Search

Dopamine D2 receptor partial agonist antipsychotic drugs can modulate dopaminergic neurotransmission as functional agonists or functional antagonists. The effects of antipsychotics on presynaptic dopaminergic functions, such as dopamine synthesis capacity, might also be related to their therapeutic efficacy. Positron emission tomography (PET) was used to examine the effects of the partial agonist antipsychotic drug aripiprazole on presynaptic dopamine synthesis in relation to dopamine D2 receptor occupancy and the resulting changes in dopamine synthesis capacity in healthy men. On separate days, PET studies with [11C]raclopride and L-[β-11 C]DOPA were performed under resting condition and with single doses of aripiprazole given orally. Occupancy of dopamine D2 receptors corresponded to the doses of aripiprazole, but the changes in dopamine synthesis capacity were not significant, nor was the relation between dopamine D2 receptor occupancy and these changes. A significant negative correlation was observed between baseline dopamine synthesis capacity and changes in dopamine synthesis capacity by aripiprazole, indicating that this antipsychotic appears to stabilize dopamine synthesis capacity. The therapeutic effects of aripiprazole in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity. [ABSTRACT FROM AUTHOR]

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

Background: Tau aggregates are one of key pathological features of Alzheimer's disease (AD) and other neurodegenerative diseases. Recently, PET probes for tau have been developed for in vivo detection of tau accumulation, but have limitations such as off‐target binding and lower ability to detect tau in non‐AD tauopathies. Preclinically, a tau tracer, 18F‐PI‐2620, has a high binding‐affinity and specificity for aggregated tau, and was indicated to have desirable properties for visualization of tau accumulation in both AD and non‐AD tauopathies (Kroth H. et al, Eur J Nucl Med Mol Imaging, 2019). The aim of present study is to assess the ability of 18F‐PI‐2620 to detect regional tau burden in AD and non‐AD tauopathies. Method: We recruited healthy volunteers (N=4, 64‐79 years old), patients with AD (N=4, 65‐80 years old), and with non‐AD tauopathies (three PSP cases and two CBS cases) (N=5, 65‐78 years old). One clinically diagnosed PSP case was pathologically confirmed as CBD after the autopsy. PET imaging with 18F‐PI‐2620 was performed, and its accumulation in the cortical and subcortical region were assessed by calculating standardized uptake value ratios (SUVR), along with amyloid PET using 18F‐flobetaben. Furthermore, a postmortem analysis for radio‐pathological correlation was performed in one CBD patient. Result: In AD, focal retention of 18F‐PI‐2620 was apparent in the temporal, parietal, and cingulate cortex. SUVR analysis revealed that more prominent uptake in the globus pallidus (GP) and midbrain was observed in PSP, CBS, and CBD cases in comparison to AD cases, whereas such discrepancies were not apparent in other regions with expected four repeat (4R) tau accumulation. In a CBD case, radio‐pathological analysis failed to show a strong correlation between region‐matched 18F‐PI‐2620 retention in vivo and postmortem burden of tau (AT8 immunohistochemistry). Conclusion: Although 18F‐PI‐2620 may be a promising tracer for tau in AD cases, in vivo retention of this tracer doesn't correlate with expected 4R tau burden in non‐AD tauopathies. 18F‐PI‐2620 may have limited utility for reliable detection of 4R tau pathology. [ABSTRACT FROM AUTHOR]

