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We recently developed a positron emission tomography (PET) probe, [sup18/supF]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.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.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.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.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.

BackgroundAccumulating evidence indicated decreased levels of glutamate (Glu) and N-acetylaspartate (NAA) in the posterior cingulate cortex (PCC) in Alzheimer’s disease (AD) brains. However, the levels of these metabolites in the other brain regions and the associations with abnormal protein of AD remain to be elucidated.MethodsWe enrolled 19 patients with AD and 26 healthy controls (HC). We performed magnetic resonance spectroscopic imaging (MRSI) to evaluate Glu/creatine (Cr) and NAA/Cr ratios and measure plasma neurofilament light chain (NfL) levels. We examined tau and amyloid-β depositions with standardized uptake value ratios (SUVRs) of florzolotau (18F) and11C-PiB positron emission tomography, respectively. Heatmaps were created to visualize Z scores of Glu/Cr and NAA/Cr ratios using HC data.ResultsIn the AD brains, Z-score maps demonstrated reduced Glu/Cr and NAA/Cr ratios in the gray matter, including the right dorsolateral prefrontal cortex (DLPFC) and PCC; Glu/Cr ratios negatively correlated with florzolotau (18F) SUVRs in the PCC; mini-mental state examination total scores correlated with Glu/Cr (P < 0.001, r = 0.72) and NAA/Cr ratios (P < 0.001, r = 0.75) in the right DLPFC; and blood NfL levels were increased and negatively correlated with the Glu/Cr (P = 0.040, r = −0.50) and NAA/Cr ratios (P = 0.003, r = −0.68) in the right DLPFC.ConclusionsOur findings indicated that decreased Glu/Cr levels correlated with tau pathologies of AD in the PCC. MRSI is capable of providing spatial information on neural function, enabling the identification of vulnerabilities in the right DLPFC in AD pathology.

Purpose: Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-inflammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and anti-inflammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligand 18F-T-401. Methods: Seven healthy males underwent 120-min dynamic 18F-T-401-PET scans with arterial blood sampling. Six subjects also underwent a second PET scan with 18F-T-401 within 2 weeks of the first scan. For quantification of MAGL in the human brain, kinetic analyses using one- and two-tissue compartment models (1TCM and 2TCM, respectively), along with multilinear analysis (MA1) and Logan graphical analysis were performed. Time-stability and test-retest reproducibility of 18F-T-401-PET were also evaluated.Results: 18F-T-401 showed rapid uptake and gradual washout from the brain. Logan graphical analysis showed linearity in all subjects, indicating reversible radioligand kinetics. Using a metabolite-corrected arterial input function, MA1 estimated regional total distribution volume (VT) values by best identifiability. VT values were highest in the cerebral cortex, moderate in the thalamus and putamen, and lowest in white matter and the brainstem, which was in agreement with regional MAGL expression in the human brain. Time-stability analysis showed that MA1 estimated VT values with a minimal bias even using truncated 60-min scan data. Test-retest reliability was also excellent with the use of MA1. Conclusions: Here, we provide the first demonstration of in vivo visualization of MAGL in the human brain. 18F-T-401 showed excellent test-retest reliability, reversible kinetics, and stable estimation of VT values consistent with known regional MAGL expressions. PET with 18F-T-401-PET is promising tool for measurement of central MAGL.

Purpose Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-infammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and antiinfammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligand 18F-T-401. Methods Seven healthy males underwent 120-min dynamic 18F-T-401-PET scans with arterial blood sampling. Six subjects also underwent a second PET scan with 18F-T-401 within 2 weeks of the frst scan. For quantifcation of MAGL in the human brain, kinetic analyses using one- and two-tissue compartment models (1TCM and 2TCM, respectively), along with multilinear analysis (MA1) and Logan graphical analysis, were performed. Time-stability and test–retest reproducibility of 18F-T-401-PET were also evaluated. Results 18F-T-401 showed rapid uptake and gradual washout from the brain. Logan graphical analysis showed linearity in all subjects, indicating reversible radioligand kinetics. Using a metabolite-corrected arterial input function, MA1 estimated regional total distribution volume (VT) values by best identifability. VT values were highest in the cerebral cortex, moderate in the thalamus and putamen, and lowest in white matter and the brainstem, which was in agreement with regional MAGL expression in the human brain. Time-stability analysis showed that MA1 estimated VT values with a minimal bias even using truncated 60-min scan data. Test–retest reliability was also excellent with the use of MA1. Conclusions Here, we provide the frst demonstration of in vivo visualization of MAGL in the human brain. 18F-T-401 showed excellent test–retest reliability, reversible kinetics, and stable estimation of VT values consistent with known regional MAGL expressions. PET with 18F-T-401-PET is promising tool for measurement of central MAGL.

