useful for therapeutic drug monitoring as well as an appropriate recruitment of participants to clinical trial monitoring. Furthermore, a number of novel and practical PET ligands for tau imaging have also been developed recently. Some basic and clinical evidences suggest that tau-targeting drug might bring about delay in the disease progression for tau-mediated neurodegenerative dementia, and therefore it is expected that tau imaging would promote establishing disease modifying treatments for dementia. The aim of this article is to present the current situation of molecular imaging research in dementia, and to further discuss the application possibility of the molecular imaging to innovative drug development.

DOI： 10.5692/clinicalneurol.54.1174

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Purpose: [C-11]FLB 457, a radioligand with very high affinity and selectivity for dopamine D-2/3 receptors, is used to measure receptor binding in extrastriatal regions showing low density of the receptors. The purpose of this study was to estimate the whole-body biodistribution of radioactivity and the radiation absorbed doses to organs after intravenous injection of [C-11]FLB 457 in healthy human subjects.
Methods: Whole-body images were acquired for 2 h after an injection of [C-11]FLB 457 in six healthy humans. Radiation absorbed doses were estimated by the MIRD scheme implemented in OLINDA/EXM 1.1 software.
Results: Organs with the longest residence time were the liver, lungs, and brain. The organs with the highest radiation doses were the kidneys, liver, and pancreas. The effective dose delivered by [C-11]FLB 457 is 5.9 mu Sv/MBq, similar to those of other C-11-labeled tracers.
Conclusions: This effective dose would allow multiple scans in the same individual based on prevailing maximum recommended-dose guidelines in the USA and Europe. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.nucmedbio.2013.08.008

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

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

DOI： 10.1016/j.neuron.2013.07.037

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported &gt;80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [C-11]DASB and (S,S)-[F-18]FMeNER-D-2, in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED50 was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.

DOI： 10.1017/S1461145712001009

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The aim of this study was to investigate whether amyloid deposition is associated with Alzheimer's disease (AD)-like cortical atrophy in Lewy body (LB) disease (LBD). Participants included 15 LBD with dementia patients (8 with dementia with Lewy bodies [DLB] and 7 with Parkinson's disease [PD] with dementia [PDD]), 13 AD patients, and 17 healthy controls. Age, gender, and Mini-Mental State Examination scores were matched between patient groups. All subjects underwent PET scans with [(11)C]Pittsburgh Compound B to measure brain amyloid deposition as well as three-dimensional T1-weighted MRI. Gray-matter volumes (GMVs) were estimated by voxel-based morphometry. Volumes-of-interest analyses were also performed. Forty percent of the 15 DLB/PDD patients were amyloid positive, whereas all AD patients and none of the healthy controls were amyloid positive. Amyloid-positive DLB/PDD and AD patients showed very similar patterns of cortical atrophy in the parahippocampal area and lateral temporal and parietal cortices, with 95.2% of cortical atrophy distribution being overlapped. In contrast, amyloid-negative DLB/PDD patients had no significant cortical atrophy. Compared to healthy controls, parahippocampal GMVs were reduced by 26% in both the amyloid-positive DLB/PDD and AD groups and by 10% in the amyloid-negative DLB/PDD group. The results suggest that amyloid deposition is associated with AD-like atrophy in DLB/PDD patients. Early intervention against amyloid may prevent or delay AD-like atrophy in DLB/PDD patients with amyloid deposition.

DOI： 10.1002/mds.25286

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Language：Japanese   Publisher：公益社団法人 日本薬学会  

