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No.1001193 【演題名】 Brain metabolic correlates of tau accumulation in progressive supranuclear palsy 【演題名(英文)】 Brain metabolic correlates of tau accumulation in progressive supranuclear palsy 【著者】 古川彰吾1,2， 平野茂樹1,2， 島田斉1， 篠遠仁1,3， 佐原成彦1， 遠藤浩信1， 北村総一朗1， 丹羽文 俊1， 高畑圭輔1， 木村泰之1， 山田真希子1,4， 張明栄5， 伊藤浩6,7， 樋口真人1， 桑原聡2， 須原 哲也1 【著者(英文)】 Shogo Furukawa1,2， Shigeki Hirano1,2， Hitoshi Shimada1， Hitoshi Shinotoh1,3， Naruhiko Sahara1， Hironobu Endo1， Soichiro Kitamura1， Fumitoshi Niwa1， Keisuke Takahata1， Yasuyuki Kimura1， Makiko Yamada1,4， Ming-rong Zhang5， Hiroshi Ito6,7， Makoto Higuchi1， Satoshi Kuwabara2， Tetsuya Suhara1 【所属】 1放射線医学総合研究所分子神経イメージング研究プログラム， 2千葉大学大学院医学研究院神経内科 学， 3神経内科千葉， 4科学技術振興機構 さきがけ， 5放射線医学総合研究所 分子認識研究プログラ ム， 6放射線医学総合研究所 先端生体計測研究プログラム， 7福島県立医科大学 先端臨床研究セン ター 【所属(英文)】 1Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences， 2Department of Neurology, Graduate School of Medicine, Chiba University， 3Neurology Chiba Clinic， 4Precursory Research for Embryonic Science and Technology, Japan Science and Technology， 5Molecular Probe Program,Molecular Imaging Center, National Institute of Radiological Sciences， 6Biophysics Program,Molecular Imaging Center, National Institute of Radiological Sciences， 7Advanced Clinical Research Center, Fukushima Medical University Objectives To elucidate brain regions which is associated with cortical tau loads in progressive supranuclear palsy (PSP) patients by [11C]PBB and [18F]FDG PET. Methods: Ten PSP patients [age: 70.2 (8.1),3 females, disease duration 4.6 (3.4) year, mean (SD)] were enrolled in the present study. We performed [11C] PBB3 PET and [18F] FDG PET. Cortical tau load was calculated by standardized uptake value ratio (SUVR) of [11C] PBB3 PET image using the cerebellar cortex as reference region. Regional cerebral glucose metabolism was calculated by SUVR of [18F] FDG PET image and were analyzed by statistical parametric mapping (spm8) with global normalization. Multiple regression whole brain analysis was performed with cortical tau load as a covariate. Statistical threshold was determined as P < 0.005 uncorrected, extent threshold 160 voxels. Results: Negative correlation between cortical tau load and regional cerebral glucose metabolism was detected in right anterior thalamus (Zmax = 3.45, voxel size 203).Positive correlation between cortical tau load and regional cerebral glucose metabolism was found in left paracentral lobule (Zmax = 4.39, voxel size 502) and right inferior parietal lobe (Zmax = 3.20, voxel size 225). Conclusions: Cortical tau load may explain thalamic dysfunction in PSP patients., 第56回日本神経学会学術大会

Backgrounds: Chronic traumatic encephalopathy (CTE) is a delayed-onset neurodegenerative disease, which occurs several years after traumatic brain injury (TBI). Pathologically, CTE is characterized by abnormal accumulations including tau changes, amyloid-beta proteins. Using a novel tau ligand [11C]PBB3 and amyloid ligand [11C]PIB, we explored in vivo imaging of tau and amyloid pathology in TBI patients. Methods: Three patients with repetitive mild TBI (2 wrestlers, 1 kick boxer), two patients with single severe TBI (1 diffuse axonal injury, 1 acute subdural hematoma) and 20 age-matched healthy controls (HCs) underwent MRI and PET scans using [11C]PBB3 and [11C]PIB. For each PET data, standardized uptake value ratio (SUVR) using cerebellum as a reference region was calculated. Amyloid deposition was evaluated by visual assessment of SUVR images of [11C]PIB PET. Tau deposition was evaluated by visual assessment and VOI analysis of SUVR images of [11C]PBB3 PET. Cognitive impairments were also evaluated with neuropsychological tests. Results: In HCs, none was [11C]PBB3- or [11C]PIB-positive. In TBI patients, memory impairment was the most frequent symptom. All TBI patients were [11C]PIB-negative, indicating absence of amyloid beta deposition. In contrast, four of five TBI patients showed high [11C]PBB3 binding in the medial temporal cortex. High [11C]PBB3 binding was also observed in the insular and the frontal cortex. Some of these [11C]PBB3-binding regions exhibited local cortical atrophy. Cortical atrophy was present in some of these regions. Conclusions: These preliminary findings provided the evidence of TBI-induced tau pathology consistent with postmortem studies., Annual Meeting of Society of Biological Psychiatry