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.

ObjectiveIncreasing 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 energy metabolism. It is hypothesized that lactate, a glucose metabolite, is produced in astrocytes and subsequently shuttled to neurons as an energy substrate. This study aimed to examine alterations in brain lactate levels and their association with astrocytic activities in AD.Methods30 AD and 30 cognitively unimpaired (CU) subjects were enrolled. For AD subjects, amyloid and tau depositions were confirmed by positron emission tomography using [11C]PiB and [18F]florzolotau, respectively. Lactate and myo-inositol, an astroglial marker, in the posterior cingulate cortex (PCC) were quantified by magnetic resonance spectroscopy (MRS). These MRS metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein (GFAP) as another astrocytic marker.ResultsLactate and myo-inositol levels were higher in AD than in CU (p< 0.05). Lactate levels correlated with myo-inositol levels (r= 0.272,p= 0.047). Lactate and myo-inositol 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 GFAP and tau phosphorylated at threonine 181 levels (p< 0.05).InterpretationWe found high lactate levels accompanied by an increased astrocytic marker in the PCC in AD. Thus, impaired lactate shuttle of reactive astrocytes may disrupt energy regulation, resulting in surplus lactate levels. Myo-inositol and plasma GFAP may reflect similar astrocytic changes.

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

To assess if magnetic resonance spectroscopy (MRS)-measured Glutamate (Glu) and GABA reflect excitatory and inhibitory neural activities, respectively, we conducted MRS measurements along with two-photon mesoscopic imaging of calcium signals in excitatory and inhibitory neurons of living, unanesthetized mice. For monitoring stimulus-driven activations of a brain region, MRS signals and mesoscopic neural activities were measured during two consecutive sessions of 15-min prolonged sensory stimulations. In the first session, putative excitatory neuronal activities were increased, while inhibitory neuronal activities remained at the baseline level. In the second half, while excitatory neuronal activities remained elevated, inhibitory neuronal activities were significantly enhanced. We also assessed regional neurochemical and functional statuses related to spontaneous neural firing by measuring MRS signals and neuronal activities in a mouse model of Dravet syndrome under a resting condition. Mesoscopic assessments showed that activities of inhibitory neurons in the cortex were diminished relative to wild-type mice in contrast to spared activities of excitatory neurons. Consistent with these observations, the Dravet model exhibited lower concentrations of GABA than wild-type controls. Collectively, the current investigations demonstrate that the MRS-measured Glu and GABA can reflect spontaneous and stimulated activities of neurons producing and releasing these neurotransmitters in an awake condition.

To assess if magnetic resonance spectroscopy (MRS)-measured Glutamate (Glu) and GABA reflect excitatory and inhibitory neural activities, respectively, we conducted MRS measurements along with two-photon mesoscopic imaging of calcium signals in excitatory and inhibitory neurons of living, unanesthetized mice. For monitoring stimulus-driven activations of a brain region, MRS signals and mesoscopic neural activities were measured during two consecutive sessions of 15-min prolonged sensory stimulations. In the first session, putative excitatory neuronal activities were increased, while inhibitory neuronal activities remained at the baseline level. In the second half, while excitatory neuronal activities remained elevated, inhibitory neuronal activities were significantly enhanced. We assessed regional neurochemical statuses by measuring MRS signals, which were overall in accordance with the neural activities, and neuronal activities and neurochemical statuses in a mouse model of Dravet syndrome under resting condition. Mesoscopic assessments showed that activities of inhibitory neurons in the cortex were diminished relative to wildtype mice in contrast to spared activities of excitatory neurons. Consistent with these observations, the Dravet model exhibited lower concentrations of GABA than wild-type controls. Collectively, the current investigations demonstrate that MRS-measured Glu and GABA can reflect spontaneous and stimulated activities of neurons producing and releasing these neurotransmitters in an awake condition.

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.

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.

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.