Background: Accumulation of hyperphosphorylated tau is a core feature of late‐life sequalae of mild‐repetitive traumatic brain injury (mrTBI). Brain‐bank surveys have demonstrated that chronic traumatic encephalopathy (CTE), defined as tau accumulation at the depths of cortical sulci, is a typical neurodegenerative condition associated with mrTBI exposure. In contrast, early case‐reports of dementia pugilistica (DP) in former boxers described considerable heterogeneity of late‐life neurodegenerative changes. Despite such inconsistency, topology of tau accumulation in the living brain of mrTBI patients have not been fully investigated. The present study was aimed to characterize cerebral retention patterns of 118F‐PM‐PBB3 (18F‐APN‐1607) in the former boxers. Method: Thirteen former boxers (46.2 ± 11.9 years) and 15 age‐matched healthy control (HC) subjects underwent PET scans with 18F‐PM‐PBB3 and [11C]PiB. Standard uptake value ratio (SUVR) with the cerebellar gray matter as reference was calculated. Association of SUVR with neurocognitive symptoms and years of playing boxing was investigated. Result: All subjects were [11C]PiB negative. Boxers showed higher 18F‐PM‐PBB3 accumulation than HC subjects in the gray (P = 0.0002) and white matter (P = 0.0001). There was a trend of correlation between SUVR values in the temporal cortex and years of exposure to concussions (p=0.07, r=0.40). Visual assessments revealed heterogeneity in 18F‐PM‐PBB3 retention patterns in boxers. First, the majority of boxers (7/13) demonstrated multiple 18F‐PM‐PBB3 accumulations around the depth of cerebral sulci, showing striking resemblance to previously reported tau topology of CTE. Subjects in this group tend to show severe memory impairment and depression. Second, a few boxers (3/13) showed diffuse 18F‐PM‐PBB3 accumulation, indicating some form of non‐AD tauopathy but currently unspecified. Subject in this group showed psychiatric symptoms such as psychosis and mania. Third, the other 3 boxers showed minimum 18F‐PM‐PBB3 retention regardless of clinical symptoms. Conclusion: Our results indicates different forms of tau neuropathology underlying late‐sequalae of mrTBI in agreement with the classical concept of DP. These forms vary in where and how much tau accumulate, as well as in clinical features. The present study not only supports pathological heterogeneity of late‐sequalae of mrTBI, but also suggests utility of 18F‐PM‐PBB3 PET in detection of late‐life neurodegenerative diseases following mrTBI. [ABSTRACT FROM AUTHOR]

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. First, we examined correlations between the DA synthesis capacity and DA transporter availability in the caudate and putamen using PET data with L-[β-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-[β-11C]DOPA and [11C]raclopride, respectively, obtained from other previous dual-tracer assays. 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. 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. [ABSTRACT FROM AUTHOR]

Background: The term "primary age‐related tauopathy" (PART) was recently introduced to describe a pathology that is commonly observed in the brain of aged individuals. Symptoms in persons with PART usually range from normal cognition to amnesia. The aim of the study is to explore the tau aggregates accumulation in the brain of healthy volunteers by PET with [18F]PM‐PBB3 ([18F]APN‐1607). Method: Fifty‐three healthy individuals (28 men and 25 women ranging in age from 23 to 79 years with a mean of 60) without any history of psychiatric and neurological diseases participated in this study. All subjects underwent neurological examination, cognitive tests, brain MRI, [11C]PiB PET (Aβ imaging), and [18F]PM‐PBB3 PET. [11C]PiB PET images (50‐70 min) was visually assessed. An automated analysis of the volumes of interest in [18F]PM‐PBB3 images (90‐110 min) was performed using the PNEURO module in the PMOD software. Standardized uptake value ratio (SUVR) values were obtained using the cerebellar cortex as a reference region. Pearson correlation analysis was performed between [18F]PM‐PBB3 SUVR and age. Result: Neurological examination revealed no significant finding except for hand tremors in one subject. Cognitive tests were normal in all subjects. Two men were Aβ positive and excluded from the following analysis. There was a positive correlation between age and tau PET signal in the parahippocampus (r = 0.30, P < 0.03), fusiform gyrus (r = 0.41, P < 0.003), and middle and inferior temporal cortex (r = 0.28, P < 0.05) of 51 subjects. No positive correlation between age and [18F]PM‐PBB3 SUVR was found in any other brain regions. Conclusion: The present result supports the concept of PART and the detectability of PART‐type tau deposits by PET with [18F]PM‐PBB3. [ABSTRACT FROM AUTHOR]