Objective: [11C]PBB3 has been recently introduced as a tau imaging PET ligand that has high affinity and selectivity for tau deposits. The aim of the present study is to investigate distribution of tau-pathology in progressive supranuclar palsy (PSP) and corticobasal degeneration (CBD) by [11C]PBB3 PET. Methods: Twelve patients with PSP, 8 patients with corticobasal syndrome (CBS), and 25 age-matched healthy controls (HCs) participated in this study. Seventeen patients with Alzheimer’s disease (AD) also took part in as disease control. Sequential PET scans were performed for 70 min following intravenous injection of [11C]PBB3. Standardized uptake value ratio (SUVR) at 30-50 min was calculated using the cerebellar cortex as reference region. Cerebral beta-amyloid depositions were estimated using [11C]Pittsburgh compound B PET. Results: All patients and HCs were PIB-negative except one patient with CBS and 4 HCs. SPM analysis showed high [11C]PBB3 binding in globus pallidus, putamen, thalamus, midbrain, pons, and peri-rolandic areas in PSP patients compared with 21 HCs. Seven PIB-negative CBS patients showed high [11C]PBB3 binding in peri-rolandic areas, supplementary motor area, and midbrain compared with 21 HCs. One PIB-positive patient with CBS showed high [11C]PBB3 binding in the whole cerebral cortex including limbic cortex like AD patients. Conclusion: The distribution of [11C]PBB3 binding in the patients was mostly in agreement with the known distribution of tau pathology in PSP and CBD, suggesting that [11C]PBB3-PET may be useful for the diagnosis of these disorders and therapeutic monitoring of anti-tau therapy., 12th International conference on Alzheimer’s disease and Parkinson’s disease and related neurological disorders

Background and aims: Fibrillary tau pathology is considered to be a promising target for imaging and therapy in Alzheimer’s disease (AD) and non-AD tauopathies such as progressive supuranuclear palsy (PSP), corticobasal syndrome (CBS) and frontotemporal dementia (FTD). [11C]PBB3 is a novel tau imaging PET ligand, which could visualize the tau deposition in AD and non-AD tauopathies. The aim of this study is to investigate the diagnostic utility and the clinical significance of tau PET imaging with [11C]PBB3. Methods: Participants were 16 mild cognitive impairments (MCI) patients, 21 AD patients, ten PSP patients, nine CBS patients, four FTD patients, and 34 healthy controls (HCs). We performed PET scans with [11C]PBB3, [11C]PIB and [18F]FDG PET and MRI scans. Standardized uptake value ratio was calculated for PET images using the cerebellar cortex as reference region. In a subset of patients, lumber puncture was also performed to measure levels of cerebrospinal fluid (CSF) tau proteins. We assessed diagnostic utilities of each PET by area under the curve (AUC) of the receiver-operating characteristic. Results: Ten of 16 MCI patients, 20 of 21 AD patients, one of nine CBS patient, one FTD patient, and three of 34 HCs were PIB-positive. Regional distribution of [11C] PBB3 retention relative to HCs was different among patient groups, and was associated with neurological symptoms characteristic of each disease. [11C]PBB3-PET discriminated between MCI and AD (AUC = 0•990; 95% CI, 0•964-1•000) and between HC and MCI (0•981; 0•941-1•000). [11C]PBB3 binding correlated well with cognitive dysfunctions, but not with CSF tau. Conclusions: [11C]PBB3-PET enables differentiation of patients with MCI from those with AD and HCs, and provide objective indices reflecting the disease severity. Furthermore, [11C]PBB3 PET is helpful to visualize specific distribution patterns of tau pathology associated with each neurological manifestation in a variety of non-AD tauopathies., Human Amyloid Imaging 2015

