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Background and aimsGlucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) are widely used for the treatment of type 2 diabetes, and recent studies indicate that they may be cardio- and neuroprotective. The safety and effect of a single dose of exenatide, a short-acting GLP-1RA, on cerebral and peripheral arterial function remain unknown.MethodsIn this randomized, double-blind pilot trial, we assigned elderly healthy volunteers without diabetes and no previous history of stroke to receive a single dose of subcutaneous exenatide (5 μg) or placebo. Primary outcome was immediate changes over time in blood flow velocity of the middle cerebral arteries (VMCA) assessed by repeated transcranial Doppler measurements. Secondary outcomes were changes in peripheral arterial function with finger plethysmography, ankle-brachial index (ABI), and inflammatory- and endothelial-specific biomarkers.ResultsHealthy volunteers (13 women and 17 men) were included: (mean ± standard deviation) age: 62 ± 8 years; body weight: 79.6 ± 12.7 kg; VMCA: 65.3 ± 10.7 cm/s; fasting plasma glucose: 5.5 ± 0.5 mmol/L; HbA1c: 33.9 ± 4.1 mmol/mol (5.3 ± 0.38%). No differences between exenatide and placebo group were seen regarding VMCA (p = 0.058), systolic ABI (p = 0.71), plethysmography (p = 0.45), tumor necrosis factor (p = 0.33), interleukin-6 (p = 0.11), interleukin-1β (p = 0.34), vascular cell adhesion molecule 1 (p = 0.73), intercellular adhesion molecule 1 (p = 0.74), or E-selectin (p = 0.31). No severe adverse events were observed.ConclusionA single dose of exenatide did not change cerebral blood flow velocity or peripheral vessel function in elderly healthy volunteers. The medication was safe to use in persons without diabetes allowing us to investigate this drug further in search of the neuroprotective mechanisms.Clinical Trial Registrationhttps://clinicaltrials.gov, Identifier NCT02838589.

BackgroundThe clinical high-risk for psychosis (CHR-P) paradigm was introduced to detect individuals at risk of developing psychosis and to establish preventive strategies. While current prediction of outcomes in the CHR-P state is based mostly on the clinical assessment of presenting features, several emerging biomarkers have been investigated in an attempt to stratify CHR-P individuals according to their individual trajectories and refine the diagnostic process. However, heterogeneity across subgroups is a key challenge that has limited the impact of the CHR-P prediction strategies, as the clinical validity of the current research is limited by a lack of external validation across sites and modalities. Despite these challenges, electroencephalography (EEG) biomarkers have been studied in this field and evidence suggests that EEG used in combination with clinical assessments may be a key measure for improving diagnostic and prognostic accuracy in the CHR-P state. The PSYSCAN EEG study is an international, multi-site, multimodal longitudinal project that aims to advance knowledge in this field.MethodsParticipants at 6 international sites take part in an EEG protocol including EEG recording, cognitive and clinical assessments. CHR-P participants will be followed up after 2 years and subcategorised depending on their illness progression regarding transition to psychosis. Differences will be sought between CHR-P individuals and healthy controls and between CHR-P individuals who transition and those who do not transition to psychosis using data driven computational analyses.DiscussionThis protocol addresses the challenges faced by previous studies of this kind to enable valid identification of predictive EEG biomarkers which will be combined with other biomarkers across sites to develop a prognostic tool in CHR-P. The PSYSCAN EEG study aims to pave the way for incorporating EEG biomarkers in the assessment of CHR-P individuals, to refine the diagnostic process and help to stratify CHR-P subjects according to risk of transition. This may improve our understanding of the CHR-P state and therefore aid the development of more personalized treatment strategies.