Makoto Terumitsu,1,2 Yuhei Takado,3 Ken-Ichi Fukuda,2 Eisuke Kato,2 Sei Tanaka4 1Division of Dental Anesthesiology, Department of Human Biology and Pathophysiology, Health Sciences University of Hokkaido, Hokkaido, Japan; 2Division of Special Needs Dentistry and Orofacial Pain, Department of Oral Health and Clinical Science, Tokyo Dental College, Tokyo, Japan; 3Department of Functional Brain Imaging, Institute of Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba, Japan; 4Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Tokyo, JapanCorrespondence: Makoto Terumitsu, Division of Dental Anesthesiology, Department of Human Biology and Pathophysiology, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu-cho, Ishikari-gun, Hokkaido, 061-0293, Japan, Tel/Fax +81 133 23 1445, Email terumitsu@hoku-iryo-u.ac.jpBackground: Refractory chronic pain in the orofacial region involves central sensitization (CS). However, not all chronic pain patients exhibit CS. An objective assessment of CS may be useful for pain management. Changes in the balance of excitatory and inhibitory neural activity or excessive activity of nerves and glial cells may cause CS and contribute to pain chronification.Patients and Methods: 1H-magnetic resonance spectra were acquired from the anterior cingulate cortex (ACC) and thalamus in 20 patients with chronic orofacial pain and suspected CS, and 21 healthy volunteers, using a single-voxel point-resolved spectroscopy sequence. The patients were assessed using the Central Sensitization Inventory.Results: Aspartate/total creatine (tCr) and glutathione in the ACC were significantly higher in the patient group. However, no significant difference was observed between groups in the neurometabolites measured in the thalamus. Patients also exhibited a tendency for increased gamma-aminobutyric acid (GABA)/tCr in the ACC. There were positive relationships between Central Sensitization Inventory scores and glutamate + glutamine (Glx) in the thalamus, a positive trend for Glx in the ACC and a negative relationship for GABA/tCr in the ACC.Conclusion: The high levels of aspartate/tCr and glutathione in the patient group suggest excitatory neuronal activity and hyperactivity of neurons and glial cells. The correlation analysis results suggest that excitatory and inhibitory neurometabolites are involved in the chronification of orofacial pain, including CS.Keywords: orofacial pain, central sensitization, magnetic resonance spectroscopy, Central Sensitization Inventory, anterior cingulate cortex, thalamus

Glutamatergic neurons and cingulate cortices have crucial roles in the cognitive dysfunction of Alzheimer's disease (AD). This study aimed to evaluate regional vulnerabilities of the glutamatergic system in AD at the level of the cingulate gyrus in relation to tau and amyloid-β (Aβ) depositions. Combining MRSI and PET, we found that the glutamatergic system in the posterior cingulate cortex (PCC) is vulnerable to tau deposits but not Aβ from the early stage of AD, and glutamate in the PCC region may be a marker of disease progression in AD., 2022 Joint Annual Meeting ISMRM-ESMRMB

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.

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, temporal cortex) or NAT (thalamus, pons) binding. However, in the ASD group, there were significant negative correlations between DA D1R binding (striatum, anterior cingulate cortex, 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. While 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.

Intracellular accumulation of filamentous tau aggregates with progressive neuronal loss is a common characteristic of tauopathies. Although the neurodegenerative mechanism of tau-associated pathology remains unclear, molecular elements capable of degrading and/or sequestering neurotoxic tau species may suppress neurodegenerative progression. Here, we provide evidence that p62/SQSTM1, a ubiquitinated cargo receptor for selective autophagy, acts protectively against neuronal death and neuroinflammation provoked by abnormal tau accumulation. P301S mutant tau transgenic mice (line PS19) exhibited accumulation of neurofibrillary tangles with localization of p62 mostly in the brainstem, but neuronal loss with few neurofibrillary tangles in the hippocampus. In the hippocampus of PS19 mice, the p62 level was lower compared to the brainstem, and punctate accumulation of phosphorylated tau unaccompanied by co-localization of p62 was observed. In PS19 mice deficient in p62 (PS19/p62-KO), increased accumulation of phosphorylated tau, acceleration of neuronal loss, and exacerbation of neuroinflammation were observed in the hippocampus as compared with PS19 mice. In addition, increase of abnormal tau and neuroinflammation were observed in the brainstem of PS19/p62-KO. Immunostaining and dot-blot analysis with an antibody selectively recognizing tau dimers and higher-order oligomers revealed that oligomeric tau species in PS19/p62-KO mice were significantly accumulated as compared to PS19 mice, suggesting the requirement of p62 to eliminate disease-related oligomeric tau species. Our findings indicated that p62 exerts neuroprotection against tau pathologies by eliminating neurotoxic tau species, suggesting that the manipulative p62 and selective autophagy may provide an intrinsic therapy for the treatment of tauopathy.