DOI： 10.14894/faruawpsj.49.7_650

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Background: Recently, we reported an information density theory and an analysis of three-parameter plus shorter scan than conventional method (3P+) for the amyloid-binding ligand [11C]Pittsburgh compound B (PIB) as an example of a non-highly reversible positron emission tomography (PET) ligand. This article describes an extension of 3P + analysis to noninvasive '3P++' analysis (3P + plus use of a reference tissue for input function). Methods: In 3P++ analysis for [11C]PIB, the cerebellum was used as a reference tissue (negligible specific binding). Fifteen healthy subjects (NC) and fifteen Alzheimer's disease (AD) patients participated. The k3 (index of receptor density) values were estimated with 40-min PET data and three-parameter reference tissue model and were compared with that in 40-min 3P + analysis as well as standard 90-min four-parameter (4P) analysis with arterial input function. Simulation studies were performed to explain k3 biases observed in 3P++ analysis. Results: Good model fits of 40-min PET data were observed in both reference and target regions-of-interest (ROIs). High linear intra-subject (inter-15 ROI) correlations of k3 between 3P++ (Y-axis) and 3P + (X-axis) analyses were shown in one NC (r2 = 0.972 and slope = 0.845) and in one AD (r2 = 0.982, slope = 0.655), whereas inter-subject k3 correlations in a target region (left lateral temporal cortex) from 30 subjects (15 NC + 15 AD) were somewhat lower (r2 = 0.739 and slope = 0.461). Similar results were shown between 3P++ and 4P analyses: r2 = 0.953 for intra-subject k3 in NC, r2 = 0.907 for that in AD and r2 = 0.711 for inter-30 subject k3. Simulation studies showed that such lower inter-subject k3 correlations and significant negative k3 biases were not due to unstableness of 3P++ analysis but rather to inter-subject variation of both k2 (index of brain-to-blood transport) and k3 (not completely negligible) in the reference region. Conclusions: In [11C]PIB, the applicability of 3P++ analysis may be restricted to intra-subject comparison such as follow-up studies. The 3P++ method itself is thought to be robust and may be more applicable to other non-highly reversible PET ligands with ideal reference tissue. © 2013 Sato et al.

DOI： 10.1186/2191-219X-3-76

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Language：English   Publishing type：Part of collection (book)   Publisher：Elsevier Inc.  

Recent functional imaging studies with neuropsychological measures suggest that several brain regions, which are related to dopamine (DA) neurotransmission, would be included among candidates of the major neural underpinnings of affective and cognitive functions such as pleasure and reward processing. Furthermore, evidence suggests the association of the pathophysiologies of neuropsychiatric illnesses such as schizophrenia and Parkinson's disease with the dysregulation of DA-related neurotransmission in these brain regions. Positron emission tomography (PET) is a non-invasive in-vivo imaging tool for measuring DA neurotransmission. We hereby review the evidence of human D1R function, focusing on its associations with cognitive functions including working memory, emotional processing and decision-making, as well as the pathologies of psychiatric illnesses, while introducing our D1R PET imaging studies. Although D1R dysfunction would not always be regarded as a direct cause of the disorders, that is to say, it would not be disease-specific, it might be related to the pathophysiologies by influencing cognitive functions of the individuals. In this sense, the evidence in D1R dysfunction might provide a new insight into the mechanisms of the symptoms of neuropsychiatric disorders and lead to the development of new ways of their dimensional classifications. © 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/B978-0-12-418677-4.00008-7

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Language：Japanese   Publisher：(一社)日本神経学会  

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Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported &gt;80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupa

DOI： 10.1017/s1461145712001009

DOI： 10.1017/S1461145712001009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D-2 receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D-2 receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D-2 receptors have reported inconsistent results regarding regional differences of dopamine D-2 receptor occupancy by aripiprazole.
To test the hypothesis of preferential binding to extrastriatal dopamine D-2 receptors by aripiprazole, we investigated its regional dopamine D-2 receptor occupancies in healthy young subjects.
Using PET and two radioligands with different affinities for dopamine D-2 receptors, [C-11]raclopride and [C-11]FLB457, striatal and extrastriatal dopamine D-2 receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects.
Our data showed that dopamine D-2 receptor occupancies in the striatum measured with [C-11]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [C-11]FLB457 ranging from 46.6% to 58.4%.
In the present study, preferential extrastriatal dopamine D-2 receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D-2 receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole.

DOI： 10.1007/s00213-011-2633-5

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Language：English   Publisher：WILEY-BLACKWELL  

