ORCID Profile
0000-0003-2967-9662
Current Organisations
Neuroscience Research Australia
,
University of New South Wales
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biological Psychology (Neuropsychology, Psychopharmacology, | Neurogenetics | Psychology | Health, Clinical and Counselling Psychology | Neurosciences Not Elsewhere Classified | Public Health and Health Services | Genetics | Neurosciences | Quantitative Genetics | Preventive Medicine | Mental Health | Biophysics |
ANZSRC Socio-Economic Objective (SEO)
Behavioural and cognitive sciences | Nervous system and disorders | Preventive Medicine | Health Education and Promotion | Mental health | Biological sciences | Physical sciences | Mental Health Services
Related Links
Publications
Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NN.4228
Baculoviruses expressing the human familial Alzheimer's disease presenilin 1 mutation lacking exon 9 increase levels of an amyloid beta-like protein in Sf9 cells.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2004
Differences in regional brain atrophy in genetic forms of Alzheimer's disease
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.NEUROBIOLAGING.2005.03.011
Abstract: Multiple degenerative hallmarks characterize Alzheimer's disease: insoluble protein deposition, neuronal loss and cortical atrophy. Atrophy begins in the medial temporal lobe and becomes global by end stage. In a small proportion of cases, these tissue changes are caused by mutations in three known genes. These cases are affected earlier in life and have more abundant protein deposition, which may indicate greater tissue atrophy and degeneration. This issue remains unresolved. Grey matter atrophy in different cortical regions was determined in genetic cases of Alzheimer's disease (N = 13) and compared to sporadic cases (N = 13) and non-diseased controls (N = 23). Genetic mutations were found to influence the degree and regional pattern of atrophy. The majority of cases had greater medial temporal atrophy than sporadic disease, suggesting that abnormalities affecting Abeta metabolism selectively increase hippoc al degeneration. Cases with mutations in presenilin-1 demonstrated additional increased frontotemporal atrophy. This effect may be due to the influence of presenilin-1 on tau phosphorylation and metabolism. These differences may explain the earlier onset ages in these different forms of Alzheimer's disease.
The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data
Publisher: Springer Science and Business Media LLC
Date: 08-01-2014
Association of Built Environmental Features with Rates of Infectious Diseases in Remote Indigenous Communities in the Northern Territory, Australia
Publisher: MDPI AG
Date: 17-01-2022
DOI: 10.3390/HEALTHCARE10010173
Abstract: The health of Indigenous Australians is far poorer than non-Indigenous Australians, including an excess burden of infectious diseases. The health effect of built environmental (BE) features on Indigenous communities receives little attention. This study’s objective was to determine associations between BE features and infectious disease incidence rates in remote Indigenous communities in the Northern Territory (NT), Australia. Remote Indigenous communities (n = 110) were spatially joined to 93 Indigenous Locations (ILOC). Outcomes data were extracted (NT Notifiable Diseases System) and expressed as ILOC-specific incidence rates. Counts of buildings were extracted from community asset maps and grouped by function. Age-adjusted infectious disease rates were dichotomised, and bivariate binomial regression used to determine the relationships between BE variables and infectious disease. Infrastructure Shelter BE features were universally associated with significantly elevated disease outcomes (relative risk 1.67 to 2.03). Significant associations were observed for Services, Arena, Community, Childcare, Oval, and Sports and recreation BE features. BE groupings associated with disease outcomes were those with communal and/or social design intent or use. Comparable BE groupings without this intent or use did not associate with disease outcomes. While discouraging use of communal BE features during infectious disease outbreaks is a conceptually valid countermeasure, communal activities have additional health benefits themselves, and infectious disease transmission could instead be reduced through repairs to infrastructure, and more infrastructure. This is the first study to examine these associations simultaneously in more than a handful of remote Indigenous communities to illustrate community-level rather than aggregated population-level associations.
Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease
Publisher: Proceedings of the National Academy of Sciences
Date: 05-11-2013
Abstract: Beta-amyloid plaque accumulation, glucose hypometabolism, and neuronal atrophy are hallmarks of Alzheimer’s disease. However, the regional ordering of these biomarkers prior to dementia remains untested. In a cohort with Alzheimer’s disease mutations, we performed an integrated whole-brain analysis of three major imaging techniques: amyloid PET, [ 18 F]fluro-deoxyglucose PET, and structural MRI. We found that most gray-matter structures with amyloid plaques later have hypometabolism followed by atrophy. Critically, however, not all regions lose metabolic function, and not all regions atrophy, even when there is significant amyloid deposition. These regional disparities have important implications for clinical trials of disease-modifying therapies.
Cognitive functioning in older twins: The Older Australian Twins Study
Publisher: Wiley
Date: 10-2011
DOI: 10.1111/J.1741-6612.2011.00534.X
Abstract: To examine the concordance rates of common medical conditions and neurocognitive performance in monozygotic (MZ) and dizygotic (DZ) older twins. Twins aged ≥ 65 years and living in the three Eastern states of Australia were recruited through the Australian Twin Registry and underwent detailed neuropsychological and medical assessment. Assessments were conducted on 113 MZ and 96 DZ twin pairs, with a mean age of 70.5 years. MZ twins were more concordant than DZ twins for hypertension and asthma. MZ twins had higher correlations than DZ twins on most neuropsychological tests, with the exception of some tests related to processing speed. The concordance rate for mild cognitive impairment or dementia was 76.2% in MZ twins and 42.9% in DZ twins, a non-significant difference. Except for some aspects of processing speed, most cognitive functions in older in iduals show significant heritability. The heritability of neurocognitive disorders is, however, low.
A landscape of the genetic and cellular heterogeneity in Alzheimer disease
Publisher: Cold Spring Harbor Laboratory
Date: 02-12-2021
DOI: 10.1101/2021.11.30.21267072
Abstract: Alzheimer disease (AD) has substantial genetic, molecular, and cellular heterogeneity associated with its etiology. Much of our current understanding of the main AD molecular events associated with the amyloid hypothesis ( APP, PSEN1 and PSEN2 ) and neuroimmune modulation ( TREM2 and MS4A ) is based on genetic studies including GWAS. However, the functional genes, downstream transcriptional ramifications, and the cell-type-specific effects of many GWAS loci remain poorly understood. Understanding these effects can point us to the cellular processes involved in AD and uncover potential therapeutic targets. We applied a genetic-based approach to our s le selection our cohort included carriers of AD pathogenic mutations ( APP, PSEN1) , risk variants in TREM2 , and the resilience variant (rs1582763) in the MS4A cluster associated with cerebrospinal fluid (CSF) soluble TREM2 levels. We performed single-nucleus RNA-sequencing (snRNA-seq) of 1,102,459 nuclei from the human parietal cortex of these carriers. Following initial unbiased clustering and cell-type annotation, we performed deep subclustering analysis per cell type to identify unique cellular transcriptional states associated with these genetic variants. We identified differentially expressed genes between cell states and genetic variant carriers/controls, and performed differential cell proportion analyses to determine key differences among these carriers. We analyzed sequencing data from human dorsolateral prefrontal cortex and mouse models to replicate the enrichment of unique cell states in genetic variant carriers. Finally, we leveraged these cell-state differential expression results to link genes in AD GWAS loci to their functional cell types. We identified cell-specific expression states influenced by AD genetic factors for neurons and glia. Autosomal dominant AD (ADAD) brains exhibited unique transcriptional states in all cell types. TREM2 variant carrier brains were also enriched for specific microglia and oligodendrocyte subpopulations. Carriers of the resilience MS4A variant were enriched for an altered activated-microglia expression state. We mapped AD GWAS genes to their potential functional cell types, and some, including PLCG2 and SORL1 , were expressed in a broader range of brain cell types than previously reported. AD pathogenic, risk, or resilience variants are sufficient to alter the transcriptional and cellular landscape of human brains. Overall, our results suggest that the genetic architecture contributes to the cortical cellular heterogeneity associated with disease status, which is a critical factor to consider when designing drug trials and selecting the treatment program for AD patients. Our findings suggest that integrating genetic and single-cell molecular data facilitates our understanding of the heterogeneity of pathways, biological processes and cell types modulated by genetic risk factors for AD. US National Institutes of Health, Hope Center, Archer foundation, Alzheimer Association, CZI.
No association of spastic paraparesis genes in PSEN1 Alzheimer's disease with spastic paraparesis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-08-2007
A novel subtype of muscarinic receptor identified by homology screening
Publisher: Elsevier BV
Date: 11-1987
DOI: 10.1016/0006-291X(87)91613-5
Abstract: A new member of the protein superfamily of G-protein coupled receptors has been isolated by homology screening. By virtue of its homology with other muscarinic acetylcholine receptors and its ability to bind muscarinic specific antagonists, this muscarinic receptor subtype is designated M4. The M4 mRNA is preferentially expressed in certain brain regions. The existence of multiple receptor subtypes encoded by distinct genes in the brain has functional implications for the molecular mechanisms underlying information transmission in neuronal networks.
Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.NEUROIMAGE.2007.05.011
Abstract: Loss-of-function mutations in MCPH1 and ASPM are responsible for some cases of autosomal recessive primary microcephaly. Recent studies have indicated that certain common variants of these genes have been positively selected for during the evolution of modern humans. It is therefore possible that these variants may predispose to an increase in brain size in the normal human population. We genotyped the MCPH1 G37995C and ASPM A44871G polymorphisms in a cohort of 118 healthy people who had undergone structural magnetic resonance imaging analysis. We did not detect significant association of either MCPH1 G37995C or ASPM A44871G genotype with whole brain volume, cerebral cortical volume or proportion of grey matter in this cohort. Nor did we detect an association of combined MCPH1 37995C and ASPM 44871G allele dosage with these brain measurements. These results were also confirmed in an age-restricted subcohort of 94 in iduals. This study suggests that phenotypes other than brain size may have been selected for in ASPM and MCPH1 variants during evolution of modern humans.
Built Environment Features and Cardiometabolic Mortality and Morbidity in Remote Indigenous Communities in the Northern Territory, Australia
Publisher: MDPI AG
Date: 08-2022
Abstract: Indigenous Australians experience poorer health than non-Indigenous Australians, with cardiometabolic diseases (CMD) being the leading causes of morbidity and mortality. Built environmental (BE) features are known to shape cardiometabolic health in urban contexts, yet little research has assessed such relationships for remote-dwelling Indigenous Australians. This study assessed associations between BE features and CMD-related morbidity and mortality in a large s le of remote Indigenous Australian communities in the Northern Territory (NT). CMD-related morbidity and mortality data were extracted from NT government health databases for 120 remote Indigenous Australian communities for the period 1 January 2010 to 31 December 2015. BE features were extracted from Serviced Land Availability Programme (SLAP) maps. Associations were estimated using negative binomial regression analysis. Univariable analysis revealed protective effects on all-cause mortality for the BE features of Education, Health, Disused Buildings, and Oval, and on CMD-related emergency department admissions for the BE feature Accommodation. Incidence rate ratios (IRR’s) were greater, however, for the BE features Infrastructure Transport and Infrastructure Shelter. Geographic Isolation was associated with elevated mortality-related IRR’s. Multivariable regression did not yield consistent associations between BE features and CMD outcomes, other than negative relationships for Indigenous Location-level median age and Geographic Isolation. This study indicates that relationships between BE features and health outcomes in urban populations do not extend to remote Indigenous Australian communities. This may reflect an overwhelming impact of broader social inequity, limited correspondence of BE measures with remote-dwelling Indigenous contexts, or a ‘tipping point’ of collective BE influences affecting health more than singular BE features.
Corrigendum
Publisher: Oxford University Press (OUP)
Date: 23-11-2015
DOI: 10.1093/BRAIN/AWV210
Negative association between anterior insula activation and resilience during sustained attention: an fMRI twin study
Publisher: Cambridge University Press (CUP)
Date: 11-01-2023
DOI: 10.1017/S0033291721005262
Abstract: While previous studies have suggested that higher levels of cognitive performance may be related to greater wellbeing and resilience, little is known about the associations between neural circuits engaged by cognitive tasks and wellbeing and resilience, and whether genetics or environment contribute to these associations. The current study consisted of 253 monozygotic and dizygotic adult twins, including a subs le of 187 early-life trauma-exposed twins, with functional Magnetic Resonance Imaging data from the TWIN-E study. Wellbeing was measured using the COMPAS-W Wellbeing Scale while resilience was defined as a higher level of positive adaptation (higher levels of wellbeing) in the presence of trauma exposure. We probed both sustained attention and working memory processes using a Continuous Performance Task in the scanner. We found significant negative associations between resilience and activation in the bilateral anterior insula engaged during sustained attention. Multivariate twin modelling showed that the association between resilience and the left and right insula activation was mostly driven by common genetic factors, accounting for 71% and 87% of the total phenotypic correlation between these variables, respectively. There were no significant associations between wellbeing/resilience and neural activity engaged during working memory updating. The findings suggest that greater resilience to trauma is associated with less activation of the anterior insula during a condition requiring sustained attention but not working memory updating. This possibly suggests a pattern of ‘neural efficiency’ (i.e. more efficient and/or attenuated activity) in people who may be more resilient to trauma.
Alzheimer's Disease and Brain Reserve
Publisher: Wiley
Date: 02-1999
Building new function into glycine receptors: A structural model for the activation of the glycine-gated chloride channel
Publisher: Wiley
Date: 04-11-1999
DOI: 10.1046/J.1440-1681.1999.03150.X
Abstract: 1. The glycine receptor chloride channel mediates inhibitory neurotransmission and is a member of the ligand-gated ion channel superfamily, which includes the nicotinic acetylcholine receptor channel. 2. Activation of these channels involves a movement of the pore-lining second membrane-spanning domain with respect to the remainder of the protein. 3. The present review considers the evidence that the loops that connect this domain with the rest of the protein act as crucial components of the channel activation mechanism.
Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study
Publisher: Elsevier BV
Date: 03-2018
Don't give up on GWAS
Publisher: Springer Science and Business Media LLC
Date: 09-08-2011
DOI: 10.1038/MP.2011.94
Effects of polygenic risk for suicide attempt and risky behavior on brain structure in young people with familial risk of bipolar disorder
Publisher: Wiley
Date: 02-11-2021
DOI: 10.1002/AJMG.B.32879
Abstract: Bipolar disorder (BD) is associated with a 20–30‐fold increased suicide risk compared to the general population. First‐degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide‐related polygenic risk scores (PRSs)—a quantitative index of genomic risk—and variability in brain structures implicated in SA. Participants ( n = 206 aged 12–30 years) were unrelated in iduals of European ancestry and comprised three groups: 41 BD cases, 96 BD relatives (“high risk”), and 69 controls. Genotyping employed PsychArray, followed by imputation. Three PRSs were computed using genome‐wide association data for SA in BD (SA‐in‐BD), SA in major depressive disorder (SA‐in‐MDD) (Mullins et al., 2019, The American Journal of Psychiatry , 176 (8), 651–660), and risky behavior (Karlsson Linnér et al., 2019, Nature Genetics , 51 (2), 245–257). Structural magnetic resonance imaging processing employed FreeSurfer v5.3.0. General linear models were constructed using 32 regions‐of‐interest identified from suicide neuroimaging literature, with false‐discovery‐rate correction. SA‐in‐MDD and SA‐in‐BD PRSs negatively predicted parahippoc al thickness, with the latter association modified by group membership. SA‐in‐BD and Risky Behavior PRSs inversely predicted rostral and caudal anterior cingulate structure, respectively, with the latter effect driven by the “high risk” group. SA‐in‐MDD and SA‐in‐BD PRSs positively predicted cuneus structure, irrespective of group. This study demonstrated associations between PRSs for suicide‐related phenotypes and structural variability in brain regions implicated in SA. Future exploration of extended PRSs, in conjunction with a range of biological, phenotypic, environmental, and experiential data in high risk populations, may inform predictive models for suicidal behaviors.
Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders
Publisher: Cold Spring Harbor Laboratory
Date: 17-08-2020
DOI: 10.1101/2020.08.13.249813
Abstract: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. We conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. Across disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815 p =3.2×10 −8 ), that interacts with sodium otassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence ( p ×10 −6 ) for cross-disorder GxS interaction (rs7302529, p =1.6×10 −7 rs73033497, p =8.8×10 −7 rs7914279, p =6.4×10 −7 ) implicating various functions. Gene-based analyses identified GxS interaction across disorders ( p =8.97×10 −7 ) with transcriptional inhibitor SLTM . Most significant in SCZ was a MOCOS gene locus (rs11665282 p =1.5×10 −7 ), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509 p =1.1×10 −7 ) in a locus containing IDO2 , a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD ( p FDR .05). In the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.
Attitudes of medical genetics practitioners and psychiatrists toward communicating with patients about genetic risk for psychiatric disorders
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2014
Predictive and Diagnostic Genetic Testing in Psychiatry
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.CLL.2010.07.001
Abstract: The recent advent of commercially available genetic tests for the diagnosis of several mental illnesses has led to intense controversy amongst the psychiatric research community. In this article the authors review these developments, and contrast these with the growing evidence from genomewide association studies that highly heritable psychiatric conditions such as schizophrenia are due to the contributions and interaction of multiple allelic variants, each of small effect size. There is also evidence for the contribution of some highly penetrant rare de novo copy number variants, though the lack of disease specificity for these is of concern. This article outlines the prerequisites for predictive and diagnostic genetic tests, such as clinical validity and utility, and reviews the opportunity that genetic tests for mental illnesses present. As the scientific discourse on genetic tests for complex disorders is not limited to psychiatry, the authors outline current thoughts on the significance of genome-wide association studies across health, and the phenomenon of direct-to-consumer tests in medicine. The attitudes and understanding of patients, families, and clinicians about the future (currently hypothetical) scenario of psychiatric genetic tests are discussed, as is the potential for such testing to increase, rather than diminish stigma. Finally, recommendations on the future development and availability of genetic tests in psychiatry are provided.
Altered potassium channel function in the superficial dorsal horn of thespasticmouse
Publisher: Wiley
Date: 28-09-2007
What Is the Community Pharmacists’ Role in Supporting Older Australians with Palliative Care Needs?
Publisher: MDPI AG
Date: 21-04-2021
DOI: 10.3390/HEALTHCARE9050489
Abstract: As the population ages, the number of older populations globally requiring palliative care is rapidly growing, requiring services of multidisciplinary teams—including community pharmacists. The aim of this study is to describe the community pharmacists’ perceived role in providing services to community dwelling older Australians receiving palliative care. Utilising an eight-domain End of Life Directions for Aged Care (ELDAC) care model, a national cross-sectional questionnaire was designed and undertaken online with Australian community pharmacists. Respondents were asked questions relating to socio-demographic characteristics, practice characteristics, and scope of services provided. Of the 62 pharmacists who responded to the questionnaire, 51 were included in the final data analysis and reporting. Pharmacists working in dispensing roles made up about half of the respondents, while the remainder worked in settings such as general practice, residential aged care, or providing medication review services. Pharmacists can identify patients with indicators of poor life expectancy and mostly work with older Australians daily. Dispensing and non-dispensing pharmacists offer a range of services that complement each other. Organisations caring for the aged should consider the role of the pharmacist, in caring for people with palliative care needs, along with their carers.
Community interest in predictive genetic testing for susceptibility to major depressive disorder in a large national sample
Publisher: Cambridge University Press (CUP)
Date: 15-12-2011
DOI: 10.1017/S0033291710002394
Abstract: Despite international concern about unregulated predictive genetic testing, there are surprisingly few data on both the determinants of community interest in such testing and its psychosocial impact. A large population-based public survey with community-dwelling adults ( n =1046) ascertained through random digit dialling. Attitudes were assessed by structured interviews. The study found strong interest in predictive genetic testing for a reported susceptibility to depression. Once the benefits and disadvantages of such testing had been considered, there was significantly greater interest in seeking such a test through a doctor (63%) compared to direct-to-consumer (DTC 40%) ( p .001). Personal history of mental illness [odds ratio (OR) 2.58, p .001], self-estimation of being at higher than average risk for depression (OR 1.92, p .001), belief that a genetic component would increase rather than decrease stigma (OR 1.62, p .001), and endorsement of benefits of genetic testing (OR 3.47, p .001) significantly predicted interest in having such a test. Despite finding attitudes that genetic links to mental illness would increase rather than decrease stigma, we found strong community acceptance of depression risk genotyping, even though a predisposition to depression may only manifest upon exposure to stressful life events. Our results suggest that there will be a strong demand for predictive genetic testing.
Genome-wide significant results identified for plasma apolipoprotein H levels in middle-aged and older adults
Publisher: Springer Science and Business Media LLC
Date: 31-03-2016
DOI: 10.1038/SREP23675
Abstract: Apolipoprotein H (ApoH) is a multi-functional plasma glycoprotein that has been associated with negative health outcomes. ApoH levels have high heritability. We undertook a genome-wide association study of ApoH levels using the largest s le to date and replicated the results in an independent cohort (total N = 1,255). In the discovery phase, a meta-analysis of two cohorts, the Sydney Memory and Ageing Study (Sydney MAS) and the Older Australian Twins Study (OATS) (n = 942) revealed genome-wide significant results in or near the APOH gene on chromosome 17 (top SNP, rs7211380, p = 1 × 10 −11 ). The results were replicated in an independent cohort, the Hunter Community Study (p 0.002) (n = 313). Conditional and joint analysis (COJO) confirmed the association of the chromosomal 17 region with ApoH levels. The set of independent SNPs identified by COJO explained 23% of the variance. The relationships between the top SNPs and cardiovascular/lipid/cognition measures and diabetes were assessed in Sydney MAS, with suggestive results observed for diabetes and cognitive performance. However, replication of these results in the smaller OATS cohort was not found. This work provides impetus for future research to better understand the contribution of genetics to ApoH levels and its possible impacts on health.
Localization of the adenosine A2b receptor subtype gene (ADORA2B) to chromosome 17p11.2-p12 by FISH and PCR screening of somatic cell hybrids
Publisher: Elsevier BV
Date: 1995
Meta-analysis and brain imaging data support the involvement of VRK2 (rs2312147) in schizophrenia susceptibility
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.SCHRES.2012.10.008
Abstract: Recent genome-wide association studies have reported a set of schizophrenia susceptibility genes, but many of them await further replications in additional s les. Here we analyzed 5 genome-wide supported variants in a Han Chinese s le, and the variant rs2312147 at VRK2 showed significant association, which was confirmed in the meta-analysis combining multiple Asian and European s les (P=3.17×10(-4), N=7498). Rs2312147 is also associated with brain structure in healthy subjects, including the total brain volume and the white matter volume. Gene expression analyses indicated an up-regulation of VRK2 in schizophrenia patients. Our data provide further evidence for the contribution of VRK2 to schizophrenia.
A Western Australian kindred with Dutch cerebral amyloid angiopathy
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1016/J.JNS.2005.08.002
Abstract: A family from the south of Western Australia is described with Dutch cerebral amyloid angiopathy (HCHWA-D). The proband died at age 60 from recurrent lobar haemorrhages in the brain, as did his sister and five other family members. The APP 693 mutation at position 22 of the Abetapeptide resulting in a glutamine for glutamic acid was identified in the proband and the affected sister. Pathologically lobar haemorrhages were found with cerebrovascular angiopathy neuritic plaques were found but no neurofibrilary tangles. There was a leukoencephalopathy on MRI scanning. Dementia and cognitive decline has not been observed in this family. This is the first family reported outside of Europe and the Northern Hemisphere. The discovery highlights the importance of detecting this rare cause of fatal cerebral haemorrhage as it has implications for gene testing and general medical management.
Prioritizing Built Environmental Factors to Tackle Chronic and Infectious Diseases in Remote Northern Territory (NT) Communities of Australia: A Concept Mapping Study
Publisher: MDPI AG
Date: 13-05-2021
Abstract: High prevalence of chronic and infectious diseases in Indigenous populations is a major public health concern both in global and Australian contexts. Limited research has examined the role of built environments in relation to Indigenous health in remote Australia. This study engaged stakeholders to understand their perceptions of the influence of built environmental factors on chronic and infectious diseases in remote Northern Territory (NT) communities. A preliminary set of 1120 built environmental indicators were systematically identified and classified using an Indigenous Indicator Classification System. The public and environmental health workforce was engaged to consolidate the classified indicators (n = 84), and then sort and rate the consolidated indicators based on their experience with living and working in remote NT communities. Sorting of the indicators resulted in a concept map with nine built environmental domains. Essential services and Facilities for health/safety were the highest ranked domains for both chronic and infectious diseases. Within these domains, adequate housing infrastructure, water supply, drainage system, reliable sewerage and power infrastructure, and access to health services were identified as the most important contributors to the development of these diseases. The findings highlight the features of community environments amenable to public health and social policy actions that could be targeted to help reduce prevalence of chronic and infectious diseases.
Plasma amyloid‐beta levels in a pre‐symptomatic Dutch‐type hereditary cerebral amyloid angiopathy pedigree
Publisher: MDPI AG
Date: 13-03-2021
DOI: 10.3390/IJMS22062931
Abstract: Plasma amyloid-beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aβ alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aβ measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3–4 years later (NC = 8 MC = 9). Plasma Aβ1-40 and Aβ1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aβ1-40: p = 0.001 Aβ1-42: p = 0.0004) and T2 (Aβ1-40: p = 0.001 Aβ1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aβ1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aβ1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aβ may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger s le sets are required.
Gene-microRNA interactions associated with antipsychotic mechanisms and the metabolic side effects of olanzapine
Publisher: Springer Science and Business Media LLC
Date: 15-01-2013
The human glycine receptor β subunit: primary structure, functional characterisation and chromosomal localisation of the human and murine genes
Publisher: Elsevier BV
Date: 1996
Preliminary Evidence of the Short Allele of the Serotonin Transporter Gene Predicting Poor Response to Cognitive Behavior Therapy in Posttraumatic Stress Disorder
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.BIOPSYCH.2010.03.016
Abstract: This study was intended to assess the extent to which the low-expression alleles of the serotonin transporter gene promoter predict poor response to cognitive behavior therapy in patients with posttraumatic stress disorder (PTSD). Forty-five patients with PTSD underwent an 8-week exposure-based cognitive behavior therapy program and provided mouth swabs or saliva s les to extract genomic DNA and classify in iduals according to four allelic forms (S(A), S(G), L(A), L(G)) of the 5-HTT-linked polymorphic region (5-HTTLPR). We determined whether the 5-HTTLPR genotype predicted change in PTSD severity following treatment (n = 45) and 6 months later (n = 42). After controlling for pretreatment PTSD severity and number of treatment sessions, the 5-HTTLPR low-expression genotype group (S or L(G) allele carriers) displayed more severe PTSD 6 months following treatment relative to other patients. This study suggests a genetic contribution to treatment outcome following cognitive behavior therapy and implicates the serotonergic system in response to exposure-based treatments in PTSD.
A transcript map encompassing a susceptibility locus for bipolar affective disorder on chromosome 4q35
Publisher: Springer Science and Business Media LLC
Date: 09-2002
Abstract: Bipolar affective disorder is one of the most common mental illnesses with a population prevalence of approximately 1%. The disorder is genetically complex, with an increasing number of loci being implicated through genetic linkage studies. However, the specific genetic variations and molecules involved in bipolar susceptibility and pathogenesis are yet to be identified. Genetic linkage analysis has identified a bipolar disorder susceptibility locus on chromosome 4q35, and the interval harbouring this susceptibility gene has been narrowed to a size that is amenable to positional cloning. We have used the resources of the Human Genome Project (HGP) and Celera Genomics to identify overlapping sequenced BAC clones and sequence contigs that represent the region implicated by linkage analysis. A combination of bioinformatic tools and laboratory techniques have been applied to annotate this DNA sequence data and establish a comprehensive transcript map that spans approximately 5.5 Mb. This map encompasses the chromosome 4q35 bipolar susceptibility locus, which localises to a "most probable" candidate interval of approximately 2.3 Mb, within a more conservative candidate interval of approximately 5 Mb. Localised within this map are 11 characterised genes and eight novel genes of unknown function, which together provide a collection of candidate transcripts that may be investigated for association with bipolar disorder. Overall, this region was shown to be very gene-poor, with a high incidence of pseudogenes, and redundant and novel repetitive elements. Our analysis of the interval has demonstrated a significant difference in the extent to which the current HGP and Celera sequence data sets represent this region.
A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19
Publisher: Springer Science and Business Media LLC
Date: 09-2002
Abstract: Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13 pedigree cohort consisted of 231 in iduals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P = 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several in idual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.
Kv channel interacting protein 3 expression and regulation by haloperidol in midbrain dopaminergic neurons
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.BRAINRES.2009.09.045
Abstract: Antipsychotic drugs are the main treatment for schizophrenia, despite their adverse side effects and uncertain mode of action. Gene expression studies in the brains of rodents treated with antipsychotic drugs aim to uncover this mechanism and elucidate more specific targets for schizophrenia treatment. Previous expression profiling analyses showed that K(v) channel interacting protein 3 (KChIP3) was down-regulated in the mouse brain following treatment with multiple antipsychotic drugs. In this study, we used in situ hybridization to anatomically define the expression of KChIP3 mRNA in the mouse brain and to quantify its regulation by 7-day haloperidol treatment. We used immunohistochemistry to localize KChIP3 protein expression in the midbrain, dorsal and ventral striatum and the prefrontal cortex. We found KChIP3 mRNA throughout the grey matter of the brain, with high expression in the hippoc us, specific thalamic nuclei, deeper cortical layers and in the midbrain. KChIP3 mRNA was significantly down-regulated in the dorsal striatum and the ventral tegmental area following haloperidol treatment. KChIP3 protein is expressed in the neuropil in the cortex and striatum, as well as in the soma of deeper layer cortical and striatal neurons. This study, for the first time, also localized KChIP3 protein in the cell bodies and processes of dopaminergic neurons in the midbrain. These findings indicate that regulation of KChIP3, particularly in mesocortical dopamine neurons, may be part of the action of antipsychotic drugs and that prolonged and more specific targeting of ion channel subunits may enhance the therapeutic effects of antipsychotic drugs.
Correction: Automatic Extraction of Mental Health Disorders From Domestic Violence Police Narratives: Text Mining Study
Publisher: JMIR Publications Inc.
Date: 05-04-2019
DOI: 10.2196/13007
Predictive and Diagnostic Genetic Testing in Psychiatry
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.PSC.2009.10.001
Abstract: The recent advent of commercially available genetic tests for the diagnosis of several mental illnesses has led to intense controversy amongst the psychiatric research community. In this article the authors review these developments, and contrast these with the growing evidence from genome-wide association studies that highly heritable psychiatric conditions such as schizophrenia are due to the contributions and interaction of multiple allelic variants, each of small effect size. There is also evidence for the contribution of some highly penetrant rare de novo copy number variants, though the lack of disease specificity for these is of concern. This article outlines the prerequisites for predictive and diagnostic genetic tests, such as clinical validity and utility, and reviews the opportunity that genetic tests for mental illnesses present. As the scientific discourse on genetic tests for complex disorders is not limited to psychiatry, the authors outline current thoughts on the significance of genome-wide association studies across health, and the phenomenon of direct-to-consumer tests in medicine. The attitudes and understanding of patients, families, and clinicians about the future (currently hypothetical) scenario of psychiatric genetic tests are discussed, as is the potential for such testing to increase, rather than diminish stigma. Finally, recommendations on the future development and availability of genetic tests in psychiatry are provided.
Differential effect of disease-associated ST8SIA2 haplotype on cerebral white matter diffusion properties in schizophrenia and healthy controls
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
DOI: 10.1038/S41398-017-0052-Z
Abstract: Brain white matter abnormalities are evident in in iduals with schizophrenia, and also their first-degree relatives, suggesting that some alterations may relate to underlying genetic risk. The ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 ( ST8SIA2) gene, which encodes the alpha-2,8-sialyltransferase 8B enzyme that aids neuronal migration and synaptic plasticity, was previously implicated as a schizophrenia susceptibility gene. This study examined the extent to which specific haplotypes in ST8SIA2 influence white matter microstructure using diffusion-weighted imaging of in iduals with schizophrenia ( n = 281) and healthy controls ( n = 172), recruited across five Australian sites. Interactions between diagnostic status and the number of haplotype copies (0 or ≥1) were tested across all white matter voxels with cluster-based statistics. Fractional anisotropy (FA) in the right parietal lobe was found to show a significant interaction between diagnosis and ST8SIA2 protective haplotype ( p 0.05, family-wise error rate (FWER) cluster-corrected). The protective haplotype was associated with increased FA in controls, but this effect was reversed in people with schizophrenia. White matter fiber tracking revealed that the region-of-interest was traversed by portions of the superior longitudinal fasciculus, corona radiata, and posterior limb of internal capsule. Post hoc analysis revealed that reduced FA in this regional juncture correlated with reduced IQ in people with schizophrenia. The ST8SIA2 risk haplotype copy number did not show any differential effects on white matter. This study provides a link between a common disease-associated haplotype and specific changes in white matter microstructure, which may relate to resilience or risk for mental illness, providing further compelling evidence for involvement of ST8SIA2 in the pathophysiology of schizophrenia.
Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes
Publisher: Elsevier BV
Date: 06-2018
Isoelectric charge of recombinant human follicle-stimulating hormone isoforms determines receptor affinity and in vitro bioactivity.
Publisher: The Endocrine Society
Date: 1993
DOI: 10.1210/ENDO.132.1.8419133
Abstract: Recombinant human FSH (rhFSH) was obtained by expressing the human FSH alpha- and beta-subunit complementary DNAs in the chinese hamster ovary cell line. Isoforms of rhFSH were resolved into specific isoelectric (pI) fractions by chromatofocusing. rhFSH isoforms ranged from pI 3.0-5.5 with a modal value of pI 4.2. Analysis of the biological activity of specific pI isoforms of rhFSH was undertaken using both the rat granulosa cell aromatase (in vitro) bioassay and a RRA. More acidic isoforms (e.g. pI 3.5) showed significantly lower affinity (P < 0.05) for rat testicular FSH receptors than did the less acidic isoforms (e.g. pI 4.8). Consistent with the receptor binding affinity data, the more acidic fractions resulted in significantly less activation (P < 0.05) of rat granulosa cell aromatase activity, as measured by estrogen production, than did the less acidic isoforms. The observed bioactivities and their correlation with the pI values of the rhFSH isoforms are consistent with observations of differing bioactivities seen in both pituitary and urinary FSH isoforms. These results demonstrate that rhFSH, made in the chinese hamster ovary cell line, is both biologically active and has isoform profiles, and presumably carbohydrate structures, that closely resemble those seen in natural hFSH.
Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis?
Publisher: Oxford University Press (OUP)
Date: 07-05-2015
DOI: 10.1093/BRAIN/AWV115
BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease
Publisher: Oxford University Press (OUP)
Date: 12-08-2016
DOI: 10.1093/BRAIN/AWW200
Familial idiopathic basal ganglia calcification (Fahr's disease) without neurological, cognitive and psychiatric symptoms is not linked to the IBGC1 locus on chromosome 14q
Publisher: Springer Science and Business Media LLC
Date: 04-12-2001
DOI: 10.1007/S00439-001-0650-X
Abstract: Idiopathic basal ganglia calcification (IBGC) is characterised by radiological, neurological, cognitive and psychiatric abnormalities. The associations between these abnormal phenotypes and abnormal genes remain unclear despite the recent mapping to chromosome 14q of a susceptibility locus for IBGC ( IBGC1). We identified two siblings, from a large multigenerational pedigree, who had both been diagnosed with radiological IBGC, dementia, bipolar affective disorder and Parkinsonism. We assessed (1) other family members to determine whether these four phenotypes were co-segregating as symptoms of IBGC, and (2) possible IBGC linkage to the IBGC1 locus on chromosome 14q or to any known or potential dementia genes. Nine second-generation and 21 third-generation members received radiological, neurological, neuropsychological and psychiatric assessments. We genotyped all family members for microsatellite markers at the IBGC1 locus and polymorphisms of the ApoE, VLDL, alpha1-ACT, BChE-K, APP, PS1, PS2 and tau genes and tested these for linkage to IBGC, dementia and bipolar disorder. Of the ten family members with radiological intracranial calcification, all except the two index cases were normal. There was no significant association between IBGC status and severe cognitive impairment or dementia ( P=0.335) or bipolar affective disorder or Parkinsonism ( P=1.0). Linkage to the IBGC1 locus was excluded. Of the eight dementia gene markers tested, the only positive LOD score was for the ApoE epsilon4 polymorphism and dementia/severe cognitive impairment. We have identified a form of IBGC in which calcification is inherited independently of neurological, cognitive and psychiatric symptoms. This may represent a second locus for this disorder.
Molecular studies of the GABAA receptor
Publisher: Springer Science and Business Media LLC
Date: 06-1989
DOI: 10.1007/BF01674275
Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel
Publisher: Wiley
Date: 1997
Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease
Publisher: Elsevier BV
Date: 2020
A comprehensive neuropsychiatric study of elderly twins: The Older Australian Twins Study
Publisher: Cambridge University Press (CUP)
Date: 12-2009
Abstract: The Older Australian Twins Study (OATS) was recently initiated to investigate genetic and environmental factors and their associations and interactions in healthy brain ageing and ageing-related neurocognitive disorders. The study extends the classic MZ-DZ design to include one or two equivalently aged siblings for each twin pair and utilizes the rich resources of the Australian Twin Registry. The study has a number of distinguishing features including comprehensive psychiatric, neuropsychological, cardiovascular, metabolic, and neuroimaging assessments, a longitudinal design and links with a brain donor program. The study measures many behavioral and environmental factors, but in particular lifetime physical and mental activity, physical and psychological trauma, loss of parent early in life, later losses and life events, early-life socioeconomic environment, alcohol and drug use, occupational exposure, and nutrition. It also includes comprehensive cardiovascular assessment, blood biochemistry, genetics and proteomics. The socio-demographic and health data on the first 172 pairs of twins participating in this study are presented. Prevalence of mild cognitive impairment is 12.8% and of dementia 1.5% in the s le. The target s le size is 1000, with at least 400 pairs of twins aged 65–90 years. The cohort will be assessed every two years, with in-depth assessments being repeated. OATS offers an excellent opportunity for collaboration with other similar studies as well as researchers who share the same interests.
VOICE–Validating Outcomes by Including Consumer Experience: A Study Protocol to Develop a Patient Reported Experience Measure for Aboriginal and Torres Strait Islander Peoples Accessing Primary Health
Publisher: MDPI AG
Date: 26-12-2022
Abstract: Aboriginal and Torres Strait Islander peoples’ (hereafter respectfully referred to as Indigenous Australians) experiences of health care are shaped by historical, social and cultural factors, with cultural security critical to effective care provision and engagement between services and community. Positive patient experiences are associated with better health outcomes. Consequently, it is an accreditation requirement that primary health care (PHC) services must formally gather and respond to patient feedback. However, currently available patient feedback tools were not developed with Indigenous Australians, and do not reflect their values and world views. Existing tools do not capture important experiences of care of Indigenous Australians in PHC settings, nor return information that assists services to improve care. Consistent with the principles of Indigenous Data Sovereignty, we will co-design and validate an Indigenous-specific Patient Reported Experience Measure (PREM) that produces data by and for community, suitable for use in quality improvement in comprehensive PHC services. This paper presents the protocol of the study, outlining the rationale, methodologies and associated activities that are being applied in developing the PREM. Briefly, guided by an Aboriginal and Torres Strait Islander Advisory Group, our team of Indigenous and non-Indigenous researchers, service providers and policy makers will use a combination of Indigenous methodologies, participatory, and traditional western techniques for scale development. We will engage PHC service staff and communities in eight selected sites across remote, regional, and metropolitan communities in Australia for iterative cycles of data collection and feedback throughout the research process. Yarning Circles with community members will identify core concepts to develop an “Experience of Care Framework”, which will be used to develop items for the PREM. Staff members will be interviewed regarding desirable characteristics and feasibility considerations for the PREM. The PREM will undergo cognitive and psychometric testing.
Widespread expression of GABA(A) receptor subunits in peripheral tissues
Publisher: Elsevier BV
Date: 11-1999
DOI: 10.1016/S0168-0102(99)00078-4
Abstract: The receptor subtypes involved in the physiological and pharmacological actions of gamma-amino butyric acid (GABA) in peripheral and endocrine tissues are not clear. Information about the molecular characteristics of GABA(A) receptors in peripheral endocrine tissues is only available for the pancreas and the adrenal medulla. Using reverse transcription (RT) polymerase chain reaction (PCR), the widespread expression of GABA(A) receptors subunits in rat peripheral tissues, including adrenal, ovary, testis, placenta, uterus, and small intestine is shown. It is shown that GABA(A) receptor subunits are expressed in multiple endocrine tissues in a tissue specific manner. These results give an insight into the likely pharmacological properties of these GABA(A) receptors in these tissues. The gonadal endocrine tissues such as the placenta, ovary and the testis express greater range of GABA(A) receptor subunits relative to the adrenal gland. The tissues with greater smooth muscle content, the small intestine and the uterus also express a smaller range of subunits subtypes.
Assessing oxidative pathway genes as risk factors for bipolar disorder
Publisher: Wiley
Date: 08-2010
DOI: 10.1111/J.1399-5618.2010.00834.X
Abstract: There is a growing body of evidence implicating oxidative stress and the glutathione system in the pathogenesis of major psychiatric illnesses, including schizophrenia and bipolar disorder. Here we investigate whether genes involved in oxidative stress regulation are associated with increased risk for bipolar disorder. Four candidate genes were selected a priori from two different steps in the oxidative stress pathway, specifically the synthesis of glutathione [catalytic subunit of glutamate cysteine ligase (GCLC) and regulatory subunit of glutamate cysteine ligase (GCLM)] and the removal of reactive oxygen species [superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3)]. Haplotype tagging and functional nucleotide polymorphisms were selected in each gene and tested for association with bipolar disorder under narrow (n = 240) and broad (n = 325) phenotypic models, compared to healthy controls (n = 392, comprising 166 psychiatrically assessed unaffected controls plus 226 healthy in iduals). Single marker association analysis did not reveal significant association with bipolar disorder however, haplotypes in the SOD2 gene showed nominal association (global chi(2) = 8.94, p = 0.03 broad model). Interaction analysis revealed a significant interaction between SOD2 and GPX3 haplotypes, which further increases risk for bipolar disorder (odds ratio = 2.247, chi(2) = 9.526, p = 0.002, corrected p = 0.029). Further characterization of the SOD2 and GPX3 interaction using larger cohorts is required to determine the role of these oxidative pathway genes as risk factors for bipolar disorder.
Early behavioural changes in familial Alzheimer’s disease in the Dominantly Inherited Alzheimer Network
Publisher: Oxford University Press (OUP)
Date: 14-02-2015
DOI: 10.1093/BRAIN/AWV004
Investigating the influence of KIBRA and CLSTN2 genetic polymorphisms on cross-sectional and longitudinal measures of memory performance and hippocampal volume in older individuals
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2015.09.031
Abstract: The variability of episodic memory decline and hippoc al atrophy observed with increasing age may partly be explained by genetic factors. KIBRA (kidney and brain expressed protein) and CLSTN2 (calsyntenin 2) are two candidate genes previously linked to episodic memory performance and volume of the hippoc us, a key memory structure. However, whether polymorphisms in these two genes also influence age-related longitudinal memory decline and hippoc al atrophy is still unknown. Using data from two independent cohorts, the Sydney Memory and Ageing Study and the Older Australian Twins Study, we investigated whether the KIBRA and CLSTN2 genetic polymorphisms (rs17070145 and rs6439886) are associated with episodic memory performance and hippoc al volume in older adults (65-90 years at baseline). We were able to examine these polymorphisms in relation to memory and hippoc al volume using cross-sectional data and, more importantly, also using longitudinal data (2 years between testing occasions). Overall we did not find support for an association of KIBRA either alone or in combination with CLSTN2 with memory performance or hippoc al volume, nor did variation in these genes influence longitudinal memory decline or hippoc al atrophy in two cohorts of older adults.
The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features.
Publisher: BMJ
Date: 07-2004
Emotional face processing correlates with depression/anxiety symptoms but not wellbeing in non-clinical adults: An event-related potential study
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.JPSYCHIRES.2021.11.038
Abstract: Whilst alterations in emotional face processing, as indicated by event-related potentials (ERPs), are associated with depression and anxiety symptoms in clinical and non-clinical s les, it has remained unclear whether they are related to mental wellbeing. The current study aimed to address this question in a non-clinical s le. The analysis included 402 adult twins from the TWIN-E study. The COMPAS-W and the Depression Anxiety Stress Scale (DASS-42) were used to measure mental wellbeing and depression/anxiety symptoms, respectively. Participants viewed facial expressions under Unmasked (conscious) and Masked (subliminal) conditions while ERPs were recorded. The associations of emotion processing with mental wellbeing and depression/anxiety symptoms were assessed using multivariate linear mixed models. There was a strong association between depression/anxiety symptoms and the N170 litude difference for the Fear - Happy contrast in the Masked condition after controlling for wellbeing scores (B = 0.34, p < .001). Specifically, higher depression/anxiety symptoms were associated with a lack of differentiation between fearful and happy faces. No associations were found between emotional face processing and mental wellbeing scores. These results indicate that even within a non-clinical s le, alterations in emotional ERPs, namely the N170, reflect differences in depression/anxiety symptoms rather than differences in wellbeing. Furthermore, this effect was limited to automatic processing, rather than conscious processing of emotional stimuli, suggesting the observed differences apply only to the subconscious pathway.
Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases
Publisher: BMJ
Date: 29-11-2016
Attenuated glycine receptor function reduces excitability of mouse medial vestibular nucleus neurons
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.NEUROSCIENCE.2010.06.040
Abstract: Spontaneous activity in medial vestibular nucleus (MVN) neurons is modulated by synaptic inputs. These inputs are crucial for maintaining gaze and posture and contribute to vestibular compensation after lesions of peripheral vestibular organs. We investigated how chronically attenuated glycinergic input affects excitability of MVN neurons. To this end we used three mouse strains (spastic, spasmodic, and oscillator), with well-characterized naturally occurring mutations in the inhibitory glycine receptor (GlyR). First, using whole-cell patch-cl recordings, we demonstrated that the litude of the response to rapidly applied glycine was dramatically reduced by 25 to 90% in MVN neurons from mutant mice. We next determined how reduced GlyR function affected MVN neuron output. Neurons were classified using two schemas: (1) the shape of their action potential afterhyperpolarization (AHP) and (2) responses to hyperpolarizing current injection. In the first schema, neurons were classified as types A, B and C. The prevalence of type C neurons in the mutant strains was significantly increased. In the second schema, the proportion of neurons lacking post inhibitory rebound firing (PRF-deficient) was increased. In both schemas an increase in AHP litude was a common feature of the augmented neuron group (type C, PRF-deficient) in the mutant strains. We suggest increased AHP litude reduces overall excitability in the MVN and thus maintains network function in an environment of reduced glycinergic input.
Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-01-2019
DOI: 10.1212/WNL.0000000000006851
Abstract: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10 −8 and LINC00539/ZDHHC20, p = 5.82 × 10 −9 . Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up s le or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( p value for BI, p [BI] = 9.38 × 10 −25 p [SSBI] = 5.23 × 10 −14 for hypertension), smoking ( p [BI] = 4.4 × 10 −10 p [SSBI] = 1.2 × 10 −4 ), diabetes ( p [BI] = 1.7 × 10 −8 p [SSBI] = 2.8 × 10 −3 ), previous cardiovascular disease ( p [BI] = 1.0 × 10 −18 p [SSBI] = 2.3 × 10 −7 ), stroke ( p [BI] = 3.9 × 10 −69 p [SSBI] = 3.2 × 10 −24 ), and MRI-defined white matter hyperintensity burden ( p [BI] = 1.43 × 10 −157 p [SSBI] = 3.16 × 10 −106 ), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( p ≤ 0.0022), without indication of directional pleiotropy. In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
Molecular pharmacology and drug action: structural information casts light on ligand binding
Publisher: Elsevier BV
Date: 06-1989
DOI: 10.1016/0165-6147(89)90260-5
Abstract: Oxidative stress plays an important role in the progression of vascular endothelial dysfunction. The two major systems generating vascular oxidative stress are the NADPH oxidase and the xanthine oxidase pathways. Allopurinol, a xanthine oxidase inhibitor, has been in clinical use for over 40 years in the treatment of chronic gout. Allopurinol has also been shown to improve endothelial dysfunction, reduce oxidative stress burden and improve myocardial efficiency by reducing oxygen consumption in smaller mechanistic studies involving various cohorts at risk of cardiovascular events. This article aims to explain the role of xanthine oxidase in vascular oxidative stress and to explore the mechanisms by which allopurinol is thought to improve vascular and myocardial indices.
Genetics of microstructure of the corpus callosum in older adults
Publisher: Public Library of Science (PLoS)
Date: 16-12-2014
Memory decline in healthy older people: Implications for identifying mild cognitive impairment
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-06-2001
Abstract: Criteria for mild cognitive impairment require objective evidence of a memory deficit but do not require objective evidence of memory decline. Application of these criteria may therefore result in the misclassification of older patients with memory decline as normal because their neuropsychological test performance at a single point in time may be within normal limits. This study aimed to identify and characterize older people with memory decline. Word list delayed recall (WLDR) test performance was assessed on five occasions during a 2-year period in a cohort of healthy older in iduals. Older people with declining (n = 35) and nondeclining (n = 66) WLDR scores were identified. Both subgroups were then compared on apoE genotype, Clinical Dementia Rating, and neuropsychological test performance at the fifth assessment. Thirty-four percent of the group with declining memory recorded a Clinical Dementia Rating of 0.5, compared with 5% of the nondeclining memory group. No between-group differences were observed in cognitive domains other than memory, self-reported cognitive failures, or the proportion of each group carrying the apoE epsilon 4 allele. A large proportion of healthy older in iduals show memory decline, which may represent the early stages of a potentially more severe cognitive impairment. Further investigation is necessary to determine the relationship between apoE genotype, self-reported cognitive impairment, and memory decline in older people.
Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning
Publisher: Springer Science and Business Media LLC
Date: 16-08-2200
DOI: 10.1038/S41380-022-01710-8
Abstract: Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke ( N = 53,637). We identified novel loci in the intronic region of CDH18 , and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent s le. Functional and bioinformatic analyses supported many of these loci and further implicated POC1 . We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
Publisher: Springer Science and Business Media LLC
Date: 29-11-2021
DOI: 10.1038/S41398-021-01702-2
Abstract: Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between in iduals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi + Gen www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
Raloxifene increases prefrontal activity during emotional inhibition in schizophrenia based on estrogen receptor genotype
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.EURONEURO.2016.10.009
Abstract: People with schizophrenia show decreased prefrontal cortex (PFC) activity during emotional response inhibition, a cognitive process sensitive to hormonal influences. Raloxifene, a selective estrogen receptor modulator, binds estrogen receptor alpha (ESR-α), improves memory, attention and normalizes cortical and hippoc al activity during learning and emotional face recognition in schizophrenia. Here, we tested the extent to which raloxifene restores neuronal activity during emotional response inhibition in schizophrenia. Since genetic variation in estrogen receptor alpha (ESR-1) determines cortical ESR-α production and correlates with cognition, we also predicted that genetic ESR-1 variation would differentially relate to increased cortical activity by raloxifene administration. Thirty people with schizophrenia participated in a thirteen-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of raloxifene administered at 120mg/day. Effects of raloxifene on brain activation were assessed based on ESR-1 genotype using functional magnetic resonance imaging during emotional word inhibition. Raloxifene increased PFC activity during inhibition of response to negative words and the raloxifene related increased PFC activity was greater in patients homozygous for ESR-1 rs9340799 AA relative to G carriers. Comparison to 23 healthy controls demonstrated that PFC activity of people with schizophrenia receiving raloxifene was more similar to controls than to their own brain activity during placebo. Estrogen receptor modulation by raloxifene restores PFC activity during emotional response inhibition in schizophrenia and ESR-1 genotype predicts degree of increased neural activity in response to raloxifene. While these preliminary results require replication, they suggest the potential for personalized pharmacotherapy using ESR-1 and estrogen receptor targeting compounds in schizophrenia.
Association analysis of transcripts from the bipolar susceptibility locus on chromosome 4q35, exclusion of a pathogenic role for eight positional candidate genes
Publisher: Wiley
Date: 16-02-2005
DOI: 10.1002/AJMG.B.30131
Abstract: Bipolar affective disorder is a major psychiatric illness with a population prevalence of up to 1.6%. The disorder is genetically complex. To date, no specific gene or DNA sequence variation that predisposes to the disorder has been described, however several susceptibility loci have been proposed through genetic linkage analysis. We previously identified one such susceptibility locus on chromosome 4q35, and refined the interval harboring this susceptibility gene to a size that is amenable to positional cloning. Several independent studies have now been described that support the presence of a susceptibility gene at this locus. In order to identify candidate genes for testing association with bipolar disorder, we previously established a comprehensive transcript map that encompasses the chromosome 4q35 susceptibility locus implicated in our linkage analysis. In this study, we have selected full-length genes from the transcript map and determined the genomic structure of each gene. We identified informative, intragenic single nucleotide polymorphisms (SNPs) by screening all exons and flanking intron sequences in affected in iduals from seven bipolar pedigrees that we previously reported as showing evidence for linkage to chromosome 4q35. Analysis of these SNPs was then extended to our unrelated bipolar case-control cohort to test for association with the disorder. Our data suggests that all genes analyzed can be excluded from direct involvement in the disorder. We have therefore, excluded approximately half the genes within the chromosome 4q35 candidate interval from playing a direct pathogenic role in bipolar disorder.
Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2013
Rhizobium nodulation genes involved in root hair curling (Hac) are functionally conserved
Publisher: Springer Science and Business Media LLC
Date: 03-1985
DOI: 10.1007/BF02418762
Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia
Publisher: Springer Science and Business Media LLC
Date: 18-05-2015
DOI: 10.1038/MP.2015.11
Exploring culture-specific differences in beliefs about causes, kinship and the heritability of major depressive disorder: The views of anglo-celtic and chinese-Australians
Publisher: Wiley
Date: 17-05-2013
DOI: 10.1007/S10897-013-9593-3
Abstract: The aim of this study was to explore cultural differences in causal attributions and beliefs about heritability of major depressive disorder (MDD). Face-to-face interviews with Anglo-Celtic- and Chinese-Australians community members with a family history of MDD were conducted and subjected to a rigorous qualitative analysis, using the computer software NVivo. Sixteen Anglo-Celtic-Australians and 16 Chinese-Australians were interviewed. Both groups believed that a combination of genetic and environmental factors contributed to MDD, that stress was an important cause of MDD, and that coping factors were significant moderators of the impact of stress on MDD. Both cultural groups believed that the causes of MDD affecting multiple family members included a shared family environment and a "contagion effect", in addition to genetics. Unique to the Chinese-Australian group was the beliefs that parental pressures to exceed academically contributed to MDD this cultural group also reported beliefs that depression was due to God's will or alternatively fate, which in turn was related to attributions to feng shui and auspicious dates. This study documented key culture-specific differences in beliefs about causes and inheritance of MDD such differences have major implications for clinician-patient communication about genetic risk associated with having a family history of MDD.
Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive per
Publisher: Royal College of Psychiatrists
Date: 02-2016
DOI: 10.1192/BJP.BP.114.156976
Abstract: Bipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain. We sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL. To detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippoc al volume ( n = 5775) and cognitive performance ( n = 342) among healthy in iduals. Integrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48 bipolar disorder P = 5.85×10 –5 ). Follow-up studies across multiple independent s les confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility ( P = 3.54×10 –8 ). Further exploratory analysis revealed that rs6088662 is also associated with hippoc al volume and cognitive performance in healthy in iduals. Our findings suggest that 20q11.22 is likely a risk region for bipolar disorder they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.
Public interest in predictive genetic testing, including direct-to-consumer testing, for susceptibility to major depression: Preliminary findings
Publisher: Springer Science and Business Media LLC
Date: 19-08-2010
A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19
Publisher: Springer Science and Business Media LLC
Date: 07-2002
Abstract: Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13-pedigree cohort consisted of 231 in iduals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P= 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several in idual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.
Identification of aggregation inhibitors of the human antibody light chain repertoire by phage display.
Publisher: Oxford University Press (OUP)
Date: 22-07-2014
Abstract: Protein aggregation hinders the development of biologics and underpins the molecular basis of many human diseases. Considerable variation of aggregation propensity exists not only between different proteins, but also within a single homologous family, which complicates analyses. A classic ex le is observed among human antibody light chains, which aggregate in a clonally specific manner, driven by sequence ersity within their variable domains. Here, we utilise a library versus library strategy, based on phage display and a chemical library of FDA approved drugs, to overcome this limitation. Our approach allowed the identification of small molecule drugs that inhibit the aggregation of the human light chain repertoire. It also provides a general template for the small molecule targeting of erse protein families.
Tau haplotypes regulate transcription and are associated with Parkinson's disease.
Publisher: Wiley
Date: 23-01-2004
DOI: 10.1002/ANA.10826
Abstract: A primary haplotype (H1) of the microtubule-associated protein Tau (MAPT) gene is associated with Parkinson's disease (PD). However, the mechanism for disease susceptibility remains unknown. We examined the promoter region of MAPT and identified single nucleotide polymorphisms and insertions of 1 to 11 nucleotides. These polymorphisms corresponded to the previously characterized haplotypes, H1 and H2, as well as a novel variant of the H1 haplotype, H1'. As observed in other studies, we demonstrated a significant association with the H1/H1 promoter genotype and PD in a cohort of 206 idiopathic late-onset cases. This is in contrast with a panel of 13 early-onset PD patients, for whom we did not detect any mutations in MAPT. By examining single nucleotide polymorphisms in adjacent genes, we showed that linkage disequilibrium does not extend beyond the MAPT haplotype to neighboring genes. To define the mechanism of disease susceptibility, we examined the transcriptional activity of the promoter haplotypes using a luciferase reporter assay. We demonstrated in two human cell lines, SK-N-MC and 293, that the H1 haplotype was more efficient at driving gene expression than the H2 haplotype. Our data suggest that an increase in expression of the MAPT gene is a susceptibility factor in idiopathic PD.
Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder
Publisher: American Medical Association (AMA)
Date: 09-11-2017
Randomized, open-label, comparative trial to evaluate the efficacy and safety of three antiretroviral drug combinations including two nucleoside analogues and nevirapine for previously untreated HIV-1 infection: The OzCombo 2 study
Publisher: Informa UK Limited
Date: 05-2002
DOI: 10.1310/9N21-1HG1-7N1Q-JKW1
Abstract: To assess and compare the efficacy and safety of three triple combination antiretroviral therapies in HIV-1-infected treatment-naive patients. Seventy treatment-naive HIV-infected adults with CD4+ T-cell counts >50/microL were randomized to receive either zidovudine + lamivudine + nevirapine (AZT + 3TC + NVP), stavudine + didanosine + nevirapine (d4T+ddI+NVP), or stavudine + lamivudine + nevirapine (d4T+3TC+NVP) for 52 weeks. Patient assessments were conducted monthly and included measurement of plasma HIV RNA levels and CD4+ T-cell counts and evaluations for drug toxicity. The mean time-weighted reductions in plasma HIV RNA in the AZT+3TC+NVP, d4T+3TC+NVP, and d4T+ddI+NVP groups were 1.29, 2.13, and 1.78 log(10) copies/mL, respectively (p =.389). The proportions of patients with HIV RNA <50 copies/mL in the AZT+3TC+NVP, d4T+3TC+NVP, and d4T+ddI+NVP groups were 73%, 68%, and 80%, respectively (p =.71). The mean time-weighted increases in CD4+ T-cell counts in the AZT+3TC+NVP, d4T+3TC+NVP, and d4T+ddI+NVP groups were 139, 113, and 174 cells/microL, respectively (p =.30). Three patients ceased assigned treatment due to rash (one from each treatment arm), and 5 of the 45 patients on d4T (3 from the d4T+3TC+NVP arm and 2 from the d4T+ddI+NVP arm) ceased assigned treatment due to neuropathy. All three-drug combinations were equally effective at suppressing viral load and increasing CD4+ T-cell counts. No significant differences were detected between the treatment groups in virological or immunological response or cessation of study drugs due to adverse events, although it is possible that the study was underpowered to detect differences. NVP was safe and efficacious in this setting, and efficacy was not influenced by nucleoside reverse transcriptase inhibitor backbone.
Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer's disease
Publisher: Wiley
Date: 11-05-2017
The genetics of white matter lesions.
Publisher: Wiley
Date: 07-07-2011
Genotyping cattle for inherited congenital myoclonus and maple syrup urine disease
Publisher: Wiley
Date: 11-2002
DOI: 10.1111/J.1751-0813.2002.TB11301.X
Abstract: To develop a routine procedure for establishing the inherited congenital myoclonus (ICM) genotype of cattle and to obtain an estimate of the prevalence of heterozygotes for ICM and maple syrup urine disease (MSUD) in Australian Poll Herefords. A mismatch lification procedure was developed to genotype for ICM. The ICM and MSUD genotypes of subjects from a 'neuraxial oedema' experimental breeding herd were investigated. Tail hair roots were used as a source of target DNA to determine the ICM and MSUD genotypes of 455 Poll Hereford bulls. An Acc I mismatch procedure was found to be suitable to genotype cattle for the ICM alleles using tail hair roots as the source of DNA. Based on the prevalence of heterozygotes among saleyard and sale bulls in the early 1990s, and contemporary slaughter bulls, the frequencies of the alleles responsible for ICM and MSUD were estimated to be between 0.01 and 0.02. This survey demonstrates that the mutations responsible for ICM and MSUD are present in the Australian Poll Hereford population. PCR tests could be used to advantage in differential diagnosis of neurological disease in newly born calves and in selection of Poll Hereford seed stock.
The association between the oxytocin receptor gene (OXTR) and hypnotizability
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.PSYNEUEN.2013.03.002
Abstract: Hypnosis has puzzled scientists for centuries, and particularly the reason why some people are prone to engaging in suggested experiences discordant with external reality. Absorption in internal experience is one key component of the hypnotic response. The neuropeptide oxytocin has been posited to heighten sensitivity to external cues, and it is possible that in idual differences in oxytocin-related capacity to engage in external or internal experiences influences hypnotic response. To test this proposal, 185 Caucasian in iduals provided saliva s les for analysis of polymorphisms in the oxytocin receptor gene, COMT, and independently completed standardized measures of hypnotizability and absorption. Participants with the GG genotype at rs53576 were characterized by lower hypnotizability and absorption scores than those with the A allele there was no association between hyponotizability and COMT. These findings provide initial evidence that the capacity to respond to suggestions for altered internal experience is influenced by the oxytocin receptor gene, and is consistent with evidence that oxytocin plays an important role in modulating the extent to which people engage with external versus internal experiences.
Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JAD.2017.11.068
Abstract: Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated in idual genes and gene sets were examined in post-mortem brains across lifespan. Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (P Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent s les. Gene expression was explored in controls but not in patients. Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.
Stylized transcript map of chromosome 4q35 encompassing the locus for a bipolar disorder susceptibility gene
Publisher: Springer Science and Business Media LLC
Date: 08-2002
Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder
Publisher: Springer Science and Business Media LLC
Date: 10-11-2015
DOI: 10.1038/TP.2015.159
Abstract: Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippoc al neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P -values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499 , miR-708 and miR-1908 . Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499 , four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2 . First results of functional analyses in rat hippoc al neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.
Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene1
Publisher: Elsevier BV
Date: 09-1997
DOI: 10.1016/S0168-0102(97)00073-4
Abstract: The gene for the inhibitory G-protein coupled human A3 adenosine receptor (ADORA3) was isolated and sequence analysis shows that the coding region is interrupted by a single intron of size 2.4 kb. The location of this intron in the second intracellular loop is conserved with respect to the A1, A2a and A2b adenosine receptor subtype genes. The ADORA3 gene was mapped to 1p13.3 by fluorescence in situ hybridisation. Northern blot studies show that the gene is widely expressed and is most abundant in brain and some endocrine tissues. We have mapped multiple transcription start sites in two cell lines and lung tissue by primer extension and 5' RACE (rapid lification of cDNA ends). The ADORA3 gene promoter lacks CAAT and TATA boxes but has putative binding sites for multiple transcription factors. In contrast to the A1 adenosine receptor gene we find no evidence of alternate splicing in the 5' untranslated region of the ADORA3 gene.
The chemotactic receptor EBI2 regulates the homeostasis, localization and immunological function of splenic dendritic cells
Publisher: Springer Science and Business Media LLC
Date: 17-03-2013
DOI: 10.1038/NI.2555
Abstract: Spleen-resident dendritic cell (DC) populations occupy sentinel positions for the capture and presentation of blood-borne antigens. Here we found a difference in expression of the chemotactic receptor EBI2 (GPR183) on splenic DC subsets and that EBI2 regulated the positioning and homeostasis of DCs in the spleen. EBI2 and its main ligand, 7α,25-OHC, were required for the generation of the splenic CD4(+) DC subset and the localization of DCs in bridging channels. Absence of EBI2 from DCs resulted in defects in both the activation of CD4(+) T cells and the induction of antibody responses. Regulated expression of EBI2 on DC populations is therefore critical for the generation and correct positioning of splenic DCs and the initiation of immune responses.
Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1998
DOI: 10.1097/00001756-199810050-00034
Abstract: Mutations in the presenilin-1 (PS-1) gene account for the majority of early onset autosomal-dominant familial Alzheimer's disease (FAD) cases. We identified three missense mutations in the coding sequence of the PS-1 gene in three early onset (EO), FAD pedigrees. Alzheimer's disease was confirmed in one pedigree by autopsy. Mutation analysis of PCR products lified from genomic DNA templates of affected in iduals showed two novel mutations resulting in Ser169Leu and Pro436Gln and one known mutation resulting in Glu318Gly. The two new mutations are located within predicted transmembrane domains three (TM-3) and seven (TM-7), and are associated with a very early age of onset which is consistent with a marked loss of function of the protein. The age of onset in the pedigree with Glu318Gly mutation was similar to that reported previously in a separate pedigree with this mutation.
Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer’s disease
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-07-2023
DOI: 10.1126/SCITRANSLMED.ABQ5923
Abstract: Proteomic studies for Alzheimer’s disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy in iduals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in in iduals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both in iduals with sporadic AD and healthy in iduals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF s les. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson’s disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.
Impact of the HTR3A gene with early life trauma on emotional brain networks and depressed mood
Publisher: Hindawi Limited
Date: 08-2010
DOI: 10.1002/DA.20726
Abstract: The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene-environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A -42C>T polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptor's localization to brain regions central to emotion processing. Fronto-limbic grey matter (GM) loss was measured using magnetic resonance imaging and assessed using voxel-based morphometry analysis in 397 nonclinical in iduals from the Brain Resource International Database. Negative mood symptoms were also assessed. The HTR3A CC genotype group, compared to the T carriers, demonstrated comparative loss to GM in hippoc al structures, which extended to the frontal cortices for those CC genotype in iduals also exposed to ELS. Elevations in depressed mood were also evident. These findings suggest that the HTR3A CC genotype may be associated with alterations in brain structures central to emotion processing, particularly when exposed to stress, and further highlight the potential role of the serotonin system in the pathophysiology of affective disorders. In contrast, those in iduals with the T allele, in particular the TT genotype, may be more protected from such alterations combined with minimal exposure to ELS events.
To know or not to know: an update of the literature on the psychological and behavioral impact of genetic testing for Alzheimer disease risk.
Publisher: Mary Ann Liebert Inc
Date: 08-2012
Abstract: Alzheimer disease (AD) is a genetically heterogenous disorder in rare cases autosomal dominantly inherited mutations typically cause early-onset familial AD (EOAD), whereas the risk for late-onset AD (LOAD) is generally modulated by genetic variants with relatively low penetrance but high prevalence, with variants in apolipoprotein E (APOE) being a firmly established risk factor. This article presents an overview of the current literature on the psychological and behavioral impact of genetic testing for AD. The few studies available for presymptomatic testing for EOAD showed that only a very small proportion of in iduals had poor psychological outcomes as a result. Initial interest in testing for EOAD decreases significantly after identification of a specific mutation in a kindred, suggesting that interest and potential for knowledge may not translate into actual testing uptake. The majority of in iduals from both the general population and those with a family history of AD had positive attitudes towards, and were interested in, susceptibility testing for APOE. Motivations for genetic testing included to provide information for future planning and to learn about one's own and one's children's risks of developing AD. Although susceptibility testing for APOE genotype is not currently recommended due to the lack of clinical utility, this review demonstrates that there is interest in testing and no obvious adverse psychological effects to those who have been tested.
Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies
Publisher: Public Library of Science (PLoS)
Date: 09-01-2018
Strategies to support culturally safe health and wellbeing evaluations in Indigenous settings in Australia and New Zealand: a concept mapping study
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S12939-019-1094-Z
Abstract: In recent decades, financial investment has been made in health-related programs and services to overcome inequities and improve Indigenous people’s wellbeing in Australia and New Zealand. Despite policies aiming to ‘close the gap’, limited evaluation evidence has informed evidence-based policy and practice. Indigenous leaders have called for evaluation stakeholders to align their practices with Indigenous approaches. This study aimed to strengthen culturally safe evaluation practice in Indigenous settings by engaging evaluation stakeholders, in both countries, in a participatory concept mapping study. Concept maps for each country were generated from multi-dimensional scaling and hierarchical cluster analysis. The 12-cluster Australia map identifies four cluster regions: An Evaluation Approach that Honours Community Respect and Reciprocity Core Heart of the Evaluation and Cultural Integrity of the Evaluation. The 11-cluster New Zealand map identifies four cluster regions: Authentic Evaluation Practice Building Māori Evaluation Expertise Integrity in Māori Evaluation and Putting Community First. Both maps highlight the importance of cultural integrity in evaluation. Differences include the distinctiveness of the ‘Respecting Language Protocols’ concept in the Australia map in contrast to language being embedded within the cluster of ‘Knowing Yourself as an Evaluator in a Māori Evaluation Context’ in the New Zealand map. Participant ratings highlight the importance of all clusters with some relatively more difficult to achieve, in practice. Notably, the ‘Funding Responsive to Community Needs and Priorities’ and ‘Translating Evaluation Findings to Benefit Community’ clusters were rated the least achievable, in Australia. The ‘Conduct of the Evaluation’ and the ‘Prioritising Māori Interests’ clusters were rated as least achievable in New Zealand. In both countries, clusters of strategies related to commissioning were deemed least achievable. The results suggest that the commissioning of evaluation is crucial as it sets the stage for whether evaluations: reflect Indigenous interests, are planned in ways that align with Indigenous ways of working and are translated to benefit Indigenous communities Identified strategies align with health promotion principles and relational accountability values of Indigenous approaches to research. These findings may be relevant to the commissioning and conduct of Indigenous health program evaluations in developed nations.
Correction: Automatic Extraction of Mental Health Disorders From Domestic Violence Police Narratives: Text Mining Study (Preprint)
Publisher: JMIR Publications Inc.
Date: 05-12-2018
The GABAA receptor: molecular biology reveals a complex picture
Publisher: Elsevier BV
Date: 12-1989
Cluster randomized controlled trial of a psycho-educational intervention for people with a family history of depression for use in general practice
Publisher: Springer Science and Business Media LLC
Date: 12-2013
The Long and the Short of It: Associations Between 5-HTT Genotypes and Coping With Stress
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2007
The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease
Publisher: Springer Science and Business Media LLC
Date: 21-03-2019
Primary structure of the human beta-adrenergic receptor gene
Publisher: Oxford University Press (OUP)
Date: 1987
Abstract: There is strong epidemiologic evidence to suggest that older adults who maintain an active lifestyle in terms of social, mental, and physical engagement are protected to some degree against the onset of dementia. Such factors are said to contribute to cognitive reserve, which acts to compensate for the accumulation of amyloid and other brain pathologies. We present evidence that lifelong bilingualism is a further factor contributing to cognitive reserve. Data were collected from 211 consecutive patients diagnosed with probable Alzheimer disease (AD). Patients' age at onset of cognitive impairment was recorded, as was information on occupational history, education, and language history, including fluency in English and any other languages. Following this procedure, 102 patients were classified as bilingual and 109 as monolingual. We found that the bilingual patients had been diagnosed 4.3 years later and had reported the onset of symptoms 5.1 years later than the monolingual patients. The groups were equivalent on measures of cognitive and occupational level, there was no apparent effect of immigration status, and the monolingual patients had received more formal education. There were no gender differences. The present data confirm results from an earlier study, and thus we conclude that lifelong bilingualism confers protection against the onset of AD. The effect does not appear to be attributable to such possible confounding factors as education, occupational status, or immigration. Bilingualism thus appears to contribute to cognitive reserve, which acts to compensate for the effects of accumulated neuropathology.
Adenosine A2B receptors behave as an alternative anchoring protein for cell surface adenosine deaminase in lymphocytes and cultured cells
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 2001
DOI: 10.1124/MOL.59.1.127
Anion-Cation Permeability Correlates with Hydrated Counterion Size in Glycine Receptor Channels
Publisher: Elsevier BV
Date: 11-2008
Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals
Publisher: Wiley
Date: 16-07-2015
DOI: 10.1002/AJMG.B.32344
Structure-function relationships of the human glycine receptor: insights from hyperekplexia mutations
Publisher: Wiley
Date: 04-1999
Sequence and expression of human GABAA receptor α1 and β1 subunits
Publisher: Wiley
Date: 27-02-1989
DOI: 10.1016/0014-5793(89)80563-0
Abstract: The deduced amino acid sequences of cDNA clones encoding human GABAA receptor alpha 1 and beta 1 subunits are presented. The human subunits display very high levels of sequence identity with the corresponding bovine receptor subunits. The cloned human GABAA receptor subunits induce the formation of GABA-gated chloride channels when expressed in mammalian cells.
Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults
Publisher: Springer Science and Business Media LLC
Date: 22-09-2020
DOI: 10.1038/S41467-020-18367-Y
Abstract: Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery s le comprises 22,824 in iduals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease
Publisher: Springer Science and Business Media LLC
Date: 08-2021
DOI: 10.1038/S41591-023-02476-4
Abstract: Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.
A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26
Publisher: Springer Science and Business Media LLC
Date: 29-01-2008
Abstract: Bipolar affective disorder is a heritable, relatively common, severe mood disorder with lifetime prevalence up to 4%. We report the results of a genome-wide linkage analysis conducted on a cohort of 35 Australian bipolar disorder families which identified evidence of significant linkage on chromosome 15q25-26 and suggestive evidence of linkage on chromosomes 4q, 6q and 13q. Subsequent fine-mapping of the chromosome 15q markers, using allele frequencies calculated from our cohort, gave significant results with a maximum two-point LOD score of 3.38 and multipoint LOD score of 4.58 for marker D15S130. Haplotype analysis based on pedigree-specific, identical-by-descent allele sharing, supported the location of a bipolar susceptibility gene within the Z(max-1) linkage confidence interval of 17 cM, or 6.2 Mb, between markers D15S979 and D15S816. Non-parametric and affecteds-only linkage analysis further verified the linkage signal in this region. A maximum NPL score of 3.38 (P=0.0008) obtained at 107.16 cM (near D15S130), and a maximum two-point LOD score of 2.97 obtained at marker D15S1004 (affecteds only), support the original genome-wide findings on chromosome 15q. These results are consistent with four independent positive linkage studies of mood and psychotic disorders, and raise the possibility that a common gene for susceptibility to bipolar disorder, and other psychiatric disorders may lie in this chromosome 15q25-26 region.
Common variants at 2q11.2, 8q21.3, and 11q13.2 are associated with major mood disorders
Publisher: Springer Science and Business Media LLC
Date: 11-12-2017
DOI: 10.1038/S41398-017-0019-0
Abstract: Bipolar disorder (BPD) and major depressive disorder (MDD) are primary major mood disorders. Recent studies suggest that they share certain psychopathological features and common risk genes, but unraveling the full genetic architecture underlying the risk of major mood disorders remains an important scientific task. The public genome-wide association study (GWAS) data sets offer the opportunity to examine this topic by utilizing large amounts of combined genetic data, which should ultimately allow a better understanding of the onset and development of these illnesses. Genome-wide meta-analysis was performed by combining two GWAS data sets on BPD and MDD (19,637 cases and 18,083 controls), followed by replication analyses for the loci of interest in independent 12,364 cases and 76,633 controls from additional s les that were not included in the two GWAS data sets. The single-nucleotide polymorphism (SNP) rs10791889 at 11q13.2 was significant in both discovery and replication s les. When combining all s les, this SNP and multiple other SNPs at 2q11.2 (rs717454), 8q21.3 (rs10103191), and 11q13.2 (rs2167457) exhibited genome-wide significant association with major mood disorders. The SNPs in 2q11.2 and 8q21.3 were novel risk SNPs that were not previously reported, and SNPs at 11q13.2 were in high LD with potential BPD risk SNPs implicated in a previous GWAS. The genome-wide significant loci at 2q11.2 and 11q13.2 exhibited strong effects on the mRNA expression of certain nearby genes in cerebellum. In conclusion, we have identified several novel loci associated with major mood disorders, adding further support for shared genetic risk between BPD and MDD. Our study highlights the necessity and importance of mining public data sets to explore risk genes for complex diseases such as mood disorders.
Bovine myoclonus: Model of human hyperekplexia (startle disease)
Publisher: Wiley
Date: 07-2002
DOI: 10.1002/MDS.10216
Host-specific nodulation is encoded on a 14kb DNA fragment in Rhizobium trifolii
Publisher: Springer Science and Business Media LLC
Date: 1984
DOI: 10.1007/BF00023410
Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety
Publisher: Springer Science and Business Media LLC
Date: 20-01-2009
DOI: 10.1038/MP.2008.143
Abstract: In idual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippoc al-prefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P=0.005) and symptoms (depression and anxiety, P<0.001) in the absence of main effects for BDNF. In addition, significant BDNF-ELS interactions indicated that BDNF Met carriers exposed to greater ELS have smaller hippoc al and amygdala volumes (P=0.013), heart rate elevations (P=0.0002) and a decline in working memory (P=0.022). Structural equation path modeling was used to determine if this interaction predicts anxiety and depression by mediating effects on the brain, body and cognitive measures. The combination of Met carrier status and exposure to ELS predicted reduced gray matter in hippoc us (P<0.001), and associated lateral prefrontal cortex (P<0.001) and, in turn, higher depression (P=0.005). Higher depression was associated with poorer working memory (P=0.005), and slowed response speed. The BDNF Met-ELS interaction also predicted elevated neuroticism and higher depression and anxiety by elevations in body arousal (P<0.001). In contrast, the combination of BDNF V/V genotype and ELS predicted increases in gray matter of the amygdala (P=0.003) and associated medial prefrontal cortex (P<0.001), which in turn predicted startle-elicited heart rate variability (P=0.026) and higher anxiety (P=0.026). Higher anxiety was linked to verbal memory, and to impulsivity. These effects were specific to the BDNF gene and were not evident for the related 5HTT-LPR polymorphism. Overall, these findings are consistent with the correlation of depression and anxiety, yet suggest that partially differentiated gene-brain cognition pathways to these syndromes can be identified, even in a nonclinical s le. Such findings may aid establishing an evidence base for more tailored intervention strategies.
Preferences regarding targeted education and risk assessment in people with a family history of major depressive disorder
Publisher: Wiley
Date: 10-01-2014
DOI: 10.1007/S10897-013-9685-0
Abstract: Genetic testing for susceptibility to major depressive disorder (MDD) is not available for clinical use at present. Given this, family history remains the best predictor for development of MDD, and family-history-based risk assessment and information about familial aspects of MDD may be useful to clients at increased risk for MDD attending for genetic counseling. This study uses a mixed-methods design to assess the information needs and preferences of people at increased familial risk for MDD. Telephone interviews were conducted with 23 in iduals, who had at least one first-degree relative with MDD and were recruited through advertisements placed on depression education websites. The most preferred way to access depression information was via the internet (87 % of participants), although this preference may have been due to the internet-based recruitment method. The second most preferred dissemination strategy (56 %) was face-to-face delivery through a health professional, including genetic counselors. In iduals reported a need for information about etiology and development of MDD, reproductive decision-making, early detection of symptoms and risk-reducing strategies. Nearly all participants expressed an interest in risk assessment. The present study found evidence of a high level of interest for information targeted to people at increased familial risk for MDD. Genetic counselors are likely to be called upon increasingly to provide supportive counseling to assist clients at increased familial risk in interpreting and contextualizing such information once it becomes available.
Two novel GABAA receptor subunits exist in distinct neuronal subpopulations
Publisher: Elsevier BV
Date: 09-1989
DOI: 10.1016/0896-6273(89)90257-2
Abstract: Two cDNAs encoding novel GABAA receptor subunits were isolated from a rat brain library. These subunits, gamma 2 and delta, share approximately 35% sequence identity with alpha and beta subunits and form functional GABA-gated chloride channels when expressed alone in vitro. The gamma 2 subunit is the rat homolog of the human gamma 2 subunit recently shown to be important for benzodiazepine pharmacology. Cellular localization of the mRNAs encoding the gamma 2 and delta subunits in rat brain revealed that largely distinct neuronal subpopulations express the two subunits. The delta subunit distribution resembles that of the high affinity GABAA receptor labeled with [3H]muscimol the gamma 2 subunit distribution resembles that of GABAA/benzodiazepine receptors labeled with [3H]flunitrazepam. These findings have implications for the composition of two different GABAA receptor subtypes and for information processing in networks using GABA for signaling.
Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals
Publisher: Springer Science and Business Media LLC
Date: 21-08-2019
Novel mutations in theSDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss
Publisher: Wiley
Date: 2001
DOI: 10.1002/GCC.1142
Abstract: Paraganglioma (PGL) is a rare disorder characterized by tumors of the head and neck region. Between 10% and 50% of cases of PGL are familial, and the disease is autosomal dominant and subject to age-dependent penetrance and imprinting. The paraganglioma gene (PGL1) has been mapped to 11q22.3-q23, and recently germline mutations in the SDHD gene have been identified. The SDHD region contains another gene, DPP2/TIMM8B, the homolog of which causes dystonia and deafness seen in Mohr-Tranebjaerg syndrome. Using four PGL pedigrees, two of which exhibit coinheritance of PGL and sensorineural hearing loss or tinnitus, analysis of 14 microsatellite markers provided support for linkage to the PGL1 locus. Sequence analysis identified novel mutations in exon 1 and exon 3 of the SDHD gene, including a novel two base pair deletion in exon 3 creating a premature stop codon at position 67 a novel three base pair deletion in exon 3 resulting in the loss of Tyr-93 a missense mutation in exon 3 resulting in the substitution of Leu-81 for Pro-81 and a novel G-to-C substitution in exon 1 resulting in the substitution of Met-1 for Ile-1. No base changes were detected in the DPP2/TIMM8B gene. There was no apparent loss of heterozygosity at the site of the SDHD mutations. However, RT-PCR analysis of tumor s les showed monoallelic expression of the mutant (paternal) allele as expected for imprinting. This has not previously been shown for this disorder. The inheritance and expression of the SDHD gene is consistent with the PGL1 gene being subject to genomic imprinting.
GSK3B polymorphisms alter transcription and splicing in Parkinson's disease
Publisher: Wiley
Date: 28-11-2005
DOI: 10.1002/ANA.20691
Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor symptoms. We identified two functional single nucleotide polymorphisms in the glycogen synthase kinase-3beta gene (GSK3B). A promoter single nucleotide polymorphism (rs334558) is associated with transcriptional strength in vitro in which the T allele has greater activity. An intronic single nucleotide polymorphism (rs6438552) regulates selection of splice acceptor sites in vitro. The T allele is associated with altered splicing in lymphocytes and increased levels of GSK3B transcripts that lack exons 9 and 11 (GSKDeltaexon9+11). Increased levels of GSKDeltaexon9+11 correlated with enhanced phosphorylation of its substrate, Tau. In a comparison of PD and control brains, there was increased in frequency of T allele (rs6438552) and corresponding increase in GSKDeltaexon9+11 and Tau phosphorylation in PD brains. Conditional logistic regression indicated gene-gene interaction between T/T genotype of rs334558 and H1/H1 haplotype of microtubule-associated protein Tau (MAPT) gene (p = 0.009). There was association between a haplotype (T alleles of both GSK3B polymorphisms) and disease risk after stratification by Tau haplotypes ((H1/H2+H2/H2 in iduals: odds ratio, 1.64 p = 0.007 (H1/H1 in iduals: odds ratio, 0.68 p < 0.001). Ours results suggest GSK3B polymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD.
Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations.
Publisher: Oxford University Press (OUP)
Date: 05-2000
Abstract: Genetic mutations in the tau gene on chromosome 17 are known to cause frontotemporal dementias. We have identified a novel silent mutation (S305S) in the tau gene in a subject without significant atrophy or cellular degeneration of the frontal and temporal cortices. Rather the cellular pathology was characteristic of progressive supranuclear palsy, with neurofibrillary tangles concentrating within the subcortical regions of the basal ganglia. Two affected family members presented with symptoms of dementia and later developed neurological deficits including abnormality of vertical gaze and extrapyramidal signs. The third presented with dystonia of the left arm and dysarthria, and later developed a supranuclear gaze palsy and falls. The mutation is located in exon 10 of the tau gene and forms part of a stem-loop structure at the 5' splice donor site. Although the mutation does not give rise to an amino acid change in the tau protein, functional exon-trapping experiments show that it results in a significant 4.8-fold increase in the splicing of exon 10, resulting in the presence of tau containing four microtubule-binding repeats. This study provides direct molecular evidence for a functional mutation that causes progressive supranuclear palsy pathology and demonstrates that mutations in the tau gene are pleiotropic.
Allied health professionals’ contribution to care at end of life in aged care settings
Publisher: CSIRO Publishing
Date: 06-02-2023
DOI: 10.1071/PY22178
Abstract: Background The Australian population is aging, and the proportion of older Australians will continue to grow over the coming decades. However, there is a lack of research published on the specific roles and responsibilities of allied health professionals (AHPs) providing palliative care within an aged care context. Understanding the roles and needs of AHPs providing care during the last months of life in the community and aged care facilities could contribute to workforce planning, targeted information and improved care. Methods In total, 108 eSurveys were collected between November 2019 to May 2020 from three allied health professions working in government-funded aged care the majority of these being in residential aged care. Descriptive data are reported on the provision of care in key palliative care domains, care settings and practice activity. Results Nearly all respondents reported they had worked with older Australians who had palliative care needs. However, over one-third of respondents reported low levels of confidence in supporting clients or residents with palliative care needs. The majority indicated they would benefit from additional education and training and support in palliative care. Conclusions This study investigated the role of the allied health workforce in contributing to the care of older Australians at the end of life. It has also demonstrated that there are gaps in practice activity and work role that must be addressed to ensure this workforce can support older people with palliative care needs in receipt of aged care services.
The contribution of proline 250 (P-2′) to pore diameter and ion selectivity in the human glycine receptor channel
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1016/J.NEULET.2003.08.005
Abstract: The glycine receptor-channel (GlyR) mediates neuronal inhibition by selectively allowing the passage of Cl(-) ions through its channel. The pore region for ion selectivity is localised to the constricted internal end of the M2 transmembrane domain. This paper investigates the contribution of the P-2' residue in determining pore diameter and ion charge selectivity of the GlyR. The deletion of this proline has been shown to decrease the anion/cation permeability ratio, with P(Cl)/P(Na) decreasing from approximately 27 to approximately 4. We show that the P-2' deletion by itself produces a GlyR with a larger pore diameter ( approximately 0.69 nm) than the wild type value ( approximately 0.54 nm). This confirms that the P-2' residue reduces pore size, which suggests that, in addition to electrostatic effects, pore size also contributes to ion-charge selectivity.
A molecular linkage map of nitrogenase and nodulation genes in Rhizobium trifolii
Publisher: Springer Science and Business Media LLC
Date: 11-1983
DOI: 10.1007/BF00392191
Localization of the glycine receptor α1 subunit gene (GLRA1) to chromosome 5q32 by fish
Publisher: Elsevier BV
Date: 07-1994
Abstract: The aggressive lymphoma, extranodal natural killer/T-cell lymphoma-nasal type, is strongly associated with Epstein-Barr virus (EBV) and is most common in Asia and in South and Central America. By contrast, incidence is low in the United States and Europe, where extranodal natural killer/T-cell lymphoma represents only 0.2%-0.4% of all newly diagnosed non-Hodgkin lymphomas. At diagnosis, it is important to test for EBV DNA in plasma by polymerase chain reaction and to carry out positron emission tomography/computer tomography and magnetic resonance imaging of the nasopharynx. In stage I/II disease, radiotherapy is the most important treatment modality, but in high-risk stage I/II disease (stage II, age > 60 y, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance score ≥2, primary tumor invasion), it should be combined with chemotherapy. The most optimal responses are reached with nonmultidrug resistance-based therapy (eg, asparaginase- or platinum-based therapy). Therapeutic approaches consist of either platinum-based concurrent chemoradiotherapy or sequential chemoradiotherapy. The minimum dose of radiotherapy should be 50-56 Gy. Treatment of stage III/IV disease consists of 3 cycles of chemotherapy followed by autologous hematopoietic cell transplantation. Allogeneic hematopoietic cell transplantation should only be considered in case of relapsed disease or after difficulty reaching complete remission. During treatment and follow-up, plasma EBV levels should be monitored as a marker of tumor load.
Brain network decoupling with increased serum neurofilament and reduced cognitive function in Alzheimer’s disease
Publisher: Oxford University Press (OUP)
Date: 10-01-2023
Abstract: Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in in iduals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional s le of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.
Characterization and chromosomal localization of the human A2a adenosine receptor gene: ADORA2A
Publisher: Elsevier BV
Date: 06-1996
Abstract: The gene for the stimulatory G protein-coupled human A2a adenosine receptor was isolated and sequence analysis revealed two exons that are interrupted by an intron of approximately 6.4 kb. An intron is located in the same region in the human A1 and A2b adenosine receptor genes. Comparison of the A2a genomic and cDNA sequences reveals two nucleotide differences in the coding region and the presence of an aberrant sequence in the 5'208 base pairs of the A2a cDNA including a polymorphism in the third base of codon Tyr-361 and Gly codon which was always detected at residue 392, indicated that the Arg codon present in the cDNA may be an artifact. Fluorescent in situ hybridization and PCR analysis of human-hamster hybrid cell panels shows that the A2a receptor gene is localized to chromosome 22q11.2. This is in contrast with previous reports (subsequently retracted) which mapped the A2a gene to chromosome 11q11-13.
Mutations affecting the glycine receptor agonist transduction mechanism convert the competitive antagonist, picrotoxin, into an allosteric potentiator
Publisher: Elsevier BV
Date: 06-1995
Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-08-2015
DNA sequence of Rhizobium trifolii nodulation genes reveals a reiterated and potentially regulatory sequence preceding nodABC and nodFE
Publisher: Oxford University Press (OUP)
Date: 1986
Abstract: The Rhizobium trifolii nod genes required for host-specific nodulation of clovers are located on 14 kb of Sym (symbiotic) plasmid DNA. Analysis of the nucleotide sequence of a 3.7 kb portion of this region has revealed open reading frames corresponding to the nodABCDEF genes. A DNA sequencing technique, using primer extension from within Tn5, has been used to determine the precise locations of Tn5 mutations within the nod genes and the phenotypes of the corresponding mutants correlate with their mapped locations. The predicted nodA and nodB genes overlap by four nucleotides and the nod F and nodE genes overlap by a single nucleotide, suggesting that translational coupling may ensure the synthesis of equimolar amounts of these gene products. The nodABC and nodFE genes constitute separate transcriptional units and each is preceded by a conserved 76-bp sequence which may be involved in the regulation of expression of these genes.
Transient Expression Shows Ligand Gating and Allosteric Potentiation of GABA A Receptor Subunits
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-12-1988
Abstract: Human gamma-aminobutyric acid A (GABAA) receptor subunits were expressed transiently in cultured mammalian cells. This expression system allows the simultaneous characterization of ligand-gated ion channels by electrophysiology and by pharmacology. Thus, coexpression of the alpha and beta subunits of the GABAA receptor generated GABA-gated chloride channels and binding sites for GABAA receptor ligands. Channels consisting of only alpha or beta subunits could also be detected. These homomeric channels formed with reduced efficiencies compared to the heteromeric receptors. Both of these homomeric GABA-responsive channels were potentiated by barbiturate, indicating that sites for both ligand-gating and allosteric potentiation are present on receptors assembled from either subunit.
Erratum to “Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial” [Rev. Neurol. 169 (10) (2013) 737–743]
Publisher: Elsevier BV
Date: 12-2013
Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease
Publisher: Springer Science and Business Media LLC
Date: 21-01-2019
Preclinical Alzheimer’s disease biomarkers accurately predict cognitive and neuropathological outcomes
Publisher: Oxford University Press (OUP)
Date: 22-07-2022
Abstract: Alzheimer’s disease biomarkers are widely accepted as surrogate markers of underlying neuropathological changes. However, few studies have evaluated whether preclinical Alzheimer’s disease biomarkers predict Alzheimer’s neuropathology at autopsy. We sought to determine whether amyloid PET imaging or CSF biomarkers accurately predict cognitive outcomes and Alzheimer’s disease neuropathological findings. This study included 720 participants, 42–91 years of age, who were enrolled in longitudinal studies of memory and aging in the Washington University Knight Alzheimer Disease Research Center and were cognitively normal at baseline, underwent amyloid PET imaging and/or CSF collection within 1 year of baseline clinical assessment, and had subsequent clinical follow-up. Cognitive status was assessed longitudinally by Clinical Dementia Rating®. Biomarker status was assessed using predefined cut-offs for amyloid PET imaging or CSF p-tau181/amyloid-β42. Subsequently, 57 participants died and underwent neuropathologic examination. Alzheimer’s disease neuropathological changes were assessed using standard criteria. We assessed the predictive value of Alzheimer’s disease biomarker status on progression to cognitive impairment and for presence of Alzheimer’s disease neuropathological changes. Among cognitively normal participants with positive biomarkers, 34.4% developed cognitive impairment (Clinical Dementia Rating & 0) as compared to 8.4% of those with negative biomarkers. Cox proportional hazards modelling indicated that preclinical Alzheimer's disease biomarker status, APOE ɛ4 carrier status, polygenic risk score and centred age influenced risk of developing cognitive impairment. Among autopsied participants, 90.9% of biomarker-positive participants and 8.6% of biomarker-negative participants had Alzheimer's disease neuropathological changes. Sensitivity was 87.0%, specificity 94.1%, positive predictive value 90.9% and negative predictive value 91.4% for detection of Alzheimer's disease neuropathological changes by preclinical biomarkers. Single CSF and amyloid PET baseline biomarkers were also predictive of Alzheimer’s disease neuropathological changes, as well as Thal phase and Braak stage of pathology at autopsy. Biomarker-negative participants who developed cognitive impairment were more likely to exhibit non-Alzheimer's disease pathology at autopsy. The detection of preclinical Alzheimer's disease biomarkers is strongly predictive of future cognitive impairment and accurately predicts presence of Alzheimer's disease neuropathology at autopsy.
Distinct agonist- and antagonist-binding sites on the glycine receptor
Publisher: Elsevier BV
Date: 09-1992
DOI: 10.1016/0896-6273(92)90186-H
Abstract: The distinction between receptor-binding sites for agonists and antagonists underpins the pharmacological differences between these two classes of ligands. In the glycine receptor, antagonist (strychnine) binding requires an interaction with residues Lys-200 and Tyr-202. We now demonstrate that the agonist-binding site of this receptor is located at the residue Thr-204. The agonist-binding site interaction is thus likely to be mediated by hydrogen bonding and not by ionic interactions. Our results demonstrate that, in contrast to other studies of ligand-gated ion channel receptors, agonist- and antagonist-binding sites are composed of distinct amino acid residues.
M2 pore mutations convert the glycine receptor channel from being anion- to cation-selective
Publisher: Elsevier BV
Date: 07-2000
Cover Image, Volume 186B, Number 8, December 2021
Publisher: Wiley
Date: 12-2021
DOI: 10.1002/AJMG.B.32803
BDNF genotype interacts with motor function to influence rehabilitation responsiveness poststroke
Publisher: Frontiers Media SA
Date: 17-05-2016
Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Δ9-tetrahydrocannabinol
Publisher: Springer Science and Business Media LLC
Date: 28-02-2007
DOI: 10.1007/S00213-007-0721-3
Abstract: Cannabis use may precipitate schizophrenia especially if the in idual has a genetic vulnerability to this mental disorder. Human and animal research indicates that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia. The aim of this study was to investigate whether dysfunction in the Nrg1 gene modulates the behavioural effects of Delta(9)-tetrahydrocannabinol (THC), the major psychotropic component of cannabis. Heterozygous Nrg1 transmembrane-domain knockout mice (Nrg1 HET) were treated with acute THC (0, 5 or 10 mg/kg i.p.) 30 min before being tested using open field (OF), hole board (HB), light-dark (LD), elevated plus maze (EPM), social interaction (SI) and prepulse inhibition (PPI) tests. Nrg1 HET mice showed differences in baseline behaviour with regard to locomotor activity, exploration and anxiety. More importantly, they were more sensitive to the locomotor suppressant actions of THC compared to wild type-like (WT) mice. In addition, Nrg1 HET mice expressed a greater THC-induced enhancement in % PPI than WT mice. The effects of THC on anxiety-related behaviour were task-dependent, with Nrg1 HET mice being more susceptible than WT mice to the anxiogenic effects of THC in LD, but not in the EPM, SI and OF tests. Nrg1 HET mice were more sensitive to the acute effects of THC in an array of different behaviours including those that model symptoms of schizophrenia. It appears that variation in the schizophrenia-related neuregulin 1 gene alters the sensitivity to the behavioural effects of cannabinoids.
Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia
Publisher: Springer Science and Business Media LLC
Date: 20-06-2017
DOI: 10.1038/TP.2017.115
Abstract: Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient s les worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD ( P =4.42 × 10 −7 ) and PKP4 ( P =8.67 × 10 −7 ) and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, P FDR =0.019 FDR, false discovery rate). Prior studies have implicated DPYD , PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP ( r g =0.28 [ P =2.99 × 10 −3 ]), SCZ ( r g =0.34 [ P =4.37 × 10 −5 ]) and MDD ( r g =0.57 [ P =1.04 × 10 −3 ]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
Cation-selective Mutations in the M2 Domain of the Inhibitory Glycine Receptor Channel Reveal Determinants of Ion-Charge Selectivity
Publisher: Rockefeller University Press
Date: 15-04-2002
DOI: 10.1085/JGP.20028552
Abstract: Ligand-gated ion channel receptors mediate neuronal inhibition or excitation depending on their ion charge selectivity. An investigation into the determinants of ion charge selectivity of the anion-selective α1 homomeric glycine receptor (α1 glycine receptor [GlyR]) was undertaken using point mutations to residues lining the extra- and intracellular ends of the ion channel. Five mutant GlyRs were studied. A single substitution at the intracellular mouth of the channel (A-1′E GlyR) was sufficient to convert the channels to select cations over anions with PCl/PNa = 0.34. This result delimits the selectivity filter and provides evidence that electrostatic interactions between permeating ions and pore residues are a critical factor in ion charge selectivity. The P-2′Δ mutant GlyR retained its anion selectivity (PCl/PNa = 3.81), but it was much reduced compared with the wild-type (WT) GlyR (PCl/PNa = 27.9). When the A-1′E and the P-2′Δ mutations were combined (selectivity double mutant [SDM] GlyR), the relative cation permeability was enhanced (PCl/PNa = 0.13). The SDM GlyR was also Ca2+ permeable (PCa/PNa = 0.29). Neutralizing the extracellular mouth of the SDM GlyR ion channel (SDM+R19′A GlyR) produced a more Ca2+-permeable channel (PCa/PNa = 0.73), without drastically altering monovalent charge selectivity (PCl/PNa = 0.23). The SDM+R19′E GlyR, which introduces a negatively charged ring at the extracellular mouth of the channel, further enhanced Ca2+ permeability (PCa/PNa = 0.92), with little effect on monovalent selectivity (PCl/PNa = 0.19). Estimates of the minimum pore diameter of the A-1′E, SDM, SDM+R19′A, and SDM+R19′E GlyRs revealed that these pores are larger than the α1 GlyR, with the SDM-based GlyRs being comparable in diameter to the cation-selective nicotinic acetylcholine receptors. This result provides evidence that the diameter of the ion channel is also an important factor in ion charge selectivity.
Single Channel Analysis of Conductance and Rectification in Cation-selective, Mutant Glycine Receptor Channels
Publisher: Rockefeller University Press
Date: 15-04-2002
DOI: 10.1085/JGP.20028553
Abstract: Members of the ligand-gated ion channel superfamily mediate fast synaptic transmission in the nervous system. In this study, we investigate the molecular determinants and mechanisms of ion permeation and ion charge selectivity in this family of channels by characterizing the single channel conductance and rectification of α1 homomeric human glycine receptor channels (GlyRs) containing pore mutations that impart cation selectivity. The A-1'E mutant GlyR and the selectivity double mutant ([SDM], A-1'E, P-2'Δ) GlyR, had mean inward chord conductances (at −60 mV) of 7 pS and mean outward conductances of 11 and 12 pS (60 mV), respectively. This indicates that the mutations have not simply reduced anion permeability, but have replaced the previous anion conductance with a cation one. An additional mutation to neutralize the ring of positive charge at the extracellular mouth of the channel (SDM+R19'A GlyR) made the conductance–voltage relationship linear (14 pS at both 60 and −60 mV). When this external charged ring was made negative (SDM+R19'E GlyR), the inward conductance was further increased (to 22 pS) and now became sensitive to external alent cations (being 32 pS in their absence). The effects of the mutations to the external ring of charge on conductance and rectification could be fit to a model where only the main external energy barrier height for permeation was changed. Mean outward conductances in the SDM+R19'A and SDM+R19'E GlyRs were increased when internal alent cations were absent, consistent with the intracellular end of the pore being flanked by fixed negative charges. This supports our hypothesis that the ion charge selectivity mutations have inverted the electrostatic profile of the pore by introducing a negatively charged ring at the putative selectivity filter. These results also further confirm the role of external pore vestibule electrostatics in determining the conductance and rectification properties of the ligand-gated ion channels.