BackgroundVisualization of aqueous humor flow in the human eye is difficult because gadolinium, a magnetic resonance imaging (MRI) contrast agent, does not readily cross the blood-retinal and blood-aqueous barriers of capillaries that supply water to the eye. The proton (1H) of oxygen-17 water (H217O) has a very short transverse relaxation time (T2), and the T2-weighted (T2W) 1H-MRI signal intensity of a region with H217O is lower than that with only H216O.PurposeTo observe the distribution of H217O in the human eye, and the flow into and out of the anterior chamber of H217O, using dynamic T2W 1H-MRI.Materials and MethodsSeven ophthalmologically normal adult volunteers under 40 years old participated in this study. During dynamic imaging, the subject self-administered 10 mol% H217O saline (0.92–1.37 mL) to their right eye for 1 min. Time-series images were created by subtracting the image before the eye drops from each of the images obtained after the eye drops. The “normalized signal intensity of the right anterior chamber” (rAC) in each image was obtained by dividing the signal intensity of the right anterior chamber region-of-interest by that of the left. Changes in transverse relaxation rate and H217O concentration (PO17) were calculated from the rAC. The inflow and outflow constants of H217O in the right anterior chamber were also determined.ResultsDecreased signal intensity after the H217O eye drops was observed in the anterior and posterior chambers, but not in the vitreous body. The rAC signal intensity decreased after the eye drops, and then recovered to close to rAC(0) at 40 min. The inflow and outflow constants were 0.53 ± 0.19 and 0.055 ± 0.019 min-1, respectively, and the peak value of PO17 was 0.19 ± 0.04% (mean ± SD).ConclusionH217O saline eye drops distributed in the human anterior and posterior chambers. Further, the eye drops smoothly flowed into, and slowly out of, the anterior chamber.SummaryO-17 water dropped into human eyes as a T2-weighted MRI contrast agent was distributed in the anterior and posterior chambers, with smooth flow into, and slow outflow from, the anterior chamber.Key findingsIn seven healthy volunteers, dynamic T2-weighted 1H-MRI showed that the signal intensity in the anterior chamber decreased smoothly after H217O eye drops and then slowly recovered, reaching a value close to that observed before the eye drops, after 40 minutes, with inflow and outflow constants of H217O of 0.53 ± 0.19 min-1 and 0.055 ± 0.019 min-1, respectively. The signal changes were limited to the anterior and posterior chambers and were not observed in the vitreous body.

Depositions of tau fibrils are implicated in diverse neurodegenerative disorders, including Alzheimer's disease, and precise assessments of tau pathologies and their impacts on neuronal survival are crucial for pursuing the neurodegenerative tau pathogenesis with and without potential therapies. We aimed to establish an in vivo imaging system to quantify tau accumulations with positron emission tomography (PET) and brain atrophy with volumetric MRI in rTg4510 transgenic mice modeling neurodegenerative tauopathies.A total of 91 rTg4510 and non-transgenic control mice underwent PET with a tau radiotracer,sup18/supF-PM-PBB3, and MRI at various ages (1.8-12.3 months). Using the cerebellum as reference, the radiotracer binding in target regions was estimated as standardized uptake value ratio (SUVR) and distribution volume ratio (DVR). Histopathological staining of brain sections derived from scanned animals was also conducted to investigate the imaging-neuropathology correlations.sup18/supF-PM-PBB3 SUVR at 40-60 min in the neocortex, hippocampus, and striatum of rTg4510 mice agreed with DVR, became significantly different from control values around 4-5 months of age, and progressively and negatively correlated with age and local volumes, respectively. Neocortical SUVR also correlated with the abundance of tau inclusions labeled with PM-PBB3 fluorescence, Gallyas-Braak silver impregnation, and anti-phospho-tau antibodies in postmortem assays. The in vivo and ex vivosup18/supF-PM-PBB3 binding was blocked by non-radioactive PM-PBB3.sup18/supF-PM-PBB3 yielded a 1.6-fold greater dynamic range for tau imaging than its ancestor,sup11/supC-PBB3.Our imaging platform has enabled the quantification of tau depositions and consequent neuronal loss and is potentially applicable to the evaluation of candidate anti-tau and neuroprotective drugs.

【目的】タッチパネルを用いた認知機能検査バッテリーであるUser eXperience-Trail Making Test: UX-TMTの，パーキンソン病(PD)と進行性核上性麻痺(PSP)の認知および運動機能障害検出における有用性を評価する． 【方法】健常者(HC)9例: 75.7(8.0)歳[平均(SD)]，女性56%，PD患者5例: 70.2(8.7)歳，女性60%，PSP患者6例: 70.5(7.1)歳，女性67%を対象とした．PD重症度評価にはHoehn-Yahrステージを，その他の評価にはMini-Mental State Examination (MMSE)と従来型TMT，UX-TMTを用いた．UX-TMTは認知症スクリーニングスコアの他，TMTにおけるタップダウンからタップアップまでの時間(Contact Duration:CD)を評価に用いた． 【結果】PD群のYahrは平均2.0[1-4]であった．MMSEではHC群28.4(1.1)とPD群29.0(1.0)，PSP群27.5(1.6)に有意差(Kruskal-Wallis)はなかったが，UX-TMT_part BのCD(msec)ではPD群241.8(69.3)がHC群100.6(27.6)(p=.010)とPSP群164.9(96.8) (p=.021)より有意に遅延しており，従来型TMT_part B所要時間(sec)ではPSP群178.8(49.4)がHC群87.2(14.0)(p=.000)とPD群 102.4(25.1)(p=.002)より有意に遅延していた．PDのYahrステージとUX-TMTに相関は認めなかった(Spearman)． 【結論】UX-TMTは従来型より視野範囲が狭く筆記動作がない反面，線で結ばない等認知負荷は高い為，従来型と異なる病状を捉える可能性があり，PDの前駆・潜在的認知機能障害検出に有用であることが示唆された．, 第40回日本認知症学会学術集会