Diagnosis and treatment strategies for dementia are based on the sensitive and specific detection of the incipient neuropathological characteristics, combined with emerging treatments that counteract molecular processes in its pathogenesis. Positron emission tomography (PET) is used for diverse clinical and basic studies on dementia with a wide range of radiotracers. Approaches to visualize amyloid deposition in human brains non-invasively with PET depend on imaging agents reacting with amyloid fibrils. The most widely used tracer is [11C]-6-OH-BTA-1, also known as Pittsburgh Compound-B, which has a high affinity to amyloid beta peptide (A beta) aggregates. Some 18F-labeled amyloid ligands with a longer radioactive half-life have also been developed for broader clinical applications. In addition, there have been demonstrated advantages of tracers with high specific radioactivity in the sensitive detection of amyloid, which have indicated the significance of A beta-N3-pyroglutamate as a new diagnostic and therapeutic target. Furthermore, beneficial outcomes of A beta and tau immunization in humans and mouse models have highlighted crucial roles of immunocompetent glia in the protection of neurons against amyloid toxicities. The utility of PET with a radioligand for translocator protein as a biomarker for tau-triggered toxicity, and as a complement to amyloid and tau imaging for diagnostic assessment of tauopathies with and without A beta pathologies, has also been demonstrated. Meanwhile, brain cholinergic function can be estimated by measuring acetylcholinesterase activity in the brain with PET and radiolabeled acetylcholine analogues. It has been reported that patients with early Parkinson's disease exhibit a reduction in acetylcholinesterase activity in the cerebral cortex, and this decline is more profound in patients with Parkinson's disease with dementia and dementia with Lewy bodies than in patients with Parkinson's disease without dementia. The Alzheimer's Disease Neuroimaging Initiative was a multicentre research project conducted over 6 years that studied changes in cognition, brain structure, and biomarkers in healthy elderly controls and subjects with mild cognitive impairment and Alzheimer's disease. An international workgroup of the National Institute on Aging-Alzheimer's Association has suggested that Alzheimer's disease would be optimally treated before significant cognitive impairment, defined as a presymptomatic or preclinical stage. Therefore, PET will be of technical importance for both clinical and basic research aimed at prodromal pathologies of Alzheimer's disease.

DOI： 10.1111/j.1479-8301.2012.00409.x

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Long dynamic scans (60-120 min) are often required for estimating the k(3) value, an index of receptor density, by positron emission tomography (PET). However, the precision of k(3) is usually low in kinetic analyses for reversible PET ligands compared with irreversible ligands. That is largely due to unstable estimation of the dissociation rate constant, k(4). We propose a novel '3P+' method for estimating k(3) of moderately reversible ligands, where a 3-parameter model without k(4) is applied to early-phase PET data to obtain a good model-fit of k(3) estimation. By using [(11)C] Pittsburgh compound B (PIB) (k(4) = 0.018/min) as an example of a moderately reversible ligand, the 3P+ method simulation with a 28 min PET scan yielded less than 3% k(3) relative bias with a +100% k(3) change. In [(11)C]PIB PET scans of 15 normal controls (NC) and nine patients with Alzheimer's disease (AD), the 3P+ method provided a precise k(3) estimate (mean SE of 13.6% in parietal cortex; covariance matrix method). The results revealed linear correlations (r = 0.964) of parietal k(3) values in 24 subjects between 28minute 3P+ method and conventional 90 minute 4-parameter method. A good separation of k(3) between NC and AD groups (P < 0.001; t-test) was replicated in 28 minute 3P+ method. The short-scan 3P+ method may be a practical alternative method for analyzing reversible ligands.

DOI： 10.1016/j.neuroimage.2011.10.087

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Language：Japanese   Publisher：千葉医学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D₂ receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D₂ receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D₂ receptors have reported inconsistent results regarding regional differences of dopamine D₂ receptor occupancy by aripiprazole.To test the hypothesis of preferential binding to extrastriatal dopamine D₂ receptors by aripiprazole, we investigated its regional dopamine D₂ receptor occupancies in healthy young subjects.Using PET and two radioligands with different affinities for dopamine D₂ receptors, [¹¹C]raclopride and [¹¹C]FLB457, striatal and extrastriatal dopamine D₂ receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy

DOI： 10.1007/s00213-011-2633-5

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

Both presynaptic and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET). While both presynaptic and postsynaptic dopaminergic functions would be regulated by corresponding genes and related to personality traits, the relation between presynaptic and postsynaptic functions in terms of interindividual variation has hardly been investigated. In the present study, both striatal dopamine D(2) receptor binding and endogenous dopamine synthesis rate were measured in the same healthy subjects using PET with [(11)C]raclopride and L-[beta-(11)C]DOPA, respectively, and these two parameters were compared. Two PET studies with [(11)C] raclopride and L-[beta-(11)C] DOPA were performed sequentially at rest condition on 14 healthy men. For [(11)C] raclopride PET, the binding potential was calculated by the reference tissue model method. For L-[beta-(11)C]DOPAPET, the endogenous dopamine synthesis rate was estimated by graphical analysis. A significant negative correlation was observed between the binding potential of dopamine D(2) receptors and endogenous dopamine synthesis rate (r = -0.66, p &lt; 0.05). Although the interindividual variation of binding potential of [(11)C] raclopride would be due to both the interindividual difference in the receptor density and that in the concentration of endogenous dopamine in the synaptic cleft, the negative correlation between parameters for both presynaptic and postsynaptic functions might indicate a compensative relation between the two functions.