Proteomic clusters underlie heterogeneity in preclinical Alzheimer’s disease progression
Publisher: Oxford University Press (OUP)
Date: 21-12-2022
Abstract: Heterogeneity in progression to Alzheimer's disease (AD) poses challenges for both clinical prognosis and clinical trial implementation. Multiple AD-related subtypes have previously been identified, suggesting differences in receptivity to drug interventions. We identified early differences in preclinical AD biomarkers, assessed patterns for developing preclinical AD across the amyloid-tau-(neurodegeneration) [AT(N)] framework, and considered potential sources of difference by analysing the CSF proteome. Participants (n = 10) enrolled in longitudinal studies at the Knight Alzheimer Disease Research Center completed four or more lumbar punctures. These in iduals were cognitively normal at baseline. Cerebrospinal fluid measures of amyloid-β (Aβ)42, phosphorylated tau (pTau181), and neurofilament light chain (NfL) as well as proteomics values were evaluated. Imaging biomarkers, including PET amyloid and tau, and structural MRI, were repeatedly obtained when available. In iduals were staged according to the amyloid-tau-(neurodegeneration) framework. Growth mixture modelling, an unsupervised clustering technique, identified three patterns of biomarker progression as measured by CSF pTau181 and Aβ42. Two groups (AD Biomarker Positive and Intermediate AD Biomarker) showed distinct progression from normal biomarker status to having biomarkers consistent with preclinical AD. A third group (AD Biomarker Negative) did not develop abnormal AD biomarkers over time. Participants grouped by CSF trajectories were re-classified using only proteomic profiles (AUCAD Biomarker Positive versus AD Biomarker Negative = 0.857, AUCAD Biomarker Positive versus Intermediate AD Biomarkers = 0.525, AUCIntermediate AD Biomarkers versus AD Biomarker Negative = 0.952). We highlight heterogeneity in the development of AD biomarkers in cognitively normal in iduals. We identified some in iduals who became amyloid positive before the age of 50 years. A second group, Intermediate AD Biomarkers, developed elevated CSF ptau181 significantly before becoming amyloid positive. A third group were AD Biomarker Negative over repeated testing. Our results could influence the selection of participants for specific treatments (e.g. amyloid-reducing versus other agents) in clinical trials. CSF proteome analysis highlighted additional non-AT(N) biomarkers for potential therapies, including blood–brain barrier-, vascular-, immune-, and neuroinflammatory-related targets.
Association between body mass index and subcortical brain volumes in bipolar disorders–ENIGMA study in 2735 individuals
Publisher: Springer Science and Business Media LLC
Date: 16-04-2021
DOI: 10.1038/S41380-021-01098-X
Abstract: In iduals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control in iduals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, in iduals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippoc us, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI ( Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some in iduals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.
Tn 5 mutagenesis of Rhizobium trifolii host-specific nodulation genes result in mutants with altered host-range ability
Publisher: Springer Science and Business Media LLC
Date: 08-1985
DOI: 10.1007/BF00425732
Expression of high-affinity human antibody fragments in bacteria
Publisher: Springer Science and Business Media LLC
Date: 02-2012
Abstract: Here we describe protocols for the expression of human antibody fragments in Escherichia coli. Antigen-specific clones are identified by soluble fragment ELISA and concentrated by periplasmic preparation. They are then further purified by affinity chromatography. This article provides an overview of expression and purification strategies for human antibody fragments, as well as detailed protocols for the identification of high-affinity binders and for affinity maturation.
A polymorphism of the MAOA gene is associated with emotional brain markers and personality traits on an antisocial index
Publisher: Springer Science and Business Media LLC
Date: 04-02-2009
DOI: 10.1038/NPP.2009.1
Abstract: Association studies suggest that the low activity variant of the monoamine oxidase A (MAOA)-uVNTR polymorphism confers risk for emotional disturbances associated with antisocial traits, particularly in males. Here, we assessed the low (MAOA-L) activity variant in relation to both brain function and a behavioral index of antisocial traits. From an initial s le of 290 healthy participants, 210 had low (MAOA-L) or high (MAOA-H) activity variants. Participants underwent a brief assessment of personality traits and event-related potential (ERP) recording during an emotion-processing task. Genotype differences in ERPs were localized using LORETA. The MAOA-L genotype was distinguished by elevated scores on the index of antisocial traits. These traits were related to altered ERPs elicited 120-280ms post-stimulus, particularly for negative emotion. Altered neural processing of anger in MAOA-L genotypes was localized to medial frontal, parietal, and superior temporo-occipital regions in males, but only to the superior occipital cortex in females. The MAOA low activity variant may increase susceptibility to antisocial traits through alterations to the neural systems for processing threat-related emotion, especially for males. Monoamines such as noradrenalin and serotonin may modulate these relationships, given that their metabolism varies according to MAOA variants, and that they modulate both emotional brain systems and antisocial aggression.
Structural and functional basis for GABAA receptor heterogeneity
Publisher: Springer Science and Business Media LLC
Date: 09-1988
DOI: 10.1038/335076A0
Abstract: When gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in vertebrate brain, binds to its receptor it activates a chloride channel. Neurotransmitter action at the GABAA receptor is potentiated by both benzodiazepines and barbiturates which are therapeutically useful drugs (reviewed in ref. 1). There is strong evidence that this receptor is heterogeneous. We have previously isolated complementary DNAs encoding an alpha- and a beta-subunit and shown that both are needed for expression of a functional GABAA receptor. We have now isolated cDNAs encoding two additional GABAA receptor alpha-subunits, confirming the heterogeneous nature of the receptor/chloride channel complex and demonstrating a molecular basis for it. These alpha-subunits are differentially expressed within the CNS and produce, when expressed with the beta-subunit in Xenopus oocytes, receptor subtypes which can be distinguished by their apparent sensitivity to GABA. Highly homologous receptor subtypes which differ functionally seem to be a common feature of brain receptors.
Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification
Publisher: Springer Science and Business Media LLC
Date: 20-01-2013
Sequence of Alzheimer disease biomarker changes in cognitively normal adults
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2020
DOI: 10.1212/WNL.0000000000010747
Abstract: To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal in iduals. Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [ 11 C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal in iduals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers. Accelerated changes in CSF Aβ 1-42 (Aβ 42 ) occurred at 48.28 years of age and in Aβ 42 /Aβ 40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippoc al volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ 42 and Aβ 42 /Aβ 40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other. Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.
Association of polygenic score for major depression with response to lithium in patients with bipolar disorder
Publisher: Springer Science and Business Media LLC
Date: 16-03-2200
DOI: 10.1038/S41380-020-0689-5
Abstract: Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi
Integrating objective gene-brain-behavior markers of psychiatric disorders
Publisher: World Scientific Pub Co Pte Lt
Date: 03-2007
DOI: 10.1142/S0219635207001465
Abstract: There is little consensus about which objective markers should be used to assess major psychiatric disorders, and predict/evaluate treatment response for these disorders. Clinical practice relies instead on subjective signs and symptoms, such that there is a "translational gap" between research findings and clinical practice. This gap arises from: a) a lack of integrative theoretical models which provide a basis for understanding links between gene-brain-behavior mechanisms and clinical entities b) the reliance on studying one measure at a time so that linkages between markers are their specificity are not established and c) the lack of a definitive understanding of what constitutes normative function. Here, we draw on a standardized methodology for acquiring multiple sources of genomic, brain and behavioral data in the same subjects, to propose candidate markers of selected psychiatric disorders: depression, post-traumatic stress disorder, schizophrenia, attention-deficit/hyperactivity disorder and dementia disorders. This methodology has been used to establish a standardized international database which provides a comprehensive framework and the basis for testing hypotheses derived from an integrative theoretical model of the brain. Using this normative base, we present preliminary findings for a number of disorders in relation to the proposed markers. Establishing these objective markers will be the first step towards determining their sensitivity, specificity and treatment prediction in in idual patients.
Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder
Publisher: Springer Science and Business Media LLC
Date: 03-08-2022
DOI: 10.1038/S41398-022-02079-6
Abstract: Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peripheral blood-derived DNA was assayed using Illumina PsychArray, and Methylation-450K or -EPIC BeadChips. Polygenic risk scores (PRS) were calculated using summary statistics from recent genome-wide association studies for BD, major depressive disorder (MDD) and cross-disorder (meta-analysis of eight psychiatric disorders). Unrelated HR participants of European ancestry ( n = 103) were stratified based on their BD-PRS score within the HR-population distribution, and the top two quintiles (High-BD-PRS n = 41) compared against the bottom two quintiles (Low-BD-PRS n = 41). The High-BD-PRS stratum also had higher mean cross-disorder-PRS and MDD-PRS (ANCOVA p = 0.035 and p = 0.024, respectively). We evaluated DNA methylation differences between High-BD-PRS and Low-BD-PRS strata using linear models. One differentially methylated probe (DMP) (cg00933603 p = 3.54 × 10 −7 ) in VARS2 , a mitochondrial aminoacyl-tRNA synthetase, remained significantly hypomethylated after multiple-testing correction. Overall, BD-PRS appeared to broadly impact epigenetic processes, with 1,183 genes mapped to nominal DMPs ( p 0.05) these displayed convergence with genes previously associated with BD, schizophrenia, chronotype, and risk taking. We tested poly-methylomic epigenetic profiles derived from nominal DMPs in two independent s les ( n = 54 and n = 82, respectively), and conducted an exploratory evaluation of the effects of family environment, indexing cohesion and flexibility. This study highlights an important interplay between heritable risk and epigenetic factors, which warrant further exploration.
A novel hardness-related and starch granule-associated protein marker in wheat: LMW-GS-'S'
Publisher: Elsevier BV
Date: 03-2012
GSK3B and MAPT polymorphisms are associated with grey matter and intracranial volume in healthy individuals.
Publisher: Public Library of Science (PLoS)
Date: 12-08-2013
Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: Implications for understanding schizophrenia
Publisher: Wiley
Date: 29-11-2007
A nonsense mutation in the α1 subunit of the inhibitory glycine receptor associated with bovine myoclonus
Publisher: Elsevier BV
Date: 02-2001
Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia
Publisher: Springer Science and Business Media LLC
Date: 16-10-2012
DOI: 10.1038/MP.2012.137
Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium
Publisher: Elsevier BV
Date: 04-2015
Associations between theCOMT Val/Metpolymorphism, early life stress, and personality among healthy adults
Publisher: Informa UK Limited
Date: 2006
Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study
Publisher: Wiley
Date: 21-07-2017
Pick bodies in a family with presenilin-1 Alzheimer's disease.
Publisher: Wiley
Date: 27-12-2005
DOI: 10.1002/ANA.20366
Abstract: Presenilin-1 (PS-1) mutations can cause Pick's disease without evidence of Alzheimer's disease (AD). We describe a family with a PS-1 M146L mutation and both Pick bodies and AD. Sarkosyl-insoluble hyperphosphorylated tau showed three bands consistent with AD, although dephosphorylation showed primarily three-repeat isoforms. M146L mutant PS-1 may predispose to both Pick's disease and AD by affecting multiple intracellular pathways involving tau phosphorylation and amyloid metabolism.
Neuromarkers of the common angiotensinogen polymorphism in healthy older adults: A comprehensive assessment of white matter integrity and cognition
Publisher: Elsevier BV
Date: 2016
COMT Val108/158Met polymorphism effects on emotional brain function and negativity bias
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.NEUROIMAGE.2010.01.084
Abstract: Biases toward processing negative versus positive information vary as a function of level of awareness, and are modulated by monoamines. Excessive biases are associated with in idual differences in mood and emotional stability, and emotional disorder. Here, we examined the impact of the catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism, involved in dopamine and norepinephrine catabolism, on both emotional brain function and self-reported negativity bias. COMT genotyping and self-reported level of negativity bias were completed for 46 healthy participants taking part in the Brain Resource International Database. Functional MRI was undertaken during perception of facial expressions of fear and happiness presented under unmasked (consciously identified) and masked (to prevent conscious detection) conditions. Structural MR images were also acquired. A greater number of COMT Met alleles predicted increased activation in brainstem, amygdala, basal ganglia and medial prefrontal regions for conscious fear, but decreased activation for conscious happiness. This pattern was also apparent for brainstem activation for the masked condition. Effects were most apparent for females. These differences could not be explained by gray matter variations. The Met-related profile of activation, particularly prefrontally, predicted greater negativity bias associated with risk for emotional disorder. The findings suggest that the COMT Met allele modulates neural substrates of negative versus positive emotion processing. This effect may contribute to negativity biases, which confer susceptibility for emotional disorders.
Distinct physiological mechanisms underlie altered glycinergic synaptic transmission in the murine mutants spastic, spasmodic, and oscillator
Publisher: Society for Neuroscience
Date: 03-05-2006
DOI: 10.1523/JNEUROSCI.3991-05.2006
Abstract: Spastic ( spa ), spasmodic ( spd ), and oscillator ( ot ) mice have naturally occurring glycine receptor (GlyR) mutations, which manifest as motor deficits and an exaggerated “startle response.” Using whole-cell recording in hypoglossal motoneurons, we compared the physiological mechanisms by which each mutation alters GlyR function. Mean glycinergic miniature IPSC (mIPSC) litude and frequency were dramatically reduced ( %) compared with controls for each mutant. mIPSC decay times were unchanged in spa/spa (4.5 ± 0.3 vs 4.7 ± 0.2 ms), reduced in spd/spd (2.7 ± 0.2 vs 4.7 ± 0.2 ms), and increased in ot/ot (12.3 ± 1.2 vs 4.8 ± 0.2 ms). Thus, in spastic , GlyRs are functionally normal but reduced in number, whereas in spasmodic , GlyR kinetics is faster. The oscillator mutation results in complete absence of α1-containing GlyRs however, some non-α1-containing GlyRs persist at synapses. Fluctuation analysis of membrane current, induced by glycine application to outside-out patches, showed that mean single-channel conductance was increased in spa/spa (64.2 ± 4.9 vs 36.1 ± 1.4 pS), but unchanged in spd/spd (32.4 ± 2.1 vs 35.3 ± 2.1 pS). GlyR-mediated whole-cell currents in spa/spa exhibited increased picrotoxin sensitivity (27 vs 71% block for 100 μ m ), indicating α1 homomeric GlyR expression. The picrotoxin sensitivity of evoked glycinergic IPSCs and conductance of synaptic GlyRs, as determined by nonstationary variance analysis, were identical for spa/spa and controls. Together, these findings show the three mutations disrupt GlyR-mediated inhibition via different physiological mechanisms, and the spastic mutation results in “compensatory” α1 homomeric GlyRs at extrasynaptic loci.
Issues concerning feedback about genetic testing and risk of depression
Publisher: Royal College of Psychiatrists
Date: 05-2009
DOI: 10.1192/BJP.BP.107.047514
Abstract: Recent studies show that adverse life events have a significantly greater impact on depression onset for those with the s/s allele of the genotype for the 5-HT gene-linked promoter region. Research in genes related to risk of depression leads to the question of how this information is received by in iduals. To investigate factors related to the response to receiving one's own serotonin transporter genotype results. Predictors of the impact of receiving in idual genotype data were assessed in 128 participants in a study of gene–environment interaction in depression onset. Two-thirds decided to learn their in idual genotype results (receivers) and prior to disclosure this decision was associated with a perception of greater benefit from receipt of the information ( P =0.001). Receivers completing the 2-week ( n =76) and 3-month follow-up ( n =78) generally reported feeling pleased with the information and having had a more positive experience than distress. However, distress was related to genotype, with those with the s/s allele being most affected. There was high interest in, and satisfaction with, learning about one's serotonin transporter genotype. Participants appeared to understand that the gene conferred susceptibility to depression rather than a direct causal effect.
The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Predicts Response to Exposure Therapy in Posttraumatic Stress Disorder
Publisher: Elsevier BV
Date: 06-2013
Australian Brain Alliance
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.NEURON.2016.10.038
Abstract: A proposal for an Australian Brain Initiative (ABI) is under development by members of the Australian Brain Alliance. Here we discuss the goals of the ABI, its areas of research focus, its context in the Australian research setting, and its necessity for ensuring continued success for Australian brain research.
Aging, exceptional longevity and comparisons of the Hannum and Horvath epigenetic clocks
Publisher: Future Medicine Ltd
Date: 05-2017
Abstract: Aim: To examine the relationships between two epigenetic clocks, aging and exceptional longevity. Materials & methods: Participants were from three adult cohorts with blood DNA methylation data (Illumina 450 K, n = 275, 34–103 years). Epigenetic age (DNAmage) and age acceleration measures were calculated using the Hannum and Horvath epigenetic clocks. Results: Across all cohorts, DNAmage was correlated with chronological age. In the long-lived cohort (Sydney Centenarian Study 95+, n = 23), DNAmage was lower than chronological age for both clocks. Mean Sydney Centenarian Study Hannum age acceleration was negative, while the converse was observed for the Horvath model. Conclusion: Long-lived in iduals have a young epigenetic age compared with their chronological age.
Implications of genetic risk information in families with a high density of bipolar disorder: An exploratory study
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.SOCSCIMED.2004.04.016
Abstract: While major susceptibility genes for bipolar disorder are yet to be identified, the opportunity exists to systematically ascertain the important issues and societal implications of genetic risk determination for bipolar disorder prior to these technological advances becoming widely available. This study explores, in a s le of families with a high density of bipolar disorder: (i) attitudes to predictive genetic and prenatal testing, using different risk frames (ii) attributions for bipolar disorder, in particular the degree to which a genetic model is endorsed and (iii) the impact of these attributions on the perceived stigma of bipolar disorder. A qualitative methodology was selected as most appropriate as no previous research has examined this issue. Participants were ascertained through a molecular genetics study of bipolar disorder. In-depth interviews were conducted with 21 members of families with a high density of bipolar disorder. Most participants reported being interested in genetic testing if it gave a definitive answer, while expressed interest in testing was lower if it gave a probable answer only. Almost all stressed that a genetic susceptibility and environmental factors interacted. Most participants felt that a genetic explanation was likely to decrease the stigma associated with bipolar disorder as it shifted the locus of control and responsibility away from the in idual towards the role of heredity. Findings indicate that expressed interest in genetic testing depends on the certainty imparted by the test. Results suggest that families with bipolar disorder are likely to benefit psychologically from information about the genetic basis of bipolar disorder.
Follow‐up of Indigenous‐specific health assessments ‐ a socioecological analysis
Publisher: AMPCo
Date: 06-2014
DOI: 10.5694/MJA13.00256
Abstract: To describe patterns of uptake of Indigenous-specific health assessments and associated follow-up items, and examine the barriers and enablers to delivery and billing of follow-up over the first 3 years of implementation of the Indigenous Chronic Disease Package (ICDP). We used a socioecological approach to analyse data derived from the Sentinel Sites Evaluation of the ICDP - with data from 24 sites across Australia. Administrative data (1 May 2009 to 30 May 2012) and program data (1 March 2010 to 30 May 2012) were provided by the Department of Health. Data on barriers and enablers to follow-up of health assessments were obtained from community focus groups, in-depth interviews and discussions with key informants (1 November 2010 to 30 December 2012). Monthly number of Medicare Benefits Schedule items claimed for Indigenous-specific health services and follow-up qualitative data on enablers and barriers categorised according to patient, patient-health service relationship, health service or organisation, community and policy environment levels or influence. There was an increase in the uptake of health assessments, but relatively limited delivery of follow-up care and billing for Indigenous-specific follow-up items. Follow-up was constrained by factors that operated at various levels: patient, interpersonal, health service, community and policy. Constraints included practitioners' lack of awareness of item numbers, staffing, poor state of clinical information systems, billing against non-Indigenous-specific items or more general follow-up items, emphasis on health assessments with less attention to requirements for follow-up, limited capacity to arrange and facilitate follow-up, and communication and transport challenges for patients. Work is required across various levels of the system to address barriers to follow-up care. Enhancing follow-up care is vital to achieving health benefits from the large financial and human resource investment in health assessments.
Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease
Publisher: American Medical Association (AMA)
Date: 09-2014
Aggregation, stability, and formulation of human antibody therapeutics
Publisher: Elsevier
Date: 2011
Characterisation of Genetic Variation in ST8SIA2 and Its Interaction Region in NCAM1 in Patients with Bipolar Disorder
Publisher: Public Library of Science (PLoS)
Date: 30-10-0003
Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21-22
Publisher: Wiley
Date: 11-1997
Abstract: An Australian family with autosomal dominant presenile nonspecific dementia was recently described. The disease results in behavioral changes, usually disinhibition, followed by the onset of dementia accompanied occasionally by parkinsonism. Twenty-eight affected in iduals were identified with an age of onset of 39 to 66 years (mean, 53 +/- 8.9 years). We mapped the disease locus to an approximately 26-cM region of chromosome 17q21-22 with a maximum two-point LOD score of 2.87. Affected in iduals share a common haplotype between markers D17S783 and D17S808. This region of chromosome 17 contains the loci for several neurodegenerative diseases that lack distinctive pathological features, suggesting that these dementias, collectively referred to as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in the same gene. The entire coding region of five genes, mapped to the FTDP-17 candidate region, were also sequenced. This analysis included the microtubule-associated protein tau that is the major component of the paired helical filaments observed in Alzheimer's disease. No pathogenic mutations were identified in either the tau gene or in any of the other genes analyzed.
Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-03-2014
DOI: 10.1126/SCITRANSLMED.3007901
Abstract: Longitudinal cerebrospinal fluid biomarker analyses reveal decreases in neuronal injury markers in later stages of autosomal-dominant Alzheimer’s disease.
Kinetic determinants of agonist action at the recombinant human glycine receptor
Publisher: Wiley
Date: 06-2003
Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology
Publisher: Oxford University Press (OUP)
Date: 17-05-2022
Abstract: The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of ‘sporadic’ late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer’s Disease Neuroimaging Initiative. Imaging data and CSF s les were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippoc al volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.
Probing glycine receptor stoichiometry in superficial dorsal horn neurones using the spasmodic mouse.
Publisher: Wiley
Date: 13-05-2011
Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group
Publisher: Cold Spring Harbor Laboratory
Date: 05-11-2018
DOI: 10.1101/460444
Abstract: DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small s le sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3,337 in iduals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippoc us, thalamus and nucleus accumbens (NAcc) –three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of in idual CpGs revealed genome-wide significant associations with hippoc al volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. CpG sites associated with hippoc us volume were significantly enriched within cancer-related genes and within regulatory elements containing the transcriptionally repressive histone H3K27 tri-methylation mark that is vital for stem cell fate specification. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippoc al volume. DNA methylation at these loci affected expression of proximal genes involved in in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
Biphasic cortical macro‐ and microstructural changes in autosomal dominant Alzheimer's disease
Publisher: Wiley
Date: 16-11-2020
DOI: 10.1002/ALZ.12224
Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer disease brains
Publisher: Cold Spring Harbor Laboratory
Date: 05-11-2021
DOI: 10.1101/2021.11.04.21265941
Abstract: The identification of multiple genetic risk factors for Alzheimer Disease (AD) provides evidence to support that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain, including information on treatment targets. In this study, we interrogate the metabolomic and lipidomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1 , and PSEN2 (autosomal dominant AD ADAD), APOE ε4 and TREM2 risk variant carriers, and non-carrier sporadic AD (sAD). We generated metabolomic and lipidomic data from parietal cortical tissue from 366 participants with AD pathology and 26 cognitively unimpaired controls using the Metabolon global metabolomics platform. We identified 133 metabolites associated with disease status (FDR q -value .05). In sAD brains these include tryptophan betaine (b=-0.57) and N-acetylputrescine (b=-0.14). Metabolites associated with sAD and ADAD include ergothioneine (b=-0.21 and -0.26 respectively) and serotonin (b=-0.34 and -0.58, respectively). TREM2 and ADAD showed association with α-tocopherol (b=-0.12 and -0.12) and CDP-ethanolamine (b=-0.13 and -0.10). β-citrylglutamate levels are associated with sAD, ADAD, and TREM2 compared to controls (b=-0.15 -0.22 and -0.29, respectively). Additionally, we identified a signature of 16 metabolites that is significantly altered between genetic groups (sAD vs. control p = 1.05×10 -7 , ADAD vs. sAD p = 3.21×10 -5 ) and is associated with Braak tau stage and disease duration. These data are available to the scientific community through a public web browser ( ngi.pub/Metabolomics ). Our findings were replicated in an independent cohort of 327 in iduals.
Genome-wide association study reveals two new risk loci for bipolar disorder
Publisher: Springer Science and Business Media LLC
Date: 11-03-2014
DOI: 10.1038/NCOMMS4339
Abstract: Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large s les are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a s le of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.
Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies.
Publisher: Springer Science and Business Media LLC
Date: 09-2004
DOI: 10.1007/S00415-004-0489-X
Abstract: Tau gene mutations with insoluble Tau neuropathology have been identified in pedigrees with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Other neurodegenerative diseases, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are also characterised by insoluble Tau neuropathology. This study sought to determine the nature and frequency of tau gene mutations in an affected proband cohort of patients within this spectrum of neurodegenerative diseases. Sixty-four in iduals with clinical features consistent with FTD and other tauopathies were referred over a three year period. There was neuropathological confirmation of disease in 30%. In iduals were screened for mutations in the coding region and flanking intronic regions of the tau gene by direct sequencing of PCR products. Four confirmed tau gene mutations were identified representing 6.3 % for the total affected proband cohort. Tau gene mutations were found in three of twelve (25%) of the cases with a family history of dominantly inherited frontotemporal dementia, but in only one of 25 cases without a family history (4 %). Although tauopathies have been considered to result from genetic defects, screening for tau gene mutations in sporadic cases is not likely to identify pathogenic mutations.
Diurnal cortisol variation and cortisol response to an MRI stressor in schizophrenia and bipolar disorder
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.PSYNEUEN.2016.01.021
Abstract: Markers of HPA axis function, including diurnal cortisol rhythm and cortisol responses to stress or pharmacological manipulation, are increasingly reported as disrupted in schizophrenia (SZ) and bipolar disorder (BD). However, there has been no direct comparison of cortisol responses to stress in SZ and BD in the same study, and associations between cortisol dysfunction and illness characteristics remain unclear. In this study we used spline embedded linear mixed models to examine cortisol levels of SZ and BD participants at waking, during the first 45min after waking (representing the cortisol awakening response CAR), during the period of rapid cortisol decline post the awakening response, and in reaction to a stressor (MRI scan), relative to healthy controls (HC). Contrary to expectations, neither SZ nor BD showed differences in waking cortisol levels, CAR, or immediate post-CAR decline compared to HC however, waking cortisol levels were greater in BD relative to SZ. In response to the MRI stressor, the SZ group showed a significant absence of the expected increase in cortisol responsivity to stress, which was seen in both the BD and HC groups. Clinical factors affecting the CAR differed between SZ and BD. In SZ, higher antipsychotic medication dosage was associated with a steeper incline of the CAR, while greater positive symptom severity was associated with a more blunted CAR, and greater levels of anxiety were associated with the blunted cortisol response to stress. In BD, longer illness duration was associated with a steeper incline in CAR and lower levels of waking cortisol. These results suggest that cortisol responses may normalize with medication (in SZ) and longer illness duration (in BD), in line with findings of aberrant cortisol levels in the early stages of psychotic disorders.
Hedgehog Overexpression Is Associated with Stromal Interactions and Predicts for Poor Outcome in Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2011
DOI: 10.1158/0008-5472.CAN-10-3738
Abstract: Hedgehog (Hh) signaling plays an important role in several malignancies but its clinical significance in breast cancer is unclear. In a cohort of 279 patients with invasive ductal carcinoma of the breast, expression of Hh ligand was significantly associated with increased risk of metastasis, breast cancer-specific death, and a basal-like phenotype. A paracrine signature, encompassing high epithelial Hh ligand and high stromal Gli1, was an independent predictor for overall survival in multivariate analysis. In 2 independent histological progression series (n = 301), Hh expression increased with atypia. Hh ligand overexpression in a mouse model of basal breast cancer increased growth, induced a poorly differentiated phenotype, accelerated metastasis, and reduced survival. A stromal requirement for these effects was supported by the lack of similar Hh-mediated changes in vitro, and by stromal-specific expression of Hh target genes in vivo. Furthermore, inhibition of Hh ligand with a monoclonal antibody (5E1) inhibited tumor growth and metastasis. These data suggest that epithelial–stromal Hh signaling, driven by ligand expression in carcinoma cells, promotes breast cancer growth and metastasis. Blockade of Hh signaling to peritumoral stromal cells may represent a novel therapeutic approach in some basal-like breast cancers. Cancer Res 71(11) 4002–14. ©2011 AACR.
Automated Analysis of Domestic Violence Police Reports to Explore Abuse Types and Victim Injuries: Text Mining Study (Preprint)
Publisher: JMIR Publications Inc.
Date: 11-12-2018
Abstract: he police attend numerous domestic violence events each year, recording details of these events as both structured (coded) data and unstructured free-text narratives. Abuse types (including physical, psychological, emotional, and financial) conducted by persons of interest (POIs) along with any injuries sustained by victims are typically recorded in long descriptive narratives. e aimed to determine if an automated text mining method could identify abuse types and any injuries sustained by domestic violence victims in narratives contained in a large police dataset from the New South Wales Police Force. e used a training set of 200 recorded domestic violence events to design a knowledge-driven approach based on syntactical patterns in the text and then applied this approach to a large set of police reports. esting our approach on an evaluation set of 100 domestic violence events provided precision values of 90.2% and 85.0% for abuse type and victim injuries, respectively. In a set of 492,393 domestic violence reports, we found 71.32% (351,178) of events with mentions of the abuse type(s) and more than one-third (177,117 events 35.97%) contained victim injuries. “Emotional/verbal abuse” (33.46% 117,488) was the most common abuse type, followed by “punching” (86,322 events 24.58%) and “property damage” (22.27% 78,203 events). “Bruising” was the most common form of injury sustained (51,455 events 29.03%), with “cut/abrasion” (28.93% 51,284 events) and “red marks/signs” (23.71% 42,038 events) ranking second and third, respectively. he results suggest that text mining can automatically extract information from police-recorded domestic violence events that can support further public health research into domestic violence, such as examining the relationship of abuse types with victim injuries and of gender and abuse types with risk escalation for victims of domestic violence. Potential also exists for this extracted information to be linked to information on the mental health status.
Exclusion of close linkage of bipolar disorder to the Gs-α subunit gene in nine Australian pedigrees
Publisher: Elsevier BV
Date: 11-1994
DOI: 10.1016/0165-0327(94)90017-5
Abstract: Growing evidence suggests that guanine nucleotide binding proteins (G proteins) may be involved in both the pathogenesis and treatment of bipolar affective disorder. Both overactive G proteins and increased levels of the alpha subunit of the stimulatory form (Gs-alpha) have been demonstrated in peripheral leucocytes of manic patients while an increase of Gs-alpha subunit levels has also been found in a postmortem study of bipolar disorder. The function of Gs and Gi alpha subunits has now been shown to be affected by lithium. The present study aimed to determine whether bipolar affective disorder was linked to the Gs-alpha subunit gene which has been mapped to chromosomal region 20q13.2. Linkage analysis utilized the PCR lification of a portion of the Gs-alpha gene that contains a dinucleotide repeat (CA repeat) polymorphism. Linkage of bipolar disorder and recurrent depression to the Gs-alpha subunit gene was tested using a series of autosomal dominant and recessive models with varying penetrance levels. Additionally, linkage was examined using a series of levels of definitions of affective illness. Close linkage to the Gs-alpha subunit gene was strongly excluded using each model and definition. Thus, our study indicates that a genetic defect in the Gs-alpha subunit gene is unlikely to be the cause of bipolar disorder.
Organisation of nodulation and nitrogen fixation genes on a Rhizobium trifolii symbiotic plasmid
Publisher: Springer Science and Business Media LLC
Date: 10-1984
DOI: 10.1007/BF00401991
Endogenous progesterone levels and frontotemporal dementia: modulation of TDP-43 and Tau levels in vitro and treatment of the A315T TARDBP mouse model
Publisher: The Company of Biologists
Date: 2013
DOI: 10.1242/DMM.011460
Abstract: Frontotemporal dementia (FTD) is associated with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). Together, this group of disorders constitutes a major cause of young-onset dementia. One of the three clinical variants of FTD is progressive nonfluent aphasia (PNFA), which is focused on in this study. The steroid hormone progesterone (PROG) is known to have an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum s les (39 FTD, 91 controls), low serum PROG was associated with FTD overall. In subgroup analysis, low PROG levels were significantly associated with FTD-MND and CBS, but not with PSP or PNFA. PROG levels of & pg/ml were significantly correlated with lower disease severity (frontotemporal dementia rating scale) for in iduals with CBS. In the human neuroblastoma SK-N-MC cell line, exogenous PROG (9300-93,000 pg/ml) had a significant effect on overall Tau and nuclear TDP-43 levels, reducing total Tau levels by ~1.5-fold and increasing nuclear TDP-43 by 1.7- to 2.0-fold. Finally, elevation of plasma PROG to a mean concentration of 5870 pg/ml in an Ala315Thr (A315T) TARDBP transgenic mouse model significantly reduced the rate of loss of locomotor control in PROG-treated, compared with placebo, mice. The PROG treatment did not significantly increase survival of the mice, which might be due to the limitation of the transgenic mouse to accurately model TDP-43-mediated neurodegeneration. Together, our clinical, cellular and animal data provide strong evidence that PROG could be a valid therapy for specific related disorders of FTD.
Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)
Publisher: Springer Science and Business Media LLC
Date: 02-2015
DOI: 10.1038/MP.2014.188
Abstract: General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts ( N =53 949) in which the participants had undertaken multiple, erse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P =3.93 × 10 −9 , MIR2113 rs17522122, P =2.55 × 10 −8 , AKAP6 rs10119, P =5.67 × 10 −9 , APOE/TOMM40 ). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 ( P =1 × 10 −6 ). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study ( N =6617) and the Health and Retirement Study ( N =5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort ( N =5487 P =1.5 × 10 −17 ). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40 , APOE , ABCG1 and MEF2C .
Use of murine mutants to study glycine receptor function
Publisher: Wiley
Date: 11-1999
DOI: 10.1046/J.1440-1681.1999.03148.X
Abstract: 1. The accompanying articles in this symposium describe several different approaches used to examine the function of glycine and GABA receptors, including pharmacology and neurochemistry, permeability and agonist-binding approaches, the use of mutated recombinant receptors and monoclonal antibody staining to examine receptor distribution on neurons. 2. The present review focuses on the use of another, quite different, approach: the use of murine mutants, spasmodic and spastic, to study the function of native glycine receptors at synaptic connections within the central nervous system.
