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Molecular Psychiatry

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https://www.readbyqxmd.com/read/28093569/translational-evaluation-of-translocator-protein-as-a-marker-of-neuroinflammation-in-schizophrenia
#1
T Notter, J M Coughlin, T Gschwind, U Weber-Stadlbauer, Y Wang, M Kassiou, A C Vernon, D Benke, M G Pomper, A Sawa, U Meyer
Positron emission tomography (PET) imaging with radiotracers that target translocator protein 18 kDa (TSPO) has become a popular approach to assess putative neuroinflammatory processes and associated microglia activation in psychotic illnesses. It remains unclear, however, whether TSPO imaging can accurately capture low-grade inflammatory processes such as those present in schizophrenia and related disorders. Therefore, we evaluated the validity of TSPO as a disease-relevant marker of inflammation using a translational approach, which combined neurodevelopmental and neurodegenerative mouse models with PET imaging in patients with recent-onset schizophrenia and matched controls...
January 17, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28093568/gwas-meta-analysis-reveals-novel-loci-and-genetic-correlates-for-general-cognitive-function-a-report-from-the-cogent-consortium
#2
J W Trampush, M L Z Yang, J Yu, E Knowles, G Davies, D C Liewald, J M Starr, S Djurovic, I Melle, K Sundet, A Christoforou, I Reinvang, P DeRosse, A J Lundervold, V M Steen, T Espeseth, K Räikkönen, E Widen, A Palotie, J G Eriksson, I Giegling, B Konte, P Roussos, S Giakoumaki, K E Burdick, A Payton, W Ollier, M Horan, O Chiba-Falek, D K Attix, A C Need, E T Cirulli, A N Voineskos, N C Stefanis, D Avramopoulos, A Hatzimanolis, D E Arking, N Smyrnis, R M Bilder, N A Freimer, T D Cannon, E London, R A Poldrack, F W Sabb, E Congdon, E D Conley, M A Scult, D Dickinson, R E Straub, G Donohoe, D Morris, A Corvin, M Gill, A R Hariri, D R Weinberger, N Pendleton, P Bitsios, D Rujescu, J Lahti, S Le Hellard, M C Keller, O A Andreassen, I J Deary, D C Glahn, A K Malhotra, T Lencz
The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT)...
January 17, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28093567/beta-amyloid-sequelae-in-the-eye-a-critical-review-on-its-diagnostic-significance-and-clinical-relevance-in-alzheimer-s-disease
#3
REVIEW
T M Shah, S M Gupta, P Chatterjee, M Campbell, R N Martins
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. There is no test for its definitive diagnosis in routine clinical practice. Although phase III clinical trials have failed, only symptomatic treatment is currently available; a possible reason for these failed trials is that intervention commenced at an advanced stage of the disease. The hallmarks of an AD brain include plaques comprising of extracellular beta-amyloid (Aβ) protein aggregates and intracellular hyperphosphorylated neurofibrillary tangles of tau...
January 17, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28093566/estrogen-dependent-association-of-hdac4-with-fear-in-female-mice-and-women-with-ptsd
#4
S A Maddox, V Kilaru, J Shin, T Jovanovic, L M Almli, B G Dias, S D Norrholm, N Fani, V Michopoulos, Z Ding, K N Conneely, E B Binder, K J Ressler, A K Smith
Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels. This study evaluated the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women. We evaluated DNA methylation from blood of female participants in the Grady Trauma Project and found that serum estradiol levels associates with DNA methylation across the genome...
January 17, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28070126/lipocalin-2-protects-the-brain-during-inflammatory-conditions
#5
S S Kang, Y Ren, C-C Liu, A Kurti, K E Baker, G Bu, Y Asmann, J D Fryer
Sepsis is a prevalent health issue that can lead to central nervous system (CNS) inflammation with long-term behavioral and cognitive alterations. Using unbiased proteomic profiling of over 100 different cytokines, we found that Lipocalin-2 (LCN2) was the most substantially elevated protein in the CNS after peripheral administration of lipopolysaccharide (LPS). To determine whether the high level of LCN2 in the CNS is protective or deleterious, we challenged Lcn2(-/-) mice with peripheral LPS and determined effects on behavior and neuroinflammation...
January 10, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28070124/an-endophenotype-approach-to-the-genetics-of-alcohol-dependence-a-genome-wide-association-study-of-fast-beta-eeg-in-families-of-african-ancestry
#6
J L Meyers, J Zhang, J C Wang, J Su, S I Kuo, M Kapoor, L Wetherill, S Bertelsen, D Lai, J E Salvatore, C Kamarajan, D Chorlian, A Agrawal, L Almasy, L Bauer, K K Bucholz, G Chan, V Hesselbrock, L Koganti, J Kramer, S Kuperman, N Manz, A Pandey, M Seay, D Scott, R E Taylor, D M Dick, H J Edenberg, A Goate, T Foroud, B Porjesz
Fast beta (20-28 Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power...