DOI： 10.1523/JNEUROSCI.6024-10.2011

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In conventional pharmacological research in the field of mental disorders, pharmacological effect and dose have been estimated by ethological approach and in vitro data of affinity to the site of action. In addition, the frequency of administration has been estimated from drug kinetics in blood. However, there is a problem regarding an objective index of drug effects in the living body. Furthermore, the possibility that the concentration of drug in blood does not necessarily reflect the drug kinetics in target organs has been pointed out. Positron emission tomography (PET) techniques have made progress for more than 20 years, and made it possible to measure the distribution and kinetics of small molecule components in living brain. In this article, we focused on rational drug dosing using receptor occupancy and proof-of-concept of drugs in the drug development process using PET.

DOI： 10.9758/cpn.2011.9.1.9

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本自律神経学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：English   Publisher：日本神経化学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Background: Microglial activation and disrupted neurotransmissions may herald symptomatic manifestations in neurodegenerative tauopathies.
Methods: We investigated microglial activation with [(11)C]DAA1106 positron emission tomography (PET), striatal dopaminergic function with L-[beta-(11)C]dopa PET, acetylcholinesterase (AChE) activity with [(11)C]N-methylpiperidin-4-yl acetate PET, and morphologic brain changes with MRI in three persons (aged 38-41 years) with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), who were presymptomatic gene carriers (PGCs) from an American kindred with pallidopontonigral degeneration. The results from these 3 PGCs were compared with [(11)C]DAA1106 PET results from age-matched 9 healthy volunteers (HV), and with L-[beta-(11)C]dopa and [(11)C]MP4A PET results from 10 HV. Values considered significant were more than 2 SDs greater or less than the normal control mean, as the number of subjects was small for group comparisons.
Results: Glial activities were increased in the frontal cortex of one PGC, the occipital cortex of two PGCs, and the posterior cingulate cortex of one PGC, although none of the PGCs showed overt glial activation in the brain. Only one of the PGCs showed reduced AChE activity in the temporo-parietal cortex. Three PGCs showed low dopamine synthesis rates in the putamen. Hippocampal atrophy was observed in two PGCs.
Conclusions: Hippocampal atrophy and striatal dopaminergic dysfunction may be early disease processes in the pathogenesis of FTDP-17. Neuroinflammation may also be an in vivo signature of tau pathology at a prodromal stage, although current PET techniques may not constantly reveal it as the earliest neuroimaging abnormality. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.parkreldis.2010.04.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [(11)C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6 +/- 5.9 years), 12 with progressive supranuclear palsy (68.5 +/- 4.1 years), eight with frontotemporal dementia (59.8 +/- 6.9 years) and 16 healthy controls (61.2 +/- 8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k(3) value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k(3) images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k(3) images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k(3) values) in the paracentral region, frontal, parietal and occipital cortices (P &lt; 0.05, cluster corrected). The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P &lt; 0.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P &lt; 0.001), 9.4% in progressive supranuclear palsy (P &lt; 0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P &lt; 0.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy.