Patients with chronic schizophrenia often display enlarged striatal volumes, and antipsychotic drugs may contribute via the dopamine D2/3 receptor (D2/3R) blockade. Separating the effects of disease from medication is challenging due to the lack of a proper placebo-group. To address this, we conducted a longitudinal study of antipsychotic-naïve, first-episode schizophrenia patients to test the hypothesis that selective blockade of D2/3R would induce a dose-dependent striatal volume increase. Twenty-one patients underwent structural magnetic resonance imaging (sMRI), single-photon emission computed tomography (SPECT), and symptom severity ratings before and after six weeks of amisulpride treatment. Twenty-three matched healthy controls underwent sMRI and baseline SPECT. Data were analyzed using repeated measures and multiple regression analyses. Correlations between symptom severity decrease, volume changes, dose and receptor occupancy were explored. Striatal volumes did not differ between patients and controls at baseline or follow-up, but a significant group-by-time interaction was found (p = 0.01). This interaction was explained by a significant striatal volume increase of 2.1% in patients (Cohens d = 0.45). Striatal increase was predicted by amisulpride dose, but not by either D2/3R occupancy or baseline symptom severity. A significant reduction in symptom severity was observed at a mean dose of 233.3 (SD = 109.9) mg, corresponding to D2/3R occupancy of 44.65%. Reduction in positive symptoms correlated significantly with striatal volume increase, driven by reductions in hallucinations. Our data demonstrate a clear link between antipsychotic treatment and striatal volume increase in antipsychotic-naïve schizophrenia patients. Moreover, the treatment-induced striatal volume increase appears clinically relevant by correlating to reductions in core symptoms of schizophrenia.

This study investigates the association between intelligence and brain power responses to a passive audiovisual stimulation. We measure the power of gamma-range steady-state responses (SSRs) as well as intelligence and other aspects of neurocognitive function in 40 healthy males born in 1953. The participants are a part of a Danish birth cohort study and the data therefore include additional information measured earlier in life. Our main power measure is the difference in power between a visual stimulation and a combined audiovisual stimulation. We hypothesize and establish empirically that the power measure is associated with intelligence. In particular, we find a highly significant correlation between the power measure and present intelligence scores. The association is robust to controlling for size-at-birth measures, length of education, speed of processing as well as a range of other potentially confounding factors. Interestingly, we find that intelligence scores measured earlier in life (childhood, youth, late midlife), are also correlated with the present-day power measure, suggesting a deep connection between intelligence and the power measure. Finally, we find that the power measure has a high sensitivity for detection of an intelligence score below the average.

Background: High-intensity interval training (HIIT) is superior to moderate-intensity continuous training in improving cardiorespiratory fitness in patients with cardiovascular disease, but is it safe, feasible and effective in patients with stroke? We investigated feasibility and effect of early, home-based HIIT in patients with lacunar stroke combined with usual care vs. usual care, only.Methods: Patients with minor stroke (severity: 55/58 point on the Scandinavian Stroke Scale) were randomized to HIIT or usual care in a randomized, controlled trial. We measured the following outcomes at baseline and post-intervention: cardiorespiratory fitness monitored as power output from the Graded Cycling Test with Talk Test (GCT-TT; primary outcome), physical activity, fatigue, depression, well-being, stress, cognition, endothelial function, blood pressure, body mass index, and biomarkers.Results: We included 71 patients (mean age 63.7 ± 9.2), 49 men, 31 in intervention group. Home-based HIIT was feasible with no reported adverse events in relation to the intervention. No significant change between the groups in GCT-TT power output was detected (p = 0.90). The change in time spent on vigorous-intensity activity was 2 h/week and 0.6 h/week, intervention and usual care, respectively (p = 0.045). There were no significant differences between groups in the remaining secondary outcomes.Conclusion: HIIT was feasible and safe in patients with lacunar stroke. Patients can engage early in home-based HIIT when involved in choosing exercise modality and guided by weekly motivational phone calls. Within 3 months, HIIT did, however, not yield effect on cardiorespiratory fitness. We await further evaluation of long-term effects of this intervention on continued regular physical exercise and cardiovascular event.Clinical Trial Registration:https://clinicaltrials.gov, identifier NCT02731235

Progressive loss of brain tissue is seen in some patients with schizophrenia and might be caused by increased levels of glutamate and resting cerebral blood flow (rCBF) alterations. Animal studies suggest that the normalisation of glutamate levels decreases rCBF and prevents structural changes in hippocampus. However, the relationship between glutamate and rCBF in anterior cingulate cortex (ACC) of humans has not been studied in the absence of antipsychotics and illness chronicity. Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist that transiently induces schizophrenia-like symptoms and neurobiological disturbances in healthy volunteers (HVs). Here, we used S-ketamine challenge to assess if glutamate levels were associated with rCBF in ACC in 25 male HVs. Second, we explored if S-ketamine changed the neural activity as reflected by rCBF alterations in thalamus (Thal) and accumbens that are connected with ACC. Glutamatergic metabolites were measured in ACC with magnetic resonance (MR) spectroscopy and whole-brain rCBF with pseudo-continuous arterial spin labelling on a 3-T MR scanner before, during, and after infusion of S-ketamine (total dose 0.375 mg/kg). In ACC, glutamate levels were associated with rCBF before (p