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Glucagon-like peptide-1 receptor agonists for major neurocognitive disorders.
Disease-modifying treatments for major neurocognitive disorders, including Alzheimer's disease, Parkinson's disease and other cognitive deficits, are among the main unmet needs in modern medicine. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently licensed for the treatment of type 2 diabetes mellitus and obesity, offer a novel, multilayered mechanism for intervention in neurodegeneration through intermediate, aetiology-agnostic pathways, likely involving metabolic, inflammatory and several other relevant neurobiological processes. In vitro and animal studies have revealed promising signals of neuroprotection, with preliminary supportive evidence emerging from recent pharmacoepidemiological investigations and clinical trials. In this article, we comprehensively review studies that investigate the impact of GLP-1RAs on the various aetiologies of cognitive impairment and dementia syndromes. Focusing on evidence from human studies, we highlight how brain energy homeostasis, neurogenesis, synaptic functioning, neuroinflammation and other cellular stress responses, pathological protein aggregates, proteostasis, cerebrovascular system and blood-brain barrier dynamics may underlie GLP-1RA putative neuroprotective effects. We then report and appraise evidence from clinical studies, including observational investigations, clinical trials and pooled analyses. Finally, we discuss current challenges and perspectives ahead for research and clinical implementation of GLP-1RAs for the care of people with major neurocognitive disorders, including their individual brain penetrance potential, the need for response biomarkers and disease stage-based indications, their possible non-specific effects on brain health, their profile in terms of adverse events and other unwanted effects, the lack of long-term data for efficacy and safety, and issues surrounding cost and availability of treatment.
Cognitive and neuropsychiatric profiles distinguish atypical parkinsonian syndromes.
Atypical parkinsonian syndromes are distinguished from Parkinson's disease by additional neurological signs and characteristic underlying neuropathology. However, they can be diagnostically challenging, rapidly progressive, and are often diagnosed late in disease course. Their different demographic features and prognoses are well studied, but the accompanying cognitive and psychiatric features may also facilitate diagnosis. Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may cause cognitive and behavioural manifestations that overlap with frontotemporal dementia, including non-fluent aphasia, apathy and impulsivity. Clinical diagnostic criteria have limited sensitivity, with pathologically confirmed PSP often having presented an initial clinical syndrome other than PSP-Richardson's syndrome. Here we integrate cross-sectional multi-centre baseline data from the PROSPECT and Oxford Discovery cohorts. This allowed us to compare cognitive and psychiatric features across a total of 1138 people with PSP, CBS, multiple-system atrophy (MSA), and idiopathic Parkinson's disease (PD). Data from the different cohorts were harmonised and compared using multiple linear regression. There were five key results. 1. Different syndromes showed distinctive cognitive profiles, using readily applicable 'bedside' screening tools. Frontal executive dysfunction was most evident in PSP, visuospatial deficits in CBS, with milder deficits in memory and executive function in MSA, as compared with PD. 2. The most prevalent neuropsychiatric features were depression and anxiety in CBS, apathy in PSP, with sleep disturbances common in PD. As expected, apathy correlated positively with impulsivity across all disorders. Neuropsychiatric features were generally better at discriminating between atypical parkinsonian syndromes than were the cognitive domains. 3. Both cognitive function and motor severity declined with disease duration, and motor function predicted cognition in PSP, CBS and PD but not in MSA, suggesting that in MSA cognitive and motor dysfunction are decoupled. 4. Plasma neurofilament light chain (NFL) levels, measured in a subset of patients, correlated with cognitive deficits in PSP, but not motor deficits. 5. Cognitive deficits contributed to the impairment in activities of daily living after controlling for motor severity, with every two points on the MoCA worsening the Schwab and England score by one point. In anticipation of future neuroprotective therapies, we present a classifier to improve diagnostic accuracy for atypical parkinsonian syndromes in vivo. Longitudinal cohort studies with resources for neuropathological gold-standard diagnosis remain important to validate better diagnostic tools for people with PSP, CBD, MSA and atypical parkinsonism.
Do biological alterations precede the onset of psychosis? A systematic review and meta-analysis of immune, cardiometabolic, prolactin and HPA axis alterations in clinical high-risk for psychosis.