DOI： 10.1093/brain/awq120

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Language：Japanese   Publisher：認知神経科学会  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objectives: Estimate the value of in vivo plasma IC50 of donepezil, the concentration of donepezil in plasma that inhibits brain acetylcholinesterase (AChE) activity by 50% at the steady-state conditions of donepezil between the plasma and the brain.
Methods: N-[C-11] methylpiperidin-4-yl acetate ([C-11]MP4A) positron emission tomography was performed in 16 patients with probable Alzheimer disease (AD) before and during the treatment of donepezil (5 mg/day) with a mean interval of 5.3 months. The plasma IC50 value of donepezil was estimated from plasma donepezil concentrations and cerebral cortical mean AChE inhibition rates measured by positron emission tomography, using one-parameter model.
Results: Donepezil reduced AChE activity uniformly in the cerebral cortex compared with the baseline in each AD patient, and the mean reduction rate in the cerebral cortex was 34.6%. The donepezil concentrations in the plasma ranged from 18.5 to 43.9 ng/mL with a mean of 28.9 +/- 7.3 ng/mL. The plasma IC50 value was estimated to be 53.6 +/- 4.0 ng/mL.
Conclusions: Once the plasma IC50 of donepezil is determined, the brain AChE inhibition rate could be estimated from the plasma concentration of donepezil in each subject based on the plasma IC50. Now that the mean donepezil concentrations in the plasma, when the patients took 5 mg/day, remained 28.9 ng/mL, approximately half of the plasma IC50, higher dose of donepezil might provide further benefits for patients with AD. This technique can be also applied to measure the in vivo plasma IC50 of other cholinesterase inhibitors such as rivastigmine and galantamine.

DOI： 10.1097/WNF.0b013e3181c71be9

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Background: Pure autonomic failure (PAF) is a selective peripheral disorder in which Lewy bodies form within the autonomic ganglia. Patients with this disorder usually have no central lesions; however, chronic autonomic failure may secondarily affect the central nervous system. This study evaluated brain perfusion in patients with PAF by using N-isopropyl-p-123I iodoamphetamine (123I-IMP) single photon emission computed tomography (SPECT). Methods: Six patients with PAF (all men; mean (SD) age 68±5 years) who had experienced autonomic symptoms for more than 5 years and six age-matched healthy control subjects (all men; mean (SD) age 67±5 years) were included in this study. The regions of interest (ROI) on spacially normalized 123I-IMP SPECT images were automatically computed for both groups. Results: Perfusion of the dorsal anterior cingulate cortex was decreased in the PAF group compared with the healthy control group (0.93 vs 1.01; p<0.001). In the other brain regions measured, there was no significant difference in regional perfusion between the two groups. Conclusions: The dorsal anterior cingulate cortex is poorly perfused andmay be functionally altered in patients with PAF. The reduced perfusion in such individuals may be a secondary change that results from chronic autonomic failure.

DOI： 10.1136/jnnp.2008.152678

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Language：Japanese   Publisher：(一社)日本認知症学会  

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OBJECTIVE: To characterize brain cholinergic deficits in Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB). METHODS: Participants included 18 patients with PD, 21 patients with PDD/DLB, and 26 healthy controls. The PD group consisted of nine patients with early PD, each with a disease duration of less than 3 years, five of whom were de novo PD patients, and nine patients with advanced PD, each with a disease duration greater than or equal to 3 years. The PDD/DLB group consisted of 10 patients with PDD and 11 patients with DLB. All subjects underwent PET scans with N-[C]-methyl-4-piperidyl acetate to measure brain acetylcholinesterase (AChE) activity. Brain AChE activity levels were estimated voxel-by-voxel in a three-compartment analysis using the arterial input function, and compared among our subject groups through both voxel-based analysis using the statistical parametric mapping software SPM5 and volume-of-interest analysis. RESULTS: Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = -12%) (false discovery rate-corrected p value <0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = -27%) (p < 0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced. CONCLUSIONS: Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies. © 2009 AAN Enterprises, Inc.

DOI： 10.1212/WNL.0b013e3181ab2b58

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本脳循環代謝学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

A subgroup of limbic encephalitis is associated with antibodies against voltage-gated potassium channels (VGKC), and responds well to immuno-modulating therapies. Anti-VGKC antibodies are also found in Isaacs' syndrome and Morvan's syndrome, both of which are sometimes complicated by thymoma. We describe a 52-years-old man with limbic encephalitis, thymoma, and anti-VGKC antibodies, who presented with autonomic dysfunctions such as severe intestinal pseudo-obstruction, hyperhidrosis and hypertension. Thymectomy and corticosteroid therapy remarkably improved his symptoms. Brain magnetic resonance imaging showed hypothalamic lesions, in addition to the bilateral involvement of the medial temporal lobes. This patient had severe autonomic dysfunctions resembling those of Morvan's syndrome. This case may represent a subgroup of VGKC-antibody associated syndromes with a wide spectrum of symptoms, including Isaacs' syndrome, Morvan's syndrome, and limbic encephalitis. (C) 2008 Published by Elsevier B.V.

