In Vivo Assessment of Astrocyte Reactivity in Patients with Progressive Supranuclear Palsy.

OBJECTIVE: Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. METHODS: We included 30 patients with PSP-Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F-florzolotau positron emission tomography. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. RESULTS: The levels of myo-inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo-inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. INTERPRETATION: We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo-inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024;96:247-261.

Altered Brain Energy Metabolism Related to Astrocytes in Alzheimer's Disease.

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.

Serotonergic Neurotransmission in Limbic Regions May Reflect Therapeutic Response of Depressive Patients: A PET Study With 11C-WAY-100635 and 18F-MPPF.

BACKGROUND: 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. METHODS: Eleven patients with depression, including 9 treated with antidepressants, and 16 age- and sex-matched healthy individuals underwent PET scans with 11C-WAY-100635 and 18F-MPPF. Radioligand binding was determined by calculating the nondisplaceable binding potential (BPND). RESULTS: 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. CONCLUSIONS: 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.

Association of protein distribution and gene expression revealed by positron emission tomography and postmortem gene expression in the dopaminergic system of the human brain.

PURPOSE: The topological distribution of dopamine-related proteins is determined by gene transcription and subsequent regulations. Recent research strategies integrating positron emission tomography with a transcriptome atlas have opened new opportunities to understand the influence of regulation after transcription on protein distribution. Previous studies have reported that messenger (m)-RNA expression levels spatially correlate with the density maps of serotonin receptors but not with those of transporters. This discrepancy may be due to differences in regulation after transcription between presynaptic and postsynaptic proteins, which have not been studied in the dopaminergic system. Here, we focused on dopamine D1 and D2/D3 receptors and dopamine transporters and investigated their region-wise relationship between mRNA expression and protein distribution. METHODS: We examined the region-wise correlation between regional binding potentials of the target region relative to that of non-displaceable tissue (BPND) values of 11C-SCH-23390 and mRNA expression levels of dopamine D1 receptors (D1R); regional BPND values of 11C-FLB-457 and mRNA expression levels of dopamine D2/D3 receptors (D2/D3R); and regional total distribution volume (VT) values of 18F-FE-PE2I and mRNA expression levels of dopamine transporters (DAT) using Spearman's rank correlation. RESULTS: We found significant positive correlations between regional BPND values of 11C-SCH-23390 and the mRNA expression levels of D1R (r = 0.769, p = 0.0021). Similar to D1R, regional BPND values of 11C-FLB-457 positively correlated with the mRNA expression levels of D2R (r = 0.809, p = 0.0151) but not with those of D3R (r = 0.413, p = 0.3095). In contrast to D1R and D2R, no significant correlation between VT values of 18F-FE-PE2I and mRNA expression levels of DAT was observed (r = -0.5934, p = 0.140). CONCLUSION: We found a region-wise correlation between the mRNA expression levels of dopamine D1 and D2 receptors and their respective protein distributions. However, we found no region-wise correlation between the mRNA expression levels of dopamine transporters and their protein distributions, indicating different regulatory mechanisms for the localization of pre- and postsynaptic proteins. These results provide a broader understanding of the application of the transcriptome atlas to neuroimaging studies of the dopaminergic nervous system.

An optimized reference tissue method for quantification of tau protein depositions in diverse neurodegenerative disorders by PET with 18F-PM-PBB3 (18F-APN-1607).

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.

Pharmacokinetic and pharmacodynamic assessment of histamine H3 receptor occupancy by enerisant: a human PET study with a novel H3 binding ligand, [11C]TASP457.

PURPOSE: Histamine H3 receptor antagonists and inverse agonists have been extensively developed to treat sleep-wake, neurocognitive, and allied disorders. However, potential adverse effects, including insomnia, hampered the clinical use of these drugs, possibly due to their persistent interaction with the target molecules. The purpose of the present study was to estimate the pharmacokinetics and pharmacodynamics of enerisant, a novel antagonist and inverse agonist for histamine H3 receptors. METHODS: To measure the histamine H3 receptor occupancy by enerisant, positron emission tomography studies using [11C]TASP457, a specific radioligand for histamine H3 receptors, were performed in 12 healthy men at baseline and at 2 h after oral administration of enerisant hydrochloride. For three of these subjects, two additional scans were performed at 6 and 26 h after the administration. Relationships between the receptor occupancy by enerisant and its dose and plasma concentrations were then analyzed. RESULTS: Administration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels (> 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h. CONCLUSION: The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine H3 receptors by enerisant at 2 h can be predicted by applying the plasma concentration of enerisant to Hill's plot. The preliminary time-course investigation showed persistently high brain occupancy with high doses of enerisant despite the decreasing plasma concentration of the drug. Five milligrams or less dose would be appropriate for the treatment for narcolepsy with initially high occupancy allowing for effective treatment of narcolepsy, and then the occupancy level would be expected to decrease to a level to avoid this drug's unwanted side effect of insomnia at night, although further research is warranted to confirm the statement since the expected decrease is based on the finding in one subject. TRIAL REGISTRATION: This study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.

