Reduced cortical cerebral blood flow in antipsychotic-free first-episode psychosis and relationship to treatment response.

BACKGROUND: Altered cerebral blood flow (CBF) has been found in people at risk for psychosis, with first-episode psychosis (FEP) and with chronic schizophrenia (SCZ). Studies using arterial spin labelling (ASL) have shown reduction of cortical CBF and increased subcortical CBF in SCZ. Previous studies have investigated CBF using ASL in FEP, reporting increased CBF in striatum and reduced CBF in frontal cortex. However, as these people were taking antipsychotics, it is unclear whether these changes are related to the disorder or antipsychotic treatment and how they relate to treatment response. METHODS: We examined CBF in FEP free from antipsychotic medication (N = 21), compared to healthy controls (N = 22). Both absolute and relative-to-global CBF were assessed. We also investigated the association between baseline CBF and treatment response in a partially nested follow-up study (N = 14). RESULTS: There was significantly lower absolute CBF in frontal cortex (Cohen's d = 0.84, p = 0.009) and no differences in striatum or hippocampus. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal and frontal cortices (Threshold-Free Cluster Enhancement (TFCE)-corrected <0.05). No differences were found in relative-to-global CBF in the selected region of interests and in voxel-wise analysis. Relative-to-global frontal CBF was correlated with percentage change in total Positive and Negative Syndrome Scale after antipsychotic treatment (r = 0.67, p = 0.008). CONCLUSIONS: These results show lower cortical absolute perfusion in FEP prior to starting antipsychotic treatment and suggest relative-to-global frontal CBF as assessed with magnetic resonance imaging could potentially serve as a biomarker for antipsychotic response.

Dopamine dysregulation in psychotic relapse after antipsychotic discontinuation: an [18F]DOPA and [11C]raclopride PET study in first-episode psychosis.

Although antipsychotic drugs are effective for relieving the psychotic symptoms of first-episode psychosis (FEP), psychotic relapse is common during the course of the illness. While some FEPs remain remitted even without medication, antipsychotic discontinuation is regarded as the most common risk factor for the relapse. Considering the actions of antipsychotic drugs on presynaptic and postsynaptic dopamine dysregulation, this study evaluated possible mechanisms underlying relapse after antipsychotic discontinuation. Twenty five FEPs who were clinically stable and 14 matched healthy controls were enrolled. Striatal dopamine activity was assessed as Kicer value using [18F]DOPA PET before and 6 weeks after antipsychotic discontinuation. The D2/3 receptor availability was measured as BPND using [11C]raclopride PET after antipsychotic discontinuation. Healthy controls also underwent PET scans according to the corresponding schedule of the patients. Patients were monitored for psychotic relapse during 12 weeks after antipsychotic discontinuation. 40% of the patients showed psychotic relapse after antipsychotic discontinuation. The change in Kicer value over time significantly differed between relapsed, non-relapsed patients and healthy controls (Week*Group: F = 4.827, df = 2,253.193, p = 0.009). In relapsed patients, a significant correlation was found between baseline striatal Kicer values and time to relapse after antipsychotic discontinuation (R2 = 0.518, p = 0.018). BPND were not significantly different between relapsed, non-relapsed patients and healthy controls (F = 1.402, df = 2,32.000, p = 0.261). These results suggest that dysfunctional dopamine autoregulation might precipitate psychotic relapse after antipsychotic discontinuation in FEP. This finding could be used for developing a strategy for the prevention of psychotic relapse related to antipsychotic discontinuation.

Nearly half of the adolescents in an Italian school-based study exceeded the recommended upper limits for daily caffeine consumption.

AIM: No data are available on caffeine consumption among Italian adolescents. We investigated caffeine intake from coffee, soft drinks and energy drinks in a sample of Italian adolescents and determined if they exceeded the recommended limits. METHODS: The study comprised 1213 adolescents with a mean age of 15.1 years (range 12-19) from four schools in Foggia, southern Italy. Caffeine intake was assessed using an anonymous self-reported questionnaire during the 2013/2014 school year. We calculated the percentage of daily caffeine consumers, their mean intake of caffeine from beverages and the contribution of each beverage category to the total caffeine intake. RESULTS: Approximately 76% of the sample consumed caffeine every day, amounting to 125.5 ± 69.2 mg/day and 2.1 ± 1.2 mg/kg/day. When we applied the reference values from the Academy of Pediatrics, we found that 46% of the adolescents exceeded the recommended upper limits. Coffee was the most frequently consumed caffeinated drink and the main contributor to daily caffeine intake. CONCLUSION: More than three quarters (76%) of the Italian adolescents in our study drank coffee on a daily basis and nearly half (46%) exceeded the recommended upper limits. Strategies are needed to reduce caffeine consumption by adolescents.