Risk Factors for Mild Cognitive Impairment, Dementia and Mortality: The Sydney Memory and Ageing Study
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.JAMDA.2016.10.014
Abstract: The nature and commonality of late-life risk factors for mild cognitive impairment (MCI), dementia, and mortality remain unclear. Our aim was to investigate potential risk factors, simultaneously in a single cohort including many in iduals initially with normal cognition and followed for 6 years. We classified 873 community-dwelling in iduals (70-90 years old and without dementia at baseline) from the Sydney Memory and Ageing Study as cognitively normal (CN), having MCI or dementia, or deceased 6 years after baseline. Associations with baseline demographic, lifestyle, health, and medical factors were investigated, including apolipoprotein (APOE) genotype, MCI at baseline, and reversion from MCI to CN within 2 years of baseline. Eighty-three (9.5%) participants developed dementia and 114 (13%) died within 6 years nearly 33% had MCI at baseline, of whom 28% reverted to CN within 2 years. A core set of baseline factors was associated with MCI and dementia at 6 years, including older age (per year: odds ratios and 95% confidence intervals = 1.08, 1.01-1.14 for MCI 1.19, 1.09-1.31 for dementia), MCI at baseline (5.75, 3.49-9.49 8.23, 3.93-17.22), poorer smelling ability (per extra test point: 0.89, 0.79-1.02 0.80, 0.68-0.94), slower walking speed (per second: 1.12, 1.00-1.25 1.21, 1.05-1.39), and being an APOE ε4 carrier (1.84, 1.07-3.14 3.63, 1.68-7.82). All except APOE genotype were also associated with mortality (age: 1.11, 1.03-1.20 MCI: 3.87, 1.97-7.59 smelling ability: 0.83, 0.70-0.97 walking speed: 1.18, 1.03-1.34). Compared with stable CN participants, in iduals reverting from MCI to CN after 2 years were at greater risk of future MCI (3.06, 1.63-5.72). Those who reverted exhibited some different associations between baseline risk factors and 6-year outcomes than in iduals with stable MCI. A core group of late-life risk factors indicative of physical and mental frailty are associated with each of dementia, MCI, and mortality after 6 years. Tests for slower walking speed and poorer smelling ability may help screen for cognitive decline. In iduals with normal cognition are at greater risk of future cognitive impairment if they have a history of MCI.
In vivo somatic delivery of plasmid DNA and retrograde transport to obtain cell-specific gene expression in the central nervous system
Publisher: Wiley
Date: 16-08-2004
Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder
Publisher: Research Square Platform LLC
Date: 26-06-2023
DOI: 10.21203/RS.3.RS-3068352/V1
Abstract: The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi + Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p 1x10 − 4 values, including HAS3 , CNTNAP5 and NFIB . Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP’s age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4 , XKR4 , NRXN1 , NRG1/3 and GRK5 . Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.
Altered gene expression in mice treated with the mood stabilizer sodium valproate
Publisher: Oxford University Press (OUP)
Date: 28-06-2006
Association of SORL1 gene variants with hippocampal and cerebral atrophy and Alzheimer's disease.
Publisher: Bentham Science Publishers Ltd.
Date: 31-07-2014
DOI: 10.2174/1567205011666140618101408
Abstract: Sortilin-related receptor, Sorl1, is a neuronal receptor that interacts with the amyloid precursor protein to regulate amyloidogenesis. Variants in the gene encoding Sorl1 are associated with Alzheimer's disease (AD), as well as its neuroimaging markers. To investigate the relationship between SORL1 gene variants with ADrelated brain morphologies and AD, testing for sex-specific effects. The s le comprised 292 in iduals aged ≥ 75 years participating in the longitudinal Sydney Older Persons Study. A sub-s le also underwent a brain MRI scan (n=102, 53 males 49 females). The relationships of three SORL1 single nucleotide polymorphisms (SNPs): rs4935774, rs2298813, rs1133174 with brain MRI measures, and AD were determined. Significant associations of SORL1 variants with cross-sectional brain MRI measures and AD were observed only when the s le was stratified by sex. The most common haplotype (H1), comprising rs4935774-T, rs2298813-G, and rs1133174-G alleles (T/G/G) was associated with whole brain atrophy in both males and females (p=0.012 & p=0.013 respectively). Only SNP rs1133174 was in idually associated with hippoc al atrophy in males (p= 0.039) and females (p=0.025). Of the 292 participants, 111 had either probable or possible AD. A significant association of H1 with AD (p = 0.017) was observed in females. A nominally significant association of SNP rs1133174 with AD (p = 0.051) was also observed in the whole cohort. The results provide evidence that the association of polymophisms in the sortilin-related receptor gene (SORL1) with AD and its MRI biomarkers of brain and hippoc al atrophy are moderated by sex.
Genetic markers of cholesterol transport and gray matter diffusion: a preliminary study of the CETP I405V polymorphism
Publisher: Springer Science and Business Media LLC
Date: 08-08-2015
Automatic Extraction of Mental Health Disorders From Domestic Violence Police Narratives: Text Mining Study
Publisher: JMIR Publications Inc.
Date: 13-09-2018
DOI: 10.2196/11548
Phenotypic and genetic analysis of a wellbeing factor score in the UK Biobank and the impact of childhood maltreatment and psychiatric illness
Publisher: Springer Science and Business Media LLC
Date: 19-03-2022
DOI: 10.1038/S41398-022-01874-5
Abstract: Wellbeing is an important aspect of mental health that is moderately heritable. Specific wellbeing-related variants have been identified via GWAS meta-analysis of in idual questionnaire items. However, a multi-item within-subject index score has potential to capture greater heritability, enabling improved delineation of genetic and phenotypic relationships across traits and exposures that are not possible on aggregate-data. This research employed data from the UK Biobank resource, and a wellbeing index score was derived from indices of happiness and satisfaction with family/friendship/finances/health, using principal component analysis. GWAS was performed in Caucasian participants ( N = 129,237) using the derived wellbeing index, followed by polygenic profiling (independent s le N = 23,703). The wellbeing index, its subcomponents, and negative indicators of mental health were compared via phenotypic and genetic correlations, and relationships with psychiatric disorders examined. Lastly, the impact of childhood maltreatment on wellbeing was investigated. Five independent genome-wide significant loci for wellbeing were identified. The wellbeing index had SNP-heritability of ~8.6%, and stronger phenotypic and genetic correlations with its subcomponents (0.55–0.77) than mental health phenotypes (−0.21 to −0.39). The wellbeing score was lower in participants reporting various psychiatric disorders compared to the total s le. Childhood maltreatment exposure was also associated with reduced wellbeing, and a moderate genetic correlation ( r g = ~−0.56) suggests an overlap in heritability of maltreatment with wellbeing. Thus, wellbeing is negatively associated with both psychiatric disorders and childhood maltreatment. Although notable limitations, biases and assumptions are discussed, this within-cohort study aids the delineation of relationships between a quantitative wellbeing index and indices of mental health and early maltreatment.
A Susceptibility Locus for Bipolar Affective Disorder on Chromosome 4q35
Publisher: Elsevier BV
Date: 05-1998
DOI: 10.1086/301826
Expression of human thyrotropin in cell lines with different glycosylation patterns combined with mutagenesis of specific glycosylation sites: Characterization of a novel role for the oligosaccharides in the in vitro and in vivo bioactivity
Publisher: Elsevier BV
Date: 12-1995
Brain derived neurotrophic factor Val66Met polymorphism, the five factor model of personality and hippocampal volume: Implications for depressive illness
Publisher: Wiley
Date: 11-06-2009
DOI: 10.1002/HBM.20592
Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
Publisher: Springer Science and Business Media LLC
Date: 29-05-2018
DOI: 10.1038/S41467-018-04362-X
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486 age 16–102) and find 148 genome-wide significant independent loci ( P 5 × 10 −8 ) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent s les. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Attitudes towards childbearing, causal attributions for bipolar disorder and psychological distress: a study of families with multiple cases of bipolar disorder.
Publisher: Cambridge University Press (CUP)
Date: 31-05-2007
DOI: 10.1017/S0033291707000852
Abstract: For families with multiple cases of bipolar disorder this study explored: attitudes towards childbearing causal attributions for bipolar disorder, in particular the degree to which a genetic model is endorsed and its impact on the perceived stigma of bipolar disorder and predictors of psychological distress. Two hundred in iduals (95 unaffected and 105 affected with either bipolar disorder, schizo-affective disorder – manic type, or recurrent major disorder) were surveyed, using mailed, self-administered questionnaires. Thirty-five (35%) participants reported being ‘not at all willing to have children’ or ‘less willing to have children’ as a result of having a strong family history of bipolar disorder. Being not at all or less willing to have children was associated with perceived stigma of bipolar disorder [odds ratio (OR) 2·42, p =0·002], endorsement of a genetic model (OR 1·76, p =0·046), and being affected (OR 2·16, p =0·01). Among unaffected participants only, endorsement of a genetic model was strongly correlated with perceived stigma ( r s =0·30, p =0·004). Perceiving the family environment as an important factor in causing bipolar disorder was significantly associated with psychological distress (OR 1·58, p =0·043) among unaffected participants. Among affected participants, perceived stigma was significantly correlated with psychological distress (OR 2·44, p =0·02), controlling for severity of symptoms ( p ·001). Having a genetic explanation for bipolar disorder may exacerbate associative stigma among unaffected members from families with multiple cases of bipolar disorder, while it does not impact on perceived stigma among affected family members. Affected family members may benefit from interventions to ameliorate the adverse effects of perceived stigma.
A role for transcription factor GTF2IRD2 in executive function in Williams-Beuren syndrome.
Publisher: Public Library of Science (PLoS)
Date: 31-10-2012
Both of the β-subunit carbohydrate residues of follicle-stimulating hormone determine the metabolic clearance rate and in vivo potency
Publisher: The Endocrine Society
Date: 06-1995
DOI: 10.1210/ENDO.136.6.7750487
Abstract: FSH is a glycoprotein hormone required for the development and maturation of the ovarian follicle and for spermatogenesis. FSH is glycosylated at asparagine residues 52 and 78 on the alpha-subunit and residues 7 and 24 on the beta-subunit. In vitro, the carbohydrate residue at position alpha 52 is required for signal transduction. To define the contribution of the carbohydrate residues to FSH potency in vivo, we assessed the MCR and in vivo bioactivity of site-specifically deglycosylated recombinant human FSH variants. The removal of the beta-subunit carbohydrate residues significantly (P < 0.05) affected the MCR and resulted in significantly (P < 0.05) reduced in vivo bioactivity. For all recombinant human FSH variants, a strong correlation (r = 0.90 P < 0.01) was observed between MCR and in vivo potency, indicating that the circulatory half-life of the hormone appears to be the primary determinant of in vivo bioactivity. Although the beta-subunit carbohydrate residues have the greatest effect in determining FSH potency in vivo the alpha 52 residue, important in vitro, has no effect on either MCR or in vivo potency. This study highlights the difficulties of translating in vitro results to whole animal physiology.
Alzheimer's disease with spastic paraparesis and 'cotton wool' plaques: two pedigrees with PS-1 exon 9 deletions.
Publisher: Oxford University Press (OUP)
Date: 04-2003
DOI: 10.1093/BRAIN/AWG084
Abstract: Several pedigrees have recently been reported in which dominantly inherited familial Alzheimer's disease is associated in some family members with spastic paraparesis and non-neuritic 'cotton wool' plaques. Here we report clinical, genetic and neuropathological findings in two further large pedigrees in which this combination of phenotypes is associated with a deletion of exon 9 of the presenilin-1 (PS-1) gene caused by mutations at the splice acceptor site. In both pedigrees, in iduals with paraparesis at presentation had a later than average age at onset of symptoms. In addition, one subject with paraparesis had a much less prominent dementia syndrome than his dementia-affected siblings. As PS-1 mutations are almost always associated with a particularly aggressive form of presenile dementia, these findings suggest the existence of a protective or delaying factor in in iduals with spastic paraparesis.
Disturbances in selective information processing associated with the BDNF Val66Met polymorphism: Evidence from cognition, the P300 and fronto-hippocampal systems
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.BIOPSYCHO.2008.09.001
Abstract: In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated with selective disruptions to task-relevant information processing. In 475 non-clinical participants for whom BDNF genotype status was determined we used the 'IntegNeuro' computerized battery of neuropsychological tests to assess cognitive performance, an auditory oddball task to elicit the P300 event-related potential (ERP) and, in smaller subsets of these subjects, high resolution structural MRI imaging to quantify fronto-hippoc al grey matter (n=161), and functional magnetic resonance imaging to assess fronto-hippoc al BOLD activation (n=37). Met/Met (MM) homozygotes had higher verbal recall errors, in the absence of differences in attention, executive function, verbal ability or sensori-motor function. Further, MM homozygotes demonstrated a slowed P300 ERP during the oddball task, with corresponding alterations in hippoc al and lateral prefrontal activation, and a localized reduction in hippoc al grey matter. These results are consistent with a subtle impact of the Met allele on fronto-hippoc al systems involved in selective information processing of stimulus context and memory updating within the normal population. The findings also indicate that heritable endophenotypes such as the P300 have value in elucidating genotype-phenotype relationships.
Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1086/376547
Abstract: Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for s le size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.
Vanadium oxide supported on non-stoichiometric strontium hydroxyapatite catalysts for the oxidative dehydrogenation of n-octane
Publisher: Elsevier BV
Date: 12-2014
Bovine hyperekplexia
Publisher: Elsevier
Date: 2005
GLYCINE RECEPTORS: WHAT GETS IN AND WHY?
Publisher: Wiley
Date: 04-11-1999
DOI: 10.1046/J.1440-1681.1999.03149.X
Abstract: 1. The glycine receptor channel (GlyR), a member of the ligand-gated ion channel superfamily, shares many similar permeation properties with the GABAA receptor channel. 2. The GlyR is anion permeable, with PK/PCl < 0.05, has a 5-6 A minimum pore diameter and a permeation selectivity sequence dominated by hydration energies. 3. The channels, which display multiple subconductance states, can be multiply occupied. 4. Two positive arginine rings at the ends of the pore region may contribute to the anion selectivity of the GlyR. 5. Mutation of the extracellular charged arginine ring can impair channel function by decreasing the sensitivity of glycine activation, reducing channel conductance, shifting the normal multi-subconductance states to lower values and by decoupling the link between ligand binding and channel gating. 6. These and other site-directed mutagenesis studies of recombinant GlyR, together with studies of native GlyR, are providing further insights into what controls gating and ion permeation and selectivity through this channel.
Vulnerability of white matter tracts and cognition to the SOD2 polymorphism: A preliminary study of antioxidant defense genes in brain aging
Publisher: Elsevier BV
Date: 06-2017
Carrier-bound odorant delivery to olfactory receptors
Publisher: Elsevier BV
Date: 1988
Investigating Olfactory Gene Variation and Odour Identification in Older Adults
Publisher: MDPI AG
Date: 29-04-2021
Abstract: Ageing is associated with a decrease in odour identification. Additionally, deficits in olfaction have been linked to age-related disease and mortality. Heritability studies suggest genetic variation contributes to olfactory identification. The olfactory receptor (OR) gene family is the largest in the human genome and responsible for overall odour identification. In this study, we sought to find olfactory gene family variants associated with in idual and overall odour identification and to examine the relationships between polygenic risk scores (PRS) for olfactory-related phenotypes and olfaction. Participants were Caucasian older adults from the Sydney Memory and Ageing Study and the Older Australian Twins Study with genome-wide genotyping data (n = 1395, mean age = 75.52 ± 6.45). The Brief-Smell Identification Test (BSIT) was administered in both cohorts. PRS were calculated from independent GWAS summary statistics for Alzheimer’s disease (AD), white matter hyperintensities (WMH), Parkinson’s disease (PD), hippoc al volume and smoking. Associations with olfactory receptor genes (n = 967), previously identified candidate olfaction-related SNPs (n = 36) and different PRS with BSIT scores (total and in idual smells) were examined. All of the relationships were analysed using generalised linear mixed models (GLMM), adjusted for age and sex. Genes with suggestive evidence for odour identification were found for 8 of the 12 BSIT items. Thirteen out of 36 candidate SNPs previously identified from the literature were suggestively associated with several in idual BSIT items but not total score. PRS for smoking, WMH and PD were negatively associated with chocolate identification. This is the first study to conduct genetic analyses with in idual odorant identification, which found suggestive olfactory-related genes and genetic variants for multiple in idual BSIT odours. Replication in independent and larger cohorts is needed.
Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia
Publisher: Oxford University Press (OUP)
Date: 04-2003
DOI: 10.1093/BRAIN/AWG090
Abstract: The majority of cases with frontotemporal dementia (FTD) have no tau deposition in the brain, yet mutations in the tau gene lead to a similar clinical phenotype with insoluble tau depositing in neuropathological lesions. We report two tau gene mutations at positions +19 and +29, in the intronic sequences immediately following the stem loop structure in exon 10, which segregate with FTD. Exon-trapping experiments showed that these gene mutations alter the splicing out of exon 10 and produce an increase in tau isoforms with three microtubule binding domains (three repeat tau). Mutagenesis experiments demonstrated that the +19 mutation was responsible for the increase in three repeat tau, possibly by altering an intron silencer modulator sequence element found at this region of the gene. Microtubule binding experiments revealed a significant decrease in microtubule assembly with increasing amounts of three and decreasing amounts of four repeat tau. Brain autopsy was available in one case. Analysis of the type of soluble tau isoforms revealed an increase in three repeat tau and an absence of tau isoforms with exon 3 inserts. No insoluble tau was isolated in the tissue fractions, consistent with the absence of tau-positive histopathology. There was also an increase in tau degradation products suggestive of increased proteolysis. This increase in tau breakdown products was associated with TUNEL- and activated caspase-3-positive neurons identified histologically. These studies show that increases in soluble three repeat tau can be responsible for FTD in cases with tau gene mutations in the intronic region immediately adjacent to the stem loop in exon 10. These cases of FTD have tau isoforms (without exon 3 inserts) that do not form abnormal aggregates and appear more prone to proteolysis. The increase in tau proteolysis was associated with increased evidence of apoptosis. This mechanism of neurodegeneration may be more applicable to the majority of FTD cases, which do not accumulate insoluble tau deposits.
Longitudinal clinical, cognitive, and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease.
Publisher: Oxford University Press (OUP)
Date: 18-10-2023
The Roles and Responsibilities of Community Pharmacists Supporting Older People with Palliative Care Needs: A Rapid Review of the Literature
Publisher: MDPI AG
Date: 12-08-2020
Abstract: Globally, the number of older people requiring appropriate and safe management of medicines is growing. This review aimed to identify the roles and responsibilities of pharmacists supporting older people living in a community setting with their palliative care needs and to synthesise key themes emerging from the data, as well as any gaps in knowledge. The literature search included Medline (Ovid), Scopus, and Cinahl (Ebsco) databases. An English language limit was applied. The search included all international articles and any date of publication. Data were synthesised utilizing a systematic text condensation technique and presented according to Theme, Domain, and Meaning Units. Fourteen studies met the inclusion criteria. Selected papers predominantly focused on care provided by the pharmacists supporting people receiving residential aged care services. Clinical review, supply of medicines, and clinical governance were identified as key pharmacist roles. Pharmacists’ communication skills, personal behavioural approach, and positive attitude emerged as supportive characteristics for effective person-centered care. Minimal, or no information, were available related to pharmacists located in general medical practices and in Aboriginal health services sector, respectively. The multifaceted role of pharmacists presents an opportunity to provide comprehensive health care for older populations at the end of their life.
Quantitative measurement of cerebral haemodynamics in early vascular dementia and Alzheimer’s disease
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.JOCN.2005.04.017
Abstract: Alzheimer's disease (AD) and vascular dementia (VaD) both share significant vascular risk factors. The present study measures the haemodynamics of these diseases in absolute rather than relative terms. Twenty-four patients were classified as either early AD or VaD and were compared with 12 non-cognitively impaired subjects. Magnetic resonance imaging flow quantification was used to measure arterial inflow and arterial pulse volume. Mean vascular resistance and compliance were calculated. In AD, the arterial inflow was lower by 18%, resistance was higher by 23% and compliance of the arterial tree was lower by 20% compared with normal (p=0.01, 0.02 and 0.05, respectively). In VaD, the arterial pulse volume was higher by 24% and compliance was higher by 35% compared with normal (p=0.05 for both). Early VaD is characterized by normal blood flow, but increased pulsation. Reduced blood flow and an incompliant arterial tree characterize early AD.
Sex differences in the shared genetics of dimensions of self-reported depression and anxiety
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.JAD.2015.08.053
Abstract: The prevalence of depression and anxiety symptoms and their comorbidity varies between males and females for reasons still unknown. This study aims to test whether differences between males and females in self-reported symptoms and their covariation are caused by variations in the magnitude of genetic and environmental factors. 750 monozygotic and dizygotic healthy twin pairs (18-60 years M=39.77 years) participated in the TWIN-E project. Univariate and multivariate genetic modelling was undertaken using the Depression Anxiety Stress Scale (DASS-42). Additive genetics and unique environment contributed to self-reported depression (heritability, h(2): 34%), anxiety (h(2): 30%) and stress (h(2): 34%) scores in univariate models, and to the common latent factor (h(2): 39%) in the multivariate model. No sex differences in magnitude of estimates for DASS-42 scores were found in the univariate model. However when considering correlated depression and anxiety symptomatology only shared genetic factors between depression and anxiety contributed to depression scores in males, but both specific and shared genetic factors contributed to depression scores in females. The results are limited to the s le of healthy, community, adult, same sex twin pairs who participated in the study. Differences in males and females in genetic aetiology of self-reported dimensions of depression are only apparent when taking into consideration the covariation with self-reported anxiety. This difference is highlighted by the finding that both common and specific genetic factors contribute to self-reported depression in females but not males. This novel finding may help explain the increased incidence of depression symptoms in females.
The glycine receptor
Publisher: Elsevier BV
Date: 1997
DOI: 10.1016/S0163-7258(96)00163-5
Abstract: The inhibitory glycine receptor (GlyR) is a member of the ligand-gated ion channel receptor superfamily. The GlyR comprises a pentameric complex that forms a chloride-selective transmembrane channel, which is predominantly expressed in the spinal cord and brain stem. We review the pharmacological and physiological properties of the GlyR and relate this information to more recent insights that have been obtained through the cloning and recombinant expression of the GlyR subunits. We also discuss insights into our understanding of GlyR structure and function that have been obtained by the genetic characterisation of various heritable disorders of glycinergic neurotransmission.
Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder
Publisher: Oxford University Press (OUP)
Date: 21-06-2016
DOI: 10.1093/HMG/DDW181
Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease
Publisher: Massachusetts Medical Society
Date: 30-08-2012
Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology
Publisher: Springer Science and Business Media LLC
Date: 04-1989
DOI: 10.1038/338582A0
Abstract: Neurotransmission effected by GABA (gamma-aminobutyric acid) is predominantly mediated by a gated chloride channel intrinsic to the GABAA receptor. This heterooligomeric receptor exists in most inhibitory synapses in the vertebrate central nervous system (CNS) and can be regulated by clinically important compounds such as benzodiazepines and barbiturates. The primary structures of GABAA receptor alpha- and beta-subunits have been deduced from cloned complementary DNAs. Co-expression of these subunits in heterologous systems generates receptors which display much of the pharmacology of their neural counterparts, including potentiation by barbiturates. Conspicuously, however, they lack binding sites for, and consistent electrophysiological responses to, benzodiazepines. We now report the isolation of a cloned cDNA encoding a new GABAA receptor subunit, termed gamma 2, which shares approximately 40% sequence identity with alpha- and beta-subunits and whose messenger RNA is prominently localized in neuronal subpopulations throughout the CNS. Importantly, coexpression of the gamma 2 subunit with alpha 1 and beta 1 subunits produces GABAA receptors displaying high-affinity binding for central benzodiazepine receptor ligands.
Association between the serotonin 2A receptor gene and bipolar affective disorder in an Australian cohort
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2009
The heritability of mental health and wellbeing defined using COMPAS-W, a new composite measure of wellbeing
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.PSYCHRES.2014.04.033
Abstract: Mental health is not simply the absence of mental illness rather it is a distinct entity representing wellness. Models of wellbeing have been proposed that emphasize components of subjective wellbeing, psychological wellbeing, or a combination of both. A new 26-item scale of wellbeing (COMPAS-W) was developed in a cohort of 1669 healthy adult twins (18-61 years). The scale was derived using factor analysis of multiple scales of complementary constructs and confirmed using tests of reliability and convergent validity. Bivariate genetic modeling confirmed its heritability. From an original 89 items we identified six independent subcomponents that contributed to wellbeing. The COMPAS-W scale and its subcomponents showed construct validity against psychological and physical health behaviors, high internal consistency (average r=0.71, Wellbeing r=0.84), and 12-month test-retest reliability (average r=0.62, Wellbeing r=0.82). There was a moderate contribution of genetics to total Wellbeing (heritability h(2)=48%) and its subcomponents: Composure (h(2)=24%), Own-worth (h(2)=42%), Mastery (h(2)=40%), Positivity (h(2)=42%), Achievement (h(2)=32%) and Satisfaction (h(2)=43%). Multivariate genetic modeling indicated genetic variance was correlated across the scales, suggesting common genetic factors contributed to Wellbeing and its subcomponents. The COMPAS-W scale provides a validated indicator of wellbeing and offers a new tool to quantify mental health.
CXCR4 involvement in neurodegenerative diseases
Publisher: Springer Science and Business Media LLC
Date: 11-04-2018
DOI: 10.1038/S41398-017-0049-7
Abstract: Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12 , TLR2, RALB, and CCR5 . Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT , we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.
Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group
Publisher: Springer Science and Business Media LLC
Date: 02-05-2017
DOI: 10.1038/MP.2017.73
Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume
Publisher: Springer Science and Business Media LLC
Date: 26-09-2018
DOI: 10.1038/S41467-018-06234-W
Abstract: The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly in iduals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes ( ρ genetic = −0.59, p -value = 3.14 × 10 −6 ), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.
Association between serotonin transporter promoter polymorphisms and psychological distress in a diabetic population
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.PSYCHRES.2012.07.008
Abstract: Investigations into serotonin transporter and anxiety and depression have shown an association between stress, depression onset and genotype. We investigated the relationship between 5-HTTLPR genotype and depression and anxiety in a population with diabetes mellitus, a condition associated with high rates of stress and depression. Participants were classified according to 'S' and 'L' alleles as well as the modification of the single nucleotide polymorphism (SNP) rs25531. The 5-HTTLPR low-expression genotype group (S or L(G) allele carriers) had significantly higher psychological distress (K10) scores (N=234, P=0.047). Subsequent analysis revealed that the effect of genotype was related to anxiety symptoms rather than depression symptoms. Furthermore, the main effect of genotype was not observed when the modification of the SNP polymorphism was not taken into account. Findings suggest that 5-HTTLPR/rs25531 genotype is associated with psychological distress in a s le of subjects with diabetes.
Common genetic variants influence human subcortical brain structures
Publisher: Springer Science and Business Media LLC
Date: 21-01-2015
DOI: 10.1038/NATURE14101
Similar early clinical presentations in familial and non-familial frontotemporal dementia.
Publisher: BMJ
Date: 12-2004
A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer's disease
Publisher: Elsevier BV
Date: 10-1995
DOI: 10.1016/0304-3940(95)12046-7
Abstract: DNA from the probands of seven Australian families with hereditary Alzheimer's disease was screened for the presence of known mutations in the amyloid precursor protein (APP) gene on chromosome 21 using single stranded conformational polymorphism (SSCP) analysis [14]. One subject was found to have a mutation causing a Val-->Ile substitution at position 717. This was confirmed by restriction enzyme digestion and sequencing. The mutation has been found in both the other affected family members available for study and in two at-risk relatives. It was not present in the only living unaffected relative who has passed the usual age of onset in this family. There is so far no evidence that apolipoprotein E (APOE) genotype influences age of onset in this family, though numbers are small. Two other families with autopsy confirmation and age of onset in the fifth decade had no APP mutation and are thought likely to have a mutation on chromosome 14 on the basis of their earlier onset age.
Molecular cloning and amino acid sequence of human enkephalinase (neutral endopeptidase)
Publisher: Wiley
Date: 29-02-1988
DOI: 10.1016/0014-5793(88)80828-7
Abstract: We have isolated a cDNA clone encoding human enkephalinase (neutral endopeptidase, EC 3.4.24.11) in a lambda gt10 library from human placenta, and present the complete 742 amino acid sequence of human enkephalinase. The human enzyme displays a high homology with rat and rabbit enkephalinase. Like the rat and rabbit enzyme, human enkephalinase contains a single N-terminal transmembrane region and is likely to be inserted through cell membranes with the majority of protein, including its carboxy-terminus, located extracellularly.
Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study
Publisher: Research Square Platform LLC
Date: 03-10-2023
Shared versus distinct genetic contributions of mental wellbeing with depression and anxiety symptoms in healthy twins
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.PSYCHRES.2016.07.016
Abstract: Mental wellbeing and mental illness symptoms are typically conceptualized as opposite ends of a continuum, despite only sharing about a quarter in common variance. We investigated the normative variation in measures of wellbeing and of depression and anxiety in 1486 twins who did not meet clinical criteria for an overt diagnosis. We quantified the shared versus distinct genetic and environmental variance between wellbeing and depression and anxiety symptoms. The majority of participants (93%) reported levels of depression and anxiety symptoms within the healthy range, yet only 23% reported a wellbeing score within the "flourishing" range: the remainder were within the ranges of "moderate" (67%) or "languishing" (10%). In twin models, measures of wellbeing and of depression and anxiety shared 50.09% of variance due to genetic factors and 18.27% due to environmental factors the rest of the variance was due to unique variation impacting wellbeing or depression and anxiety symptoms. These findings suggest that an absence of clinically-significant symptoms of depression and anxiety does not necessarily indicate that an in idual is flourishing. Both unique and shared genetic and environmental factors may determine why some in iduals flourish in the absence of symptoms while others do not.
The role of receptor subtype diversity in the CNS
Publisher: Elsevier BV
Date: 1990
DOI: 10.1016/0166-2236(90)90052-C
Abstract: The molecular characterization of neuroreceptors and voltage-gated ion channels has revealed that receptor subtype heterogeneity is a common feature of chemical and electrical signal reception. The use of distinct genes encoding receptor subtypes is a favoured mechanism for generation of this ersity. We propose that the significance of the multiplicity and ersity of signal reception proteins is to increase the information-handling capacity of neurons. This may contribute to neural plasticity.
Preferential degradation of cognitive networks differentiates Alzheimer’s disease from ageing
Publisher: Oxford University Press (OUP)
Date: 07-03-2018
DOI: 10.1093/BRAIN/AWY053
Expression of enzymatically active enkephalinase (neutral endopeptidase) in mammalian cells
Publisher: Wiley
Date: 03-1989
Abstract: A cDNA encoding the rat enkephalinase protein (neutral endopeptidase EC 3.4.24.11) has been constructed from overlapping lambda gt10 cDNA clones. This cDNA was inserted into an expression plasmid containing the cytomegalovirus enhancer and promoter. When transfected with this plasmid, Cos 7 cells transiently expressed the enkephalinase protein in a membrane-bound state. Recombinant enkephalinase recovered in solubilized extracts from transfected Cos 7 cells was enzymatically active and displayed properties similar to those of the native enzyme with respect to sensitivity to classical enkephalinase inhibitors.
Implications of the use of genetic tests in psychiatry, with a focus on major depressive disorder: A review
Publisher: Hindawi Limited
Date: 14-09-2013
DOI: 10.1002/DA.22000
Abstract: Advances in technology have enabled research to link many genetic markers to specific disease risk. This has led to the commercialization of genetic tests across a wide range of medical disorders. Public interest in one's own future health and an increasing desire for autonomy over one's health care have facilitated a large and growing market for such genetic tests to be sold direct to the consumer (DTC). Amidst a plethora of tests for a broad range of medical conditions, DTC genetic tests currently include a number of tests related to risk for various psychiatric illnesses including major depressive disorder (MDD), bipolar disorder, schizophrenia, and obsessive-compulsive disorder and also for prediction of in idual response to psychotropic medication. Although a large number of studies show that there is strong public interest in genetic susceptibility testing for psychiatric disorders, little is known about the impact on in iduals of receiving the results of genetic tests. Moreover, the low predictive power and uncertain clinical validity and utility of DTC genetic tests for psychiatric disorders have led to both controversy and difficulties of interpretation of results. This review summarizes the rationale for using genetic risk tests in psychiatry, as an intervention for protective cognitive and behavioral change, and to predict medication response, with a focus on MDD. Since genetic risk information has the potential to influence major life-changing health decisions, there is an imperative to ensure that there is an appropriate evidence base to support the use of such genetic tests.
Role of Charged Residues in Coupling Ligand Binding and Channel Activation in the Extracellular Domain of the Glycine Receptor
Publisher: Elsevier BV
Date: 12-2003
'Negativity bias' in risk for depression and anxiety: Brain-body fear circuitry correlates, 5-HTT-LPR and early life stress
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.NEUROIMAGE.2009.05.009
Abstract: The INTEGRATE Model draws on the framework of 'integrative neuroscience' to bring together brain-body and behavioral concepts of emotion, thinking and feeling and their regulation. The key organizing principle is the drive to 'minimize danger and maximize reward' that determines what is significant to us at each point in time. Traits of 'negativity bias' reflect the tendency to perceive danger rather than reward related information, and this bias influences emotion, thinking and feeling processes. Here, we examined a self-report measure of Negativity Bias in relation to its impact on brain and body correlates of emotion processing. The contributions of the serotonin transporter (5-HTT-LPR) allelic variants and early life stress to both negativity bias and these correlates were also examined. Data were accessed in collaboration with the Brain Resource International Database (BRID) which provides standardized data across these domains of measurement. From an initial s le of 303 nonclinical subjects from the BRID, subjects scoring one standard deviation below (n=55) and above (n=47) the mean on the measure of negativity bias were identified as 'Negativity Bias' and 'Positivity Bias' groups for analysis, respectively. These subjects had been genotyped for 5-HTT-LPR Short allele versus LL homozygote status, and completed the early life stress scale, and recording of startle responses and heart rate for conscious and nonconscious fear conditions. A matched subset (n=39) of BRID subjects completed functional MRI with the same facial emotion tasks. The Negativity Bias (compared to Positivity Bias) group was distinguished by both arousal and brain function correlates: higher startle litude, higher heart rate for conscious and nonconscious fear conditions, and heightened activation in neural circuitry for both fear conditions. Regions of heightened activation included brainstem and bilateral amygdala, anterior cingulate and ventral and dorsal medial prefrontal cortex (mPFC) for conscious fear, and brainstem and right-sided amygdala, anterior cingulate and ventral, mPFC for nonconscious fear. The 5-HTT-LPR Short allele (versus LL) conferred a similar pattern of arousal and neural activation. For those with the 5-HTT-LPR Short allele, the addition of early life stress contributed to enhanced negativity bias, and to further effects on heart rate and neural activation for nonconscious fear in particular. These findings suggest that traits of negativity bias impact brain-body arousal correlates of fear circuitry. Both genetic variation and life stressors contribute to the impact of negativity bias. Given that negativity bias is a feature of conditions such as depression and associated biological alterations, the findings have implications for translation into clinical decision support.