DOI： 10.1016/j.jns.2007.12.019

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J02615&link_issn=&doc_id=20231208290021&doc_link_id=10.15082%2Fjsnt.40.4_516&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.40.4_516&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J02615&link_issn=&doc_id=20230825280022&doc_link_id=10.15082%2Fjsnt.40.3_259&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.40.3_259&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：日本メジフィジックス(株)  

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Language：Japanese   Publisher：(一社)日本内科学会  

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本認知症学会  

J-GLOBAL

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本脳循環代謝学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J02615&link_issn=&doc_id=20221114240031&doc_link_id=10.15082%2Fjsnt.39.6_S118&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.39.6_S118&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J02615&link_issn=&doc_id=20221114240088&doc_link_id=10.15082%2Fjsnt.39.6_S175&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.39.6_S175&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)Neuroscience Laboratory Japan  

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Language：Japanese   Publisher：日本早期認知症学会  

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J02615&link_issn=&doc_id=20230120480033&doc_link_id=10.15082%2Fjsnt.39.4_598&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.39.4_598&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(株)ワールドプランニング  

レビー小体型認知症(DLB)においては、脳内にα-シヌクレインの異常凝集体がみられることが病理学的特徴であるが、しばしばアルツハイマー病(AD)でみられるアミロイドβ(Aβ)やタウタンパクの蓄積も認められる。近年、脳内異常蓄積タンパクの生体イメージング技術開発の進歩は著しく、Aβとタウタンパクについては、すでに実用的な可視化技術を用いた多くの知見が得られている。シヌクレインイメージングの実現にはさまざまな課題があるものの、着実に技術開発が進んでいる。(著者抄録)

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：Japanese   Publisher：新潟県医師会  

アルツハイマー病やパーキンソン病などに代表される神経変性疾患では、どのような脳内環境異常が引き起こされているのか、また脳病態イメージングによる可視化標的はどこにあるのかについて概説した。さらに、脳病態イメージングの中でも脳内異常蛋白を可視化するアミロイドイメージングならびにタウイメージングに焦点をあて、筆者の研究成果および国際的な研究動向を紹介した。

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Language：Japanese   Publisher：(株)自然科学社  

アルツハイマー病(AD)の臨床診断において各種画像バイオマーカーが果たす役割は大きい。CTやMRIによる形態学的な評価で海馬周囲の脳萎縮がみられることや、脳血流SPECTやFDG PETで特徴的な脳循環代謝の変化がみられることは広く周知された知見である。さらに統計画像解析技術の発達は、専門医のみならず非専門医においてもこれらの画像バイオマーカーを活用することを容易にした。一方、これらの画像バイオマーカーを利用するにあたっては、その感度・特異度に関わる問題点や画像所見の意義をよく理解することが重要である。近年、ADの特徴的な脳病理であるアミロイドβやタウ病変を可視化する神経病理イメージング技術の発達も目覚ましく、ADを中心とする認知症病態の理解は大きく深化した。新規治療薬の臨床試験においても、すでにさまざまな形で神経病理イメージング技術は活用されており、創薬分野において欠かすことのできない基盤的な技術となってきている。(著者抄録)

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Language：Japanese   Publisher：(一社)日本神経学会  

日本神経学会では,脳神経内科領域の研究・教育・診療,特に研究の方向性や学会としてのあるべき姿について審議し,水澤代表理事が中心となり国などに対して提言を行うために作成委員*が選ばれ,2013年に「脳神経疾患克服に向けた研究推進の提言」が作成された.2014年に将来構想委員会が設立され,これらの事業が継続.今回将来構想委員会で,2020年から2021年の最新の提言が作成された.本稿で,総論部分1)脳神経疾患とは,2)脳神経疾患克服研究の現状,3)脳神経疾患克服研究の意義・必要性,4)神経疾患克服に向けた研究推進体制,5)脳・神経・筋疾患克服へのロードマップ,6)提言の要約版を報告する.(著者抄録)

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Language：Japanese   Publisher：放射線診療研究会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J02615&link_issn=&doc_id=20211126190111&doc_link_id=10.15082%2Fjsnt.38.6_S198&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.38.6_S198&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(株)南江堂  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00974&link_issn=&doc_id=20210824060071&doc_link_id=10.15106%2Fj_naika128_604&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_naika128_604&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本脳循環代謝学会  

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Language：Japanese   Publisher：金原出版(株)  

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Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：(公社)日本放射線技術学会  