頭部外傷によって引き起こされる症状は、出現時期によって、(1)意識障害や知覚•運動障害などの急性期に生じる症状、(2)失語、記銘力障害、遂行機能障害などの亜急性期に顕在化する高次脳機能障害、(3)精神病症状、抑うつ、認知症などの受傷後、数ヶ月から数年後の期間を経て出現する遅発性の症状に分けられる(DeKosky et al., 2013)。特に、最近のトピックとなっているのが慢性外傷性脳症(Chronic Traumatic Encephalopathy, CTE)である。CTEは、頭部外傷から数年後に抑うつ、人格変化などの精神症状、記銘力低下、注意障害などの認知機能障害、パーキンソニズムや筋力低下などの運動症状が出現する進行性の病態である。神経病理学的には、神経原線維変化が出現することが特徴であり、アルツハイマー病やピック病と同様に、CTEもタウオパチーの一員であると考えられている。 頭部に打撃が繰り返されることにより、進行性の精神神経症状が遅発性に出現することは、20世紀初頭から報告がなされており、パンチドランク(Martland, 1928)やボクサー脳症(Millspaugh, 1937)の名で知られてきた。当初、CTEはボクシングのように頭部に強い打撃が繰り返される職業のみに生じると考えられてきたが、近年の調査では、従来考えられてきたよりもはるかに多く存在する可能性が示唆されている。米国では、引退後に自殺した米著名なアスリートが、生前にCTEを発症していたことが剖検により判明したことや、元選手による集団訴訟が起きたことが、センセーショナルに報道されたことにより、社会で大きな注目を浴びるようになった。現時点でCTEの治療法は存在せず、スポーツ選手においては早期に発見し、頭部への打撃を回避することが重要であるが、生前診断法は確立されていない。 近年、アミロイドβなどの脳内に蓄積する異常タンパク質に対する特異的プローブが開発され、病理変化を非侵襲的にイメージングする技術が飛躍的に進歩した。放医研は、タウ選択的なプローブである [11C]PBB3を開発し、世界に先駆けて人の脳内に沈着したタウ蛋白病変を明瞭に画像化することに成功した(Maruyama et al., 2013)。現在、我々は、[11C]PBB3によるPETを用い、頭部外傷患者におけるタウとアミロイド病理と症候との関係を明らかにするための研究を行っている。頭部外傷患者のタウ病理を非侵襲的に可視化することができれば、CTEの生前診断に大きく寄与すると期待される。 頭部外傷による遅発性の精神障害は、CTEだけでなく、頭部外傷後精神病性障害(PDFTBI)がある。PDFTBIは、頭部外傷から平均4〜5年後に妄想、幻覚などの精神病症状が出現する病態である(大東、2009)。外傷から数年のインターバルをもって出現し、しばしば進行して荒廃状態に陥るケースが存在することは、何らかの変性過程の存在を示唆するが、病態は不明である。PDFTBIのうちの一定数はCTEに該当すると予想され、両者の関係についても考察する。, 第38回 日本高次脳機能障害学会にて発表

Background and aims: [11C]PBB3 has been recently developed as a tau imaging PET ligand that has high affinity and selectivity for tau deposits in the preclinical studies. Our initial PET study with [11C]PBB3 demonstrated high [11C]PBB3 binding in the cerebral cortex including medial temporal lobes in patients with Alzheimer’s disease (AD) compared with age-matched controls. The aim of the present study is to test the hypothesis that [11C]PBB3 PET is a in vivo imaging method for detecting tau lesions in non-AD tauopathies such as progressive supranuclar palsy (PSP) and corticobasal degeneration (CBD). Methods: Ten patients with PSP, five patients with corticobasal syndrome (CBS), and 18 age-matched healthy controls (HCs) participated in this study. Sequential PET scans were performed for 70 min following intravenous injection of [11C]PBB3. PET images were anatomically normalized to the Montreal Neurological Institute space using T1 weighted MRI, and standardized uptake value ratio (SUVR) at 30-50 min was calculated using the cerebellar cortex as reference region. One-way ANOVA test was performed among PSP, CBS patients, and HCs using statistical parametric mapping software (SPM 8). Statistical threshold was set to 0.01 with extent threshold of 50 voxels without correction for multiple comparisons. Cerebral beta-amyloid depositions were also estimated using SUVR images at 50-70 min after [11C]Pittsburgh compound B injection in all patients and HCs. Results: All patients and HCs were PIB-negative except one PIB-positive patient with CBS and one HC. SPM analysis showed high [11C]PBB3 binding in globus pallidus, putamen, thalamus, subthalamus, midbrain, pons, and peri-rolandic areas in PSP patients compared with HCs. PIB-negative CBS patients (n=4) showed high [11C]PBB3 binding in peri-rolandic areas, supplementary motor area, subthalamus, and midbrain compared with HCs. SUVR images of one PIB-positive patient with CBS showed high [11C]PBB3 binding in the whole cerebral cortex including limbic cortex like advanced AD patients. Conclusions: The distribution of [11C]PBB3 binding in the patients was in accord with the known distribution of tau pathology in PSP and CBD. The present study supports the utility of [11C]PBB3-PET for detecting tau deposition in non-AD tauopathies including PSP and CBD., Alzheimer Imaging Conrence