First episode psychosis (FEP) individuals show biological abnormalities preceding antipsychotic treatment. However, it remains unclear whether such alterations are also present before the onset of psychosis. We aim to provide estimates of standardized mean differences for immune, cardiometabolic, prolactin, and HPA axis parameters in individuals at clinical high-risk for psychosis (CHR-P) compared to healthy controls (HC) and FEP individuals, and between CHR-P transitioning to psychosis (CHR-T) compared non-transitioning (CHR-NT). A multistep literature search was performed from database inception until September 25, 2023. PRISMA/MOOSE-compliant and pre-registered (PROSPERO: CRD42024507670) systematic review identified studies reporting on immune, cardiovascular or endocrine parameters in CHR-P samples compared with HC or FEP samples or comparing CHR-T vs CHR-NT. Inter-group differences in magnitude of effect were estimated using Hedges g and estimates were pooled using random-effects meta-analysis. Heterogeneity was high for most outcomes. 37 studies were included, total sample 2509 CHR-P, 710 FEP, and 1444 HC individuals. A statistically significant elevation of pro-inflammatory proteins was found among CHR-P compared with HC (k = 12; N = 1710; g = 0.16; p
The romanticisation of mental health problems in adolescents and its implications: a narrative review.
Romanticisation is the perception and portrayal of a phenomenon as more attractive, interesting, cool, profound or desirable than it really is. There are concerns that mental health problems are increasingly romanticised, particularly among adolescents, but there is limited research on this topic. This narrative review investigated: (1) what romanticisation is in the context of adolescent mental health problems, (2) why adolescents might romanticise mental health problems, (3) the implications of romanticising mental health problems in adolescence, and (4) what interventions might reduce this phenomenon. Sixty-one publications were reviewed, including qualitative and quantitative analyses, cross-sectional and longitudinal self-report studies and conceptual reviews. Most investigated romanticisation of mental health problems online, with most researchers situated in a Western context. Identity formation, popular media influences and peer influences arose as potential explanatory factors. Negative outcomes to romanticisation were indicated, including the reinforcement of mental health problems and reduced help-seeking; few interventions to reduce the phenomenon have been proposed to date.
Effect of Ketamine on Human Neurochemistry in Posterior Cingulate Cortex: A Pilot Magnetic Resonance Spectroscopy Study at 3 Tesla
Ketamine is a powerful glutamatergic long-lasting antidepressant, efficient in intractable major depression. Whereas ketamine’s immediate psychomimetic side-effects were linked to glutamate changes, proton MRS (1H-MRS) showed an association between the ratio of glutamate and glutamine and delayed antidepressant effect emerging ∼2 h after ketamine administration. While most 1H-MRS studies focused on anterior cingulate, recent functional MRI connectivity studies revealed an association between ketamine’s antidepressant effect and disturbed connectivity patterns to the posterior cingulate cortex (PCC), and related PCC dysfunction to rumination and memory impairment involved in depressive pathophysiology. The current study utilized the state-of-the-art single-voxel 3T sLASER 1H-MRS methodology optimized for reproducible measurements. Ketamine’s effects on neurochemicals were assessed before and ∼3 h after intravenous ketamine challenge in PCC. Concentrations of 11 neurochemicals, including glutamate (CRLB ∼ 4%) and glutamine (CRLB ∼ 13%), were reliably quantified with the LCModel in 12 healthy young men with between-session coefficients of variation (SD/mean) <8%. Also, ratios of glutamate/glutamine and glutamate/aspartate were assessed as markers of synaptic function and activated glucose metabolism, respectively. Pairwise comparison of metabolite profiles at baseline and 193 ± 4 min after ketamine challenge yielded no differences. Minimal detectable concentration differences estimated with post hoc power analysis (power = 80%, alpha = 0.05) were below 0.5 μmol/g, namely 0.39 μmol/g (∼4%) for glutamate, 0.28 μmol/g (∼10%) for Gln, ∼14% for glutamate/glutamine and ∼8% for glutamate/aspartate. Despite the high sensitivity to detect between-session differences in glutamate and glutamine concentrations, our study did not detect delayed glutamatergic responses to subanesthetic ketamine doses in PCC.