Portrayal of psychiatric genetics in Australian print news media, 1996-2009
Publisher: AMPCo
Date: 10-2011
DOI: 10.5694/MJA10.10167
Abstract: To investigate how Australian print news media portray psychiatric genetics. Content and framing analysis of a structured s le of print news items about psychiatric genetics published in Australian newspapers between 1996 and 2009. Identify dominant discourses about aetiology of mental illness, and perceived clinical outcomes and implications of psychiatric genetics research. We analysed 406 eligible items about the genetics of psychiatric disorders. News coverage of psychiatric genetics has steadily increased since 1996. Items attributing the aetiology of psychiatric disorders to gene-environment interactions (51%) outnumbered items attributing only genetic (30%) or only environmental factors (20%). Of items that referred to heritability of mental illness, frames of genetic determinism (78%) occurred more frequently than probabilistic frames (22%). Of frames related to genetic prophesy, genetic optimism frames (78%) were used more frequently than frames of genetic pessimism (22%). Psychosocial and ethical implications of psychiatric genetics received comparatively relatively little coverage (23%). The analysis identified 22 predictions about psychiatric genetic discoveries and the availability of molecular-based interventions in psychiatry, most of which (20/22, 91%) failed to manifest by the predicted year. Excessive optimism about the power of genetic technology in psychiatric health care, perceived clinical benefits, and largely unfulfilled predictions about availability of these benefits could encourage unrealistic expectations about future molecular-based treatment options for mental health.
Starch swelling power and amylose content of triticale and Triticum timopheevii germplasm
Publisher: Elsevier BV
Date: 05-2009
Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease
Publisher: Cold Spring Harbor Laboratory
Date: 22-03-2023
DOI: 10.1101/2023.03.21.23287468
Abstract: Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying erse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aβ, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. - Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions. - The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD. - Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.
Positional effects of presenilin-1 mutations on tau phosphorylation in cortical plaques
Publisher: Elsevier BV
Date: 02-2004
DOI: 10.1016/J.NBD.2003.10.008
Abstract: Mutations in presenilin-1 (PS-1) account for the majority of familial Alzheimer's disease (AD). While increasing Abeta42 is one mechanism whereby PS-1 mutations are thought to exert their pathogenic effect, little is known about the role of tau in PS-1 AD. This study compares staining (AT8 and tau-2), morphology and quantity of tau-immunoreactive cortical plaques in six PS-1 and five sporadic AD cases. The densities of tau-positive plaques differentiated PS-1 from sporadic AD cases. All PS-1 cases demonstrated a greater than 6-fold increase in tau-2-positive plaques. In PS-1 cases with mutations in exons 5 and 6, there was an increase in classical AD plaques containing hyperphosphorylated tau (AT8- and tau 2-positive). However, cases with exon 8 and 9 mutations had numerous cotton wool plaques containing nonhyperphosphorylated tau (tau-2-positive, AT8-negative). These findings suggest that PS-1 mutations increase tau deposition while mutation-specific cellular responses determine phosphorylation events and may influence cell death mechanisms.
Novel genetic loci associated with hippocampal volume
Publisher: Springer Science and Business Media LLC
Date: 18-01-2017
DOI: 10.1038/NCOMMS13624
Abstract: The hippoc al formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippoc al volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippoc al structure here we perform a genome-wide association study (GWAS) of 33,536 in iduals and discover six independent loci significantly associated with hippoc al volume, four of them novel. Of the novel loci, three lie within genes ( ASTN2 , DPP4 and MAST4 ) and one is found 200 kb upstream of SHH . A hippoc al subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippoc al volume are also associated with increased risk for Alzheimer’s disease ( r g =−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippoc al volume and risk for neuropsychiatric illness.
Intelligence, educational attainment, and brain structure in those at familial high‐risk for schizophrenia or bipolar disorder
Publisher: Wiley
Date: 07-10-2020
DOI: 10.1002/HBM.25206
Abstract: First‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show ergent patterns on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD‐FDRs are inconsistent. Here, we performed a meta‐analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 in iduals (1,103 SZ‐FDRs, 867 BD‐FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ‐FDRs showed a pattern of widespread thinner cortex, while BD‐FDRs had widespread larger cortical surface area. IQ was lower in SZ‐FDRs ( d = −0.42, p = 3 × 10 −5 ), with weak evidence of IQ reductions among BD‐FDRs ( d = −0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group‐effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ‐FDRs and more pronounced effects in BD‐FDRs. To conclude, SZ‐FDRs and BD‐FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ‐FDRs and BD‐FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Early Life Stress Combined with Serotonin 3A Receptor and Brain-Derived Neurotrophic Factor Valine 66 to Methionine Genotypes Impacts Emotional Brain and Arousal Correlates of Risk for Depression
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.BIOPSYCH.2010.06.025
Abstract: Depression will be the second largest burden of disease by 2020. Developing new tools for identifying risk and ultimately prevention of depression relies on elucidating the integrative relationships between susceptibility markers from gene-stress interactions and how they impact emotional brain and arousal systems. They have largely been studied in isolation. We examined how genetic (brain-derived neurotrophic factor [BDNF] valine 66 to methionine [Val66Met] and serotonin receptor gene 3A [HTR3A]) and early life stress susceptibility factors interact in predicting electroencephalogram (EEG) asymmetry, emotion-elicited heart rate, and self-reported negativity bias, each correlates of risk for depression. Caucasian volunteers (n = 363) were derived from the Brain Resource International Database, via the Brain Research And Integrative Neuroscience Network. In iduals with both BDNF methionine and HTR3A CC risk genotypes and early life stressors demonstrated a profile of elevated emotion-elicited heart rate and right frontal hyper-activation with right parietotemporal hypoactivation in EEG asymmetry. Elevations in heart rate were a moderator of negativity bias. The findings provide new evidence that these gene-stress susceptibility factors contribute to a brain-arousal profile indicative of risk for depression. They are a step toward identifying biological markers for detecting risk before overt symptoms. It would be valuable for future studies to examine comorbidity and specificity issues for instance, whether these gene-stress factors contribute in different ways to the partially distinct EEG asymmetry profiles found with anxiety.
Genetics, an alternative way to discover, characterize and understand ion channels
Publisher: Wiley
Date: 2001
DOI: 10.1046/J.1440-1681.2001.03409.X
Abstract: 1. The conventional approach to understanding the structure and properties of ion channels has been to use physiological characterization. 2. Purification and molecular cloning of ion channel genes has enabled more detailed structure–function analyses to be undertaken. 3. An alternative approach to the identification of genes of pathophysiological importance has been the use of genetic linkage approaches and positional cloning or positional candidate analysis of ion channel genes. 4. Using genetic approaches, mutations have been described that cause inherited neurological disorders of neurons (e.g. epilepsy, migraine, deafness, ataxia and startle disease), skeletal muscle (myotonia, malignant hyperthermia, periodic paralysis and myasthenia) and cardiac muscle (long QT syndrome and ventricular fibrillation). 5. For each disease, gene structure–function analyses of the mutant alleles have provided further insights into the biology of ion channels. 6. The present brief review examines the methods used in genetic linkage studies and positional cloning of disease genes. Understanding how ion channel gene mutations give rise to dysfunctional channels will be important in defining and treating the episodic and chronic channelopathies.
C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementia patients.
Publisher: Public Library of Science (PLoS)
Date: 20-02-2013
Correction: Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
Publisher: Springer Science and Business Media LLC
Date: 11-07-2022
Molecular cloning and amino acid sequence of rat enkephalinase
Publisher: Elsevier BV
Date: 04-1987
DOI: 10.1016/S0006-291X(87)80475-8
Abstract: cDNA clones encoding rat enkephalinase (neutral endopeptidase, EC 3.4.24.11) have been isolated in lambda gt10 libraries from both brain and kidney mRNAs and the complete 742 amino acid sequence of rat enkephalinase is presented. The enzyme possesses a single transmembrane spanning domain near the N-terminal of the molecule but lacks a signal sequence. Because enkephalinase has it active site located extracellularly and is thus an ectopeptidase, we suggest that the N-terminal transmembrane region of the enzyme anchors the protein in membranes and that the majority of the protein, including the carboxy terminus, is extracellular. Enkephalinase, a zinc-containing metallo enzyme, displays homology with other zinc metallo enzymes such as carboxypeptidase A, B and E, suggesting enzymatic similarities in these enzymes.
Investigating the Genetics of Hippocampal Volume in Older Adults without Dementia
Publisher: Public Library of Science (PLoS)
Date: 27-01-2015
Thermodynamics of full agonist, partial agonist, and antagonist binding to wild-type and mutant adenosine A1 receptors
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0006-2952(98)00202-0
Abstract: A thermodynamic analysis of the binding of a full agonist (N6-cyclopentyladenosine), a partial agonist (8-butylamino-N6-cyclopentyladenosine) and an antagonist (8-cyclopentyltheophylline) to human wild-type and mutant (mutation of a threonine (Thr) to an alanine (Ala) residue at position 277) adenosine A1 receptors expressed on Chinese hamster ovary (CHO) cells, and to rat brain adenosine A1 receptors was undertaken. The thermodynamic parameters deltaGo (standard free energy), deltaHo (standard enthalpy) and deltaSo (standard entropy) of the binding equilibrium to rat brain receptors were determined by means of affinity measurements carried out at four different temperatures (0, 10, 20 and 25 degrees) and van't Hoff plots. Two temperatures (0 and 25 degrees) were considered for human receptors. Affinity constants were obtained from inhibition assays on membrane preparations of rat brain and CHO cells by use of the antagonist [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) as selective adenosine A1 receptor radioligand. As for rat brain receptors, full agonist binding was totally entropy driven, whereas antagonist binding was essentially enthalpy driven. Partial agonist binding appeared both enthalpy and entropy driven. As for human receptors, full agonist affinity was highly dependent on the presence of Thr277. Moreover, affinity to both wild-type and mutant receptors was enhanced by temperature increase, suggesting a totally entropy-driven binding. Antagonist binding did not depend on the presence of Thr277. Antagonist affinity decreased with an increase in temperature, suggesting a mainly enthalpy-driven binding. Partial agonist binding was significantly dependent on the presence of Thr277 at 25 degrees, whereas such a dependence was not evident at 0 degrees. It is concluded that Thr277 contributes only to the binding of adenosine derivatives and that its role changes drastically with the receptor conformation and with the type of agonist (full or partial) interacting with the adenosine A1 receptors.
Neuroimaging within the Dominantly Inherited Alzheimer’s Network (DIAN): PET and MRI
Publisher: Cold Spring Harbor Laboratory
Date: 30-03-2022
DOI: 10.1101/2022.03.25.485799
Abstract: The Dominantly Inherited Alzheimer Network (DIAN) Observational Study is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). This rare form of Alzheimer disease (AD) is caused by mutations in the presenilin 1 (PSEN1) , presenilin 2 (PSEN2) , or amyloid precursor protein ( APP ) genes. As in iduals from these families have a 50% chance of inheriting the familial mutation, this provides researchers with a well-matched cohort of carriers vs non-carriers for case-control studies. An important trait of ADAD is that the age at symptom onset is highly predictable and consistent for each specific mutation, allowing researchers to estimate an in idual’s point in their disease time course prior to symptom onset. Although ADAD represents only a small proportion (approximately 0.1%) of all AD cases, studying this form of AD allows researchers to investigate preclinical AD and the progression of changes that occur within the brain prior to AD symptom onset. Furthermore, the young age at symptom onset (typically 30-60 years) means age-related comorbidities are much less prevalent than in sporadic AD, thereby allowing AD pathophysiology to be studied independent of these confounds. A major goal of the DIAN Observational Study is to create a global resource for AD researchers. To that end, the current manuscript provides an overview of the DIAN magnetic resonance imaging (MRI) and positron emission tomography (PET) protocols and highlights the key imaging results of this study to date.
General strategy for the generation of human antibody variable domains with increased aggregation resistance
Publisher: Proceedings of the National Academy of Sciences
Date: 27-06-2012
Abstract: The availability of stable human antibody reagents would be of considerable advantage for research, diagnostic, and therapeutic applications. Unfortunately, antibody variable heavy and light domains (V H and V L ) that mediate the interaction with antigen have the propensity to aggregate. Increasing their aggregation resistance in a general manner has proven to be a difficult and persistent problem, due to the high level of sequence ersity observed in human variable domains and the requirement to maintain antigen binding. Here we outline such an approach. By using phage display we identified specific positions that clustered in the antigen binding site (28, 30–33, 35 in V H and 24, 49–53, 56 in V L ). Introduction of aspartate or glutamate at these positions endowed superior biophysical properties (non-aggregating, well-expressed, and heat-refoldable) onto domains derived from common human germline families (V H 3 and V κ 1). The effects of the mutations were highly positional and independent of sequence ersity at other positions. Moreover, crystal structures of mutant V H and V L domains revealed a surprising degree of structural conservation, indicating compatibility with V H /V L pairing and antigen binding. This allowed the retrofitting of existing binders, as highlighted by the development of robust high affinity antibody fragments derived from the breast cancer therapeutic Herceptin. Our results provide a general strategy for the generation of human antibody variable domains with increased aggregation resistance.
Conformational changes in extracellular loop 2 associated with signal transduction in the glycine receptor
Publisher: Wiley
Date: 21-10-2010
DOI: 10.1111/J.1471-4159.2010.07021.X
Abstract: Ligand-gated ion channels efficiently couple neurotransmitter binding to the opening of an intrinsic ion channel to generate the post-synaptic potentials that are characteristic of fast synaptic transmission. In the Cys-loop family of ligand-gated ion channels, the ligand-binding site is approximately 60 Å above the channel gate. Structural modelling of related proteins and mutagenesis studies led to the hypothesis that loops 2 and 7 of the extracellular domain may couple ligand binding to receptor activation. Mutating loop 2 residues of the glycine receptor to cysteine reveals an alternating pattern of effect upon receptor function. Mutations A52C, T54C and M56C produced a threefold right-shift in EC(50) . In contrast, a 30-fold right-shift was seen for mutations E53C, T55C and D57C. Loop 2 conformational changes associated with ligand binding were assessed by measuring the rate of covalent modification of substituted cysteines by charged methane thiosulfonate reagents. We show for the first time state-dependent differences in the rate of reaction. A52C and T54C are more accessible in the resting state and M56C is more accessible in the activated state. These results demonstrate that loop 2 does undergo a conformational change as part of the mechanism that couples ligand binding to channel opening.
Prevalence of Mental Illnesses in Domestic Violence Police Records: Text Mining Study
Publisher: JMIR Publications Inc.
Date: 24-12-2020
DOI: 10.2196/23725
Abstract: The New South Wales Police Force (NSWPF) records details of significant numbers of domestic violence (DV) events they attend each year as both structured quantitative data and unstructured free text. Accessing information contained in the free text such as the victim’s and persons of interest (POI's) mental health status could be useful in the better management of DV events attended by the police and thus improve health, justice, and social outcomes. The aim of this study is to present the prevalence of extracted mental illness mentions for POIs and victims in police-recorded DV events. We applied a knowledge-driven text mining method to recognize mental illness mentions for victims and POIs from police-recorded DV events. In 416,441 police-recorded DV events with single POIs and single victims, we identified 64,587 events (15.51%) with at least one mental illness mention versus 4295 (1.03%) recorded in the structured fixed fields. Two-thirds (67,582/85,880, 78.69%) of mental illnesses were associated with POIs versus 21.30% (18,298/85,880) with victims depression was the most common condition in both victims (2822/12,589, 22.42%) and POIs (7496/39,269, 19.01%). Mental illnesses were most common among POIs aged 0-14 years (623/1612, 38.65%) and in victims aged over 65 years (1227/22,873, 5.36%). A wealth of mental illness information exists within police-recorded DV events that can be extracted using text mining. The results showed mood-related illnesses were the most common in both victims and POIs. Further investigation is required to determine the reliability of the mental illness mentions against sources of diagnostic information.
Genetics of dementia
Publisher: Elsevier BV
Date: 03-2014
Automatic Extraction of Mental Health Disorders From Domestic Violence Police Narratives: Text Mining Study (Preprint)
Publisher: JMIR Publications Inc.
Date: 12-07-2018
Abstract: ast numbers of domestic violence (DV) incidents are attended by the New South Wales Police Force each year in New South Wales and recorded as both structured quantitative data and unstructured free text in the WebCOPS (Web-based interface for the Computerised Operational Policing System) database regarding the details of the incident, the victim, and person of interest (POI). Although the structured data are used for reporting purposes, the free text remains untapped for DV reporting and surveillance purposes. n this paper, we explore whether text mining can automatically identify mental health disorders from this unstructured text. e used a training set of 200 DV recorded events to design a knowledge-driven approach based on lexical patterns in text suggesting mental health disorders for POIs and victims. he precision returned from an evaluation set of 100 DV events was 97.5% and 87.1% for mental health disorders related to POIs and victims, respectively. After applying our approach to a large-scale corpus of almost a half million DV events, we identified 77,995 events (15.83%) that mentioned mental health disorders, with 76.96% (60,032/77,995) of those linked to POIs versus 16.47% (12,852/77,995) for the victims and 6.55% (5111/77,995) for both. Depression was the most common mental health disorder mentioned in both victims (22.30%, 3258) and POIs (18.73%, 8918), followed by alcohol abuse for POIs (12.24%, 5829) and various anxiety disorders (eg, panic disorder, generalized anxiety disorder) for victims (11.43%, 1671). he results suggest that text mining can automatically extract targeted information from police-recorded DV events to support further public health research into the nexus between mental health disorders and DV.
Genetics of ageing-related changes in brain white matter integrity - a review.
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.ARR.2012.10.003
Abstract: White matter (WM) plays a vital role in the efficient transfer of information between grey matter regions. Modern imaging techniques such as diffusion tensor imaging (DTI) have enabled the examination of WM microstructural changes across the lifespan, but there is limited knowledge about the role genetics plays in the pattern and aetiology of age-related WM microstructural changes. Family and twin studies suggest that the heritability of WM integrity measures changes over the lifespan, with the common DTI measure, fractional anisotropy (FA), showing moderate to high heritability in adults. However, few heritability studies have been undertaken in older adults. Linkage studies in middle-aged adults suggest that specific regions on chromosomes 3 and 15 may harbour genetic variants for WM integrity. A number of studies have investigated candidate genes, with the APOE ɛ4 polymorphism being the most frequently studied. Although these candidate gene studies suggest associations of particular genes with WM integrity measures in some specific brain regions, the findings remain inconsistent due to differences in their methodologies, s les and the outcome measures used. The APOE ɛ4 allele has been associated with decreased WM integrity (FA) in the cingulum, corpus callosum and parahippoc al gyrus. Only one genome-wide association study of global WM integrity measures in older adults has been published, and reported suggestive single nucleotide polymorphisms await replication. Overall, genetic age-related WM integrity studies are lacking and a concerted effort to examine the genetic determinants of age-related decline in WM integrity is clearly needed to improve our understanding of the ageing brain.
Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative
Publisher: Elsevier BV
Date: 10-2007
Compound heterozygosity and nonsense mutations in the α1-subunit of the inhibitory glycine receptor in hyperekplexia
Publisher: Springer Science and Business Media LLC
Date: 02-08-2001
Abstract: The alpha(1)-inhibitory glycine receptor is a ligand-gated chloride channel composed of three ligand-binding alpha1-subunits and two structural beta-subunits that are clustered on the postsynaptic membrane of inhibitory glycinergic neurons. Dominant and recessive mutations in GLRA1 subunits have been associated with a proportion of in iduals and families with startle disease or hyperekplexia (MIM: 149400). Following SSCP and bi-directional di-deoxy fingerprinting mutational analysis of 22 unrelated in iduals with hyperekplexia and hyperekplexia-related conditions, we report further novel missense mutations and the first nonsense point mutations in GLRA1, the majority of which localise outside the regions previously associated with dominant, disease-segregating mutations. Population studies reveal the unique association of each mutation with disease, and reveals that a proportion of sporadic hyperekplexia is accounted for by the homozygous inheritance of recessive GLRA1 mutations or as part of a compound heterozygote.
Specific roles for the asparagine-linked carbohydrate residues of recombinant human follicle stimulating hormone in receptor binding and signal transduction
Publisher: The Endocrine Society
Date: 06-1994
DOI: 10.1210/ME.8.6.722
Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study
Publisher: Elsevier BV
Date: 03-2016
Grey matter covariation and the role of emotion reappraisal in mental wellbeing and resilience after early life stress exposure
Publisher: Springer Science and Business Media LLC
Date: 26-02-2022
DOI: 10.1038/S41398-022-01849-6
Abstract: Resilience is a process of adaptive recovery crucial in maintaining mental wellbeing after stress exposure. A psychological factor known to buffer stress and promote positive wellbeing outcomes is the ability to regulate emotions. However, the neural networks underlying resilience, and the possible mediating role of emotion regulation, remain largely unknown. Here, we examined the association between resilience and grey matter covariation (GMC) in healthy adults with and without early life stress (ELS) exposure, and whether emotion regulation mediated this brain-resilience association. Source-based morphometry was used to identify spatial patterns of common GMC in 242 healthy participants. Wellbeing was measured using the COMPAS-W Wellbeing Scale. Linear mixed models were run to establish associations between GMC and wellbeing scores. Moderated mediation models were used to examine a conditional mediating effect of emotion regulation on the brain-wellbeing relationship, moderated by ELS exposure. Distinct ELS-related morphometric patterns were found in association with resilience. In participants without ELS exposure, decreased GMC in the temporo-parietal regions was associated with wellbeing. In participants with ELS exposure, we observed increased patterns of covariation in regions related to the salience and executive control networks, and decreased GMC in temporo-parietal areas, which were associated with resilience. Cognitive reappraisal mediated the brain-wellbeing relationship in ELS-exposed participants only. Patterns of stronger GMC in regions associated with emotional and cognitive functioning in ELS-exposed participants with high levels of wellbeing may indicate possible neural signatures of resilience. This may be further heightened by utilising an adaptive form of emotion regulation.
Community attitudes towards mental health interventions for healthy people on the basis of genetic susceptibility
Publisher: SAGE Publications
Date: 11-2009
Disentangling Alzheimer’s disease neurodegeneration from typical brain ageing using machine learning
Publisher: Oxford University Press (OUP)
Date: 02-05-2022
DOI: 10.1093/BRAINCOMMS/FCAC117
Abstract: Neuroimaging biomarkers that distinguish between changes due to typical brain ageing and Alzheimer’s disease are valuable for determining how much each contributes to cognitive decline. Supervised machine learning models can derive multivariate patterns of brain change related to the two processes, including the Spatial Patterns of Atrophy for Recognition of Alzheimer’s Disease (SPARE-AD) and of Brain Aging (SPARE-BA) scores investigated herein. However, the substantial overlap between brain regions affected in the two processes confounds measuring them independently. We present a methodology, and associated results, towards disentangling the two. T1-weighted MRI scans of 4054 participants (48–95 years) with Alzheimer’s disease, mild cognitive impairment (MCI), or cognitively normal (CN) diagnoses from the Imaging-based coordinate SysTem for AGIng and NeurodeGenerative diseases (iSTAGING) consortium were analysed. Multiple sets of SPARE scores were investigated, in order to probe imaging signatures of certain clinically or molecularly defined sub-cohorts. First, a subset of clinical Alzheimer’s disease patients (n = 718) and age- and sex-matched CN adults (n = 718) were selected based purely on clinical diagnoses to train SPARE-BA1 (regression of age using CN in iduals) and SPARE-AD1 (classification of CN versus Alzheimer’s disease) models. Second, analogous groups were selected based on clinical and molecular markers to train SPARE-BA2 and SPARE-AD2 models: amyloid-positive Alzheimer’s disease continuum group (n = 718 consisting of amyloid-positive Alzheimer’s disease, amyloid-positive MCI, amyloid- and tau-positive CN in iduals) and amyloid-negative CN group (n = 718). Finally, the combined group of the Alzheimer’s disease continuum and amyloid-negative CN in iduals was used to train SPARE-BA3 model, with the intention to estimate brain age regardless of Alzheimer’s disease-related brain changes. The disentangled SPARE models, SPARE-AD2 and SPARE-BA3, derived brain patterns that were more specific to the two types of brain changes. The correlation between the SPARE-BA Gap (SPARE-BA minus chronological age) and SPARE-AD was significantly reduced after the decoupling (r = 0.56–0.06). The correlation of disentangled SPARE-AD was non-inferior to amyloid- and tau-related measurements and to the number of APOE ε4 alleles but was lower to Alzheimer’s disease-related psychometric test scores, suggesting the contribution of advanced brain ageing to the latter. The disentangled SPARE-BA was consistently less correlated with Alzheimer’s disease-related clinical, molecular and genetic variables. By employing conservative molecular diagnoses and introducing Alzheimer’s disease continuum cases to the SPARE-BA model training, we achieved more dissociable neuroanatomical biomarkers of typical brain ageing and Alzheimer’s disease.
Common polymorphisms in dopamine-related genes combine to produce a 'schizophrenia-like' prefrontal hypoactivity
Publisher: Springer Science and Business Media LLC
Date: 04-02-2014
DOI: 10.1038/TP.2013.125
Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity
Publisher: Proceedings of the National Academy of Sciences
Date: 12-05-2014
Abstract: Antibodies are selected to bind microbial but not self-antigens, because binding to self would compete with binding microbes, shorten antibody half-life, and cause autoimmunity. Self-tolerance is actively acquired in part by discarding self-binding antibodies before the body is exposed to a microbe or vaccine. The experiments here provide evidence of an opposite mechanism, allowing antibodies that initially bind both foreign and self-antigens to acquire self/non-self discrimination during the course of an immune response through somatic hypermutation away from self-reactivity. In addition to selection for lower-affinity binding to self, antibody variants were selected with fewer binding sites available to bind self-antigen because most were occupied by N-linked carbohydrate, possibly explaining the frequent occurrence of N-linked glycosylation of antibody variable domains.
DBH −1021C>T and COMT Val108/158Met genotype are not associated with the P300 ERP in an auditory oddball task
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.CLINPH.2012.11.008
Abstract: The litude and latency of the P300 may be associated by variations in dopaminergic genes. The current study was conducted to determine whether functional variants of the catechol-O-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) gene were associated with P300 litude and latency in an auditory oddball task. The P300 ERP was assessed by a two-tone auditory oddball paradigm in a large s le of 320 healthy volunteers. The Val108/158Met polymorphism (rs4680) of the COMT gene and the -1021C>T polymorphism (rs1611115) of the DBH gene were genotyped. P300 litude and latency were compared across genotype groups using analysis of variance. There were no differences in demographic characteristics in subjects for genotypic subgroups. No genotype associations were observed for the P300 litude and latency on frontal, central and parietal electrode positions. COMT Val108/158Met and DBH -1021C>T polymorphisms do not show evidence of association with characteristics of the P300 ERP in an auditory oddball paradigm in healthy volunteers. We failed to find evidence for the association between dopaminergic enzymatic polymorphisms and the P300 ERP in healthy volunteers, in the largest study undertaken to date.
Comprehensive cross-disorder analyses of CNTNAP2 suggest it is unlikely to be a primary risk gene for psychiatric disorders
Publisher: Public Library of Science (PLoS)
Date: 26-12-2018
Identification of shared risk loci and pathways for bipolar disorder and schizophrenia
Publisher: Public Library of Science (PLoS)
Date: 06-02-2017
Ligand-gated ion channels: mechanisms underlying ion selectivity
Publisher: Elsevier BV
Date: 10-2004
Mental Illness Concordance Between Hospital Clinical Records and Mentions in Domestic Violence Police Narratives: Data Linkage Study
Publisher: JMIR Publications Inc.
Date: 20-10-2022
DOI: 10.2196/39373
Abstract: To better understand domestic violence, data sources from multiple sectors such as police, justice, health, and welfare are needed. Linking police data to data collections from other agencies could provide unique insights and promote an all-of-government response to domestic violence. The New South Wales Police Force attends domestic violence events and records information in the form of both structured data and a free-text narrative, with the latter shown to be a rich source of information on the mental health status of persons of interest (POIs) and victims, abuse types, and sustained injuries. This study aims to examine the concordance (ie, matching) between mental illness mentions extracted from the police’s event narratives and mental health diagnoses from hospital and emergency department records. We applied a rule-based text mining method on 416,441 domestic violence police event narratives between December 2005 and January 2016 to identify mental illness mentions for POIs and victims. Using different window periods (1, 3, 6, and 12 months) before and after a domestic violence event, we linked the extracted mental illness mentions of victims and POIs to clinical records from the Emergency Department Data Collection and the Admitted Patient Data Collection in New South Wales, Australia using a unique identifier for each in idual in the same cohort. Using a 2-year window period (ie, 12 months before and after the domestic violence event), less than 1% (3020/416,441, 0.73%) of events had a mental illness mention and also a corresponding hospital record. About 16% of domestic violence events for both POIs (382/2395, 15.95%) and victims (101/631, 16.01%) had an agreement between hospital records and police narrative mentions of mental illness. A total of 51,025/416,441 (12.25%) events for POIs and 14,802/416,441 (3.55%) events for victims had mental illness mentions in their narratives but no hospital record. Only 841 events for POIs and 919 events for victims had a documented hospital record within 48 hours of the domestic violence event. Our findings suggest that current surveillance systems used to report on domestic violence may be enhanced by accessing rich information (ie, mental illness) contained in police text narratives, made available for both POIs and victims through the application of text mining. Additional insights can be gained by linkage to other health and welfare data collections.
Mechanisms of channel gating of the ligand-gated ion channel superfamily inferred from protein structure
Publisher: Wiley
Date: 19-02-2004
A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease
Publisher: Springer Science and Business Media LLC
Date: 03-2020
Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1997
DOI: 10.1097/00001756-199704140-00043
Abstract: Eleven early-onset dementia families, all with affected in iduals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products lified from genomic DNA templates of affected in iduals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290-319 of PS-1 (PS-1 delta 290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 delta 290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.
Impaired default network functional connectivity in autosomal dominant Alzheimer disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-07-2013
Microarray gene expression profiling of mouse brain mRNA in a model of lithium treatment
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2008
Glycogen synthase kinase-3β and tau genes interact in Alzheimer's disease
Publisher: Wiley
Date: 10-2008
DOI: 10.1002/ANA.21476
Abstract: We examined the epistatic effect between haplotypes of glycogen synthase kinase-3beta (GSK3B) gene and microtubule-associated protein Tau (MAPT) gene in Alzheimer's disease (AD). A genetic association study of three AD cohorts was made. Linear regression analyses were used to examine effects of MAPT polymorphisms on gene expression and alternative splicing. beta-Catenin levels and signaling were determined using Western blot and luciferase reporter assays in cells transfected with a combination of GSK3B and MAPT complementary DNA. Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in in iduals with at least one H2 haplotype (odds ratio, 1.68-2.33 p = 0.005-0.036). The GSK3B haplotype was significantly protective in the Chinese cohort (odds ratio, 0.33 p = 0.016), after adjusting for the effect of age and sex. There are significant differences in in vivo transcriptional efficiency between the two MAPT haplotypes (H1 and H2) as determined by measurement of cerebellar transcripts (p < 0.001). Overexpression of either MAPT or GSK3B resulted in decreased beta-catenin levels compared with a control vector (p < 0.001). Conversely, cotransfection of both of these molecules increased beta-catenin signaling. Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3beta in late-onset AD causative factors. Our data are consistent with an epistatic model of interaction where discordant levels of GSK3B and MAPT gene expression can lead to altered beta-catenin levels and pathogenicity.
Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-03-2021
DOI: 10.1212/WNL.0000000000011542
Abstract: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize in iduals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD). Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease. Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippoc al volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year). Our study highlights factors associated with the development of CMHs in in iduals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.
An Analysis of PubMed Abstracts From 1946 to 2021 to Identify Organizational Affiliations in Epidemiological Criminology: Descriptive Study
Publisher: JMIR Publications Inc.
Date: 05-12-2022
DOI: 10.2196/42891
Abstract: Epidemiological criminology refers to health issues affecting incarcerated and nonincarcerated offender populations, a group recognized as being challenging to conduct research with. Notwithstanding this, an urgent need exists for new knowledge and interventions to improve health, justice, and social outcomes for this marginalized population. To better understand research outputs in the field of epidemiological criminology, we examined the lead author’s affiliation by analyzing peer-reviewed published outputs to determine countries and organizations (eg, universities, governmental and nongovernmental organizations) responsible for peer-reviewed publications. We used a semiautomated approach to examine the first-author affiliations of 23,904 PubMed epidemiological studies related to incarcerated and offender populations published in English between 1946 and 2021. We also mapped research outputs to the World Justice Project Rule of Law Index to better understand whether there was a relationship between research outputs and the overall standard of a country’s justice system. Nordic countries (Sweden, Norway, Finland, and Denmark) had the highest research outputs proportional to their incarcerated population, followed by Australia. University-affiliated first authors comprised 73.3% of published articles, with the Karolinska Institute (Sweden) being the most published, followed by the University of New South Wales (Australia). Government-affiliated first authors were on 8.9% of published outputs, and prison-affiliated groups were on 1%. Countries with the lowest research outputs also had the lowest scores on the Rule of Law Index. This study provides important information on who is publishing research in the epidemiological criminology field. This has implications for promoting research ersity, independence, funding equity, and partnerships between universities and government departments that control access to incarcerated and offending populations.
Emerging health and social policy considerations for safe and quality end-of-life care in Australia – the evidence, gaps and challenges
Publisher: CSIRO Publishing
Date: 12-09-2023
DOI: 10.1071/AH23166
Association between BDNF Val66Met polymorphism and trait depression is mediated via resting EEG alpha band activity
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.BIOPSYCHO.2008.07.004
Abstract: A functional polymorphism of the brain-derived neurotrophic factor, BDNF Val66Met, is associated with risk for major depression alongside impairments in memory and selective attention. This study aims to identify the mediating neural mechanisms in links between BDNF and depression using highly heritable electroencephalographic (EEG) recordings. In 305 healthy subjects, BDNF Val66Met genotypes were compared in terms of trait depression, neural function (EEG during a resting state) and cognitive performance. The mediating effects of the EEG brain imaging endophenotypes were also examined using structural equation (path) modeling. A genotype-endophenotype-phenotype path model showed that Met homozygosity predicted elevated working memory commission errors and altered EEG activity that is elevated relative theta and delta power coupled with reduced alpha power. In turn, reduced EEG alpha activity mediated the relationship between the Met/Met genotype and trait depression. These findings demonstrate the utility of an integrative endophenotype approach. They suggest that the BDNF Met/Met homozygote has a direct impact on memory systems, but impacts trait depression via the secondary effects of neural changes.