【目的】非アルツハイマー型認知症のタウオパチーである進行性核上性麻痺(PSP)において，18F-PM-PBB3をプローブとするタウ病変PET画像による客観的な自動診断法を開発する．【方法】対象は健常高齢者(HC) 43例 (69.2 ± 7.0 [平均 ± 標準偏差]歳，女性 48.8%)，PSP 42例 (71.5 ± 7.1歳，女性 35.7%，MDS-PSP診断基準でprobable)，疾患対照としてパーキンソン病患者(PD) 8例 (70.6 ± 6.4歳，女性 12.5%) で，機械学習訓練用(75%)と診断能評価用(25%)に分けて解析した(stratified shuffle splitで10セット分作成)．マルチアトラス法を用いて脳実質112カ所の関心領域(ROI)を同定し，病変が少ない小脳皮質とのプローブ集積比(SUVR)を算出した．値は年齢，性別で補正し標準化した．各領域のSUVRと重み係数の積の総和(PSP tauスコア)によるPSP群対，HC+PD群の弁別能が最も高くなるように，機械学習(elastic net CV)により重み係数の最適化を行った．得られたスコアと重症度の相関も解析した．【結果】淡蒼球，中脳，被殻などが重み係数の高い弁別に重要なROIであった．評価用10セットデータのPSP tauスコアを平均化して解析した診断能は正確度 96.7%, 感度 95.1%, 特異度 98.0%であった．PSP tauスコアと重症度(PSP rating scale)は有意な相関を認めた(Spearman’s rs = 0.4, p = 0.009).【結論】18F-PM-PBB3 PETを用いてPSPの自動診断および重症度の予測に有望な手法を開発した．, 第40回日本認知症学会学術集会

目的： 18F-PM-PBB3 PETは進行性核上性麻痺（PSP）を含む前頭側頭葉変性症（FTLD）のタウ病変を可視化するが、FTLDでは小脳にもタウが沈着しうるため、小脳以外を参照領域とした薬剤の定量が望ましい場合がある。本研究ではヒストグラムによるFTLDの参照領域の最適化を目的とした。 方法：健常者（HC）39例、PSP患者40例および他のFTLD患者5例の18F-PM-PBB3 PET画像を解析した。位置合わせしたMR画像をもとに灰白質・白質のボクセル値をそれぞれヒストグラム化し、二峰性ガウス分布にフィットさせた。低い方の分布から参照領域を抽出し、小脳皮質を参照領域とした場合とそれぞれSUVR画像を作成し、鑑別能について比較した。 結果： HCとPSP患者とで、ROC曲線に基づくAUCは灰白質（0.928）、白質（0.917）、小脳（0.908）を参照領域とした順に高かった。また他のFTLD患者においても、灰白質を参照領域とすることで、高感度に視覚評価での弁別が可能だった。 結論：ヒストグラムを用いた参照領域の最適化は、FTLDにおける18F-PM-PBB3 PETの診断能を改善させる可能性がある。, 第61回に本核医学会学術総会

[背景]：双極性障害において気分変動が繰り返し出現する機序として、「ドーパミン制御障害仮説」が提唱されてきたが、ドーパミン受容体や生成能をターゲットとするドーパミンイメージング研究では一致した所見が得られていない。近年の死後脳研究やゲノム研究では、ドーパミン神経伝達におけるセカンドメッセンジャー系の異常が繰り返し指摘されており、特にホスホジエステラーゼ10A (PDE10A)は、cyclic AMP (cAMP)の分解を介してドーパミン神経伝達の制御に関与していることから、双極性障害の有力な病態関連分子であると考えられている。本研究は、双極性障害患者における脳内PDE10Aの変化を明らかにすることを目的とし、双極性障害患者および健常者を対象にPDE10Aに対するリガンドである[18F]MNI659によるPET撮像を行なった。 [方法]：25名の双極性障害I型患者 (50.3±11.4歳) (躁状態：4名、うつ状態：1名、寛解期：20名)および20名の健常者 (53.8±13.0歳)を対象として、[18F]MNI659を用いたPET撮像を行った。小脳を参照領域とした解析により、線条体の各領域 (被殻、尾状核)におけるリガンド結合能 (BPND)を求めた。患者群と健常群のBPNDを比較し、BPNDと各種臨床評価尺度との関連も検討した。本研究は量子科学技術研究開発機構 量子生命・医学部門 量子医科学研究所の倫理委員会の承認を受けている。 [結果]：患者群では健常群に比較して、尾状核(analysis of covariance, F = 17.32, p < 0.001)、被殻(analysis of covariance, F = 6.17, p = 0.017)におけるBPNDの有意な低下を認めた。また、BPNDと過去12ヶ月間のエピソード回数は負の相関を認めた。 [結論]：双極性障害患者では尾状核、被殻におけるPDE10Aの密度が低下していることが示された。cAMPを介したドーパミン神経伝達の制御の障害、セカンドメッセンジャー系の異常の可能性が示唆される。今後は、病相期ごとにPET撮像を行い、PDE10Aの変化と双極性障害における症候との関連性を検討する必要がある。, 第40回 躁うつ病の薬理・生化学的研究懇話会