Summer and SERT: Effect of daily sunshine hours on SLC6A4 promoter methylation in seasonal affective disorder
Objectives: Knowledge on how sunlight impacts SERT activity via SLC6A4 promoter methylation in Seasonal Affective Disorder (SAD) remains limited. This study aimed to investigate the effect of daily sunshine duration on SLC6A4 promoter methylation in 28 patients with SAD and 40 healthy controls (HC). Methods: Daily sunlight data for Vienna, Austria (mean of 28 days before blood sampling), were obtained from ©GeoSphere Austria. A general linear model analysed SLC6A4 promoter methylation as the dependent variable, with sunlight hours as the independent variable, and group (SAD, HC), age, sex, and 5-HTTLPR/rs25531 as covariates. Exploratory analyses examined the effects of sunlight hours and methylation on Beck Depression Inventory (BDI) scores. Results: Sunlight had a significant effect on SLC6A4 promoter methylation (p = 0.03), with more sunlight hours resulting in lower methylation (r = −0.25). However, the interaction between sunlight and group was non-significant, suggesting a rather general effect across both groups. Sunlight also influenced BDI scores (p < 0.01), with fewer sunlight hours leading to higher scores (r = −0.25), which aligns with previous research. SLC6A4 promoter methylation had no significant effect on BDI scores. Conclusions: Our findings suggest that sunlight influences SLC6A4 methylation without SAD specificity.
Gender Dysphoria and Sexual Euphoria: A Bayesian Perspective on the Influence of Gender-Affirming Hormone Therapy on Sexual Arousal.
Self-reported sexual orientation of transgender individuals occasionally changes over transition. Using functional magnetic resonance imaging, we tested the hypothesis that neural and behavioral patterns of sexual arousal in transgender individuals would shift from the assigned to the experienced gender (e.g., trans women's responses becoming more dissimilar to those of cis men and more similar to those of cis women). To this aim, trans women (N = 12) and trans men (N = 20) as well as cisgender women (N = 24) and cisgender men (N = 14) rated visual stimuli showing male-female, female-female or male-male intercourse for sexual arousal before and after four months of gender-affirming hormone therapy. A Bayesian framework allowed us to incorporate previous behavioral findings. The hypothesized changes could indeed be observed in the behavioral responses with the strongest results for trans men and female-female scenes. Activation of the ventral striatum supported our hypothesis only for female-female scenes in trans women. The respective application or depletion of androgens in trans men and trans women might partly explain this observation. The prominent role of female-female stimuli might be based on the differential responses they elicit in cis women and men or, in theory, the controversial concept of autogynephilia. We show that correlates of sexual arousal in transgender individuals might change in the direction of the experienced gender. Future investigations should elucidate the mechanistic role of sex hormones and the cause of the differential neural and behavioral findings.The study was registered at ClinicalTrials.gov (NCT02715232), March 22, 2016.
Changes to hypothalamic volume and associated subunits during gender-affirming hormone therapy.
BACKGROUND: Among its pleiotropic properties, gender-affirming hormone therapy (GHT) affects regional brain volumes. The hypothalamus, which regulates neuroendocrine function and associated emotional and cognitive processes, is an intuitive target for probing GHT effects. We sought to assess changes to hypothalamus and hypothalamic subunit volumes after GHT, thereby honouring the region's anatomical and functional heterogeneity. METHODS: Individuals with gender dysphoria and cisgender controls underwent 2 MRI measurements, with a median interval of 145 days (interquartile range [IQR] 128.25-169.75 d, mean 164.94 d) between the first and second MRI. Transgender women (TW) and transgender men (TM) underwent the first MRI before GHT and the second MRI after approximately 4.5 months of GHT, which comprised estrogen and anti-androgen therapy in TW or testosterone therapy in TM. Hypothalamic volumes were segmented using FreeSurfer, and effects of GHT were tested using repeated-measures analysis of covariance. RESULTS: The final sample included 106 participants: 38 TM, 15 TW, 32 cisgender women (CW) and 21 cisgender men (CM). Our analyses revealed group × time interaction effects for total, left and right hypothalamus volume, and for several subunits (left and right inferior tubular, left superior tubular, right anterior inferior, right anterior superior, all p corr < 0.01). In TW, volumes decreased between the first and second MRI in these regions (all p corr ≤ 0.01), and the change from the first to second MRI in TW differed significantly from that in CM and CW in several subunits (p corr < 0.05). LIMITATIONS: We did not address the influence of transition-related psychological and behavioural changes. CONCLUSION: Our results suggest a subunit-specific effect of GHT on hypothalamus volumes in TW. This finding is in accordance with previous reports of positive and negative effects of androgens and estrogens, respectively, on cerebral volumes.
