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      Metabotropic glutamate receptor 5 tracer [ 18F]-FPEB displays increased binding potential in postcentral gyrus and cerebellum of male individuals with autism: a pilot PET study

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          Abstract

          Background

          Autism is a neurodevelopmental disorder that is first manifested during early childhood. Postmortem experiments have identified significantly elevated expression of metabotropic glutamate receptor 5 (mGluR5) in cerebellar vermis and prefrontal cortex of individuals with autism.

          Methods

          In the current study we employed the mGluR5 tracer [ 18F]-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([ 18F]-FPEB) to quantify mGluR5 binding in vivo in adults with autism vs. healthy controls using positron emission tomography (PET).

          Results

          We identified significantly higher [ 18F]-FPEB binding potential in the postcentral gyrus and cerebellum of individuals with autism. There was a significant negative correlation between age and [ 18F]-FPEB binding potential in the cerebellum but not in the postcentral gyrus. In the precuneus, [ 18F]-FPEB binding potential correlated positively with the lethargy subscale score for the Aberrant Behavioral Checklist (ABC). In cerebellum, there were significant negative correlations between [ 18F]-FPEB binding potential and ABC total score, ABC hyperactivity subscale score, and the ABC inappropriate speech subscale score.

          Conclusions

          These novel findings demonstrate for the first time that mGluR5 binding is altered in critical brain areas of subjects with autism, suggesting abnormal glutamate signaling in these regions. Finally, the correlations between altered [ 18F]-FPEB binding potential in the cerebellum and precuneus suggest that some autistic symptoms may be influenced by abnormal glutamate signaling.

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          Most cited references51

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          Consensus paper: pathological role of the cerebellum in autism.

          There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.
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            Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010.

            (2014)
            Autism spectrum disorder (ASD). 2010. The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance system in the United States that provides estimates of the prevalence of ASD and other characteristics among children aged 8 years whose parents or guardians live in 11 ADDM sites in the United States. ADDM surveillance is conducted in two phases. The first phase consists of screening and abstracting comprehensive evaluations performed by professional providers in the community. Multiple data sources for these evaluations include general pediatric health clinics and specialized programs for children with developmental disabilities. In addition, most ADDM Network sites also review and abstract records of children receiving special education services in public schools. The second phase involves review of all abstracted evaluations by trained clinicians to determine ASD surveillance case status. A child meets the surveillance case definition for ASD if a comprehensive evaluation of that child completed by a qualified professional describes behaviors consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for any of the following conditions: autistic disorder, pervasive developmental disorder-not otherwise specified (including atypical autism), or Asperger disorder. This report provides updated prevalence estimates for ASD from the 2010 surveillance year. In addition to prevalence estimates, characteristics of the population of children with ASD are described. For 2010, the overall prevalence of ASD among the ADDM sites was 14.7 per 1,000 (one in 68) children aged 8 years. Overall ASD prevalence estimates varied among sites from 5.7 to 21.9 per 1,000 children aged 8 years. ASD prevalence estimates also varied by sex and racial/ethnic group. Approximately one in 42 boys and one in 189 girls living in the ADDM Network communities were identified as having ASD. Non-Hispanic white children were approximately 30% more likely to be identified with ASD than non-Hispanic black children and were almost 50% more likely to be identified with ASD than Hispanic children. Among the seven sites with sufficient data on intellectual ability, 31% of children with ASD were classified as having IQ scores in the range of intellectual disability (IQ ≤70), 23% in the borderline range (IQ = 71-85), and 46% in the average or above average range of intellectual ability (IQ >85). The proportion of children classified in the range of intellectual disability differed by race/ethnicity. Approximately 48% of non-Hispanic black children with ASD were classified in the range of intellectual disability compared with 38% of Hispanic children and 25% of non-Hispanic white children. The median age of earliest known ASD diagnosis was 53 months and did not differ significantly by sex or race/ethnicity. These findings from CDC's ADDM Network, which are based on 2010 data reported from 11 sites, provide updated population-based estimates of the prevalence of ASD in multiple communities in the United States. Because the ADDM Network sites do not provide a representative sample of the entire United States, the combined prevalence estimates presented in this report cannot be generalized to all children aged 8 years in the United States population. Consistent with previous reports from the ADDM Network, findings from the 2010 surveillance year were marked by significant variations in ASD prevalence by geographic area, sex, race/ethnicity, and level of intellectual ability. The extent to which this variation might be attributable to diagnostic practices, underrecognition of ASD symptoms in some racial/ethnic groups, socioeconomic disparities in access to services, and regional differences in clinical or school-based practices that might influence the findings in this report is unclear. ADDM Network investigators will continue to monitor the prevalence of ASD in select communities, with a focus on exploring changes within these communities that might affect both the observed prevalence of ASD and population-based characteristics of children identified with ASD. Although ASD is sometimes diagnosed by 2 years of age, the median age of the first ASD diagnosis remains older than age 4 years in the ADDM Network communities. Recommendations from the ADDM Network include enhancing strategies to address the need for 1) standardized, widely adopted measures to document ASD severity and functional limitations associated with ASD diagnosis; 2) improved recognition and documentation of symptoms of ASD, particularly among both boys and girls, children without intellectual disability, and children in all racial/ethnic groups; and 3) decreasing the age when children receive their first evaluation for and a diagnosis of ASD and are enrolled in community-based support systems.
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              A brief mental health outcome scale-reliability and validity of the Global Assessment of Functioning (GAF).