First-in-human in vivo imaging and quantification of monoacylglycerol lipase in the brain: a PET study with 18F-T-401.

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.

A Machine Learning-Based Approach to Discrimination of Tauopathies Using [18 F]PM-PBB3 PET Images.

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.

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

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-ß (Aß) 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 Aß 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.

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

BACKGROUND: The dopamine (DA) neurotransmission has been implicated in fundamental brain functions, exemplified by movement controls, reward-seeking, motivation, and cognition. Although dysregulation of DA neurotransmission in the striatum is known to be involved in diverse neuropsychiatric disorders, it is yet to be clarified whether components of the DA transmission, such as synthesis, receptors, and reuptake are coupled with each other to homeostatically maintain the DA neurotransmission. The purpose of this study was to investigate associations of the DA synthesis capacity with the availabilities of DA transporters and D2 receptors in the striatum of healthy subjects. METHODS: First, we examined correlations between the DA synthesis capacity and DA transporter availability in the caudate and putamen using PET data with L-[ß-11C]DOPA and [18F]FE-PE2I, respectively, acquired from our past dual-tracer studies. Next, we investigated relationships between the DA synthesis capacity and D2 receptor availability employing PET data with L-[ß-11C]DOPA and [11C]raclopride, respectively, obtained from other previous dual-tracer assays. RESULTS: We found a significant positive correlation between the DA synthesis capacity and DA transporter availability in the putamen, while no significant correlations between the DA synthesis capacity and D2 receptor availability in the striatum. CONCLUSION: The intimate association of the DA synthesis rate with the presynaptic reuptake of DA indicates homeostatic maintenance of the baseline synaptic DA concentration. In contrast, the total abundance of D2 receptors, which consist of presynaptic autoreceptors and postsynaptic modulatory receptors, may not have an immediate relationship to this regulatory mechanism.

Relationship between regional gray matter volumes and dopamine D2 receptor and transporter in living human brains.

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D2 receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D2 receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [11 C]raclopride and [18 F]FE-PE2I, respectively, were acquired along with T1-weighted magnetic resonance imaging data in our previous studies, and were re-analyzed in this work. We quantified the binding potentials (BPND ) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BPND and regional GM volume were then examined by voxel-based morphometry. In line with the functional and anatomical connectivity, [11 C]raclopride BPND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BPND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BPND in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [18 F]FE-PE2I BPND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D2 receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT.

A first-in-human study of 11C-MTP38, a novel PET ligand for phosphodiesterase 7.

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.

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

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.

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

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.

Tau-induced focal neurotoxicity and network disruption related to apathy in Alzheimer's disease.

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-ß (Aß) 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 Aß 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.

Affinity States of Striatal Dopamine D2 Receptors in Antipsychotic-Free Patients with Schizophrenia.

Background: Dopamine D2 receptors are reported to have high-affinity (D2High) and low-affinity (D2Low) states. Although an increased proportion of D2High has been demonstrated in animal models of schizophrenia, few clinical studies have investigated this alteration of D2High in schizophrenia in vivo. Methods: Eleven patients with schizophrenia, including 10 antipsychotic-naive and 1 antipsychotic-free individuals, and 17 healthy controls were investigated. Psychopathology was assessed by Positive and Negative Syndrome Scale, and a 5-factor model was used. Two radioligands, [11C]raclopride and [11C]MNPA, were employed to quantify total dopamine D2 receptor and D2High, respectively, in the striatum by measuring their binding potentials. Binding potential values of [11C]raclopride and [11C]MNPA and the binding potential ratio of [11C]MNPA to [11C]raclopride in the striatal subregions were statistically compared between the 2 diagnostic groups using multivariate analysis of covariance controlling for age, gender, and smoking. Correlations between binding potential and Positive and Negative Syndrome Scale scores were also examined. Results: Multivariate analysis of covariance demonstrated a significant effect of diagnosis (schizophrenia and control) on the binding potential ratio (P=.018), although the effects of diagnosis on binding potential values obtained with either [11C]raclopride or [11C]MNPA were nonsignificant. Posthoc test showed that the binding potential ratio was significantly higher in the putamen of patients (P=.017). The Positive and Negative Syndrome Scale "depressed" factor in patients was positively correlated with binding potential values of both ligands in the caudate. Conclusions: The present study indicates the possibilities of: (1) a higher proportion of D2High in the putamen despite unaltered amounts of total dopamine D2 receptors; and (2) associations between depressive symptoms and amounts of caudate dopamine D2 receptors in patients with schizophrenia.

Occupancy of Norepinephrine Transporter by Duloxetine in Human Brains Measured by Positron Emission Tomography with (S,S)-[18F]FMeNER-D2.

Background: 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. Methods: 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. Results: 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. Conclusions: 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.