Description, Intake of specific seven essential amino acids affects the pathology of the brain., Protein malnutrition is epidemiologically suggested as a potential risk factor for senile dementia, although molecular mechanisms linking dietary proteins and amino acids to neurodegeneration remain unknown. Here, we show that a low-protein diet resulted in down-regulated expression of synaptic components and a modest acceleration of brain atrophy in mice modeling neurodegenerative tauopathies. Notably, these abnormal phenotypes were robustly rescued by the administration of seven selected essential amino acids. The up-regulation of inflammation-associated gene expression and progressive brain atrophy in the tauopathy model were profoundly suppressed by treatment with these essential amino acids without modifications of tau depositions. Moreover, the levels of kynurenine, an initiator of a pathway inducing neuroinflammatory gliosis and neurotoxicity in the brain, were lowered by treatment through inhibition of kynurenine uptake in the brain. Our findings highlight the importance of specific amino acids as systemic mediators of brain homeostasis against neurodegenerative processes.

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.Sixteen CBS cases diagnosed by Cambridge's criteria and 12 cognitively healthy controls (HCs) underwent PET scans withSixteen 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 ofPET-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

Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-inflammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and anti-inflammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligandSeven healthy males underwent 120-min dynamicHere, we provide the first demonstration of in vivo visualization of MAGL in the human brain.

Positron emission tomography (PET) allows biomolecular tracking but PET monitoring of brain networks has been hampered by a lack of suitable reporters. Here, we take advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP, to facilitate in vivo imaging in the brain. Peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expression in mice. This technique can be used to the visualize neuronal circuit activity elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR‐PET allows mapping of neuronal projections in non‐human primate brains, demonstrating the applicability of ecDHFR‐based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET studies of turnover and self‐assembly of proteins tagged with ecDHFR mutants. These results establish opportunities for a broad spectrum of previously unattainable PET analyses of mammalian brain circuits at the molecular level., Application of bacterial dihydrofolate reductase ecDHFR and its unique antagonist TMP achieves a broad spectrum of previously unattainable in vivo PET analyses of mammalian brain circuits at the molecular level.

【目的】近年の死後脳研究やtau PET (positron emission tomography)による検討により、老年期に発症する気分障害の背景病態として脳内に病的蛋白が蓄積する神経変性疾患の関与が示されている。今回、高齢で発症した双極性障害患者に対して神経心理検査、臨床症状、MRIによる脳構造評価、tau、amyloid PETを縦断的に実施し得た３例のケースを経験したため報告する。【方法】50歳以上発症の双極性障害患者3名に対し、MRI検査、18F-PM-PBB3（tau）、11C-PiB（amyloid）を用いたPET検査、神経心理検査を1年以上空けて2回行った。ligand蓄積量は、小脳皮質を参照領域とするSUVR(standardized uptake value ratio)法にて算出した。【結果】1例目は72歳時に躁状態で発症し、1回目のPETでは18F-PM-PBB3の側頭葉前部への局所的集積を認め、前頭側頭葉変性症であることが示唆された。その後、脱抑制、反社会的行動、食行動の変化を認めるようになり、２回目のPETでは18F-PM-PBB3集積分布の増加を認めた。2例目は72歳時に躁状態を呈した症例であり、1回目のPETで11C-PiB陽性であったことからAlzheimer病が示唆された。その後、風呂とトイレを間違える、歯磨きの仕方が分からくなる等の認知機能低下を認め、2回目のPETでは11C-PiB 、18F-PM-PBB3集積の増加を認めた。3例目は50代後半からうつ状態、躁状態を呈し、1回目のPETでは左下側頭葉に18F-PM-PBB3の局所的集積を認めた。病歴から脳震盪への長期暴露が明らかとなり慢性外傷性脳症が示唆された。その後、認知機能低下および社会行動障害を呈するようになり、2回目のPETでは18F-PM-PBB3の集積増加を認めた。【考察】高齢発症の双極性障害においては、amyloid蓄積の有無、tau蓄積の分布、経時的変化から、背景に複数の神経変性疾患が存在することが示唆された。明らかな認知機能低下や行動異常が出現する前にamyloid、tau PETを行うことは治療方針を定める上で参考になると考える。, 第45回日本神経心理学会学術集会