The influence of sex steroid treatment on insular connectivity in gender dysphoria.
BACKGROUND: Sex-specific differences in brain connectivity were found in various neuroimaging studies, though little is known about sex steroid effects on insular functioning. Based on well-characterized sex differences in emotion regulation, interoception and higher-level cognition, gender-dysphoric individuals receiving gender-affirming hormone therapy represent an interesting cohort to investigate how sex hormones might influence insular connectivity and related brain functions. METHODS: To analyze the potential effect of sex steroids on insular connectivity at rest, 11 transgender women, 14 transgender men, 20 cisgender women, and 11 cisgender men were recruited. All participants underwent two magnetic resonance imaging sessions involving resting-state acquisitions separated by a median time period of 4.5 months and also completed the Bermond-Vorst alexithymia questionnaire at the initial and final examination. Between scans, transgender subjects received gender-affirming hormone therapy. RESULTS: A seed based functional connectivity analysis revealed a significant 2-way interaction effect of group-by-time between right insula, cingulum, left middle frontal gyrus and left angular gyrus. Post-hoc tests demonstrated an increase in connectivity for transgender women when compared to cisgender men. Furthermore, spectral dynamic causal modelling showed reduced effective connectivity from the posterior cingulum and left angular gyrus to the left middle frontal gyrus as well as from the right insula to the left middle frontal gyrus. Alexithymia changes were found after gender-affirming hormone therapy for transgender women in both fantasizing and identifying. CONCLUSION: These findings suggest a considerable influence of estrogen administration and androgen suppression on brain networks implicated in interoception, own-body perception and higher-level cognition.
Effect of MAOA DNA Methylation on Human in Vivo Protein Expression Measured by [11C]harmine Positron Emission Tomography.
BACKGROUND: Epigenetic modifications like DNA methylation are understood as an intermediary between environmental factors and neurobiology. Cerebral monoamine oxidase A (MAO-A) levels are altered in depression, as are DNA methylation levels within the MAOA gene, particularly in the promoter/exon I/intron I region. An effect of MAOA methylation on peripheral protein expression was shown, but the extent to which methylation affects brain MAO-A levels is not fully understood. METHODS: Here, the influence of MAOA promoter/exon I/intron I region DNA methylation on global MAO-A distribution volume (VT), an index of MAO-A density, was assessed via [11C]harmine positron emission tomography in 22 patients (14 females) suffering from seasonal affective disorder and 30 healthy controls (17 females). RESULTS: No significant influence of MAOA DNA methylation on global MAO-A VT was found, despite correction for health status, sex, season, and MAOA variable number of tandem repeat genotype. However, season affected average methylation in women, with higher levels in spring and summer (Puncorr = .03). We thus did not find evidence for an effect of MAOA DNA methylation on brain MAO-A VT. CONCLUSIONS: In contrast to a previous study demonstrating an effect of methylation of a MAOA promoter region located further 5' on brain MAO-A, MAOA methylation of the region assessed here appears to affect brain protein levels to a limited extent at most. The observed effect of season on methylation levels is in accordance with extensive evidence for seasonal effects within the serotonergic system. CLINICALTRIALS.GOV IDENTIFIER: NCT02582398 (https://clinicaltrials.gov/ct2/show/NCT02582398).
First-in-Humans Brain PET Imaging of the GluN2B-Containing N-methyl-d-aspartate Receptor with (R)-11C-Me-NB1.