Objectives: [11C]PBB3 is a novel tau imaging PET ligand, which could visualize the tau deposition in Alzheimer’s disease (AD) and non-AD tauopathies. The aim of the present study was to investigate characteristics of [11C]PBB3 binding and its relation with clinical aspects in cognitively healthy subjects and patients with cognitive impairments. Methods: Participants included 15 AD patients, 15 mild cognitive impairments (MCI) patients, few patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) and 23 healthy controls (HCs). We performed [11C]PBB3 PET and [11C]PIB PET. Standardized uptake value ratio (SUVR) was calculated for each PET image using the cerebellar cortex as reference region. Results: All HCs and patients with non-AD tauopaties were PIB-negative, and all AD patients and 9 of 15 MCI patients were PIB-positive. [11C]PBB3 was highly accumulated in the medial temporal cortex of all AD and PIB-positive MCI patients, in which binding of [11C]PIB was minimal. Distribution of [11C]PBB3 accumulation observed in AD and PIB-positive MCI patients extended to the entire limbic system and subsequently to the neocortex as a function of the disease severity. Mean cortical [11C]PBB3 binding showed significantly positive correlation with dementia severity among AD and PIB-positive MCI patients. Furthermore, [11C] PBB3 was also accumulated in lesions associated with neurological symptoms in CBS, PSP and FTD patients, as well as some PIB-negative MCI patients and HCs. Conclusions: The present study demonstrated the spread of [11C]PBB3 binding reflect the dementia severity in AD and MCI due to AD patients. Furthermore, [11C]PBB3 binding could explain the neurological manifestations in CBS, PSP and FTD patients. Research support: “Integrated research on neuropsychiatric disorders”, “J-AMP”, Young Scientists 21791158, Scientific Research (B) 23390235, Core Research for Evolutional Science and Technology and Scientific Research on Innovative Areas 23111009 from the MEXT, Japan, Comprehensive Research on Dementia (No. 11103404) from MHLW, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research., Society of Nuclear Medicine and Molecular Imaging 2014

Objective: To investigate characteristics of [11C]PBB3 binding and its relation with clinical aspects in patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Background: [11C]PBB3 is a novel tau imaging positron emission tomography (PET) ligand, which could visualize the tau deposition in Alzheimer’s disease (AD) and non-AD tauopathies such as PSP, CBS and frontotemporal dementia. Methods: Participants included 10 PSP patients, 9 patients with corticobasal syndrome (CBS), 19 AD patients, and 20 age and gender matched healthy controls (HCs). A dose (about 10 mCi) of [11C]PBB3 was intravenously injected and sequential PET scans were performed for 70 min. We also performed PET scan with a plaque-binding agent, [11C]PIB (about 10 mCi), for 70 min and threedimensional T1-weighted MRI. Standardized uptake value ratio (SUVR) was calculated for each PET image using the cerebellar cortex as reference region. Amyloid deposition was verified by visual assessment of SUVR images of [11C]PIB PET. As for [11C]PBB3 PET data, group analysis among each group was performed by oneway ANOVA using statistical parametric mapping software (spm5). Results: One CBS patient and 17 of 19 AD patients were PIBpositive, and all the rest participants were PIB-negative. One PIBpositive CBS and two PIB-negative AD patients were excluded from group analysis. [11C]PBB3 was accumulated in lesions associated with neurological symptoms in PSP, CBS and AD patients. To be specific, [11C]PBB3 binding was significantly increased in the brainstem, basal ganglia, thalamus and dentate nucleus in PSP patients compared to HCs. In PIB-negative CBS patients, remarkable uptake of [11C]PBB3 was observed in basal ganglia and the neocortex including the supplementary motor area (SMA) and the peri-Rolandic area compared to HCs. Furthermore, [11C]PBB3 retention observed in PIB-positive CBS patient extended the neocortex as well as the entire limbic system, resembling AD patients with profound cognitive decline. Some brain lesions with [11C]PBB3 binding exhibited brain atrophy in PSP, CBS and AD patients. Conclusions: The present study demonstrated that distribution patterns of [11C]PBB3 binding reflect the differences in tau distribution in PSP, CBS and AD patients, which are highly compatible with neurological manifestation in each disorder., 第18回国際パーキンソン病・運動障害疾患会議（MDS2014）