A study published in Translational Neurodegeneration introduces a new blood-based biomarker, the plasma p-tau181 assay, which accurately reflects tau pathology in Alzheimer's disease (AD). Unlike current assays, this new biomarker is not affected by amyloid accumulation and shows higher specificity for tau pathology. It has the potential to detect and stage AD tau pathologies in the brain, offering a more accessible and functional alternative to PET scans. The assay may also help predict therapeutic response to current treatments and identify suitable patients for anti-amyloid therapies. However, more research with larger sample sizes is needed to confirm these findings. [Extracted from the article]

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 [ABSTRACT FROM AUTHOR]

Previous studies have developed and explored magnetic resonance imaging (MRI)-based machine learning models for predicting Alzheimer's disease (AD). However, limited research has focused on models incorporating diverse patient populations. This study aimed to build a clinically useful prediction model for amyloid-beta (Aβ) deposition using source-based morphometry, using a data-driven algorithm based on independent component analyses. Additionally, we assessed how the predictive accuracies varied with the feature combinations. Data from 118 participants clinically diagnosed with various conditions such as AD, mild cognitive impairment, frontotemporal lobar degeneration, corticobasal syndrome, progressive supranuclear palsy, and psychiatric disorders, as well as healthy controls were used for the development of the model. We used structural MR images, cognitive test results, and apolipoprotein E status for feature selection. Three-dimensional T1-weighted images were preprocessed into voxel-based gray matter images and then subjected to source-based morphometry. We used a support vector machine as a classifier. We applied SHapley Additive exPlanations, a game-theoretical approach, to ensure model accountability. The final model that was based on MR-images, cognitive test results, and apolipoprotein E status yielded 89.8% accuracy and a receiver operating characteristic curve of 0.888. The model based on MR-images alone showed 84.7% accuracy. Aβ-positivity was correctly detected in non-AD patients. One of the seven independent components derived from source-based morphometry was considered to represent an AD-related gray matter volume pattern and showed the strongest impact on the model output. Aβ-positivity across neurological and psychiatric disorders was predicted with moderate-to-high accuracy and was associated with a probable AD-related gray matter volume pattern. An MRI-based data-driven machine learning approach can be beneficial as a diagnostic aid. [ABSTRACT FROM AUTHOR]

Background: Although there is growing evidence of alterations in the neurometabolite status associated with the pathophysiology of schizophrenia, how treatments influence these metabolite levels in patients with schizophrenia remains poorly studied.Methods: We conducted a literature search using Embase, Medline, and PsycINFO to identify proton magnetic resonance spectroscopy studies that compared neurometabolite levels before and after treatment in patients with schizophrenia. Six neurometabolites (glutamate, glutamine, glutamate + glutamine, gamma-aminobutyric acid, N-acetylaspartate, myo-inositol) and six regions of interest (frontal cortex, temporal cortex, parieto-occipital cortex, thalamus, basal ganglia, hippocampus) were investigated.Results: Thirty-two studies (n = 773 at follow-up) were included in our meta-analysis. Our results demonstrated that the frontal glutamate + glutamine level was significantly decreased (14 groups; n = 292 at follow-up; effect size = -0.35, P = 0.0003; I2 = 22%) and the thalamic N-acetylaspartate level was significantly increased (7 groups; n = 184 at follow-up; effect size = 0.47, P < 0.00001; I2 = 0%) after treatment in schizophrenia patients. No significant associations were found between neurometabolite changes and age, gender, duration of illness, duration of treatment, or baseline symptom severity.Conclusions: The current results suggest that glutamatergic neurometabolite levels in the frontal cortex and neuronal integrity in the thalamus in schizophrenia might be modified following treatment. [ABSTRACT FROM AUTHOR]

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 [11C]PiB and [18F]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 2024;95:104–115 [ABSTRACT FROM AUTHOR]