Erratum to "Posterior reversible encephalopathy syndrome (PRES) in a 6-year-old child with nephrotic syndrome" [Radiology Case Reports 16 (2021) 140-144].

[This corrects the article DOI: 10.1016/j.radcr.2020.10.057.].

The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls.

BACKGROUND: Evidence from post-mortem studies and in vivo imaging studies suggests there may be reduced N-methyl-d-aspartate receptor (NMDAR) levels in the hippocampus in patients with schizophrenia. Other studies have reported increased glutamate in striatum in schizophrenia patients. It has been hypothesised that NMDAR hypofunction leads to the disinhibition of glutamatergic signalling; however, this has not been tested in vivo. METHODS: In this study, we investigated the relationship between hippocampal NMDAR and striatal glutamate using simultaneous positron emission tomography-magnetic resonance (PET-MR) imaging. We recruited 40 volunteers to this cross-sectional study; 21 patients with schizophrenia, all in their first episode of illness, and 19 healthy controls. We measured hippocampal NMDAR availability using the PET ligand [18F]GE179. This was indexed relative to whole brain as the distribution volume ratio (DVR). Striatal glutamatergic indices (glutamate and Glx) were acquired simultaneously, using combined PET-MR proton magnetic resonance spectroscopy (1H-MRS). RESULTS: A total of 33 individuals (15 healthy controls, 18 patients) were included in the analyses (mean (SD) age of controls, 27.31 (4.68) years; mean (SD) age of patients, 24.75 (4.33), 27 male and 6 female). We found an inverse relationship between hippocampal DVR and striatal glutamate levels in people with first-episode psychosis (rho = -0.74, p < 0.001) but not in healthy controls (rho = -0.22, p = 0.44). CONCLUSION: This study show that lower relative NMDAR availability in the hippocampus may drive increased striatal glutamate levels in patients with schizophrenia. Further work is required to determine whether these findings may yield new targets for drug development in schizophrenia.

A potential biomarker for treatment stratification in psychosis: evaluation of an [18F] FDOPA PET imaging approach.

[18F]FDOPA PET imaging has shown dopaminergic function indexed as Kicer differs between antipsychotic treatment responders and non-responders. However, the theragnostic potential of this biomarker to identify non-responders has yet to be evaluated. In view of this, we aimed to evaluate this as a theragnostic test using linear and non-linear machine-learning (i.e., Bernoulli, support vector, random forest and Gaussian processes) analyses and to develop and evaluate a simplified approach, standardised uptake value ratio (SUVRc). Both [18F]FDOPA PET approaches had good test-rest reproducibility across striatal regions (Kicer ICC: 0.68-0.94, SUVRc ICC: 0.76-0.91). Both our linear and non-linear classification models showed good predictive power to distinguish responders from non-responders (receiver operating curve area under the curve for region-of-interest approach: Kicer = 0.80, SUVRc = 0.79; for voxel-wise approach using a linear support vector machine: 0.88) and similar sensitivity for identifying treatment non-responders with 100% specificity (Kicer: ~50%, SUVRc: 40-60%). Although the findings were replicated in two independent datasets, given the total sample size (n = 84) and single setting, they warrant testing in other samples and settings. Preliminary economic analysis of [18F]FDOPA PET to fast-track treatment-resistant patients with schizophrenia to clozapine indicated a potential healthcare cost saving of ~£3400 (equivalent to $4232 USD) per patient. These findings indicate [18F]FDOPA PET dopamine imaging has potential as biomarker to guide treatment choice.

Posterior reversible encephalopathy syndrome (PRES) in a 6-year-old child with nephrotic syndrome.

Posterior reversible encephalopathy syndrome (PRES) is a variable etiology clinical syndrome with similar neuroimaging results and clinical symptoms. PRES can develop in both adults and children and is characterized by headaches, disorders of consciousness, seizures and especially focal visual disturbances, often associated with hypertensive state. In most cases, symptoms resolve without neurological consequences. The treatment strategy concerns early diagnosis and general measures to correct the underlying cause of PRES. Here, we report a case of PRES that occurs in a 6-year-old child with nephrotic syndrome.

Automated Data Quality Control in FDOPA brain PET Imaging using Deep Learning.