The N-methyl-d-aspartate receptor (NMDAR) plays a crucial role in neurodegenerative diseases such as Alzheimer disease and in the treatment of major depression by fast-acting antidepressants such as ketamine. Given their broad implications, GluN2B-containing NMDARs have been of interest as diagnostic and therapeutic targets. Recently, (R)-11C-Me-NB1 was investigated preclinically and shown to be a promising radioligand for imaging GluN2B subunits. Here, we report on the performance characteristics of this radioligand in a first-in-humans PET study. Methods: Six healthy male subjects were scanned twice on a fully integrated PET/MR scanner with (R)-11C-Me-NB1 for 120 min. Brain uptake and tracer distribution over time were investigated by SUVs. Test-retest reliability was assessed with the absolute percentage difference and the coefficient of variation. Exploratory total volumes of distribution (VT) were computed using an arterial input function and the Logan plot as well as a constrained 2-tissue-compartment model with the ratio of rate constants between plasma and tissue compartments (K1/k2) coupled (2TCM). SUV was correlated with VT to investigate its potential as a surrogate marker of GluN2B expression. Results: High and heterogeneous radioligand uptake was observed across the entire gray matter with reversible kinetics within the scan time. SUV absolute percentage difference ranged from 6.9% to 8.5% and coefficient of variation from 4.9% to 6.0%, indicating a high test-retest reliability. A moderate correlation was found between SUV averaged from 70 to 90 min and VT using Logan plot (Spearman ρ = 0.44). Correlation between VT Logan and 2TCM was r = 0.76. Conclusion: The radioligand (R)-11C-Me-NB1 was highly effective in mapping GluN2B-enriched NMDARs in the human brain. With a heterogeneous uptake and a high test-retest reliability, this radioligand offers promise to deepen our understanding of the GluN2B-containing NMDAR in the pathophysiology and treatment of neuropsychiatric disease such as Alzheimer disease and major depression. Additionally, it could help in the selection of appropriate doses of GluN2B-targeting drugs.
Effects of sex hormones on brain GABA and glutamate levels in a cis- and transgender cohort.
Sex hormones affect the GABAergic and glutamatergic neurotransmitter system as demonstrated in animal studies. However, human research has mostly been correlational in nature. Here, we aimed at substantiating causal interpretations of the interaction between sex hormones and neurotransmitter function by using magnetic resonance spectroscopy imaging (MRSI) to study the effect of gender-affirming hormone treatment (GHT) in transgender individuals. Fifteen trans men (TM) with a DSM-5 diagnosis of gender dysphoria, undergoing GHT, and 15 age-matched cisgender women (CW), receiving no therapy, underwent MRSI before and after at least 12 weeks. Additionally, sex differences in neurotransmitter levels were evaluated in an independent sample of 80 cisgender men and 79 cisgender women. Mean GABA+ (combination of GABA and macromolecules) and Glx (combination of glutamate and glutamine) ratios to total creatine (GABA+/tCr, Glx/tCr) were calculated in five predefined regions-of-interest (hippocampus, insula, pallidum, putamen and thalamus). Linear mixed models analysis revealed a significant measurement by gender identity effect (pcorr. = 0.048) for GABA+/tCr ratios in the hippocampus, with the TM cohort showing decreased GABA+/tCr levels after GHT compared to CW. Moreover, analysis of covariance showed a significant sex difference in insula GABA+/tCr ratios (pcorr. = 0.049), indicating elevated GABA levels in cisgender women compared to cisgender men. Our study demonstrates GHT treatment-induced GABA+/tCr reductions in the hippocampus, indicating hormone receptor activation on GABAergic cells and testosterone-induced neuroplastic processes within the hippocampus. Moreover, elevated GABA levels in the female compared to the male insula highlight the importance of including sex as factor in future MRS studies. DATA AVAILABILITY STATEMENT: Due to data protection laws processed data is available from the authors upon reasonable request. Please contact rupert.lanzenberger@meduniwien.ac.at with any questions or requests.
Serotonergic modulation of effective connectivity in an associative relearning network during task and rest.