Objectives: [11C]PBB3 is a novel tau imaging PET ligand, showing high affinity and selectivity for tau deposits. The aim of the present study was to investigate characteristics of [11C]PBB3 binding and its relation with clinical aspects in cognitively healthy subjects and patients with cognitive impairments. Methods: Participants included 17 AD patients, 15 mild cognitive impairments (MCI) patients and 17 age and gender matched cognitively healthy controls (HCs). The PET study was approved by the institutional review board. Written informed consent was obtained from all subjects. PET scans with [11C]PBB3 and an amyloid radioligand, [11C]PIB, and T1-weighted MRI were performed for each individual. Standardized uptake value ratio (SUVR) was calculated for PET images using the cerebellar cortex as reference region. Tau and amyloid deposits were visually assessed using SUVR images for [11C]PBB3 and [11C]PIB, respectively. Correlation between clinical dementia rating scale (CDR) sum of boxes and mean cortical [11C]PBB3 or [11C]PIB SUVR was analyzed among [11C]PIB-positive MCI and AD patients. Results: All HCs and 6 MCI patients were [11C]PIB-negative, and all AD patients and 9 of 15 MCI patients were [11C]PIB-positive. [11C]PBB3 was highly accumulated in the medial temporal cortex of all AD and [11C]PIB-positive MCI patients, in contrast to the modest binding of [11C]PIB in the corresponding region. Distribution of [11C]PBB3 accumulation observed in [11C]PIB-positive MCI patients was restricted within the temporal cortex, while AD patients showed [11C]PBB3 accumulation extending to the neocortex. Some HCs showed accumulation of [11C] PBB3 in the temporal cortex, despite no increase in cortical [11C]PIB binding. Dementia severity (CDR sum of boxes) among AD and [11C]PIB-positive MCI patients showed significant positive correlation with mean cortical [11C]PBB3 binding, but no association with [11C]PIB binding measures.. Conclusions: Distribution of [11C]PBB3 binding observed in AD and [11C]PIB-positive MCI patients extended from the temporal area to the entire limbic system and subsequently to the neocortex as a function of disease severity. Some HCs showed noticeable [11C]PBB3 binding in the limbic system, implying that tau deposition may be initiated in a manner independent of amyloid accumulation., 第55回日本神経学会学術大会

Question: Fluency tasks have been widely used to evaluate executive functions mainly implemented in the frontal lobes. Meanwhile, a recent PET study showed that divergent thinking, which was associated with fluency tasks, was related to dopamine D2 receptor densities in the thalamus, but the role of D2 in the frontal lobes remains unclear. In the current study, we were interested to understand how dopaminergic neurotransmission in the frontal lobes and thalamus were associated to fluency performance, in relation with a specific psychiatric symptom of depersonalization. Methods: We performed PET studies on 24 healthy male subjects. Extrastriatal dopamine D2 receptor bindings were measured by 60 min PET scans using [11C]FLB457). For each PET scan, BPND were calculated using SRTM using the cerebellum as a reference region. Outside the scanner, all participants performed ideational and word fluency tasks and 15 subjects fulfilled Cambridge Depersonalization Scale (CDS). Results: Voxel-by-voxel analysis revealed that dopamine D2 receptor binding potentials (D2 BPND) in the right prefrontal cortex were negatively correlated with performance of idea fluency task, but no region was found for word fluency. We conducted an additional ROI analysis for thalamus using thalamic connectivity atlas to investigate whether a specific thalamo-cortical connection played a role in idea fluency. Negative correlation between D2 BPND and idea fluency performance was found in the thalamic region that had projections onto prefrontal cortex. We further revealed performance of ideational fluency was positively correlated with CDS scores. Conclusions: Tendency of depersonalization scale was related to idea fluency, which was associated with dopaminergic transmission in the prefrontal cortex and its anatomically connected region in the thalamus., 30th International Congress of Clinical Neurophysiology (ICCN) of the IFCN