《背景》役に立たず不要に思われるが患者にとっては意味のある物を収集する行動は病的収集活動と呼ばれ、前頭側頭葉変性症や前頭葉損傷で引き起こされることが知られている。われわれは、重度頭部外傷から遅発性に病的収集活動を呈した症例を経験し、過去に本学会で報告した。近年、頭部への受傷から長期間が経過した後に引き起こされる精神神経症状は遅発性脳障害と呼ばれており、その代表的な病態が慢性外傷性脳症である。慢性外傷性脳症は脳内にタウ凝集体が蓄積する神経変性疾患であり、その脳内タウ蓄積はポジトロン断層撮影（PET）により画像化が可能である。今回、[18F]PM-PBB3および[11C]PiBをプローブとするPETによって、それぞれ脳内タウおよびアミロイド病変を評価しため、本症例の脳画像所見について報告する。《症例》症例は48歳の右利き男性。33歳時、自動車事故によるびまん性軸索損傷にて約3週間の意識障害が遷延した。神経学的な後遺症はなかったが、自発性低下のため無為な日々を送った。41歳時、病的収集活動（同一機種の型番を全て揃えたカメラなどで家は寝床もないほどだった）が始まった。46歳時に精査加療目的で当院初診。各種神経心理学検査で、処理速度で顕著な低下を認めるが知能は正常、記憶障害、遂行機能障害、保続を認めず、ギャンブリング課題ではハイリスクの山を引き続け、-125000円で終了した。頭部MRIでは、脳挫傷や脳表ヘモジデリン沈着を認めず、SWI（susceptibility-weighted imaging）で左頭頂葉白質、脳梁体部、左側頭葉白質、左小脳半球に微小出血を認め、びまん性軸索損傷に矛盾しなかった。[11C]PiB PETは陰性、[18F]PM-PBB3 PETは右前頭葉の脳溝深部に近い灰白質白質境界部および後頭葉白質に局所的集積を認めた。《考察》本症例では、頭部外傷から遅発性に病的収集活動を呈し、PETにより慢性外傷性脳症に特徴的な分布様式のタウ蓄積を認めたことから、頭部外傷によって引き起こされた脳内タウ蓄積が遅発性の症候に関与している可能性が示唆された。, 第45回日本神経心理学会学術集会

【背景】慢性外傷性脳症(chronic traumatic encephalopathy: CTE)は、反復性軽度頭部外傷によって引き起こされるタウオパチーである。タウPETの開発により頭部外傷による脳内タウ病変を生存中に可視化することが可能となったが、第1世代タウPET薬では単一症例レベルの高精度な診断を行うことは困難であった。量研機構は、第２世代タウPET薬である18F-PM-PBB3を開発し、多様なタウオパチーを高精度に評価することに成功した。本研究では、ボクサーを対象に18F-PM-PBB3を用いたPETを行い、タウ病変の分布を検討するとともに、脳局所におけるタウ蓄積量と外傷歴や精神神経症状との関連を検討した。【方法】元ボクサー 18名(ボクシング従事年数 15.4年)、および同年代の健常被験者に対して18F-PM-PBB3を用いたタウPET、11C-PiB によりアミロイドPET、MRIおよび神経心理検査を実施した。脳内タウ蓄積量は、小脳を参照領域とするSUVR(standard uptake tissue ratio)法にて定量した。18F-PM-PBB3の集積分布に関しては、２名以上の医師によって定性的評価を行なった。【結果】ボクサー群は、健常群に比較して、大脳皮質、白質、皮質-白質境界部において18F-PM-PBB3のSUVR値が有意に高く (P = 0.0002)、タウ蓄積量の増加が示唆された。ボクサーにおける18F-PM-PBB3集積分布は、(A)脳内に有意な集積を認めないタイプ(4名)、(B)脳の局所にびまん性の集積を認めるタイプ(5名)、(C)皮質-白質境界部の脳溝深部に多発散在性の集積を認めるタイプ(8名)の3つの類型に分類された。特に(C)はCTE/ボクサー脳症の死後脳所見に非常に類似していた。また、(A)-(C)の集積パターンと、精神神経症状には一定の関係性が認められた。11C-PiBによるアミロイドPETは全例で陰性であった。【考察】18F-PM-PBB3によるPETにより、ボクシングによって引き起こされる脳内タウ蓄積には複数の類型が存在し、それぞれ異なる精神神経症状を呈する傾向が示された。本結果は、頭部外傷による遅発性脳障害の発現機序を解明するための重要な知見と考えられる。, 第43回日本生物学的精神医学会・第51回日本神経精神薬理学会 合同年会