An essential core function of one's cognitive flexibility is the use of acquired knowledge and skills to adapt to ongoing environmental changes. Animal models have highlighted the influence serotonin has on neuroplasticity. These effects have been predominantly demonstrated during emotional relearning which is theorized as a possible model for depression. However, translation of these mechanisms is in its infancy. To this end, we assessed changes in effective connectivity at rest and during associative learning as a proxy of neuroplastic changes in healthy volunteers. 76 participants underwent 6 weeks of emotional or non-emotional (re)learning (face-matching or Chinese character-German noun matching). During relearning participants either self-administered 10 mg/day of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo in a double-blind design. Associative learning tasks, resting-state and structural images were recorded before and after both learning phases (day 1, 21 and 42). Escitalopram intake modulated relearning changes in a network encompassing the right insula, anterior cingulate cortex and right angular gyrus. Here, the process of relearning during SSRI intake showed a greater decrease in effective connectivity from the right insula to both the anterior cingulate cortex and right angular gyrus, with increases in the opposite direction when compared to placebo. In contrast, intrinsic connections and those at resting-state were only marginally affected by escitalopram. Further investigation of gray matter volume changes in these functionally active regions revealed no significant SSRI-induced structural changes. These findings indicate that the right insula plays a central role in the process of relearning and SSRIs further potentiate this effect. In sum, we demonstrated that SSRIs amplify learning-induced effective connections rather than affecting the intrinsic task connectivity or that of resting-state.
Escitalopram administration, relearning, and neuroplastic effects: A diffusion tensor imaging study in healthy individuals.
BACKGROUND: Neuroplastic processes are influenced by serotonergic agents, which reportedly alter white matter microstructure in humans in conjunction with learning. The goal of this double-blind, placebo-controlled imaging study was to investigate the neuroplastic properties of escitalopram and cognitive training on white matter plasticity during (re)learning as a model for antidepressant treatment and environmental factors. METHODS: Seventy-one healthy individuals (age=25.6 ± 5.0, 43 females) underwent three diffusion magnetic resonance imaging scans: at baseline, after 3 weeks of associative learning (emotional/non-emotional content), and after relearning shuffled associations for an additional 3 weeks. During the relearning phase, participants received a daily dose of 10 mg escitalopram or placebo orally. Fractional anisotropy (FA), and mean (MD), axial (AD), and radial diffusivity (RD) were calculated within the FMRIB software library and analyzed using tract-based spatial statistics. RESULTS: In a three-way repeated-measures marginal model with sandwich estimator standard errors, we found no significant effects of escitalopram and content on AD, FA, MD, and RD during both learning and relearning periods (pFDR>0.05). When testing for escitalopram or content effects separately, we also demonstrated no significant findings (pFDR>0.05) for any of the diffusion tensor imaging metrics. LIMITATIONS: The intensity of the study interventions might have been too brief to induce detectable white matter changes. DISCUSSION: Previous studies examining the effects of SSRIs on white matter tracts in humans have yielded inconclusive outcomes. Our results indicate that relearning under escitalopram does not affect the white matter microstructures in healthy individuals when administered for 3 weeks.
Escitalopram modulates learning content-specific neuroplasticity of functional brain networks.
Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, selective serotonin reuptake inhibitors (SSRIs) have been shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in patients. To investigate a comparable modulation of neuroplasticity in humans, 99 healthy subjects underwent three weeks of emotional (matching faces) or non-emotional learning (matching Chinese characters to unrelated German nouns). Shuffled pairings of the original content were subsequently relearned for the same time. During relearning, subjects received either a daily dose of the SSRI escitalopram or placebo. Resting-state functional magnetic resonance imaging was performed before and after the (re-)learning phases. FC changes in a network comprising Broca's area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus were modulated by escitalopram intake. More specifically, it increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and the connectivity from medial prefrontal cortex to Broca's area for emotional relearning. The context dependence of these effects together with behavioral correlations supports the assumption that SSRIs in clinical practice improve neuroplasticity rather than psychiatric symptoms per se. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on human neuroplasticity.