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Language：Japanese   Publisher：(株)ワールドプランニング  

今回のプレナリーセッションでは、バイオマーカーと混合病理をテーマとした症例検討を行った。近年、臨床診断基準にもバイオマーカーに関する記載が含まれるようになってきており、臨床医もバイオマーカーに関する正確な知識をもつことが求められる。第1症例は、臨床診断を行う際にバイオマーカーを活用するうえでのピットフォールを学ぶために示唆的な症例であった。また第2症例は、脳病態や臨床診断は経時的に変化しうることを学び、さらには動的に変化する病態を評価するうえでのバイオマーカーの有用性を考察するために教育的な症例であった。本プレナリーセッションが参加者のスキルアップと明日のよりよい認知症診療の実現に少しでも寄与できたのであれば、オーガナイザーとして望外の喜びである。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J02464&link_issn=&doc_id=20200302110003&doc_link_id=%2Faj2rsizd%2F2020%2F0031s1%2F004%2F0022-0035%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faj2rsizd%2F2020%2F0031s1%2F004%2F0022-0035%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)ワールドプランニング  

現在の認知症診療において画像バイオマーカーが臨床診断に果たす役割は大きく、認知症診療に従事するすべての医師に画像検査に関する正確な理解が求められる。近年の画像研究の進歩により脳病態の詳細な評価が可能になってきたが、一方でその意義の解釈はますます複雑となってきている。各検査の感度や特異度とそれを規定する要因について習熟することで、精緻な病態理解に基づくよりよい日常診療の実現につながるものと期待したい。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J02464&link_issn=&doc_id=20200302110001&doc_link_id=%2Faj2rsizd%2F2020%2F0031s1%2F002%2F0008-0013%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faj2rsizd%2F2020%2F0031s1%2F002%2F0008-0013%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：日本早期認知症学会  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：千葉医学会  

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

頭部外傷は受傷直後に明らかな神経障害を認めなかった場合でも、数年から数十年の後に認知症、うつ、パーキンソン症状などの精神神経障害を発症するリスク要因となる。軽度の外傷でも反復した受傷が慢性外傷性脳症のリスクとなるほか、重度の外傷では単発の受傷でも頭部外傷後精神障害を発症するリスクとなり得る。頭部外傷を避けることが最も肝要であるが、コンタクトスポーツの競技者では反復した頭部外傷が慢性外傷性脳症の発症リスクを高めるため、早期診断法の確立と予防・治療法の確立、ならびに競技者を守るための啓発活動と社会的合意形成に基づくルール作りを進めることが重要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本内科学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2018&ichushi_jid=J01552&link_issn=&doc_id=20181214110010&doc_link_id=%2Fao1clphd%2F2018%2F004712%2F010%2F1397-1402%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fao1clphd%2F2018%2F004712%2F010%2F1397-1402%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：English   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：エーザイ(株)  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本早期認知症学会  

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Language：Japanese   Publisher：日本早期認知症学会  

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Language：English   Publisher：東京医科大学医学会  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本未病学会  

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Language：Japanese   Publisher：南江堂  

近年実用的な技術が開発されたタウPETは,多くの変性性認知症の脳内に認められるタウ病変を生体内で可視化する画像検査である.すでに複数のタウPET用薬剤が研究利用されており,検査の感度・特異度・汎用性を高めるための新たな薬剤開発も進んでいる.脳内タウ病変は神経障害に密接に関与していることが示されつつあり,タウPETは客観的な重症度評価の指標として,さらに認知症の進行抑制を目的とした新規認知症治療薬開発における薬効評価の指標として,重要な役割を担うものと期待されている.近未来の認知症診療において,タウPETは認知症の早期鑑別診断に寄与するのみならず,認知症進行抑制薬使用におけるコンパニオン診断薬としての役割が期待される.(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2017338848

Language：Japanese   Publisher：[千葉核医学研究会]  

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：English   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

DOI： 10.1016/j.neuroimage.2017.04.042

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：Japanese   Publisher：(公社)日本アイソトープ協会  

わが国では高齢化に伴い認知症患者数が増加している。最も頻度の高い認知症はアルツハイマー病(AD)で、ADの主要な病理所見は、1)アミロイドβ(Aβ)の凝集体である老人斑、2)過剰燐酸タウ蛋白質(TP)の凝集した神経原線維変化の蓄積、3)神経細胞死、である。Aβは主にADで見られるが、TPはADの他に進行性核上麻痺、大脳皮質基底核症候群などでも見られ、神経障害に密接に関与すると考えられ、画像診断ならびに治療の重要な標的と認識されつつある。タウイメージング(TI)用PETリガンド開発の現状、TIの実際、期待される近未来の認知症診断展望について概説した。