Background: Plasma biomarkers have emerged as promising screening tools for Alzheimer's disease (AD) because of their potential to detect amyloid β (Aβ) accumulation in the brain. One such candidate is the plasma Aβ42/40 ratio (Aβ42/40). Unlike previous research that used traditional immunoassay, recent studies that measured plasma Aβ42/40 using fully automated platforms reported promising results. However, its utility should be confirmed using a broader patient population, focusing on the potential for early detection. Methods: We recruited 174 participants, including healthy controls (HC) and patients with clinical diagnoses of AD, frontotemporal lobar degeneration, dementia with Lewy bodies/Parkinson's disease, mild cognitive impairment (MCI), and others, from a university memory clinic. We examined the performance of plasma Aβ42/40, measured using the fully automated high-sensitivity chemiluminescence enzyme (HISCL) immunoassay, in detecting amyloid-positron emission tomography (PET)-derived Aβ pathology. We also compared its performance with that of Simoa-based plasma phosphorylated tau at residue 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). Results: Using the best cut-off derived from the Youden Index, plasma Aβ42/40 yielded an area under the receiver operating characteristic curve (AUC) of 0.949 in distinguishing visually assessed 18F-Florbetaben amyloid PET positivity. The plasma Aβ42/40 had a significantly superior AUC than p-tau181, GFAP, and NfL in the 167 participants with measurements for all four biomarkers. Next, we analyzed 99 participants, including only the HC and those with MCI, and discovered that plasma Aβ42/40 outperformed the other plasma biomarkers, suggesting its ability to detect early amyloid accumulation. Using the Centiloid scale (CL), Spearman's rank correlation coefficient between plasma Aβ42/40 and CL was -0.767. Among the 15 participants falling within the CL values indicative of potential future amyloid accumulation (CL between 13.5 and 35.7), plasma Aβ42/40 categorized 61.5% (8/13) as Aβ-positive, whereas visual assessment of amyloid PET identified 20% (3/15) as positive. Conclusion: Plasma Aβ42/40 measured using the fully automated HISCL platform showed excellent performance in identifying Aβ accumulation in the brain in a well-characterized cohort. This equipment may be useful for screening amyloid pathology because it has the potential to detect early amyloid pathology and is readily applied in clinical settings. [ABSTRACT FROM AUTHOR]

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

Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD, abnormal tau accumulates within neurons of the brain, facilitated by extracellular β‐amyloid deposition, leading to neurodegeneration, and eventually, cognitive impairment. As this process is thought to be irreversible, early identification of abnormal tau in the brain is crucial for the development of new therapeutic interventions. Aims: 18F‐PI‐2620 is one of the second‐generation tau PET tracers with presumably less off‐target binding than its predecessors. Although a few clinical studies have recently reported the use of 18F‐PI‐2620 tau PET in patients with AD, its applicability to AD is yet to be thoroughly examined. Methods: In the present pilot study, we performed 18F‐PI‐2620 tau PET in seven cases of probable AD (AD group) and seven healthy controls (HC group). Standardized uptake value ratios (SUVR) in regions of interest (ROIs) in the medial temporal region and neocortex were compared between the AD and HC groups. Furthermore, correlations between regional SUVR and plasma p‐tau181 as well as cognitive test scores were also analyzed. Results: The uptake of 18F‐PI‐2620 was distinctly increased in the AD group across all the ROIs. SUVR in all the target ROIs were significantly correlated with plasma p‐tau181 levels, as well as with MMSE and ADAS‐cog scores. Discussion & Conclusion: Our results add to accumulating evidence suggesting that 18F‐PI‐2620 is a promising tau PET tracer that allows patients with AD to be distinguished from healthy controls, although a study with a larger sample size is warranted. [ABSTRACT FROM AUTHOR]

Background: We recently developed a positron emission tomography (PET) probe, [18F]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 [ABSTRACT FROM AUTHOR]