Increased left dorsolateral prefrontal cortex density following escitalopram intake during relearning: a randomized, placebo-controlled trial in healthy humans
Background: Serotonergic agents affect brain plasticity and reverse stress-induced dendritic atrophy in key fronto-limbic brain areas associated with learning and memory. Objectives: The aim of this study was to investigate effects of the antidepressant escitalopram on gray matter during relearning in healthy individuals to inform a model for depression and the neurobiological processes of recovery. Design: Randomized double blind placebo control, monocenter study. Methods: In all, 76 (44 females) healthy individuals performed daily an associative learning task with emotional or non-emotional content over a 3-week period. This was followed by a 3-week relearning period (randomly shuffled association within the content group) with concurrent daily selective serotonin reuptake inhibitor (i.e., 10 mg escitalopram) or placebo intake. Results: Via voxel-based morphometry and only in individuals that developed sufficient escitalopram blood levels over the 21-day relearing period, an increased density of the left dorsolateral prefrontal cortex was found. When investigating whether there was an interaction between relearning and drug intervention for all participants, regardless of escitalopram levels, no changes in gray matter were detected with either surfaced-based or voxel-based morphometry analyses. Conclusion: The left dorsolateral prefrontal cortex affects executive function and emotional processing, and is a critical mediator of symptoms and treatment outcomes of depression. In line, the findings suggest that escitalopram facilitates neuroplastic processes in this region if blood levels are sufficient. Contrary to our hypothesis, an effect of escitalopram on brain structure that is dependent of relearning content was not detected. However, this may have been a consequence of the intensity and duration of the interventions. Registration: ClinicalTrials.gov Identifier: NCT02753738; Trial Name: Enhancement of learning associated neural plasticity by Selective Serotonin Reuptake Inhibitors; URL: https://clinicaltrials.gov/ct2/show/NCT02753738.
Biodistribution and dosimetry of the GluN2B-specific NMDA receptor PET radioligand (R)-[11C]Me-NB1
Background: The NMDA receptor (NMDAR) plays a key role in the central nervous system, e.g., for synaptic transmission. While synaptic NMDARs are thought to have protective characteristics, activation of extrasynaptic NMDARs might trigger excitotoxic processes linked to neuropsychiatric disorders. Since extrasynaptic NMDARs are typically GluN2B-enriched, the subunit is an interesting target for drug development and treatment monitoring. Recently, the novel GluN2B-specific PET radioligand (R)-[11C]Me-NB1 was investigated in rodents and for the first time successfully translated to humans. To assess whether (R)-[11C]Me-NB1 is a valuable radioligand for (repeated) clinical applications, we evaluated its safety, biodistribution and dosimetry. Methods: Four healthy subjects (two females, two males) underwent one whole-body PET/MR measurement lasting for more than 120 min. The GluN2B-specific radioligand (R)-[11C]Me-NB1 was administered simultaneously with the PET start. Subjects were measured in nine passes and six bed positions from head to mid-thigh. Regions of interest was anatomically defined for the brain, thyroid, lungs, heart wall, spleen, stomach contents, pancreas, liver, kidneys, bone marrow and urinary bladder contents, using both PET and MR images. Time-integrated activity coefficients were estimated to calculate organ equivalent dose coefficients and the effective dose coefficient. Additionally, standardized uptake values (SUV) were computed to visualize the biodistribution. Results: Administration of the radioligand was safe without adverse events. The organs with the highest uptake were the urinary bladder, spleen and pancreas. Organ equivalent dose coefficients were higher in female in almost all organs, except for the urinary bladder of male. The effective dose coefficient was 6.0 µSv/MBq. Conclusion: The GluN2B-specific radioligand (R)-[11C]Me-NB1 was well-tolerated without reported side effects. Effective dose was estimated to 1.8 mSv when using 300 MBq of presented radioligand. The critical organ was the urinary bladder. Due to the low effective dose coefficient of this radioligand, longitudinal studies for drug development and treatment monitoring of neuropsychiatric disorders including neurodegenerative diseases are possible. Trial registration Registered on 11th of June 2019 at https://www.basg.gv.at (EudraCT: 2018-002933-39).