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：南江堂  

パーキンソン病はドパミン神経系以外にもさまざまな神経系が障害される"多系統障害症"とでも称すべき疾患である.アセチルコリン神経系は,注意力,集中力,記憶などに関与し,パーキンソン病においても病初期から障害を認める.アセチルコリン神経系の障害は,パーキンソン病の認識機能障害や幻視の発現と密接に関与し,認知症を呈する症例ではアルツハイマー病以上に重度の障害を認める.パーキンソン病においても,とくに認知症を伴う症例においては,しばしばアルツハイマー病でみられるようなアミロイドβや過剰リン酸化タウ蛋白の脳内蓄積を認める.アミロイドβやタウ蛋白病変を伴うパーキンソン病においては,アルツハイマー病に酷似する傍海馬領域などの脳萎縮を認め,近時記憶障害も顕著である.(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2016309848

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：English   Publisher：(一社)日本神経精神薬理学会  

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Language：Japanese   Publisher：ワールドプランニング  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：Japanese   Publisher：群馬県核医学研究会  

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Other Link： http://search.jamas.or.jp/link/ui/2016211679

Language：Japanese   Publisher：エーザイ(株)  

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Language：Japanese   Publisher：(株)朝日新聞社  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2016&ichushi_jid=J02615&link_issn=&doc_id=20160926310036&doc_link_id=%2Fcq3neuro%2F2016%2F003302%2F038%2F0185-0185%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcq3neuro%2F2016%2F003302%2F038%2F0185-0185%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)ライフメディコム  

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Language：Japanese   Publisher：(公社)日本医学放射線学会  

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Language：Japanese   Publisher：Japan Society for Higher Brain Dysfunction  

&amp;ensp;&amp;ensp;Traumatic brain injury (TBI) can cause delayed-onset neurocognitive dysfunctions including such as chronic traumatic encephalopathy (CTE) and psychotic disorder following TBI (PDFTBI) . Initially, CTE was called punch-drunk syndrome since only athletes exposed to recurrent concussions in high-impact sports such as boxing were believed to develop such symptoms. However, it has been revealed that CTE can occur in the wider population including American football players, wrestlers, ice-hockey players and military persons. Pathologically, CTE is characterized by abnormal accumulations of tau proteins and less apparent amyloid-beta proteins, and definitive diagnosis of CTE can be made only at autopsy and no reli able biomarkers of CTE are available. PDFTBI is schizophrenia-like psychosis, which typically occurs several years after single severe TBI. About 3.4-8.9% of single-severe TBI patients develop PDFTBI in later life, and mean onset time after TBI is about 5 years. This temporal interval between onset of psychosis and time of head injury indicates that a neurodegeneration is involved in development of PDFTBI. Al though clinical subtypes associated these post-TBI syndromes are different, evidence suggest that single-severe and mild-repetitive TBI share similar neuropathological features. In this review, we discuss clinical characteristics of CTE and PDFTBI. Next, we describe how novel neuroimaging methods to detect tau and amyloid pathology improve diagnosis and prevention of post-TBI syndromes. Recent development of tau-selective radioligand such as［&lt;sup&gt;11&lt;/sup&gt;C］PBB3 may be a powerful tool to detect tau pathology in the living brain of TBI patients.

DOI： 10.2496/hbfr.35.276

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Language：Japanese   Publisher：(一社)日本脳循環代謝学会  

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Other Link： http://search.jamas.or.jp/link/ui/2015400138

Language：Japanese   Publisher：(一社)日本神経治療学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Language：Japanese   Publisher：診断と治療社  

＜Headline＞1 PETイメージングにより、ADの中核病理であるAβとタウ蛋白蓄積を画像化することができる。2 アミロイドイメージングのAβ蓄積評価は、AD診断のバイオマーカとして有用である。3 タウイメージングのタウ蛋白蓄積評価は、重症度の評価や鑑別診断の一助となりうる。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2015321420

Language：Japanese   Publisher：[千葉核医学研究会]  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SOC NUCLEAR MEDICINE INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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