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development. [Display omitted] • A novel imaging agent for α-synuclein pathologies, C05-05, was developed • C05-05 enabled visualization of α-synuclein depositions in Parkinson's disease • C05-05 retentions in the midbrain correlated with the severity of motor symptoms • C05-05 offered microscopic and macroscopic α-synuclein imaging in animal models Endo et al. developed a positron emission tomography agent, 18F-C05-05, for α-synuclein pathologies in animal models and provided the first demonstration of α-synuclein imaging in patients with Parkinson's disease and dementia with Lewy bodies. This technology offers neuropathology-based translational assessments for diagnostic and therapeutic purposes. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

• 18F-PM-PBB3 PET captures diverse tau lesions in FTLD-tau as well as in AD. • We developed a new workflow to extract optimal reference regions using histograms. • Reference regions extracted from gray matter increased the sensitivity of FTLD-tau. • The methodology enabled accurate quantification of tau lesions in diverse illnesses. 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. [ABSTRACT FROM AUTHOR]

Self-disturbance, a core feature of schizophrenia, recently has been explained from the standpoint of an abnormal sense of agency (SoA). Previous studies showed that aberrant SoA in schizophrenia arise from imprecise predictions about the sensory consequences of actions. However, the nature of the malfunctioning predictions remains unclear. We examined the temporally “delayed” nature of inadequate predictions. We studied 30 patients with schizophrenia and 30 healthy controls. Our original SoA task evaluates explicit experience of the temporal causal relationship between an intentional action and an effect on a computer screen under the presence of temporal biases. We introduced an adaptation with a “trial-by-trial” method that prolonged or shortened the temporal biases. We hypothesized that delayed prediction signals in schizophrenia could lead to a match in timing between predictions and actual outcomes, resulting in self-agency. The adjustment courses to changing temporal biases were evaluated. Patients with schizophrenia continued to feel self-agency even when the adjusted temporal bias was longer than 1000 ms. This result indicated that patient's prediction would be delayed in each trial. Our study empirically showed behavioral evidence for “delayed” prediction signals in a SoA paradigm for the first time. [ABSTRACT FROM AUTHOR]

The majority of individuals evaluate themselves as superior to average. This is a cognitive bias known as the "superiority illusion." This illusion helps us to have hope for the future and is deep-rooted in the process of human evolution. In this study, we examined the default states of neural and molecular systems that generate this illusion, using resting-state functional MRI and PET. Resting-state functional connectivity between the frontal cortex and striatum regulated by inhibitory dopaminergic neurotransmission determines individual levels of the superiority illusion. Our findings help elucidate how this key aspect of the human mind is biologically determined, and identify potential molecular and neural targets for treatment for depressive realism. [ABSTRACT FROM AUTHOR]

[Display omitted] • The first report of an antemortem diagnosis of PSP-C using [18F]PM-PBB3 tau PET. • [18F]PM-PBB3 retention is consistent with typical PSP neuropathology. • [18F]PM-PBB3 is a potentially reliable imaging modality for atypical PSP. [ABSTRACT FROM AUTHOR]

A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer's disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of 18F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick's disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis. • A new probe, PM-PBB3, captures pathological tau deposits in vivo with high contrast • PM-PBB3 allows an individual-based identification of AD and non-AD tauopathies • Autopsy assays of PET-scanned patients supported the in vivo performance of PM-PBB3 Tagai et al. developed a positron emission tomography probe, 18F-PM-PBB3, for tau deposits in Alzheimer's and non-Alzheimer's disease tauopathies. This probe was demonstrated to enable individual- and pathology-based diagnosis, differentiation, and staging of these disorders in addition to translational research and development on tauopathies from mouse models to humans. [ABSTRACT FROM AUTHOR]

