Mitochondrial complex I density is associated with IQ and cognition in cognitively healthy adults: an in vivo [F]BCPP-EF PET study.

Background: Mitochondrial function plays a key role in regulating neurotransmission and may contribute to general intelligence. Mitochondrial complex I (MC-I) is the largest enzyme of the respiratory chain. Recently, it has become possible to measure MC-I distribution in vivo, using a novel positron emission tomography tracer [F]BCPP-EF, thus, we set out to investigate the association between MC-I distribution and measures of cognitive function in the living healthy brain.

Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of SV2A.

Background: The synaptic hypothesis is an influential theory of the pathoetiology of schizophrenia (SCZ), which is supported by the finding that there is lower uptake of the synaptic terminal density marker [C]UCB-J in patients with chronic SCZ than in control participants. However, it is unclear whether these differences are present early in the illness. To address this, we investigated [C]UCB-J volume of distribution (V) in antipsychotic-naïve/free patients with SCZ who were recruited from first-episode services compared with healthy volunteers.

Neurophysiological and psychosocial mechanisms of fibromyalgia: A comprehensive review and call for an integrative model.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives.

Gamma Oscillations and Potassium Channel Modulation in Schizophrenia: Targeting GABAergic Dysfunction.

Impairments in gamma-aminobutyric acid (GABAergic) interneuron function lead to gamma power abnormalities and are thought to underlie symptoms in people with schizophrenia. Voltage-gated potassium 3.1 (Kv3.

Emotion regulation and the salience network: a hypothetical integrative model of fibromyalgia.

Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances and other symptoms, and has a substantial socioeconomic impact. Current biomedical and psychosocial treatments are unsatisfactory for many patients, and treatment progress has been hindered by the lack of a clear understanding of the pathogenesis of fibromyalgia. We present here a model of fibromyalgia that integrates current psychosocial and neurophysiological observations.

The effect of AUT00206, a Kv3 potassium channel modulator, on dopamine synthesis capacity and the reliability of [F]-FDOPA imaging in schizophrenia.

Background: Current treatments for schizophrenia act directly on dopamine (DA) receptors but are ineffective for many patients, highlighting the need to develop new treatment approaches. Striatal DA dysfunction, indexed using [F]-FDOPA imaging, is linked to the pathoetiology of schizophrenia. We evaluated the effect of a novel drug, AUT00206, a Kv3.

The effects of AUT00206, a novel Kv3.1/3.2 potassium channel modulator, on task-based reward system activation: a test of mechanism in schizophrenia.

The pathophysiology of schizophrenia involves abnormal reward processing, thought to be due to disrupted striatal and dopaminergic function. Consistent with this hypothesis, functional magnetic resonance imaging (fMRI) studies using the monetary incentive delay (MID) task report hypoactivation in the striatum during reward anticipation in schizophrenia. Dopamine neuron activity is modulated by striatal GABAergic interneurons.

Real-world clinical and cost-effectiveness of community clozapine initiation: mirror cohort study.

Background: Clozapine is the only drug licensed for treatment-resistant schizophrenia (TRS) but the real-world clinical and cost-effectiveness of community initiation of clozapine is unclear.

Aims: The aim was to assess the feasibility and cost-effectiveness of community initiation of clozapine.

Method: This was a naturalistic study of community patients recommended for clozapine treatment.

Dynamic and Static Cognitive Deficits in Schizophrenia and Bipolar Disorder After the First Episode.

Few studies have comprehensively examined the profile of cognitive functioning in first episode psychosis patients throughout the lifespan, and from first episode to chronic stage. We assessed functioning in general and specific cognitive functions, comparing both schizophrenia (N = 64) and bipolar I (N = 19) patients to controls (N = 103). Participants were from a population-based, case-control study of first episode psychosis patients, who were followed prospectively up to 10 years post first admission.

The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study.

Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ).

Adenosine A receptor in schizophrenia: an in vivo brain PET imaging study.

Adenosine A receptors are highly enriched in the basal ganglia system, a region that is functionally implicated in schizophrenia. Preclinical evidence suggests a cross-regulation between adenosine A and dopamine D receptors in this region and that it is linked to the sensitization of the dopamine system. However, the relationship between A receptor availability and schizophrenia has not been directly examined in vivo in patients with this disorder.

Monitoring and Managing Lorlatinib Adverse Events in the Portuguese Clinical Setting: A Position Paper.

Rearrangements in the anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) genes characterise two distinct molecular subsets of non-small cell lung cancer (NSCLC) tumours. Lorlatinib is a third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) shown to have systemic and intracranial activity in treatment-naive patients and in those who progressed on first- and second-generation TKIs. Despite being generally well tolerated, lorlatinib has a unique and challenging safety profile that includes hyperlipidaemia and central and peripheral nervous system adverse events (AEs).

Structural Covariance of Cortical Gyrification at Illness Onset in Treatment Resistance: A Longitudinal Study of First-Episode Psychoses.

Treatment resistance (TR) in patients with first-episode psychosis (FEP) is a major cause of disability and functional impairment, yet mechanisms underlying this severe disorder are poorly understood. As one view is that TR has neurodevelopmental roots, we investigated whether its emergence relates to disruptions in synchronized cortical maturation quantified using gyrification-based connectomes. Seventy patients with FEP evaluated at their first presentation to psychiatric services were followed up using clinical records for 4 years; of these, 17 (24.

Specific and non-specific binding of a tracer for the translocator-specific protein in schizophrenia: an [11C]-PBR28 blocking study.

Objective: The mitochondrial 18-kDa translocator protein (TSPO) is expressed by activated microglia and positron emission tomography enables the measurement of TSPO levels in the brain. Findings in schizophrenia have shown to vary depending on the outcome measure used and this discrepancy in TSPO results could be explained by lower non-displaceable binding (V) in schizophrenia, which could obscure increases in specific binding. In this study, we have used the TSPO ligand XBD173 to block the TSPO radioligand [C]-PBR28 and used an occupancy plot to quantify V in patients with schizophrenia.

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively.

Parametric Mapping for TSPO PET Imaging with Spectral Analysis Impulsive Response Function.

Purpose: The aim of this study was to investigate the use of spectral analysis (SA) for voxel-wise analysis of TSPO PET imaging studies. TSPO PET quantification is methodologically complicated by the heterogeneity of TSPO expression and its cell-dependent modulation during neuroinflammatory response. Compartmental models to account for this complexity exist, but they are unreliable at the high noise typical of voxel data.

Acute acetate administration increases endogenous opioid levels in the human brain: A [C]carfentanil molecular imaging study.

Introduction: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including β-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain.

Patterns of Mitochondrial TSPO Binding in Cerebral Small Vessel Disease: An PET Study With Neuropathological Comparison.

Small vessel disease (SVD) is associated with cognitive impairment in older age and be implicated in vascular dementia. Post-mortem studies show proliferation of activated microglia in the affected white matter. However, the role of inflammation in SVD pathogenesis is incompletely understood and better biomarkers are needed.

GABA-A receptor differences in schizophrenia: a positron emission tomography study using [C]Ro154513.

A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABARs are altered in vivo or related to symptoms.

Impaired theta phase coupling underlies frontotemporal dysconnectivity in schizophrenia.

Frontotemporal dysconnectivity is a key pathology in schizophrenia. The specific nature of this dysconnectivity is unknown, but animal models imply dysfunctional theta phase coupling between hippocampus and medial prefrontal cortex (mPFC). We tested this hypothesis by examining neural dynamics in 18 participants with a schizophrenia diagnosis, both medicated and unmedicated; and 26 age, sex and IQ matched control subjects.