Background and aims: [11C]PBB3 is a novel tau imaging PET ligand, showing high affinity and selectivity for tau deposits. Our preliminary clinical data suggested [11C]PBB3 binding could reflect the dementia severity in AD patients. The aim of the present study was to investigate characteristics of [11C]PBB3 binding and its relation with clinical aspects in cognitively healthy subjects and patients with cognitive impairments. Methods: Participants were 14 AD patients, 13 mild cognitive impairments (MCI) patients and 22 healthy controls (HCs). We performed [11C]PBB3 PET as well as [11C]PIB PET. Standardized uptake value ratio (SUVR) was calculated for each PET image using the cerebellar cortex as reference region. Three-dimensional T1-weighted MRI was also acquired, and brain atrophy was also assessed using voxel-based morphometry technique. Results: All HCs were PIB-negative, and all AD patients and 7 of 13 MCI patients were PIB-positive. [11C]PBB3 was highly accumulated in the medial temporal cortex of all AD and PIB-positive MCI patients, in which binding of [11C]PIB was minimal. Distribution of [11C]PBB3 accumulation observed in AD and PIB-positive MCI patients extended to the entire limbic system and subsequently to the neocortex as a function of the disease severity. Mean cortical [11C]PBB3 binding showed significantly positive correlation with dementia severity assessed with clinical dementia rating scale (CDR) sum of boxes among AD and PIB-positive MCI patients (r = 0.67, p = 0.02; adjusted by age and educational background). Some PIB-negative MCI patients and HCs showed noticeable accumulation of [11C] PBB3. Interestingly, one PIB-negative MCI patients showed asymmetrical cortical atrophy around ambient gyrus resembling argyrophilic grain dementia (AGD), a sporadic 4-repeat tauopathy, accompanying high uptake of [11C]PBB3. Conclusions: The present study supported the spread of [11C]PBB3 binding reflect the dementia severity in AD and MCI due to AD patients. Furthermore, [11C]PBB3 PET could enable the antemortem diagnosis of AGD. \nKeywords Tau imaging, [11C]PBB3, Alzheimer’s disease, mild cognitive impairment, argyrophilic grain dementia, Human Amyloid Imaging Conference (HAI) 2014

The Alzheimer's Association International Conference

Alzheimer's Imaging Consortium

The belief that actions and external events are under control of conscious will is pervasive, and it is rarely doubted. This belief is built on a feeling that ones intentional actions caused specific events in the outside world (sense of agency). However, people often make misjudgment on causality depending on rewarding or punishing outcomes of action. One wellknown phenomenon is selfserving bias; when ones voluntary action caused negative outcome, subject tend to build a post-hoc account that negative outcome was caused by external factors. In contrast, patients with depression show opposite causality bias: they tend to attribute cause of negative event more to themselves than external factors. Although these self-serving and selfblaming biases imply that rewarding and punishing outcome of action exercise different effects on agency depending on subjects internal affective states, empirical evidence to this issue is lacking. In the present study, using a variant of actioneffect binding(intentional binding)paradigm combined with classical conditioning procedures, we investigated postdictive influence of affective valence of action on agency in healthy young subjects and depressive patients. We found that non-depressive and depressive subjects showed different pattern of modulation of action-effect binding by action outcomes. In healthy subjects, consistent with selfserving bias, actioneffect binding was attenuated when their action produced negative events. In contrast, depressive patients showed same degree of actioneffect binding irrespective of valence of action outcome, possibly reflecting depressive realism. Our study provides a new insight for cognitive mechanism underlying human causality bias and psychopathology of depression., 17th Meeting of the association for the scientific study of consciousness