【背景】頭部外傷(TBI)から数年以上の期間を経て慢性外傷性脳症や外傷後精神病などの遅発性脳障害が引き起こされることがある。TBIの慢性期には、蛋白質蓄積症、慢性炎症、脳構造変化など様々な変化が引き起こされるが、その詳細は未だ謎に包まれている。我々は、TBIによる遅発性脳障害の精神病症状が脳内タウ蓄積と関連することを報告したが、タウ病変が局所脳活動に及ぼす影響については未だ検討されていない。本研究では、TBIの長期経過例における糖代謝と認知機能障害との関係、および糖代謝とタウ蓄積との関係を検討した。 【方法】TBIの長期経過例 21名(平均47.6歳、経過年数 24.6年)、および健常被験者(平均43.2歳)に対してタウPET(11C-PBB3)、アミロイドPET(11C-PiB)、18F-FDG による糖代謝PET、MRIおよび神経心理検査を実施した。タウ蓄積、アミロイド蓄積は小脳を参照領域とするSUVR(standard uptake tissue ratio)法にて、糖代謝は白質を参照領域とするSUVR法で定量した。 【結果】健常群に比して、TBI群は皮質全体、尾状核、視床、海馬、前頭葉皮質、帯状回、小脳で18F-FDG SUVR値の有意な低下を認めた。大脳皮質全体の18F-FDG SUVR値は、MMSE、論理的記憶(遅延再生)、レイの複雑図形などのスコアと正の相関を認め、糖代謝が低下するほど認知機能障害が重度になる傾向が示された。一方、18F-FDG SUVR値とタウ蓄積量との間には正の相関が認められ、タウ凝集体による神経毒性が局所の脳活動を亢進させている可能性が示唆された。 【考察】本研究により、TBIの長期経過例において糖代謝の低下が認知機能障害の指標となることが示された。TBIによる遅発性脳障害は複合的な病態であり、個々の病態に対応したイメージングバイオマーカーを開発する必要がある。, 第43回日本生物学的精神医学会・第51回日本神経精神薬理学会 合同年会

【背景】22q11.2欠失症候群(22q11DS)は、第22染色体の長腕11.2領域欠失により生じ、先天性心疾患、パーキンソン病、統合失調症、強迫性障害、知的障害など幅広い臨床症状を有する遺伝的症候群である。22q11DSでは、特に線条体外において、シナプス間隙のドーパミン（DA）濃度を調節する酵素であるcatechol-O-methyl-transferase（COMT）遺伝子のハプロ不全をもたらすことから、22q11DSではDA神経伝達異常が起こっている可能性がある。本研究では、22q11DSにおける脳内ドーパミン神経伝達の変化を明らかにすることを目的とし、成人22q11DS患者および健常者を対象に、PETにより線条体外におけるドーパミンD1およびD2受容体密度を調べた。 【方法】22q11DS 5名(平均36.3歳)、および同年代の健常被験者10名(平均35.8歳)に対して11C-SCH23390を用いたD1受容体PET、11C-FLB457を用いたD2受容体PET検査を実施した。11C-SCH23390および11C-FLB457 PETでは、小脳を参照領域としたsimplified reference tissue model法により各々D1およびD2受容体密度の指標 (BPND) を求めた。 【結果】患者群では健常群に比較して、側頭葉における11C-SCH23390 PETによるBPNDの有意な上昇を認めたが (analysis of covariance, F = 6.34, p = 0.027)、そのほかの領域ではBPNDに有意な群間差を認めなかった。また、患者群において、11C-FLB457 PETによるBPNDでも上昇傾向を側頭葉において認めたが有意ではなく(analysis of covariance, F = 2.46, p = 0.145)、そのほかの領域ではBPNDに有意な群間差を認めなかった。また、両群とも、全領域にて11C-SCH23390 BPNDと、11C-FLB457 BPNDは、加齢に伴い低下する傾向を認めた。 【考察】本研究により、22q11DSでは側頭葉におけるD1およびD2受容体密度が上昇している可能性が示され、ドーパミン神経伝達機構の制御が障害されている可能性が示唆された。少数例の検討であるため、今後はさらに症例数を増やす必要がある。, 第43回日本生物学的精神医学会・第51回日本神経精神薬理学会 合同年会