Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models ...suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40—120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.
Objective
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation of the X‐linked MECP2 gene and characterized by developmental regression during the first few years of life. The ...objective of this study was to investigate if the visual evoked potential (VEP) could be used as an unbiased, quantitative biomarker to monitor brain function in RTT.
Methods
We recorded pattern‐reversal VEPs in Mecp2 heterozygous female mice and 34 girls with RTT. The amplitudes and latencies of VEP waveform components were quantified, and were related to disease stage, clinical severity, and MECP2 mutation type in patients. Visual acuity was also assessed in both mice and patients by modulating the spatial frequency of the stimuli.
Results
Mecp2 heterozygous female mice and RTT patients exhibited a similar decrease in VEP amplitude that was most striking in the later stages of the disorder. RTT patients also displayed a slower recovery from the principal peak of the VEP response that was impacted by MECP2 mutation type. When the spatial frequency of the stimulus was increased, both patients and mice displayed a deficit in discriminating smaller patterns, indicating lower visual spatial acuity in RTT.
Interpretation
VEP is a method that can be used to assess brain function across species and in children with severe disabilities like RTT. Our findings support the introduction of standardized VEP analysis in clinical and research settings to probe the neurobiological mechanism underlying functional impairment and to longitudinally monitor progression of the disorder and response to treatment. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696
Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to ...antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear.
To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites.
The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data.
In total, 45 1H-MRS studies contributed data.
Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor.
Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL).
In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean SD age, 30.3 10.4 years) and 1197 healthy volunteers (mean SD age, 27.5 8.8 years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose.
Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.
Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in ...schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.
Objective
To measure the efficacy of mecasermin (recombinant human insulin‐like growth factor 1, rhIGF‐1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double‐blind ...crossover study design.
Methods
Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF‐1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28‐week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory‐ and electroencephalography (EEG)‐based biomarkers were also analyzed.
Results
There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication.
Interpretation
As in the phase 1 trial, rhIGF‐1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.
A major challenge in human genetics is identifying the molecular basis of common heritable disorders. In contrast to rare single-gene diseases, multifactorial disorders are thought to arise from the ...combined effect of multiple gene variants, such that any single variant may have only a modest effect on disease susceptibility. We present a method to identify genes that may harbor a significant proportion of the genetic variation that predisposes individuals to a given multifactorial disorder. First, we perform an automated literature analysis that predicts physical interactions (edges) among candidate disease genes (seed nodes, selected on the basis of prior information) and other molecular entities. We derive models of molecular networks from this analysis and map the seed nodes to them. We then compute the graph-theoretic distance (the minimum number of edges that must be traversed) between the seed nodes and all other nodes in the network. We assume that nodes that are found in close proximity to multiple seed nodes are the best disease-related candidate genes. To evaluate this approach, we selected four seed genes, each with a proven role in Alzheimer's disease (AD). The method performed well in predicting additional network nodes that match AD gene candidates identified manually by an expert. We also show that the method prioritizes among the seed nodes themselves, rejecting false-positive seeds that are derived from (noisy) whole-genome genetic-linkage scans. We propose that this strategy will provide a valuable means to bridge genetic and genomic knowledge in the search for genetic determinants of multifactorial disorders.
Using a Monte Carlo model, we analyze the evolution of the vapor plume emanating from the Lunar Crater Observation and Sensing Satellite (LCROSS) impact into Cabeus as seen by the Lyman Alpha Mapping ...Project (LAMP), a far‐ultraviolet (FUV) imaging spectrograph onboard the Lunar Reconnaissance Orbiter. The best fit to the data utilizes a bulk velocity between 3.0 and 4.0 km/s. The fits to the light curve comprised of Hg, Ca, and Mg are not strongly dependent on the temperature. In contrast, the best fit to the light curve from H2 and CO corresponds to a 500 K thermal velocity distribution. The LAMP field of view primarily encounters particles released at low angles to the horizontal and misses fast moving particles released at more vertical angles. The isotropic model suggests that 117 ± 16 kg H2, 41 ± 3 kg CO, 16 ± 1 kg Ca, 12.4 ± 0.8 kg Hg, and 3.8 ± 0.3 kg Mg are released by the LCROSS impact. Additional errors could arise from an anisotropic plume, which cannot be distinguished with LAMP data. Mg and Ca are likely incompletely volatilized owing to their high vapor temperatures. The highly volatile components (H2 and CO) might derive from a greater mass of material. To agree with predicted abundances by weight of 0.047%, 0.023%, 11%, 0.28% and 3.4% for H2, CO, Ca, Hg, and Mg, respectively, the species would be released from 250,000 kg, 180,000 kg, 140 kg, 4400 kg, and 110 kg of regolith, respectively. This is consistent with the relative volatility of these species.
Key Points
LCROSS released 117 kg H2, 41 kg CO, 16 kg Ca, 12.4 kg Hg, and 3.8 kg Mg
Modeling suggests a vapor plume bulk velocity of 3‐4 km/s
The vapor observed by LAMP was released promptly by LCROSS
Energy Returns on Ethanol Production Cleveland, Cutler J.; Charles A. S. Hall; Herendeen, Robert A. ...
Science (American Association for the Advancement of Science),
06/2006, Letnik:
312, Številka:
5781
Journal Article
This study compares demographic and clinical characteristics of 52 individuals with schizophrenia or schizoaffective disorder who had attempted suicide with those of 104 individuals with ...schizophrenia or schizoaffective disorder who had not made a suicide attempt.
Participants were interviewed with the Diagnostic Interview for Genetic Studies.
Most suicide attempts were of moderate to severe lethality, required medical attention, and involved significant suicidal intent. Individuals who had and had not attempted suicide did not differ with respect to demographic variables, duration of illness, rate of depression, or substance abuse. The two groups are affected differentially when depressed.
Biopsychosocial assessments and interventions are essential for reducing the risk for suicidal behavior in individuals with schizophrenia.
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