Regional alterations in extracellular dopamine levels can be observed in the striatum during performance of neuropsychological tasks using PET1. To increase detection of the alteration, dopamine reuptake inhibitor could be useful for producing a greater magnitude of change in 11C-raclopride binding2. Mazindol is a non-selective catecholamine reuptake inhibitor, which blocks dopamine reuptake and thus could be used as an enhancer of dopamine release by neuropsyhological tasks3. To investigate basic potency of mazindol in human, we measured occupancy of the dopamine transporter and change in 11C-raclopride binding using PET after single oral administration of mazindol. Methods: Two sets of PET scans were acquired on six healthy volunteers after oral administration of placebo and 1.5 mg of mazindol. 11C-raclopride was injected at 3 hours after the administration of placebo or mazindol, and 18F-FE-PE2I was injected at 5 hours. In the brain, preset volumes of interest were applied on the spatially normalized PET images. Binding potential of sub-regions of striatum was calculated by the simplified reference tissue model using cerebellum as reference region. Dopamine transporter occupancy was calculated by the % change of the binding potential of 18F-FE-PE2I, and change in extracellular dopamine levels was measured by the % change of that of 11C-raclopride. Results: After oral administration of 1.5 mg of mazindol, the binding potential of 18F-FE-PE2I significantly reduced by 20 – 25 % (p < 0.01, paired t-test), indicating 20 – 25 % of dopamine transporters in the striatum was occupied by mazindol. Meanwhile, the binding potential of 11C-raclopride reduced by 4 – 6%, but the reduction was not significant, indicating the change in extracellular dopamine levels by mazindol without neuropsyhological tasks was small. The correlation between the occupancy of dopamine transporter and the change in 11C-raclopride binding was not significant, but there seemed a tendency that the occupancy was negatively related to the change in 11C-raclopride binding among subjects in the associative striatum. Conclusions: After oral administration of 1.5 mg of mazindol, dopamine transporters were occupied in a small proportion, and the change in extracellular dopamine levels was minimal. Further studies with a larger sample size would be needed to investigate the relationship between the occupancy of dopamine transporter and the change in extracellular dopamine levels by oral administration of mazindol., Brain'13 & BrainPET'13

Background: It has been proposed that prefrontal damage can sometimes give rise to an unexpected enhancement of specific cognitive abilities. In 1998, Miller reported 5 cases where patients developed artistic skills in the early stage of Front-temporal dementia (FTD). These 5 cases, called acquired savant syndrome, share a feature that their paintings are characterized by intensive focus on spatial information. Although such features indicate a background change of visuo-spatial abilities, it remains an open issue. Here, we investigated prefrontal functions and visuo-spatial abilities of the patient who showed enhanced artistic skills after left frontal infarction. Method: The patient was 65 years old man. He suffered from focal brain infarction in left prefrontal cortex. After brain infarction, the patient developed painting skills. Prefrontal functions of the patients were examined using neuropsychological tests before and after brain infarction. Next, to characterize painting skills of the patient, professional reviewers made blind evaluations of two paintings that had been painted before and after brain infarction. Finally, we compared patient's performance of three visuo-spatial cognitive tasks ( line bisection task, dots estimation task and dots comparison task) with those of 7 healthy controls. Results: Neuropsychological examinations revealed prefrontal dysfunctions. Nevertheless, painting ability was rather promoted after infarction, and shared features similar to those of previously reported cases. Furthermore, results of numerical cognitive tasks showed superior performance compared to healthy controls. Conclusion: Our data provide supportive evidence that acquired savant skills after left prefrontal infarction are related to enhanced visuo-spatial abilities., Bennial Meeting of World Federation of Neurology Research Group on Aphasia and Cognitive Disorders

Background: The partial agonist antipsychotic drugs of dopamine D2 receptors can modulate dopaminergic neurotransmission as functional agonists or functional antagonists. Effects of antipsychotics on the presynaptic functions of dopaminergic neurotransmission might also be related to their therapeutic effects. Recently, we found that the antagonist antipsychotic drug risperidone can be considered to stabilize dopamine synthesis capacity in healthy human subjects [1]. In the present study, changes in dopamine synthesis capacity by the partial agonist antipsychotic drug aripiprazole were measured by PET. \nMethods: PET studies were performed on 12 healthy men under resting condition (baseline study) and oral administration of single dose of aripiprazole of 3–9 mg, (drug challenge study) on separate days. In each study, both PET scans with [C-11]raclopride and [C-11]DOPA were performed sequentially. The occupancy of dopamine D2 receptors by aripiprazole was calculated from binding potential values in the striatum for baseline and drug challenge studies with [C-11]raclopride determined by the SRTM method using the cerebellum as a reference region. The uptake rate constant, Ki, for [C-11]DOPA in the striatum indicating the dopamine synthesis capacity was estimated by graphical analysis using the occipital cortex as a reference region. \nResults: The occupancies of dopamine D2 receptors were 53%-77%. The dopamine synthesis capacity Ki were 0.0128+-0.0016 and 0.0128+-0.0014 (1/min) for the baseline and drug challenge studies, respectively, and no significant change in Ki by aripiprazole was observed. No significant correlation between occupancies of dopamine D2 receptors and changes in Ki by aripiprazole was observed. A significant negative correlation was observed between the baseline Ki and the change in Ki by aripiprazole (r-0.65). The plasma concentrations of aripiprazole during [C-11]raclopride and [C-11]DOPA PET studies ranged from 9.3 to 40.4ng/mL (23.7+-11.3ng/mL, mean+-SD) and from 9.1 to 39.7ng/mL (21.5+-11.0ng/mL), respectively. \nConclusion: The negative correlation between the baseline Ki and the change in Ki by aripiprazole, and smaller coefficient of variation of Ki in drug challenge studies than in baseline studies indicate that aripiprazole can be assumed to stabilize the level of dopamine synthesis capacity same as antagonist antipsychotic drugs. An abnormal responsivity in both phasic and tonic dopamine release, which might be related to the modulation of dopaminergic neurotransmission, has been considered in the pathophysiology of schizophrenia [2]. Therapeutic effects of aripiprazole on schizophrenia might be related to stabilizing effects on dopaminergic neurotransmission responsivity in dopamine release. \nReferences \n[1] Ito H et al. Effects of the antipsychotic risperidone on dopamine synthesis in human brain measured by positron emission tomography with L-[beta-C-11]DOPA: a stabilizing effect for dopaminergic neurotransmission? J Neurosci 29:13730-13734, 2009. \n[2] Grace AA. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41:1-24, 1991., The 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM12)

