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Synaptic phenotypes in living patients with psychiatric disorders are poorly characterized. Excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a fundamental component for neurotransmission. We recently developed a positron emission tomography (PET) tracer for AMPAR, [11C]K-2, the first technology to visualize and quantify AMPARs density in living human brain. In this study, we characterized patients with major psychiatric disorders with [11C]K-2. One hundred forty-nine patients with psychiatric disorders (schizophrenia, n = 42; bipolar disorder, n = 37; depression, n = 35; and autism spectrum disorder, n = 35) and 70 healthy participants underwent a PET scan with [11C]K-2 for measurement of AMPAR density. We detected brain regions that showed correlation between AMPAR density and symptomatology scores in each of four disorders. We also found brain areas with significant differences in AMPAR density between patients with each psychiatric disorder and healthy participants. Some of these areas were observed across diseases, indicating that these are commonly affected areas throughout psychiatric disorders. Schizophrenia, bipolar disorder, depression, and autism spectrum disorder are uniquely characterized by AMPAR distribution patterns. Our approach to psychiatric disorders using [11C]K-2 can elucidate the biological mechanisms across diseases and pave the way to develop novel diagnostics and therapeutics based on the synapse physiology.

DOI： 10.1038/s41380-024-02785-1

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Long COVID primarily presents with persistent cognitive impairment (Cog-LC), imposing a substantial and lasting global burden. Even after the pandemic, there remains a critical global need for diagnostic and therapeutic strategies targeting Cog-LC. Nevertheless, the underlying neural mechanisms remain poorly understood. Given the central role of synapses in brain function, investigation of synaptic molecular changes may provide vital insights into Cog-LC pathophysiology. In this study, we used [11C]K-2 PET to characterize the density of AMPA receptors (AMPARs) on the post-synaptic cell surface, which are crucial synaptic components in brain signalling. Statistical parametrical mapping was used to spatially normalize and apply independent t-test for a voxel-based comparison. We selected patients with Cog-LC (n = 30) based on Repeatable Battery for the Assessment of Neuropsychological Status assessed persistent cognitive impairment and healthy controls (n = 80) with no diagnosed neuropsychiatric disorders. The primary objective was to compare [11C]K-2 standardized uptake value ratio with white matter (SUVRWM) as a reference region between patients with Cog-LC and healthy controls, and to define the regional extent of differences. The secondary objective was to examine associations between [11C]K-2 SUVRWM and plasma concentrations of cytokines or chemokines. As an exploratory objective, we tested whether [11C]K-2 PET data could distinguish Cog-LC from healthy controls using a partial least squares based classification algorithm. A voxel-based comparison (P < 0.05, T > 1.66, one-tailed, false discovery rate control) and a volume of interests analysis (P < 0.05, Bonferroni multiple comparison) demonstrated that increased index of AMPAR density in large parts of the brains of patients with Cog-LC compared with that in healthy controls. A voxel-based correlation analysis also showed the brain regions where [11C]K-2 SUVRWM correlated positively with plasma TNFSF12 and negatively with plasma CCL2 concentrations. A partial least squares model trained on the index of AMPAR density data demonstrated high diagnostic accuracy, achieving 100% sensitivity and 91.2% specificity. [11C]K-2 PET signal represents the index of AMPAR density on the post-synaptic neural cell surface, not on the glial cell surface. A systemic increase in synaptic AMPARs across the brain may drive abnormal information processing in Cog-LC and, through excessive excitatory signalling, pose a risk of excitotoxic neuronal damage. We derived the hypothesis that [11C]K-2 PET would be helpful in establishing a diagnostic framework for Cog-LC and that antagonists for cell surface AMPARs, such as perampanel, would be a potential therapeutic target. These hypotheses should be investigated in future large-scale clinical studies.

DOI： 10.1093/braincomms/fcaf337

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An accurate diagnostic method using biological indicators is critically needed for bipolar disorder (BD) and major depressive disorder (MDD). The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is a crucial regulator of synaptic function, and its dysregulation may play a central role in the pathophysiology of psychiatric disorders. Our recently developed positron emission tomography (PET) tracer, [11C]K-2, enables the quantitative visualization of AMPAR distribution and is considered useful for characterizing synaptic phenotypes in patients with psychiatric disorders. This study aimed to develop a machine learning-based method to differentiate bipolar disorder from major depressive disorder using AMPAR density. Sixteen patients with BD and 27 patients with MDD, all in depressive episodes, underwent PET scans with [11C]K-2 and structural magnetic resonance imaging. AMPAR density was estimated using the standardized uptake value ratio from 30 to 50 min after tracer injection, normalized to whole brain radioactivity. A partial least squares model was trained to predict diagnoses based on AMPAR density, and its performance was evaluated using a leave-one-pair-out cross-validation. Significant differences in AMPAR density were observed in the parietal lobe, cerebellum, and frontal lobe, notably the dorsolateral prefrontal cortex between patients with BD and patients with MDD during a depressive episode. The model achieved an area under the curve of 0.80, sensitivity of 75.0%, and specificity of 77.8%. These findings suggest that AMPAR density measured with [11C]K-2 can effectively distinguish BD from MDD and may aid diagnosis, especially in patients with ambiguous symptoms or incomplete clinical presentation.

DOI： 10.3389/fncir.2025.1624179

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AIM: Although the antidepressant effect of ketamine on treatment-resistant depression (TRD) has been frequently reported in North American and European countries, evidence is scarce among the Asian population. We aimed to evaluate the efficacy and safety of intravenous ketamine in Japanese patients with TRD. METHODS: In this double-blind randomized placebo-controlled trial, 34 Japanese patients with TRD were randomized to receive either intravenous ketamine (0.5 mg/kg) or placebo, administered over 40 min, twice a week, for 2 weeks. The primary outcome was the change in the Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to post-treatment. Secondary outcomes included changes in other depressive symptomatology scores and remission, response, and partial response rates. We also examined the association between baseline clinical demographic characteristics and changes in the MADRS total score. RESULTS: Intention-to-treat analysis indicated no significant difference in the decrease in MADRS total score between the groups (-8.1 ± 10.0 vs -2.5 ± 5.2, t[32] = 2.02, P = 0.052), whereas per-protocol analysis showed a significant reduction in the ketamine group compared to the placebo group (-9.1 ± 10.2 vs -2.7 ± 5.3, t[29] = 2.22, P = 0.034). No significant group differences were observed in other outcomes. Adverse events were more frequent in the ketamine group than in the placebo group, and no serious adverse events were reported. A higher baseline MADRS total score and body mass index were associated with a greater reduction in the MADRS total score. CONCLUSION: Intravenous ketamine outperformed placebo in Japanese patients with TRD who completed the study, suggesting that ketamine could alleviate depressive symptoms of TRD across diverse ethnic populations.

DOI： 10.1111/pcn.13734

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The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

DOI： 10.1016/j.xcrm.2023.101020

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DOI： 10.1097/MCD.0000000000000386

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