Background: To establish simple screening tests to suspect Alzheimer's disease (AD) pathology, the clinical sign "head-turning sign" (HTS), which is a patient's behavior of turning their head towards their partner to seek assistance with questions posed by the examiner during the interview, and the simple screening questionnaire for dementia named "Neucop-Q" were validated in participants diagnosed with amyloid and tau positron emission tomography (PET)., Methods: We enrolled 155 patients: 47 cognitive normal, 36 with mild cognitive impairment, 64 with dementia, and 8 with psychiatric disorders. All participants underwent Neucop-Q [three questions: Consciousness/self-awareness of cognitive disabilities (C) normal/impaired (nor/imp), Pleasure/pastime (P) nor/imp, and News/knowledge on current topics (N) nor/imp] and amyloid/tau PET. Additionally, we measured plasma amyloid β (Aβ) 42/40 ratio, phosphorylated tau 181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) levels and compared with HTS and Neucop-Q results., Results: The specificity and positive predictive value (PPV) of HTS positivity (HTSpos) were the highest (amyloid PET: 0.930 and 0.870, tau PET: 0.944 and 0.957, respectively), while Cimp and Nimp had a high negative predictive value (NPV) for amyloid PET (negativity) (0.750 and 0.725). Pimp showed high specificity for predicting non-AD tau positivity among non-AD participants without amyloid PET positivity (0.854). To validate these findings with PET results, we examined the correlation between well-established AD blood biomarkers and results obtained from these screening tests. HTSpos, Cimp, and Nimp were strongly associated with Aβ42/40 ratio (P < 0.0001, P = 0.0022, and P = 0.001), pTau181 (P < 0.0001, P = 0.0095, and P = 0.001), GFAP (P = 0.0372, P = 0.0088, and P = 0.0002), and amyloid PET Centiloid (P < 0.0001, P = 0.0210, and P = 0.0006), whereas Pimp increased neuroinflammation (GFAP; P = 0.0061) and was associated with non-AD tauopathy. The combination of Neucop-Q questions showed that Cimp/Pnor/Nimp subjects have the highest specificity and PPV (0.972 and 0.833) and were strongly associated with Aβ42/40 ratio (P = 0.0006), pTau181 (P = 0.0006), and amyloid PET Centiloid (P < 0.0001)., Conclusion: HTSpos, Cimp, and Nimp have diagnostic utility in suspecting MCI due to AD and AD, and Pimp has diagnostic value in non-AD tauopathy. HTSpos, Cimp, and Nimp were associated with biomarkers of Aβ pathology. HTS and Neucop-Q may serve as powerful first-line screening in memory clinics., Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR) under registration numbers 000032027 (Registration date: 2018/03/31) and 000030248 (Registration date: 2018/01/01)., Competing Interests: Declarations. Ethics approval and consent to participate: The Certified Review Board of Keio University (#N20170237) approved the study design and protocol. The study was conducted in accordance with the Declaration of Helsinki. All participants (plus their proxies as needed) provided written informed consent for participation in the study. The study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; https://www.umin.ac.jp/ctr/index.htm , ID# UMIN000032027) and Japan Registry of Clinical Trials (jRCT; https://jrct.niph.go.jp/ , ID# jRCTs031180225). Consent for publication: Not applicable. Competing interests: Daisuke Ito has received honorariums from Daiichi Sankyo, Nihon Medi-Physics, KOWA, and Eizai; there are no other relationships or activities that could appear to have influenced the submitted work., (© 2024. The Author(s).)

Background: Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD)., Objective: To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using 18 F-florzolotau PET and examine correlations with cognitive function., Methods: Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent 18 F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess 18 F-florzolotau binding to tau deposits., Results: EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant 18 F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples., Conclusions: This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. 18 F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD., Competing Interests: Declaration of conflicting interestsHitoshi Shimada, Ming-Rong Zhang, and Makoto Higuchi hold patents on compounds related to the present report (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672). All other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[ 18 F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([ 18 F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [ 18 F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = -0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target., (© 2024. The Author(s).)

Tau positron emission tomography (PET) is a neuroimaging technique that visualizes tau deposition using PET tracers that selectively bind to tau aggregates. Studies have reported the diagnostic and prognostic value of tau PET in Alzheimer's disease and other tauopathies. However, the binding profiles of tau PET drugs vary widely across tauopathies; therefore, an accurate understanding of the disease-specific characteristics is essential for interpretation of tau PET findings. In this review, we discuss the properties of tau-PET agents and their applications in various diseases.