              The Global Assessment of Functioning (GAF) is a quick and simple measure of overall psychological disturbance. However, there is little research on the reliability and validity of this measure in severely mentally ill populations. Multidisciplinary keyworkers assessed 103 patients at monthly intervals over a 6-month period. Overall GAF scores were obtained, with additional separate ratings for symptoms and disability. These were compared with changes in antipsychotic medication and support needs over the same period. Satisfactory reliability was obtained for total GAF score and for symptom and disability measures, in spite of raters having only one brief training session. All GAF scores were associated with current support needs of patients. Symptom and disability scores were associated with changes in antipsychotic medication in the previous month. Only symptom score was associated with increases in antipsychotic medication at time of rating. GAF proved to be a reliable and, within the limits of the indicators used, a valid measure of psychiatric disturbance in our sample of the severely mentally ill. Differences in relationships between the three GAF scores and medication/support needs indicate the usefulness of obtaining all three scores for monitoring levels and type of psychiatric disturbance in this population.
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                Author and article information

                Contributors
                612-626-3633 , fatem002@umn.edu
                dfwong@jhmi.edu
                brasic@jhmi.edu
                hkuwaba1@jhmi.edu
                amathur4@jhmi.edu
                folso013@umn.edu
                sjacob@umn.edu
                realm001@umn.edu
                jvpardo@umn.edu
                leexx310@umn.edu
                Journal
                Cerebellum Ataxias
                Cerebellum Ataxias
                Cerebellum & Ataxias
                BioMed Central (London )
                2053-8871
                12 February 2018
                12 February 2018
                2018
                : 5
                : 3
                Affiliations
                [1 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Psychiatry, Division of Neuroscience Research, , University of Minnesota Medical School, ; 420 Delaware St SE, MMC 392, Minneapolis, MN 55455 USA
                [2 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Neuroscience, , University of Minnesota Medical School, ; 321 Church St. SE, Minneapolis, MN 55455 USA
                [3 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, The Russell H. Morgan Department of Radiology and Radiological Science, Section of High Resolution Brain PET Imaging, Division of Nuclear Medicine, and Molecular Imaging, , The Johns Hopkins School of Medicine, Johns Hopkins Medical Institutions, ; Baltimore, MD USA
                [4 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Neurology, , Johns Hopkins University School of Medicine, Johns Hopkins University, ; Baltimore, MD USA
                [5 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Psychiatry and Behavioral Sciences, , Johns Hopkins University School of Medicine, ; Baltimore, MD USA
                [6 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Neuroscience, , Johns Hopkins University, ; Baltimore, MD USA
                [7 ]Department of Psychiatry, Veterans Affairs Medical Center, 1 Veterans Drive, Minneapolis, MN 55417-2399 USA
                Author information
                http://orcid.org/0000-0002-6859-2626
                Article
                82
                10.1186/s40673-018-0082-1
                5810020
                29449954
                37cc7095-4a3a-47c0-8727-bd3423144410
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 15 November 2017
                : 26 January 2018
                Funding
                Funded by: Winston and Maxine Wallin Neuroscience Discovery Fund
                Award ID: NA
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                pet,autism,mglur5,cerebellum,postcentral gyrus,precuneus,[18f]-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile

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