January 10, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28070123/a-meta-analysis-of-peripheral-blood-nerve-growth-factor-levels-in-patients-with-schizophrenia
#7
X-Y Qin, H-T Wu, C Cao, Y P Loh, Y Cheng
Neurotrophins particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are crucial modulators in the neurodevelopment and maintenance of central and peripheral nervous systems. Neurotrophin hypothesis of schizophrenia (SCZ) postulated that the changes in the brains of SCZ patients are the result of disturbances of developing processes involving neurotrophic factors. This hypothesis was mainly supported by the abnormal regulation of BDNF in SCZ, especially the decreased peripheral blood BDNF levels in SCZ patients validated by several meta-analyses...
January 10, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28070121/nrsf-dependent-epigenetic-mechanisms-contribute-to-programming-of-stress-sensitive-neurons-by-neonatal-experience-promoting-resilience
#8
A Singh-Taylor, J Molet, S Jiang, A Korosi, J L Bolton, Y Noam, K Simeone, J Cope, Y Chen, A Mortazavi, T Z Baram
Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF)...
January 10, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28070120/the-protocadherin-17-gene-affects-cognition-personality-amygdala-structure-and-function-synapse-development-and-risk-of-major-mood-disorders
#9
H Chang, N Hoshina, C Zhang, Y Ma, H Cao, Y Wang, D-D Wu, S E Bergen, M Landén, C M Hultman, M Preisig, Z Kutalik, E Castelao, M Grigoroiu-Serbanescu, A J Forstner, J Strohmaier, J Hecker, T G Schulze, B Müller-Myhsok, A Reif, P B Mitchell, N G Martin, P R Schofield, S Cichon, M M Nöthen, H Walter, S Erk, A Heinz, N Amin, C M van Duijn, A Meyer-Lindenberg, H Tost, X Xiao, T Yamamoto, M Rietschel, M Li
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers...
January 10, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28070119/ocd-like-behavior-is-caused-by-dysfunction-of-thalamo-amygdala-circuits-and-upregulated-trkb-erk-mapk-signaling-as-a-result-of-spred2-deficiency
#10
M Ullrich, M Weber, A M Post, S Popp, J Grein, M Zechner, H Guerrero González, A Kreis, A G Schmitt, N Üçeyler, K-P Lesch, K Schuh
Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling...
January 10, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28044064/asd-and-schizophrenia-show-distinct-developmental-profiles-in-common-genetic-overlap-with-population-based-social-communication-difficulties
#11
B St Pourcain, E B Robinson, V Anttila, B B Sullivan, J Maller, J Golding, D Skuse, S Ring, D M Evans, S Zammit, S E Fisher, B M Neale, R J L Anney, S Ripke, M V Hollegaard, T Werge, A Ronald, J Grove, D M Hougaard, A D Børglum, P B Mortensen, M J Daly, G Davey Smith
Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic influences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait...
January 3, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28044063/molecular-mechanisms-underlying-noncoding-risk-variations-in-psychiatric-genetic-studies
#12
REVIEW
X Xiao, H Chang, M Li
Recent large-scale genetic approaches such as genome-wide association studies have allowed the identification of common genetic variations that contribute to risk architectures of psychiatric disorders. However, most of these susceptibility variants are located in noncoding genomic regions that usually span multiple genes. As a result, pinpointing the precise variant(s) and biological mechanisms accounting for the risk remains challenging. By reviewing recent progresses in genetics, functional genomics and neurobiology of psychiatric disorders, as well as gene expression analyses of brain tissues, here we propose a roadmap to characterize the roles of noncoding risk loci in the pathogenesis of psychiatric illnesses (that is, identifying the underlying molecular mechanisms explaining the genetic risk conferred by those genomic loci, and recognizing putative functional causative variants)...
January 3, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28044062/opening-up-the-dna-methylome-of-dementia
#13
R Delgado-Morales, M Esteller
Dementia is a complex clinical condition characterized by several cognitive impairments that interfere with patient independence in executing everyday tasks. Various neurodegenerative disorders have dementia in common among their clinical manifestations. In addition, these diseases, such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies and frontotemporal dementia, share molecular alterations at the neuropathological level. In recent years, the field of neuroepigenetics has expanded massively and it is now clear that epigenetic processes, such as DNA methylation, are mechanisms involved in both normal and pathological brain function...
January 3, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28044061/in-silico-identification-and-in-vivo-validation-of-mir-495-as-a-novel-regulator-of-motivation-for-cocaine-that-targets-multiple-addiction-related-networks-in-the-nucleus-accumbens
#14
R M Bastle, R J Oliver, A S Gardiner, N S Pentkowski, F Bolognani, A M Allan, T Chaudhury, M St Peter, N Galles, C Smith, J L Neisewander, N I Perrone-Bizzozero
MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression and are implicated in the etiology of several neuropsychiatric disorders, including substance use disorders (SUDs). Using in silico genome-wide sequence analyses, we identified miR-495 as a miRNA whose predicted targets are significantly enriched in the Knowledgebase for Addiction Related Genes (ARG) database (KARG; http://karg.cbi.pku.edu.cn). This small non-coding RNA is also highly expressed within the nucleus accumbens (NAc), a pivotal brain region underlying reward and motivation...