Objectives: The partial agonist antipsychotic drugs of dopamine D2 receptors can modulate the dopaminergic neurotransmission as functional agonists or functional antagonists. Effects of antipsychotics on the presynaptic functions of dopaminergic neurotransmission might also be related to therapeutic effects of them. In the present study, changes in dopamine synthesis capacity by partial agonist antipsychotic drug aripiprazole were measured by PET. Methods: PET studies were performed on 12 healthy men under resting condition (baseline study) and oral administration of single dose of aripiprazole of 3-9 mg, (drug challenge study) on separate days. In each study, both PET scans with [C-11]raclopride and [C-11]DOPA were performed sequentially. The occupancy of dopamine D2 receptors by aripiprazole was calculated from binding potential values in the striatum for baseline and drug challenge studies with [C-11]raclopride determined by the SRTM method. The uptake rate constant, Ki, for [C-11]DOPA in the striatum indicating the dopamine synthesis capacity was estimated by the graphical analysis. Results: The occupancies of dopamine D2 receptors were 53%-77%. The dopamine synthesis capacity Ki were 0.0128+/-0.0016 and 0.0128+/-0.0014 (1/min) for the baseline and drug challenge studies, respectively, and no significant change in Ki by aripiprazole was observed. A significant negative correlation was observed between the baseline Ki and the change in Ki by aripiprazole (r=-0.65). Conclusions: The negative correlation between the baseline Ki and the change in Ki by aripiprazole, and smaller coefficient of variation of Ki in drug challenge studies than in baseline studies indicate that aripiprazole can be assumed to stabilize the level of dopamine synthesis capacity. Therapeutic effects of aripiprazole on schizophrenia might be related to stabilizing effects on dopaminergic neurotransmission responsivity in dopamine release., SNM 2012 Annual Meeting

Sense of agency (SoA) refers to the subjective experience that a voluntary action causes specific outcome in the outside world. The core questions in SoA research are (1) whether it is built on a predictive or postditive way, and (2) how the valence of the outcome influences SoA. These questions are remained unclear, but behavioral studies of self-serving bias indicate that the valence of the outcome biases action atribution or SoA retrospectively. To investigate the relationship between SoA and the outcome of action, intentional binding (IB) will be useful. As Haggard propesed origninally, IB is an implicit measure of SoA. Here, we show the results of 15 healthy subjects using a modified version of Libet clock timing paradigm. In the conditioning block, subject learned the combination of tones and valences (positive, neutral and negative monetary outcome). After conditioning, subjects played slots while watching a clockhand rotation. They were asked to press a key at a time of their own choice. Then, one of 3 beeps was presented randomly after a 250 ms delay, which informed the outcome of the slot. After a clock hand disappeared, subjects reported the perceived timing of either an action or a beep. These timing estimates were compared with baseline blocks where subjects judged either an action or a beep in a single event trial. In our study, subjects showed considerable binding effects regardless of the valence of outcome. However, the degree of temporal compression was attenuated significantly when negative outcome occurred as compared to positive and neutral outcomes. Our results not only confirm the postdictive account of SoA, but also demonstrate that the valence of the outcome influence SoA., 国際意識学会：Association for scientific study for consciousness (ASSC)