INTRODUCTION: With biomedical imaging research increasingly using large datasets, it becomes critical to find operator-free methods to quality control the data collected and the associated analysis. Attempts to use artificial intelligence (AI) to perform automated quality control (QC) for both single-site and multi-site datasets have been explored in some neuroimaging techniques (e.g. EEG or MRI), although these methods struggle to find replication in other domains. The aim of this study is to test the feasibility of an automated QC pipeline for brain [18F]-FDOPA PET imaging as a biomarker for the dopamine system. METHODS: Two different Convolutional Neural Networks (CNNs) were used and combined to assess spatial misalignment to a standard template and the signal-to-noise ratio (SNR) relative to 200 static [18F]-FDOPA PET images that had been manually quality controlled from three different PET/CT scanners. The scans were combined with an additional 400 scans, in which misalignment (200 scans) and low SNR (200 scans) were simulated. A cross-validation was performed, where 80% of the data were used for training and 20% for validation. Two additional datasets of [18F]-FDOPA PET images (50 and 100 scans respectively with at least 80% of good quality images) were used for out-of-sample validation. RESULTS: The CNN performance was excellent in the training dataset (accuracy for motion: 0.86 ± 0.01, accuracy for SNR: 0.69 ± 0.01), leading to 100% accurate QC classification when applied to the two out-of-sample datasets. Data dimensionality reduction affected the generalizability of the CNNs, especially when the classifiers were applied to the out-of-sample data from 3D to 1D datasets. CONCLUSIONS: This feasibility study shows that it is possible to perform automatic QC of [18F]-FDOPA PET imaging with CNNs. The approach has the potential to be extended to other PET tracers in both brain and non-brain applications, but it is dependent on the availability of large datasets necessary for the algorithm training.

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study.

N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [18F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (VT). Hippocampal DVR, but not VT, was significantly lower in patients relative to controls (p = 0.02, Cohen's d = 0.81; p = 0.15, Cohen's d = 0.49), and negatively associated with total (rho = -0.47, p = 0.04), depressive (rho = -0.67, p = 0.002), and general symptom severity (rho = -0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality.

Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study.

Preclinical models of psychosis propose that hippocampal glutamatergic neuron hyperactivity drives increased striatal dopaminergic activity, which underlies the development of psychotic symptoms. The aim of this study was to examine the relationship between hippocampal glutamate and subcortical dopaminergic function in people at clinical high risk for psychosis, and to assess the association with the development of psychotic symptoms. 1H-MRS was used to measure hippocampal glutamate concentrations, and 18F-DOPA PET was used to measure dopamine synthesis capacity in 70 subjects (51 people at clinical high risk for psychosis and 19 healthy controls). Clinical assessments were undertaken at baseline and follow-up (median 15 months). Striatal dopamine synthesis capacity predicted the worsening of psychotic symptoms at follow-up (r = 0.35; p < 0.05), but not transition to a psychotic disorder (p = 0.22), and was not significantly related to hippocampal glutamate concentration (p = 0.13). There were no differences in either glutamate (p = 0.5) or dopamine (p = 0.5) measures in the total patient group relative to controls. Striatal dopamine synthesis capacity at presentation predicts the subsequent worsening of sub-clinical total and psychotic symptoms, consistent with a role for dopamine in the development of psychotic symptoms, but is not strongly linked to hippocampal glutamate concentrations.

The role of dopamine dysregulation and evidence for the transdiagnostic nature of elevated dopamine synthesis in psychosis: a positron emission tomography (PET) study comparing schizophrenia, delusional disorder, and other psychotic disorders.

There have been few studies performed to examine the pathophysiological differences between different types of psychosis, such as between delusional disorder (DD) and schizophrenia (SZ). Notably, despite the different clinical characteristics of DD and schizophrenia (SZ), antipsychotics are deemed equally effective pharmaceutical treatments for both conditions. In this context, dopamine dysregulation may be transdiagnostic of the pathophysiology of psychotic disorders such as DD and SZ. In this study, an examination is made of the dopamine synthesis capacity (DSC) of patients with SZ, DD, other psychotic disorders, and the DSC of healthy subjects. Fifty-four subjects were recruited to the study, comprising 35 subjects with first-episode psychosis (11 DD, 12 SZ, 12 other psychotic disorders) and 19 healthy controls. All received an 18F-DOPA positron emission tomography (PET)/magnetic resonance (MR) scan to measure DSC (Kocc;30-60 value) within 1 month of starting antipsychotic treatment. Clinical assessments were also made, which included Positive and Negative Syndrome Scale (PANSS) measurements. The mean Kocc;30-60 was significantly greater in the caudate region of subjects in the DD group (ES = 0.83, corrected p = 0.048), the SZ group (ES = 1.40, corrected p = 0.003) and the other psychotic disorder group (ES = 1.34, corrected p = 0.0045), compared to that of the control group. These data indicate that DD, SZ, and other psychotic disorders have similar dysregulated mechanisms of dopamine synthesis, which supports the utility of abnormal dopamine synthesis in transdiagnoses of these psychotic conditions.