January 3, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28044060/molecular-interaction-between-type-2-diabetes-and-alzheimer-s-disease-through-cross-seeding-of-protein-misfolding
#15
I Moreno-Gonzalez, G Edwards Iii, N Salvadores, M Shahnawaz, R Diaz-Espinoza, C Soto
Numerous epidemiological studies have shown a significantly higher risk for development of Alzheimer's disease (AD) in patients affected by type 2 diabetes (T2D), but the molecular mechanism responsible for this association is presently unknown. Both diseases are considered protein misfolding disorders associated with the accumulation of protein aggregates; amyloid-beta (Aβ) and tau in the brain during AD, and islet amyloid polypeptide (IAPP) in pancreatic islets in T2D. Formation and accumulation of these proteins follows a seeding-nucleation model, where a misfolded aggregate or 'seed' promotes the rapid misfolding and aggregation of the native protein...
January 3, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28044059/the-esc-e-z-complex-an-effector-of-response-to-ovarian-steroids-manifests-an-intrinsic-difference-in-cells-from-women-with-premenstrual-dysphoric-disorder
#16
N Dubey, J F Hoffman, K Schuebel, Q Yuan, P E Martinez, L K Nieman, D R Rubinow, P J Schmidt, D Goldman
Clinical evidence suggests that mood and behavioral symptoms in premenstrual dysphoric disorder (PMDD), a common, recently recognized, psychiatric condition among women, reflect abnormal responsivity to ovarian steroids. This differential sensitivity could be due to an unrecognized aspect of hormonal signaling or a difference in cellular response. In this study, lymphoblastoid cell line cultures (LCLs) from women with PMDD and asymptomatic controls were compared via whole-transcriptome sequencing (RNA-seq) during untreated (ovarian steroid-free) conditions and following hormone treatment...
January 3, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/27994221/dynamic-modulation-of-inflammatory-pain-related-affective-and-sensory-symptoms-by-optical-control-of-amygdala-metabotropic-glutamate-receptor-4
#17
C Zussy, X Gómez-Santacana, X Rovira, D De Bundel, S Ferrazzo, D Bosch, D Asede, F Malhaire, F Acher, J Giraldo, E Valjent, I Ehrlich, F Ferraguti, J-P Pin, A Llebaria, C Goudet
Contrary to acute pain, chronic pain does not serve as a warning signal and must be considered as a disease per se. This pathology presents a sensory and psychological dimension at the origin of affective and cognitive disorders. Being largely refractory to current pharmacotherapies, identification of endogenous systems involved in persistent and chronic pain is crucial. The amygdala is a key brain region linking pain sensation with negative emotions. Here, we show that activation of a specific intrinsic neuromodulatory system within the amygdala associated with type 4 metabotropic glutamate receptors (mGlu4) abolishes sensory and affective symptoms of persistent pain such as hypersensitivity to pain, anxiety- and depression-related behaviors, and fear extinction impairment...
December 20, 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/27994220/structural-dysconnectivity-of-key-cognitive-and-emotional-hubs-in-young-people-at-high-genetic-risk-for-bipolar-disorder
#18
G Roberts, A Perry, A Lord, A Frankland, V Leung, E Holmes-Preston, F Levy, R K Lenroot, P B Mitchell, M Breakspear
Emerging evidence suggests that psychiatric disorders are associated with disturbances in structural brain networks. Little is known, however, about brain networks in those at high risk (HR) of bipolar disorder (BD), with such disturbances carrying substantial predictive and etiological value. Whole-brain tractography was performed on diffusion-weighted images acquired from 84 unaffected HR individuals with at least one first-degree relative with BD, 38 young patients with BD and 96 matched controls (CNs) with no family history of mental illness...
December 20, 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/27987558/recent-developments-in-molecular-brain-imaging-of-neuropsychiatric-disorders
#19
REVIEW
Mark Slifstein, Anissa Abi-Dargham
Molecular imaging with PET or SPECT has been an important research tool in psychiatry for as long as these modalities have been available. Here, we discuss two areas of neuroimaging relevant to current psychiatry research. The first is the use of imaging to study neurotransmission. We discuss the use of pharmacologic probes to induce changes in levels of neurotransmitters that can be inferred through their effects on outcome measures of imaging experiments, from their historical origins focusing on dopamine transmission through recent developments involving serotonin, GABA, and glutamate...
January 2017: Seminars in Nuclear Medicine
https://www.readbyqxmd.com/read/27956748/association-of-rare-missense-variants-in-the-second-intracellular-loop-of-nav1-7-sodium-channels-with-familial-autism
#20
M Rubinstein, A Patowary, I B Stanaway, E McCord, R R Nesbitt, M Archer, T Scheuer, D Nickerson, W H Raskind, E M Wijsman, R Bernier, W A Catterall, Z Brkanac
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes...
December 13, 2016: Molecular Psychiatry
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