Structure of the Precursor to an Enzyme Mediating COOH-Terminal Amidation in Peptide Biosynthesis
Publisher: The Endocrine Society
Date: 11-1987
Abstract: Many bioactive peptides terminate with an amino acid alpha-amide at their COOH terminus. The enzyme responsible for this essential posttranslational modification is known as peptidyl-glycine alpha-amidating monooxygenase or PAM. We identified cDNAs encoding the enzyme by using antibodies to screen a bovine intermediate pituitary lambda gt11 expression library. Antibodies to a beta-galactosidase/PAM fusion protein removed PAM activity from bovine pituitary homogenates. The 108,207 dalton protein predicted by the complete cDNA is approximately twice the size of purified PAM. An NH2-terminal signal sequence and short propeptide precede the NH2 terminus of purified PAM. The sequences of several PAM cyanogen bromide peptides were localized in the NH2-terminal half of the predicted protein. The cDNA encodes an additional 430 amino acid intragranular domain followed by a putative membrane spanning domain and a hydrophilic cytoplasmic domain. The forms of PAM purified from bovine neurointermediate pituitary may be generated by endoproteolytic cleavage at a subset of the 10 pairs of basic amino acids in the precursor. High levels of PAM mRNA were found in bovine pituitary and cerebral cortex. In corticotropic tumor cells, levels of PAM mRNA and pro-ACTH/endorphin mRNA were regulated in parallel by glucocorticoids and CRF.
Chromosomal localization of GABAA receptor subunit genes: relationship to human genetic disease
Publisher: Elsevier BV
Date: 11-1989
DOI: 10.1016/0896-6273(89)90275-4
Abstract: Hybridization of GABAA receptor probes to human chromosomes in situ and to DNA from sorted human chromosomes has localized the genes encoding a beta subunit and three isoforms of the alpha subunit. The alpha 2 and beta genes are both located on chromosome 4 in bands p12-p13 and may be adjacent. The alpha 1 gene is on chromosome 5 (bands q34-q35) and the alpha 3 gene is on the X chromosome. The alpha 3 locus was mapped also on the mouse X chromosome using genetic break-point analysis in an interspecies pedigree. The combined results locate the human alpha 3 gene within band Xq28, in a location that makes it a candidate gene for the X-linked form of manic depression.
Human Embryonic Stem Cell Research: An Australian Perspective
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.CELL.2007.01.008
Abstract: A conscience vote of in idual parliamentarians in the Australian government last month regarding amendments to current legislation regulating human embryonic stem cell research yielded a surprising outcome. Despite opposition by the Australian Prime Minister, the Senate and House of Representatives voted to adopt the recommendations of the Lockhart Review and approve human somatic cell nuclear transfer, thus providing a consistent national policy for all researchers in Australia.
Genetic correlations between wellbeing, depression and anxiety symptoms and behavioral responses to the emotional faces task in healthy twins
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.PSYCHRES.2018.03.042
Abstract: Currently there is a very limited understanding of how mental wellbeing versus anxiety and depression symptoms are associated with emotion processing behaviour. For the first time, we examined these associations using a behavioural emotion task of positive and negative facial expressions in 1668 healthy adult twins. Linear mixed model results suggested faster reaction times to happy facial expressions was associated with higher wellbeing scores, and slower reaction times with higher depression and anxiety scores. Multivariate twin modelling identified a significant genetic correlation between depression and anxiety symptoms and reaction time to happy facial expressions, in the absence of any significant correlations with wellbeing. We also found a significant negative phenotypic relationship between depression and anxiety symptoms and accuracy for identifying neutral emotions, although the genetic or environment correlations were not significant in the multivariate model. Overall, the phenotypic relationships between speed of identifying happy facial expressions and wellbeing on the one hand, versus depression and anxiety symptoms on the other, were in opposing directions. Twin modelling revealed a small common genetic correlation between response to happy faces and depression and anxiety symptoms alone, suggesting that wellbeing and depression and anxiety symptoms show largely independent relationships with emotion processing at the behavioral level.
Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1
Publisher: Springer Science and Business Media LLC
Date: 25-08-2016
DOI: 10.1007/S12035-016-0041-X
Abstract: Genome-wide analysis (GWA) is an effective strategy to discover extreme effects surpassing genome-wide significant levels in studying complex disorders however, when s le size is limited, the true effects may fail to achieve genome-wide significance. In such case, there may be authentic results among the pools of nominal candidates, and an alternative approach is to consider nominal candidates but are replicable across different s les. Here, we found that mRNA expression of the choline dehydrogenase gene (CHDH) was uniformly upregulated in the brains of bipolar disorder (BPD) patients compared with healthy controls across different studies. Follow-up genetic analyses of CHDH variants in multiple independent clinical datasets (including 11,564 cases and 17,686 controls) identified a risk SNP rs9836592 showing consistent associations with BPD (P
A missense mutation in the gene encoding the α1 subunit of the inhibitory glycine receptor in the spasmodic mouse
Publisher: Springer Science and Business Media LLC
Date: 06-1994
DOI: 10.1038/NG0694-131
Abstract: Hereditary hyperekplexia, an autosomal dominant neurologic disorder characterized by an exaggerated startle reflex and neonatal hypertonia, can be caused by mutations in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor (GLRA1). Spasmodic (spd), a recessive neurologic mouse mutant, resembles hyperekplexia phenotypically, and the two disease loci map to homologous chromosomal regions. Here we describe a Glra1 missense mutation in spd that results in reduced agonist sensitivity in glycine receptors expressed in vitro. We conclude that spd is a murine homologue of hyperekplexia and that mutations in GLRA1/Glra1 can produce syndromes with different inheritance patterns.
Prevalence of Mental Illnesses in Domestic Violence Police Records: Text Mining Study (Preprint)
Publisher: JMIR Publications Inc.
Date: 24-08-2020
Abstract: he New South Wales Police Force (NSWPF) records details of significant numbers of domestic violence (DV) events they attend each year as both structured quantitative data and unstructured free text. Accessing information contained in the free text such as the victim’s and persons of interest (POI's) mental health status could be useful in the better management of DV events attended by the police and thus improve health, justice, and social outcomes. he aim of this study is to present the prevalence of extracted mental illness mentions for POIs and victims in police-recorded DV events. e applied a knowledge-driven text mining method to recognize mental illness mentions for victims and POIs from police-recorded DV events. n 416,441 police-recorded DV events with single POIs and single victims, we identified 64,587 events (15.51%) with at least one mental illness mention versus 4295 (1.03%) recorded in the structured fixed fields. Two-thirds (67,582/85,880, 78.69%) of mental illnesses were associated with POIs versus 21.30% (18,298/85,880) with victims depression was the most common condition in both victims (2822/12,589, 22.42%) and POIs (7496/39,269, 19.01%). Mental illnesses were most common among POIs aged 0-14 years (623/1612, 38.65%) and in victims aged over 65 years (1227/22,873, 5.36%). wealth of mental illness information exists within police-recorded DV events that can be extracted using text mining. The results showed mood-related illnesses were the most common in both victims and POIs. Further investigation is required to determine the reliability of the mental illness mentions against sources of diagnostic information.
Behavioral Profile of a Heterozygous Mutant Mouse Model for EGF-Like Domain Neuregulin 1
Publisher: American Psychological Association (APA)
Date: 08-2008
DOI: 10.1037/0735-7044.122.4.748
Abstract: Human genetic studies have demonstrated that the neuregulin 1 gene (NRG1) is involved in the development of schizophrenia. Alternative splicing of NRG1 results in at least 15 distinct isoforms and all contain an extracellular epidermal growth factor (EGF)-like domain, which is sufficient for Nrg1's biological activity. Here, we characterize a heterozygous mutant model for mouse EGF-like domain neuregulin 1 (Nrg1) regarding schizophrenia-related behavioral domains. A comprehensive, multitiered phenotyping strategy was used to investigate locomotion, exploration, anxiety-related behaviors, and sensorimotor gating. Nrg1 mutant mice exhibited a hyper-locomotive phenotype and an improved ability to habituate to a new environment. Extensive analysis of anxiety-related behaviors revealed a wild type-like phenotype in this domain. However, a moderate impairment in sensorimotor gating was found after pharmacological challenge using psychoactive substances. Our study adds to the increasing behavioral data available from a variety of animal models for Nrg1 isoforms. We suggest a standardized and comprehensive behavioral phenotyping approach to distinguish between the different models and to clarify their relevance for schizophrenia research. Future behavioral investigations will focus on the negative and cognitive symptoms of schizophrenia.
Diimidazo[1,2-c : 4 ',5 '-e]pyrimidines: Adenosine agonist activity demonstrated by microphysiometry
Publisher: Elsevier BV
Date: 03-1998
DOI: 10.1016/S0960-894X(98)00102-4
Abstract: Silicon-based microphysiometry, measuring extracellular acidification rate of cells in culture, demonstrated that a series of diimidazo[1,2-c:4',5'-e]pyrimidines were agonists at the human adenosine A1 receptor. 5-amino-7,8-dihydro-3-ribofuranose-8-(R)-(phenyl)-3H-diimidazo [1,2-c:4',5'-e]pyrimidine (2a) had an EC50 of 100 microM and reached 90% of the Emax produced by R-PIA.
Variable phenotype of Alzheimer's disease with spastic paraparesis
Publisher: Wiley
Date: 08-10-2008
DOI: 10.1111/J.1471-4159.2007.05038.X
Abstract: Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected in iduals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid beta peptide (Abeta) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid beta peptide starting after the alternative beta-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected in iduals who present with dementia only, suggesting the existence of a protective factor in some in iduals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.
White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network
Publisher: Wiley
Date: 27-04-2016
DOI: 10.1002/ANA.24647
Gating mechanisms in Cys-loop receptors
Publisher: Springer Science and Business Media LLC
Date: 29-04-2009
DOI: 10.1007/S00249-009-0452-Y
Abstract: The Cys-loop receptor superfamily of ligand-gated ion channels has a prominent role in neuronal signalling. These receptors are pentamers, each subunit containing ten beta-strands in the extracellular domain and four alpha-helical transmembrane domains (M1-M4). The M2 domain of each subunit lines the intrinsic ion channel pore and residues within the extracellular domain form ligand binding sites. Ligand binding initiates a conformational change that opens the ion-selective pore. The coupling between ligand binding in the extracellular domain and opening of the intrinsic ion channel pore located in the membrane is not fully understood. Several loop structures, such as loop 2, the Cys-loop, the pre-M1 region and the M2-M3 loop have been implicated in receptor activation. The current "conformational change wave" hypothesis suggests that binding of a ligand initiates a rotation of the beta-sheets around an axis that passes through the Cys-loop. Due to this rotation, the Cys-loop and loop 2 are displaced. Movement of the M2-M3 loop then twists the M2 domain leading to a separation of the helices and opening of the pore. The publication of a crystal structure of an acetylcholine binding protein and the refined structure of the Torpedo marmorata acetylcholine receptor have improved the understanding of the mechanisms and structures involved in coupling ligand binding to channel gating. In this review, the most recent findings on some of these loop structures will be reported and discussed in view of their role in the gating mechanism.
Erratum: The chemotactic receptor EBI2 regulates the homeostasis, localization and immunological function of splenic dendritic cells
Publisher: Springer Science and Business Media LLC
Date: 19-07-2013
DOI: 10.1038/NI0813-876E
Altered inhibitory synaptic transmission in superficial dorsal horn neurones in spastic and oscillator mice
Publisher: Wiley
Date: 07-2003
Genetic and environmental determinants of variation in the plasma lipidome of older Australian twins
Publisher: Cold Spring Harbor Laboratory
Date: 07-05-2020
DOI: 10.1101/2020.05.05.075606
Abstract: The critical role of blood lipids in a broad range of health and disease states is well recognised, while an understanding of the complex genetic regulation of lipid homeostasis is emerging. Traditional blood lipids (LDL-C, HDL-C and triglycerides) are known to be substantially regulated by genetic variation. Less well explored is the interplay of genetics and environment within the broader blood lipidome. Here we use the twin model to examine heritability of the plasma lipidome among healthy older aged twins and explore gene expression and epigenetic (DNA methylation) associations of these lipids. Heritability of 209 plasma lipids quantified by liquid chromatography coupled mass spectrometry (LC-MS) was assessed in 75 monozygotic and 55 dizygotic twin pairs enrolled in the Older Australian Twins Study (OATS), aged 69-93 years. Only 27/209 lipids (13.3%) were significantly heritable under the classical ACE twin model ( h 2 = 0.28-0.59). Ceramides (Cer) and triglycerides (TG) were most heritable, while sphingomyelins (SM) and most phospholipids, especially lysophospholipids, were not significantly heritable. Lipid levels correlated with 3731 transcripts. Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, which were not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for a proportion of variability in some non-heritable lipids, especially lysophosphatidylcholine (LPC). We found a complex interplay of genetic and environmental influences on the ageing plasma lipidome, with most of the variation controlled by unique environmental influences.
A genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q
Publisher: Springer Science and Business Media LLC
Date: 07-2001
Abstract: Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. In this present study, we undertook a 10 cM genome screen using 400 microsatellite markers in a large multigenerational bipolar pedigree consisting of 40 in iduals, including six affecteds. We found strongest evidence for linkage to chromosome 13q14. A maximum NPL score of 4.09 (P = 0.008) was obtained between markers D13S1272 and D13S153 using GENEHUNTER. A maximum two-point LOD score of 2.91 (theta = 0.0) was found for marker D13S153 and a maximum three-point LOD score of 3.0 was obtained between markers D13S291 and D13S153 under a recessive model with 90% maximum age-specific penetrance and including bipolar I and unipolar in iduals as affected. Several other markers in the region, D13S175, D13S218, D13S263, and D13S156 had two-point LOD scores greater than 1.5. These results meet the criteria for evidence of suggestive linkage. Haplotype analysis enabled us to narrow the likely disease region to a 6 cM region between markers D13S1272 and D13S1319, which contains the serotonin 2A receptor candidate gene. Two single nucleotide polymorphisms were identified in this gene but we did not detect any significant differences in allele frequency in a case-control s le. The region on chromosome 13q14-32 has previously been implicated in other bipolar and schizophrenia cohorts. Our results provide further support for the existence of a susceptibility locus on chromosome 13q14.
Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group
Publisher: Springer Science and Business Media LLC
Date: 06-12-2019
DOI: 10.1038/S41380-019-0605-Z
Abstract: DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small s le sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 in iduals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippoc us, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of in idual CpGs revealed genome-wide significant associations with hippoc al volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippoc al volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
Diverse phenotypic measurements of wellbeing: Heritability, temporal stability and the variance explained by polygenic scores
Publisher: Wiley
Date: 09-09-2020
DOI: 10.1111/GBB.12694
Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities
Publisher: Cold Spring Harbor Laboratory
Date: 27-06-2019
DOI: 10.1101/683367
Abstract: We conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.
Localization of the adenosine A1 receptor subtype gene (ADORA1) to chromosome 1q32.1
Publisher: Elsevier BV
Date: 03-1995
Triallelic relationships between the serotonin transporter polymorphism and cognition among healthy older adults
Publisher: Informa UK Limited
Date: 17-10-2013
Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.MAD.2018.06.002
Abstract: Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. Five polymorphisms, ACE rs4340, APOE ε2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE ε4) to 1.45 (FOXO3A males). In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.
Automated Analysis of Domestic Violence Police Reports to Explore Abuse Types and Victim Injuries: Text Mining Study
Publisher: JMIR Publications Inc.
Date: 12-03-2019
DOI: 10.2196/13067
An examination of multiple classes of rare variants in extended families with bipolar disorder
Publisher: Springer Science and Business Media LLC
Date: 13-03-2018
DOI: 10.1038/S41398-018-0113-Y
Abstract: Bipolar disorder (BD) is a complex psychiatric condition with high heritability, the genetic architecture of which likely comprises both common variants of small effect and rare variants of higher penetrance, the latter of which are largely unknown. Extended families with high density of illness provide an opportunity to map novel risk genes or consolidate evidence for existing candidates, by identifying genes carrying pathogenic rare variants. We performed whole-exome sequencing (WES) in 15 BD families (117 subjects, of whom 72 were affected), augmented with copy number variant (CNV) microarray data, to examine contributions of multiple classes of rare genetic variants within a familial context. Linkage analysis and haplotype reconstruction using WES-derived genotypes enabled exclusion of false-positive single-nucleotide variants (SNVs), CNV inheritance estimation, de novo variant identification and candidate gene prioritization. We found that rare predicted pathogenic variants shared among ≥3 affected relatives were overrepresented in postsynaptic density (PSD) genes ( P = 0.002), with no enrichment in unaffected relatives. Genome-wide burden of likely gene-disruptive variants was no different in affected vs. unaffected relatives ( P = 0.24), but correlated significantly with age of onset ( P = 0.017), suggesting that a high disruptive variant burden may expedite symptom onset. The number of de novo variants was no different in affected vs. unaffected offspring ( P = 0.89). We observed heterogeneity within and between families, with the most likely genetic model involving alleles of modest effect and reduced penetrance: a possible exception being a truncating X-linked mutation in IRS4 within a family-specific linkage peak. Genetic approaches combining WES, CNV and linkage analyses in extended families are promising strategies for gene discovery.
Conservation of nif- and species-specific domains within repeated promoter sequences from fast-growing Rhizobium species
Publisher: Oxford University Press (OUP)
Date: 1985
Abstract: In the fast-growing Rhizobium species, repeated DNA sequences, which include the promoter region of the nif HDK operon have been described. These repeated sequences are promoters which specifically activate transcription in the endosymbiotic state. Hybridization analysis of these sequences from R. trifolii has revealed that they may be involved in the species-specific activation of the various genes whose transcription they promote. Comparative analysis of various copies of these repeated sequences, from R. trifolii (the clover symbiont) and R. meliloti (the alfalfa symbiont), reveals the presence of domains of intra- and interspecific conservation within the promoter regions. We suggest that these promoter elements represent sites which are involved in the species-specific and general, nif-specific activation of Rhizobium symbiotic genes.
Biological activity and metabolic clearance of recombinant human follicle stimulating hormone produced in Sp2/0 myeloma cells
Publisher: Springer Science and Business Media LLC
Date: 06-1996
DOI: 10.1007/BF02215667
Major leads in the search for susceptibility genes for depression
Publisher: Springer Science and Business Media LLC
Date: 11-11-2003
Identification, characterization, and association analysis of novel genes from the bipolar disorder susceptibility locus on chromosome 4q35
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2005
DOI: 10.1097/00041444-200509000-00011
Abstract: The cause of bipolar disorder remains unknown, with little knowledge of the underlying biological, anatomical, biochemical, or genetic defect. The disorder is genetically complex, with an increasing number of loci being implicated through genetic linkage studies. We previously identified a bipolar disorder susceptibility locus on chromosome 4q35 and refined the interval harboring this susceptibility gene to approximately 5 Mb, a size that is amenable to positional cloning. Several independent studies have reported the presence of a susceptibility gene at this locus. To identify candidate genes for testing for association with bipolar disorder, we previously established a transcript map that encompasses the candidate interval. We have continued to seek novel genes from this region in order to expand this transcript map. Here, we describe the further identification and characterization of eight novel genes from the chromosome 4q35 bipolar candidate interval. Expression analysis determined that six of these novel genes are expressed in the brain, and these genes were therefore analyzed for association with bipolar disorder. Single nucleotide polymorphisms were identified from the candidate genes and tested for association in our case-control cohort. Our data suggest that the six candidate genes analyzed can be excluded from involvement in the disorder.
The pathophysiology of the aqueduct stroke volume in normal pressure hydrocephalus: can co-morbidity with other forms of dementia be excluded?
Publisher: Springer Science and Business Media LLC
Date: 15-07-2005
DOI: 10.1007/S00234-005-1418-0
Abstract: Variable results are obtained from the treatment of normal pressure hydrocephalus (NPH) by shunt insertion. There is a high correlation between NPH and the pathology of Alzheimer's disease (AD) on brain biopsy. There is an overlap between AD and vascular dementia (VaD), suggesting that a correlation exists between NPH and other forms of dementia. This study seeks to (1) understand the physiological factors behind, and (2) define the ability of, the aqueduct stroke volume to exclude dementia co-morbidity. Twenty-four patients from a dementia clinic were classified as having either early AD or VaD on the basis of clinical features, Hachinski score and neuropsychological testing. They were compared with 16 subjects with classical clinical findings of NPH and 12 aged-matched non-cognitively impaired subjects. MRI flow quantification was used to measure aqueduct stroke volume and arterial pulse volume. An arterio-cerebral compliance ratio was calculated from the two volumes in each patient. The aqueduct stroke volume was elevated in all three forms of dementia, with no significant difference noted between the groups. The arterial pulse volume was elevated by 24% in VaD and reduced by 35% in NPH, compared to normal (P = 0.05 and P = 0.002, respectively), and was normal in AD. There was a spectrum of relative compliance with normal compliance in VaD and reduced compliance in AD and NPH. The aqueduct stroke volume depends on the arterial pulse volume and the relative compliance between the arterial tree and brain. The aqueduct stroke volume cannot exclude significant co-morbidity in NPH.
Identification of Sialyltransferase 8B as a Generalized Susceptibility Gene for Psychotic and Mood Disorders on Chromosome 15q25-26
Publisher: Public Library of Science (PLoS)
Date: 31-05-2012
Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder
Publisher: Frontiers Media SA
Date: 31-05-2018
The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.BIOPSYCHO.2007.03.001
Abstract: Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may exist decades before the increased risk period for Alzheimer's disease, but little is known about their effect on cognition and brain function in children and young adults. This study assessed 415 healthy epsilon2 and epsilon4 carriers and matched epsilon3/epsilon3 controls, spanning ages 6-65, on a range of cognitive tests. Subjects were also compared on a new dynamical measure of EEG activity during a visual working memory task using alphabetical stimuli. epsilon4 subjects had better verbal fluency compared to epsilon3, an effect that was strongest in 51-65 year-olds. No epsilon4 deficits in cognition were found. In 6-15 year-olds, there were differences in total spatio-temporal wave activity between epsilon3 and epsilon4 subjects in the theta band, approximately 200ms post-stimulus. Differences in brain function in younger epsilon4 subjects and superior verbal fluency across the entire age range suggest that the APOE epsilon4 allele is an ex le of antagonistic pleiotropy.
Antagonism of ligand-gated ion channel receptors: two domains of the glycine receptor alpha subunit form the strychnine-binding site.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-1992
Abstract: The inhibitory glycine receptor (GlyR) is a member of the ligand-gated ion channel receptor superfamily. Glycine activation of the receptor is antagonized by the convulsant alkaloid strychnine. Using in vitro mutagenesis and functional analysis of the cDNA encoding the alpha 1 subunit of the human GlyR, we have identified several amino acid residues that form the strychnine-binding site. These residues were identified by transient expression of mutated cDNAs in mammalian (293) cells and examination of resultant [3H]strychnine binding, glycine displacement of [3H]strychnine, and electrophysiological responses to the application of glycine and strychnine. This mutational analysis revealed that residues from two separate domains within the alpha 1 subunit form the binding site for the antagonist strychnine. The first domain includes the amino acid residues Gly-160 and Tyr-161, and the second domain includes the residues Lys-200 and Tyr-202. These results, combined with analyses of other ligand-gated ion channel receptors, suggest a conserved tertiary structure and a common mechanism for antagonism in this receptor superfamily.
Mutations in progranulin explain atypical phenotypes with variants in MAPT.
Publisher: Oxford University Press (OUP)
Date: 29-09-2006
DOI: 10.1093/BRAIN/AWL289
Abstract: Mutations in presenilin-1 (PSEN1) cause autosomal dominant Alzheimer's disease and mutations in MAPT cause the familial tauopathy Frontotemporal dementia linked to chromosome 17 (FTDP-17). However, there have been reports of mutations in PSEN1 and MAPT associated with cases of FTD with ubiquitin-positive tau-negative inclusion pathology. Here, we demonstrate that the MAPT variants are almost certainly rare benign polymorphisms as all of these cases harbour mutations in Progranulin (PGRN). Mutations in PGRN were recently shown to cause ubiquitin-positive FTDP-17.
Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer’s disease
Publisher: Cold Spring Harbor Laboratory
Date: 13-07-2018
DOI: 10.1101/2023.07.04.547688
Abstract: The balance between production, clearance, and toxicity of Aβ peptides is central to Alzheimer’s disease (AD) pathobiology. Though highly variable in terms of age at symptom onset (AAO), hundreds of variants in PSEN1 cause autosomal dominant forms of AD (ADAD) with nearly complete penetrance. PSEN1 forms the catalytic core of the γ-secretase complex and thereby directly mediates the production of longer, aggregation-prone Aβ peptides relative to shorter, non-aggregating peptides. We hypothesized that the broad AAO and biomarker heterogeneity seen across ADAD would be predictable based on mutation-specific differences in the production of Aβ species. Aβ-37, 38, 40, 42, and 43 production was quantified from 161 unique PSEN1 variants expressed in HEK293 cells. Prediction of AAO was carried out in 106 variants with available AAO and then replicated in 55 variants represented across 190 PSEN1 mutation carriers who have detailed cognitive and biomarker data from the Dominantly Inherited Alzheimer’s Network (DIAN). Variations in Aβ production across the 161 mutations examined in cell-based models were highly predictive of AAO. In those with corresponding in vivo data from the DIAN study, our cell-based γ-secretase composite was strongly associated with biomarker and cognitive trajectories. These findings elucidate the critical link between γ-secretase function, Aβ production, and AD progression and offer mechanistic support for the amyloid hypothesis. The approach used here represents a powerful tool to account for heterogeneity in disease progression in ADAD clinical trials and to assess the pathogenicity of variants of unknown significance or with limited family history.
Djinn Lite: a tool for customised gene transcript modelling, annotation-data enrichment and exploration
Publisher: Springer Science and Business Media LLC
Date: 23-01-2006
Abstract: There is an ever increasing rate of data made available on genetic variation, transcriptomes and proteomes. Similarly, a growing variety of bioinformatic programs are becoming available from many erse sources, designed to identify a myriad of sequence patterns considered to have potential biological importance within inter-genic regions, genes, transcripts, and proteins. However, biologists require easy to use, uncomplicated tools to integrate this information, visualise and print gene annotations. Integrating this information usually requires considerable informatics skills, and comprehensive knowledge of the data format to make full use of this information. Tools are needed to explore gene model variants by allowing users the ability to create alternative transcript models using novel combinations of exons not necessarily represented in current database deposits of mRNA/cDNA sequences. Djinn Lite is designed to be an intuitive program for storing and visually exploring of custom annotations relating to a eukaryotic gene sequence and its modelled gene products. In particular, it is helpful in developing hypothesis regarding alternate splicing of transcripts by allowing the construction of model transcripts and inspection of their resulting translations. It facilitates the ability to view a gene and its gene products in one synchronised graphical view, allowing one to drill down into sequence related data. Colour highlighting of selected sequences and added annotations further supports exploration, visualisation of sequence regions and motifs known or predicted to be biologically significant. Gene annotating remains an ongoing and challengingtask that will continue as gene structures, gene transcription repertoires, disease loci, protein products and their interactions become moreprecisely defined. Djinn Lite offers an accessible interface to help accumulate, enrich, and in idualise sequence annotations relating to a gene, its transcripts and translations. The mechanism of transcript definition and creation, and subsequent navigation and exploration of features, are very intuitive and demand only a short learning curve. Ultimately, Djinn Lite can form the basis for providing valuable clues to plan new experiments, providing storage of sequences and annotations for dedication to customised projects. The application is appropriate for Windows 98-ME-2000-XP-2003 operating systems.
Relieving Perception of Thirst and Xerostomia in Patients with Palliative and End-of-life Care Needs: A Rapid Review
Publisher: Elsevier BV
Date: 07-2023
Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer’s Disease: Results from the DIAN Study Group
Publisher: Public Library of Science (PLoS)
Date: 24-03-2016
Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer’s disease
Publisher: Springer Science and Business Media LLC
Date: 27-04-2017
DOI: 10.1038/S41598-017-01327-W
Abstract: The relationship between body-mass index (BMI) and Alzheimer´s disease (AD) has been extensively investigated. However, BMI alterations in preclinical in iduals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to erge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aβ brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time.
Species-specific, symbiotic plasmid-located repeated DNA sequences in Rhizobium trifolii
Publisher: Springer Science and Business Media LLC
Date: 05-1985
DOI: 10.1007/BF00330270
Neuropsychological Correlates of Changes in Driving Behavior Among Clinically Healthy Older Adults
Publisher: Oxford University Press (OUP)
Date: 23-07-2022
Abstract: To determine the extent to which cognitive domain scores moderate change in driving behavior in cognitively healthy older adults using naturalistic (Global Positioning System-based) driving outcomes and to compare against self-reported outcomes using an established driving questionnaire. We analyzed longitudinal naturalistic driving behavior from a s le (N = 161, 45% female, mean age = 74.7 years, mean education = 16.5 years) of cognitively healthy, nondemented older adults. Composite driving variables were formed that indexed “driving space” and “driving performance.” All participants completed a baseline comprehensive cognitive assessment that measured multiple domains as well as an annual self-reported driving outcomes questionnaire. Across an average of 24 months of naturalistic driving, our results showed that attentional control, broadly defined as the ability to focus on relevant aspects of the environment and ignore distracting or competing information as measured behaviorally with tasks such as the Stroop color naming test, moderated change in driving space scores over time. Specifically, in iduals with lower attentional control scores drove fewer trips per month, drove less at night, visited fewer unique locations, and drove in smaller spaces than those with higher attentional control scores. No cognitive domain predicted driving performance such as hard braking or sudden acceleration. Attentional control is a key moderator of change over time in driving space but not driving performance in older adults. We speculate on mechanisms that may relate attentional control ability to modifications of driving behaviors.
The shared and unique genetic relationship between mental well-being, depression and anxiety symptoms and cognitive function in healthy twins
Publisher: Informa UK Limited
Date: 30-09-2016
DOI: 10.1080/02699931.2016.1232242
Abstract: Alterations to cognitive function are often reported with depression and anxiety symptoms, yet few studies have examined the same associations with mental well-being. This study examined the association between mental well-being, depression and anxiety symptoms and cognitive function in 1502 healthy adult monozygotic (MZ) and dizygotic (DZ) twins, and the shared/unique contribution of genetic (G) and environmental (E) variance. Using linear mixed models, mental well-being was positively associated (p < .01) with sustained attention (β = 0.127), inhibition (β = 0.096), cognitive flexibility (β = 0.149), motor coordination (β = 0.114) and working memory (β = 0.156), whereas depression and anxiety symptoms were associated (p < .01) with poorer sustained attention (β = -0.134), inhibition (β = -0.139), cognitive flexibility (β = -0.116) and executive function (β = -0.139). Bivariate twin modelling showed well-being shared a small environmental correlation with motor coordination and a small genetic correlation with working memory. Trivariate twin modelling showed well-being shared a small genetic correlation with inhibition, whereas depression and anxiety symptoms shared a small environmental correlation with inhibition. The remaining variance was mostly driven by unique G and/or E variance. Overall, well-being and depression and anxiety symptoms show both independent and shared relationships with cognitive functions but this is largely attributable to unique G or E variance and small shared G/E variance between pairs of variables.
Molecular mechanisms of inherited startle syndromes
Publisher: Elsevier BV
Date: 02-1995
The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders
Publisher: Springer Science and Business Media LLC
Date: 10-01-2017
DOI: 10.1038/MP.2016.231
Erratum: A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19
Publisher: Springer Science and Business Media LLC
Date: 22-04-2004
Serotonin transporter gene status predicts caudate nucleus but not amygdala or hippocampal volumes in older persons with major depression
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.JAD.2006.07.010
Abstract: Although the short allele of the serotonin transporter promoter polymorphism (5-HTT) has been linked to increased risk of major depression in early adult life, its relationships with late-life depression and to changes in subcortical nuclei remain unclear. 5-HTT genotypes (SS, SL, LL) were determined for 45 older persons with major depression (mean age=52.0, sd=12.8) and 16 healthy controls (mean age=55.8, sd=10.3). MRI-derived volumes of the amygdala, hippoc us, caudate and putamen were determined by reliable tracing techniques. In those with depression, the short allele of 5-HTT was associated with smaller caudate nucleus volumes. Although hippoc al and amygdala volumes were smaller in those with depression as compared with control subjects, 5-HTT gene status did not predict this reduction in size. The findings are limited by the number of clinical and control participants. Reduced caudate nucleus volume in older patients with major depression was associated with the short allele of the 5-HTT gene. This regional brain change may be a consequence of early developmental expression as well as later vascular or degenerative effects of this genotype.
Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium
Publisher: Cold Spring Harbor Laboratory
Date: 09-09-2018
DOI: 10.1101/409649
Abstract: Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery s le comprised 22,822 in iduals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress
Publisher: Elsevier BV
Date: 12-2014
The venous manifestations of pulse wave encephalopathy: windkessel dysfunction in normal aging and senile dementia
Publisher: Springer Science and Business Media LLC
Date: 04-2008
DOI: 10.1007/S00234-008-0374-X
Abstract: Cerebral arterial, venous and cerebrospinal fluid (CSF) pulsations are closely coupled and this produces pulsation d ening or the windkessel effect. Normal pressure hydrocephalus is a manifestation of the breakdown of this windkessel effect with altered CSF and venous pulsations being noted. The aim of this study was to show that dysfunction of the windkessel mechanism is also a component of normal aging and senile dementia. The study group comprised 24 patients classified as either early senile dementia of Alzheimer's type (SDAT) or vascular dementia (VaD). The patients with dementia were compared with 12 age-matched non-cognitively impaired subjects, and 12 normal young in iduals were compared with the normal aging group. MRI flow quantification was used to measure the nonpulsatile and pulsatile components of blood flow as well as the pulsation at the tentorial incisura. With normal aging blood flow decreased but arterial pulsations increased in volume by 49% (P=0.003). The CSF vented via the tentorial incisura does not change significantly with age and therefore increased venous pulsation is necessary. In patients with VaD the arterial pulse volume was higher by 24% and the straight sinus pulsation was higher by 57% than in normal aging subjects (P=0.05 and P=0.03, respectively). In patients with SDAT the total venous pulsation volumes were similar to those in normal aging subjects but there was less basal sinus pulsation. Normal aging, SDAT and VaD are associated with alterations in venous pulsation due to a breakdown of the windkessel effect.
Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults
Publisher: Springer Science and Business Media LLC
Date: 07-2014
Mapping of the human adenosine A 2a receptor gene: relationship to potential schizophrenia loci on chromosome 22q and exclusion from the CATCH 22 region
Publisher: Springer Science and Business Media LLC
Date: 18-02-1997
Abstract: Chromosome 22 contains two potential schizophrenia loci on chromosomal regions 22q11.2 and 22q12-13. In the present study we report results from linkage mapping of the gene coding for the human A2a adenosine receptor (AR), which is one of two receptors mediating central nervous system effects of adenosine. From seven CEPH (Centre d'Etude du Polymorphisme Humain) families, 120 in iduals were typed utilizing an intragenic restriction fragment length polymorphism. Significant linkage was found with many markers on chromosome 22. A 10-cM 1000:1 support interval between markers D22S301 and D22S300 is defined on the CHLC (Cooperative Human Linkage Center) framework map of chromosome 22. Localization of the A2aAR gene outside the CATCH 22 syndrome region on 22q11.2 is demonstrated by the observation of heterozygous in iduals with defined 2-Mb deletions from this region. Thus, the A2aAR gene is not the schizophrenia susceptibility gene suspected in the CATCH 22 syndrome region on 22q11.2, but remains a candidate for a schizophrenia susceptibility gene on 22q12-13.
Presenilin-1 Mutation L271V Results in Altered Exon 8 Splicing and Alzheimer's Disease with Non-cored Plaques and No Neuritic Dystrophy
Publisher: Elsevier BV
Date: 02-2003
Genetics of hand grip strength in mid to late life
Publisher: Springer Science and Business Media LLC
Date: 02-2015
The effectiveness of in-hospital interventions on reducing hospital length of stay and readmission of patients with Type 2 Diabetes Mellitus: A systematic review
Publisher: Elsevier BV
Date: 04-2021
Nodulation of specific legumes is controlled by several distinct loci in Rhizobium trifolii
Publisher: Springer Science and Business Media LLC
Date: 1986
DOI: 10.1007/BF00027132
Correction: Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals
Publisher: Springer Science and Business Media LLC
Date: 16-09-2019
DOI: 10.1038/S41386-019-0521-6
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Community attitudes to genetic susceptibility-based mental health interventions for healthy people in a large national sample
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.JAD.2011.06.023
Abstract: Despite an apparent high interest in predictive genetic testing for common multifactorial disorders, few data describe anticipated health behaviour as a consequence of such testing. A large population-based public survey with community dwelling adults (N = 1046) ascertained through random digit dialling. Attitudes were assessed via structured interviews. Intention to start therapies or courses to learn to develop better strategies to cope with stress (80%) was significantly and positively associated with self-estimation of risk for major depressive disorder as higher than average (ß = 0.12, p = 0.001) endorsement of family environment as a causal attribution (ß = 0.11, p < 0.001) and endorsement of gene-environment interaction as a causal mechanism of mental illness (ß = 0.12, p = 0.017). Intention to modify potential life stressors (84%) was significantly and positively associated with self-estimation of risk for depression as higher than average (ß = 0.07, p = 0.029) endorsement of 'abuse' as a causal attribution (ß = 0.10, p = 0.003) and endorsement of 'gene-environment interaction' as a causal mechanism (ß = 0.10, p = 0.002). The hypothetical nature of the genetic risk scenario may have weakened participants' sensitivity to the potential personal impact of such a genetic test result. Perceptions that modifiable environmental factors strongly contribute to overall risk of major depressive disorder appeared to drive willingness to engage in risk-modifying interventions in the hypothetical scenario of a genetic predisposition. Our results suggest that screening for genetic risk in consort with environmental risk factor assessment has potential community acceptability and clinical value as an early intervention and preventive tool for high risk groups.
Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report
Publisher: Public Library of Science (PLoS)
Date: 19-06-2013
Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN)
Publisher: Springer Science and Business Media LLC
Date: 10-07-2023
DOI: 10.1038/S41593-023-01359-8
Abstract: The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case–control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an in idual’s point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of ‘sporadic’ AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.
Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: associations with β-amyloid-PET, neurodegeneration and cognition
Publisher: Research Square Platform LLC
Date: 29-06-2022
DOI: 10.21203/RS.3.RS-1752559/V1
Abstract: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.
Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: associations with β-amyloid-PET, neurodegeneration and cognition
Publisher: Research Square Platform LLC
Date: 07-07-2022
DOI: 10.21203/RS.3.RS-1752559/V2
Abstract: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.
Effects of polygenic risk for suicide attempt and risky behavior on brain structure in young people with familial risk of bipolar disorder
Publisher: Cold Spring Harbor Laboratory
Date: 14-09-2021
DOI: 10.1101/2021.09.06.21262817
Abstract: Bipolar Disorder (BD) is associated with a 20-30 fold increased suicide risk compared to the general population. First-degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide-related polygenic risk scores (PRS) – a quantitative index of genomic risk – and variability in brain structures implicated in SA. Participants (n=206 aged 12-30 years) were unrelated in iduals of European ancestry and comprised three groups: 41 BD cases, 96 BD relatives (‘high-risk’), and 69 controls. Genotyping employed PsychArray, followed by imputation. Three PRS were computed using genome-wide association data for SA in BD (SA-in-BD), SA in Major Depressive Disorder (SA-in-MDD) [Mullins et al., 2019], and risky behavior [Karlsson Linnér et al., 2019]. Structural MRI processing employed FreeSurfer v5.3.0. General linear models were constructed using 32 regions-of-interest identified from suicide neuroimaging literature, with false-discovery-rate correction. SA-in-MDD and SA-in-BD PRS negatively predicted parahippoc al thickness, with the latter association modified by group membership. SA-in-BD and Risky Behavior PRS inversely predicted rostral and caudal anterior cingulate structure, respectively, with the latter effect driven by the ‘high-risk’ group. SA-in-MDD and SA-in-BD PRS positively predicted cuneus structure, irrespective of group. This study demonstrated associations between PRS for suicide-related phenotypes and structural variability in brain regions implicated in SA. Future exploration of extended PRS, in conjunction with a range of biological, phenotypic, environmental and experiential data in high-risk populations, may inform predictive models for suicidal behaviors.
Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial
Publisher: Elsevier BV
Date: 10-2013
Partial volume correction in quantitative amyloid imaging
Publisher: Elsevier BV
Date: 02-2015
C9ORF72 repeat expansion in clinical and neuropathologic frontotemporal dementia cohorts.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-08-2012
A missense mutation in kynurenine aminotransferase-1 in spontaneously hypertensive rats.
Publisher: Elsevier BV
Date: 09-2002
Genome screen of 15 Australian bipolar affective disorder pedigrees supports previously identified loci for bipolar susceptibility genes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2008
Coregulation of genes in the mouse brain following treatment with clozapine, haloperidol, or olanzapine implicates altered potassium channel subunit expression in the mechanism of antipsychotic drug action
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2008
Pore Structure of the Cys-loop Ligand-gated Ion Channels
Publisher: Springer Science and Business Media LLC
Date: 19-04-2009
DOI: 10.1007/S11064-009-9971-2
Abstract: The Cys-loop receptor family of ligand-gated ion channels (LGICs) play a key role in synaptic transmission in the central nervous system of animals. Recent advances have led to the elucidation of two crystal structures of related prokaryotic LGICs and the electron micrograph derived structure of the acetylcholine receptor from Torpedo marmorata. Here, we review the structural and biochemical data that form our understanding of the structure of the channel pore. We introduce original data from the glycine receptor using the substituted-cysteine accessibility technique and show that while the helical structure of the segment that surrounds the channel pore is generally agreed, the location of the channel gate, the pore diameter and the structure that forms the entry to the channel pore are likely to differ between receptors. The fundamental structural differences between anion and cation selective receptors and how these differences are related to the pore structure are also considered.
White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer’s disease
Publisher: Public Library of Science (PLoS)
Date: 09-05-2018
Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-06-2014
Neuronal fiber bundle lengths in healthy adult carriers of the ApoE4 allele: A quantitative tractography DTI study
Publisher: Springer Science and Business Media LLC
Date: 10-03-2013
Genetic variants associated with longitudinal changes in brain structure across the lifespan
Publisher: Springer Science and Business Media LLC
Date: 04-2022
DOI: 10.1038/S41593-022-01042-4
Abstract: Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 in iduals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.
Pedigree with frontotemporal lobar degeneration--motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2008
Abstract: Frontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND. Clinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing. Neuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected in iduals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one in idual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree. Our reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.
Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease
Publisher: Wiley
Date: 28-10-2010
DOI: 10.1002/ANA.22274
Abstract: Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes. A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected in iduals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation. We identified a nonpolymorphic mutation (c.672*51G>T) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected in iduals from the FTLD-MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold. SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.
Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer’s disease
Publisher: Oxford University Press (OUP)
Date: 15-02-2018
DOI: 10.1093/BRAIN/AWY008
Comment: The Epidemiology of the Genetic Liability for Schizophrenia
Publisher: SAGE Publications
Date: 12-2000
DOI: 10.1080/000486700223
Novel genetic loci underlying human intracranial volume identified through genome-wide association
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/NN.4398
Functional chloride channels by mammalian cell expression of rat glycine receptor subunit
Publisher: Elsevier BV
Date: 05-1989
DOI: 10.1016/0896-6273(89)90195-5
Abstract: Cultured human cells were transfected with cloned rat glycine receptor (GlyR) 48 kd subunit cDNA. In these cells glycine elicited large chloride currents (up to 1.5 nA), which were blocked by nanomolar concentrations of strychnine. However, no corresponding high-affinity binding of [3H]strychnine was detected in membrane preparations of the transfected cells. Analysis by monoclonal antibodies specific for the 48 kd subunit revealed high expression levels of this membrane protein. After solubilization, the 48 kd subunit behaved as a macromolecular complex when analyzed by sucrose density centrifugation. Approximately 50% of the solubilized complex bound specifically to a 2-aminostrychnine affinity column, indicating the existence of low-affinity antagonist binding sites on most of the expressed GlyR protein. Thus, the 48 kd strychnine binding subunit efficiently assembles into high molecular weight complexes, resembling the native spinal cord GlyR. However, formation of functional receptor channels of high affinity for strychnine occurs with low efficiency.
The startle disease mutation Q266H, in the second transmembrane domain of the human glycine receptor, impairs channel gating
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 02-1999
DOI: 10.1124/MOL.55.2.386
Abstract: Hyperekplexia (startle disease) results from mutations in the glycine receptor chloride channel that disrupt inhibitory synaptic transmission. The Q266H missense mutation is the only hyperekplexia mutation located in the transmembrane domains of the receptor. Using recombinant expression and patch-cl ing techniques, we have investigated the functional properties of this mutation. The ability of glycine and taurine to open the channel was reduced in the mutated channel, as shown by a 6-fold shift in the concentration-response curve for both agonists. This was not accompanied by similar changes in agonist displacement of strychnine binding, suggesting that the mutation affects functions subsequent to ligand binding. Taurine was also converted to a weak partial agonist and antagonized the actions of glycine, consistent with changes in its channel gating efficacy. Because the Q266H mutation is within the pore-forming second transmembrane domain, we tested for a direct interaction with permeating ions. No change in either the cation/anion selectivity ratio or in single channel conductance levels was observed. No differential effects of Zn++, pH, and diethylpyrocarbonate were observed, implying that the histidine side chain is not exposed to the channel lumen. Single-channel recordings revealed a significant reduction in open times in the mutant receptors, at both high and low agonist concentrations, consistent with the open state of the channel being less stable. This study demonstrates that residues within the second transmembrane domain of ligand-gated ion channel receptors, even those whose side chains do not directly interact with permeating ions, can affect the kinetics of channel gating.
Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2006
Abstract: A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P=0.0002, summary odds ratio=2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative beta-catenin binding sites. Expression of Fat, Catnb (beta-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P=0.027), and Catnb and Enah were significantly upregulated (P=0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P=0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.
A Psycho‐Educational Intervention for People with a Family History of Depression: Pilot Results
Publisher: Wiley
Date: 29-09-2016
DOI: 10.1007/S10897-016-0011-5
Abstract: We developed and pilot-tested the first online psycho-educational intervention that specifically targets people with a family history of depression ('LINKS'). LINKS provides genetic risk information and evidence-rated information on preventive strategies for depression and incorporates a risk assessment tool and several videos using professional actors. LINKS was pilot-tested in the general practitioner (GP) setting. The patient s le included people with a family history of at least one first-degree relative (FDR) with major depressive disorder (MDD) or bipolar disorder (BD). Patients attending participating GP practices were invited to enroll in the study by letter from their GP. Patients who self-identified as having at least one first-degree relative (FDR) with MDD or BD were eligible. Patients completed questionnaires, pre-post viewing LINKS, with measures assessing satisfaction, relevance, emotional impact and perceived improvement of understanding. Six GP practices participated, and 24 patients completed both questionnaires. Of these, all reported that they were satisfied or very satisfied with LINKS, and 74 % reported that LINKS met their expectations, and 21 % that it exceeded their expectations. LINKS was judged highly acceptable by this s le of GP attendees, and results indicate that an assessment of its effectiveness in a larger controlled trial is warranted.
The pattern of atrophy in familial Alzheimer disease: Volumetric MRI results from the DIAN study
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-09-2013
Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17
Publisher: Springer Science and Business Media LLC
Date: 06-1998
DOI: 10.1038/31508
Abstract: Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11 the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.
Mutation of an arginine residue in the human glycine receptor transforms beta-alanine and taurine from agonists into competitive antagonists.
Publisher: Elsevier BV
Date: 1995
DOI: 10.1016/0896-6273(95)90251-1
Abstract: Agonist binding to the inhibitory glycine receptor (GlyR) initiates the opening of a chloride-selective channel that modulates the neuronal membrane potential. Point mutations of the GlyR, substituting Arg-271 with either Leu or Gln, have been shown to underlie the inherited neurological disorder startle disease (hyperekplexia). We show that these substitutions result in the redistribution of GlyR single-channel conductances to lower conductance levels. Additionally, the binding of the glycinergic agonists beta-alanine and taurine to mutated GlyRs does not initiate a chloride current, but instead competitively antagonizes currents activated by glycine. These findings are consistent with mutations of Arg-271 resulting in the uncoupling of the agonist binding process from the channel activation mechanism of the receptor.
Two-Dimensional Genome Scan Identifies Multiple Genetic Interactions in Bipolar Affective Disorder
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.BIOPSYCH.2009.10.022
Abstract: Bipolar disorder is a highly heritable psychiatric condition, the etiology of which remains largely unknown despite extensive efforts to identify susceptibility genes. Interactions between genes of small in idual effect could partially explain the difficulties of traditional one-dimensional approaches to identify genetic risk factors. A nonparametric linkage (NPL) analysis of 65 Australian extended pedigrees containing 643 genotyped in iduals (of whom 40% were diagnosed with affective disorder) was conducted. Chromosome-by-chromosome correlation analysis of family-specific NPL scores was conducted to detect evidence of genetic interaction. Interaction-specific multipoint NPL and permutation analysis was used to assess linkage interdependence, using family weights derived from the alternative interacting chromosome. Finally, a single nucleotide analysis of each interaction region was conducted using the publicly available genome-wide association, datasets (2933 cases, 2534 controls). Significant NPL peaks were detected on chromosomes 2q24-33, 7q21-31, and 17q11-25 (Z = 3.12, 3.01, and 2.95 respectively), with four additional suggestive peaks identified. Four robust interchromosomal interaction clusters exceeding Bonferroni correction at alpha = .05 (uncorrected p < 5.38e-07) were detected on 11q23-25-2p15-12, 4q32-35-1p36, 12q23-24-4p16-15, and 20q13-9q21-22. This linkage interdependence was determined significant after permutation analysis (p = .002-.0002). A suggestive interaction was observed in the combined data on 2p14-11q23 (uncorrected p = 5.76E-10, Bonferroni corrected p = .068). This study indicates a complex interplay between multiple loci underlying bipolar disorder susceptibility, and highlights the continuing usefulness of extended pedigrees in complex genetics. The challenge lies in the identification of specific gene interactions and their biological validation.
PARK2 mutations and clinical features in a Chinese population with early-onset Parkinson's disease.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2008
DOI: 10.1007/S00702-007-0011-6
Abstract: Our aim was to characterise PARK2 mutations and clinical features in Hong Kong Chinese with early-onset Parkinson's disease. Subjects were recruited from two major hospitals. Detailed data included demographics, age of onset, duration of disease, neurological manifestations, complications and disease severity. Genetic analysis for PARK2 mutations was performed. Thirty-four patients were recruited (mean age of onset = 39 years mean duration of disease = 10 years). Seven patients reported a family history. The salient clinical manifestations were resting tremor (33/34), bradykinesia (33/34), rigidity (30/34), postural instability (20/34), good response to L-dopa (33/34), asymmetry at onset (31/34) and sleep benefit (12/34). Motor complications were reported in a significant number of patients, and depression was the most common nonmotor complication. Five patients were identified to have PARK2 mutations. Two sisters were compound heterozygotes for an insertion and a deletion, a novel and rare 1 bp insertion/nonsense mutation c1378_1379insG (exon 12) and the entire deletion of exon 7. Another patient was homozygous for the entire deletion of exon 6. Two carriers were identified, one with a T1321C (Cys441Arg) missense mutation in exon 12 and another with a snp within intron 4. Our study reviewed a higher prevalence of PARK2 mutations in Chinese than that previously documented. A compound heterozygous mutation within two sisters with significant differences in age of onset and phenotypic manifestations suggest that modifier affects may be present in this family.
Glycine vs GABA receptors [4]
Publisher: Springer Science and Business Media LLC
Date: 11-1987
DOI: 10.1038/330025B0
Abstract: Acute right hemidiaphragm rupture with abdominal visceral herniation is reportedly less common than on the left. We present a complex case of blunt rupture of the right hemidiaphragm with herniation of the right colon and right lobe of the liver in a multiply injured patient. The diagnostic approach, with specific reference to the imaging studies, and surgical management is discussed, followed by a brief literature review highlighting the complexities of the case.
Attitudes to genetic testing in families with multiple cases of bipolar disorder.
Publisher: Mary Ann Liebert Inc
Date: 06-2008
Abstract: This study assesses interest in genetic testing for gene variations associated with bipolar disorder and associated information needs. Two hundred in iduals (95 unaffected and 105 affected with either bipolar disorder, schizoaffective disorder--manic type, or recurrent major depression) from families with multiple cases of bipolar disorder were assessed, using mailed, self-administered questionnaires. The percentage of participants reporting interest in genetic testing was associated with the degree of certainty with which any test would indicate the development of bipolar disorder. Interest in genetic testing, given a 25% lifetime risk scenario, was lowest (with 77% of participants indicating interest), and highest for the 100% lifetime risk scenario (92%). Eighty percent of participants indicated interest in genetic testing of their own children of these 30% reported wanting their children tested at birth, and 33% in early childhood. Forty-one percent of participants reported that they would be interested in preimplantation genetic diagnosis, and 54% in prenatal testing. The possibility of ascertainment bias cannot be ruled out. Interest in hypothetical genetic testing for bipolar disorder may not necessarily translate into actual utilization. These results indicate that uptake of genetic testing for genotyping for low-risk alleles related to bipolar disorder is likely to be lower than for testing for high-penetrance gene mutations that follow Mendelian inheritance. The discrepancy between the desired age of testing children and the accepted current practice may be a source of distress and conflict for parents and health professionals alike.
Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity
Publisher: Springer Science and Business Media LLC
Date: 17-04-2012
DOI: 10.1038/TP.2012.25
Specific roles for the asparagine-linked carbohydrate residues of recombinant human follicle stimulating hormone in receptor binding and signal transduction
Publisher: The Endocrine Society
Date: 06-1994
Abstract: FSH comprises two distinct subunits, both of which contain asparagine-linked carbohydrate residues, located at positions 52 and 78 on the alpha-subunit and positions 7 and 24 on the beta-subunit. These carbohydrate chains have been shown to regulate the biological activity of FSH, including signal transduction and receptor binding. However, the specific roles of the in idual carbohydrate chains have been poorly defined. Using site-directed mutagenesis we disrupted the consensus sequences for glycosylation and expressed the mutated cDNAs in Chinese Hamster Ovary cells. Specifically deglycosylated FSH variants were secreted from all clonal cell lines expressing the mutated FSH cDNAs except for the cell line that lacked all four glycosylation sites. Analysis of the singly or doubly deglycosylated FSH mutants revealed that removal of the carbohydrate residue at position 78 on the alpha-subunit significantly increased the receptor binding affinity of human FSH by 72%. Removal of the other carbohydrate residues had no significant effect on receptor binding. The carbohydrate residue at position 52 on the alpha-subunit was found to play an essential role in signal transduction as its removal resulted in a significant decrease in potency to 26% of wild type levels. The other in idual carbohydrate residues appear to play a minor role in signal transduction, although removal of each residue results in reduced maximal response. The removal of both alpha-subunit carbohydrates resulted in a significant decrease in biopotency, to 41% of wild type levels whereas, the removal of both beta-subunit carbohydrate chains resulted in a significant increase in biopotency, to 216% of wild type levels. These studies have allowed the identification of site-specific roles for the carbohydrate residues of human FSH. Our data suggest that the carbohydrate residues play a greater role in determining the biological activity of FSH than has been suggested in similar studies of other glycoprotein hormones.
Cerebral small vessel disease genomics and its implications across the lifespan
Publisher: Springer Science and Business Media LLC
Date: 08-12-2020
DOI: 10.1038/S41467-020-19111-2
Abstract: White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older in iduals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk in iduals and for genetically-informed prioritization of drug targets for prevention trials.
The TWIN-E Project in Emotional Wellbeing: Study Protocol and Preliminary Heritability Results Across Four MRI and DTI Measures
Publisher: Cambridge University Press (CUP)
Date: 06-2012
DOI: 10.1017/THG.2012.12
Abstract: Despite the significant advancements being made in the neurogenetics for mental health, the identification and validation of potential endophenotype markers of risk and resilience remain to be confirmed. The TWIN-E study (The Twin study in Wellbeing using Integrative Neuroscience of Emotion) aims to validate endophenotype markers of mental health across cognitive, brain, and autonomic measures by testing the heritability, clinical plausibility, and reliability of each of these measures in a large adult twin cohort. The specific gene and environmental mechanisms that moderate prospective links between endophenotype-phenotype markers and the final outcome of wellbeing will also be identified. TWIN-E is a national prospective study with three phases: I) baseline testing on a battery of online questionnaires and cognitive tasks, and EEG, MRI, and autonomic testing II) 12-month follow-up testing on the online assessments and III) randomized controlled trial of brain training. Minimum target numbers include 1,500 male/female twins (18–65 years) for the online assessments (Phase I and II), 300 twins for the EEG testing component, and 244 twins for the MRI testing component. For Phase III, each twin out of the pair will be randomized to either the treatment or waitlist control group to test the effects of brain training on mental health over a 30-day period, and to confirm the gene–environment and endophenotype contributions to treatment response. Preliminary heritability results are provided for the first 50% of the MRI subgroup ( n = 142) for the grey matter volume, thickness, and surface area measures, and white matter diffuse tensor imaging fractional anisotropy.
Carbon–concentration and carbon–climate feedbacks in CMIP6 models and their comparison to CMIP5 models
Publisher: Copernicus GmbH
Date: 18-08-2020
Abstract: Abstract. Results from the fully and biogeochemically coupled simulations in which CO2 increases at a rate of 1 % yr−1 (1pctCO2) from its preindustrial value are analyzed to quantify the magnitude of carbon–concentration and carbon–climate feedback parameters which measure the response of ocean and terrestrial carbon pools to changes in atmospheric CO2 concentration and the resulting change in global climate, respectively. The results are based on 11 comprehensive Earth system models from the most recent (sixth) Coupled Model Intercomparison Project (CMIP6) and compared with eight models from the fifth CMIP (CMIP5). The strength of the carbon–concentration feedback is of comparable magnitudes over land (mean ± standard deviation = 0.97 ± 0.40 PgC ppm−1) and ocean (0.79 ± 0.07 PgC ppm−1), while the carbon–climate feedback over land (−45.1 ± 50.6 PgC ∘C−1) is about 3 times larger than over ocean (−17.2 ± 5.0 PgC ∘C−1). The strength of both feedbacks is an order of magnitude more uncertain over land than over ocean as has been seen in existing studies. These values and their spread from 11 CMIP6 models have not changed significantly compared to CMIP5 models. The absolute values of feedback parameters are lower for land with models that include a representation of nitrogen cycle. The transient climate response to cumulative emissions (TCRE) from the 11 CMIP6 models considered here is 1.77 ± 0.37 ∘C EgC−1 and is similar to that found in CMIP5 models (1.63 ± 0.48 ∘C EgC−1) but with somewhat reduced model spread. The expressions for feedback parameters based on the fully and biogeochemically coupled configurations of the 1pctCO2 simulation are simplified when the small temperature change in the biogeochemically coupled simulation is ignored. Decomposition of the terms of these simplified expressions for the feedback parameters is used to gain insight into the reasons for differing responses among ocean and land carbon cycle models.
THE INTEGRATE MODEL OF EMOTION, THINKING AND SELF REGULATION: AN APPLICATION TO THE PARADOX OF AGING
Publisher: World Scientific Pub Co Pte Lt
Date: 09-2008
DOI: 10.1142/S0219635208001939
Abstract: This study was undertaken using the INTEGRATE Model of brain organization, which is based on a temporal continuum of emotion, thinking and self regulation. In this model, the key organizing principle of self adaption is the motivation to minimize danger and maximize reward. This principle drives brain organization across a temporal continuum spanning milliseconds to seconds, minutes and hours. The INTEGRATE Model comprises three distinct processes across this continuum. Emotion is defined by automatic action tendencies triggered by signals that are significant due to their relevance to minimizing danger-maximizing reward (such as abrupt, high contrast stimuli). Thinking represents cognitive functions and feelings that rely on brain and body feedback emerging from around 200 ms post-stimulus onwards. Self regulation is the modulation of emotion, thinking and feeling over time, according to more abstract adaptions to minimize danger-maximize reward. Here, we examined the impact of dispositional factors, age and genetic variation, on this temporal continuum. Brain Resource methodology provided a standardized platform for acquiring genetic, brain and behavioral data in the same 1000 healthy subjects. Results showed a "paradox" of declining function in the "thinking" time scale over the lifespan (6 to 80+ years), but a corresponding preservation or even increase in automatic functions of "emotion" and "self regulation". This paradox was paralleled by a greater loss of grey matter in cortical association areas (assessed using MRI) over age, but a relative preservation of subcortical grey matter. Genetic polymorphisms associated with both healthy function and susceptibility to disorder (including the BDNFVal(66)Met, COMTVal(158/108)Met, MAOA and DRD4 tandem repeat and 5HTT-LPR polymorphisms) made specific contributions to emotion, thinking and self regulatory functions, which also varied according to age.
Diagnosis of bipolar disorders and body mass index predict clustering based on similarities in cortical thickness—ENIGMA study in 2436 individuals
Publisher: Wiley
Date: 16-12-2021
DOI: 10.1111/BDI.13172
Abstract: Rates of obesity have reached epidemic proportions, especially among people with psychiatric disorders. While the effects of obesity on the brain are of major interest in medicine, they remain markedly under‐researched in psychiatry. We obtained body mass index (BMI) and magnetic resonance imaging‐derived regional cortical thickness, surface area from 836 bipolar disorders (BD) and 1600 control in iduals from 14 sites within the ENIGMA‐BD Working Group. We identified regionally specific profiles of cortical thickness using K‐means clustering and studied clinical characteristics associated with in idual cortical profiles. We detected two clusters based on similarities among participants in cortical thickness. The lower thickness cluster (46.8% of the s le) showed thinner cortex, especially in the frontal and temporal lobes and was associated with diagnosis of BD, higher BMI, and older age. BD in iduals in the low thickness cluster were more likely to have the diagnosis of bipolar disorder I and less likely to be treated with lithium. In contrast, clustering based on similarities in the cortical surface area was unrelated to BD or BMI and only tracked age and sex. We provide evidence that both BD and obesity are associated with similar alterations in cortical thickness, but not surface area. The fact that obesity increased the chance of having low cortical thickness could explain differences in cortical measures among people with BD. The thinner cortex in in iduals with higher BMI, which was additive and similar to the BD‐associated alterations, may suggest that treating obesity could lower the extent of cortical thinning in BD.
A meta-analysis of the risk of major affective disorder in relatives of individuals affected by major depressive disorder or bipolar disorder
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.JAD.2014.01.014
Abstract: To conduct a meta-analysis to estimate the incidence of major depressive disorder (MDD) and bipolar disorder (BD) in first-degree relatives (FDRs) of probands affected by MDD or BD. The risk for MDD in FDR of BD probands and vice versa is also investigated. A systematic review of case-control and cohort studies, which were published between 1977 and 2012 reported relative risks (RR) or odd ratios (OR) or equivalent raw data made an explicit distinction between MDD and BD used operational diagnostic criteria and reported systematic proband recruitment and ascertainment of relatives. Studies were obtained by electronic MEDLINE and EMBASE searches and hand-searching. Estimates were derived from pooled data using random effects methods. Of an initial s le of 241 articles, 22 were eligible for inclusion. For FDRs of one proband with MDD compared to healthy control probands, estimates for MDD were OR=2.14 (95% CI 1.72-2.67), increasing to OR=3.23 (95% CI 2.11-4.94) for two MDD probands. For FDRs of one BD proband compared to healthy control probands, estimates for BD were OR=7.92 (95% CI 2.45-25.61), and OR=6.58 (95% CI 2.64-16.43) for FDRs of two BD probands. These findings support previously published data indicating strong familiality for both MDD and BD. Data will be useful in providing in iduals with a family history of MDD or BPD with tailored risk estimates.
Genetics of dementia
Publisher: Oxford University Press
Date: 28-02-2012
Human adenosine A2a receptor (A2aAR) gene: systematic mutation screening in patients with schizophrenia
Publisher: Springer Science and Business Media LLC
Date: 12-1996
DOI: 10.1007/BF01271259
Abstract: In neuro-rehabilitation, the assessment of post-stroke patients' motor function of damaged upper extremities (UEs) is essential. Clinicians need clear and concise assessment instruments to monitor progress recorded in intensive rehabilitation sessions. One such instrument is Manual Muscle Testing (MMT), which, in our view, requires a modified scoring model aimed at improving the assessment process of patients' motor and functional UE status, and recording their step-by-step-progress, especially if patients undergo a short length of hospitalization (of about 10 therapy days). Hence, this paper presents a new scoring system developed by the authors. This systemresults in a more precise MMT grading scale, which has more grades and can provide a more specific muscular assessment, while offering more clarity in quantifying patients' progress after physical therapy. A prospective study was made of 41 post-stroke patients with upper extremity (UE) impairments. To determine the validity of the assessment tool for hypothesizing, and the unidimensionality and internal consistency of the customized model, exploratory and confirmatory factor analysis (CFA) with a structural equation model (SEM), Cronbach's Alpha, and Pearson correlation coefficients were used with Fugl-Meyer (FM) assessments, the Modified Ashworth Scale (MAS), AROM, and the Modified Rankin Scale (MRS). Considering the unidimensionality of the instrument used, we performed a linear regression to identify whether certain movements performed segmentally by the manually evaluated muscles influence the measured manual score of the whole UE. All indices suggested a good model fit, and a Cronbach's Alpha of 0.920 suggested strong internal consistency. The Pearson correlation coefficient of the MMT-customized score with AROM was 0.857,
What now for Alzheimer's disease? An epidemiological evaluation of the AD2000 trial
Publisher: Therapeutic Guidelines Limited
Date: 12-2005
Consistency of denominator data in electronic health records in Australian primary healthcare services: enhancing data quality
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/PY14071
Abstract: The quality of data derived from primary healthcare electronic systems has been subjected to little critical systematic analysis, especially in relation to the purported benefits and substantial investment in electronic information systems in primary care. Many indicators of quality of care are based on numbers of certain types of patients as denominators. Consistency of denominator data is vital for comparison of indicators over time and between services. This paper examines the consistency of denominator data extracted from electronic health records (EHRs) for monitoring of access and quality of primary health care. Data collection and analysis were conducted as part of a prospective mixed-methods formative evaluation of the Commonwealth Government’s Indigenous Chronic Disease Package. Twenty-six general practices and 14 Aboriginal Health Services (AHSs) located in all Australian States and Territories and in urban, regional and remote locations were purposively selected within geographically defined locations. Percentage change in reported number of regular patients in general practices ranged between –50% and 453% (average 37%). The corresponding figure for AHSs was 1% to 217% (average 31%). In approximately half of general practices and AHSs, the change was ≥20%. There were similarly large changes in reported numbers of patients with a diagnosis of diabetes or coronary heart disease (CHD), and Indigenous patients. Inconsistencies in reported numbers were due primarily to limited capability of staff in many general practices and AHSs to accurately enter, manage, and extract data from EHRs. The inconsistencies in data required for the calculation of many key indicators of access and quality of care places serious constraints on the meaningful use of data extracted from EHRs. There is a need for greater attention to quality of denominator data in order to realise the potential benefits of EHRs for patient care, service planning, improvement, and policy. We propose a quality improvement approach for enhancing data quality.
Metabolomic and lipidomic signatures in autosomal dominant and late‐onset Alzheimer's disease brains
Publisher: Wiley
Date: 17-10-2022
DOI: 10.1002/ALZ.12800
Abstract: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP , PSEN1 , and PSEN2 (autosomal dominant AD ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. APP / PSEN1 / PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β‐citrylglutamate is differentially abundant in autosomal dominant, TREM2 , and sporadic AD. A 16‐metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.
BDNF Val66Met polymorphism is associated with body mass index in healthy adults
Publisher: S. Karger AG
Date: 2006
DOI: 10.1159/000093341
Abstract: Although recent studies suggest a possible relationship between the brain-derived neurotrophic factor Val66Met polymorphism and eating disorders, no study has examined the possibility that the Met-Met genotype is associated with a lower body mass index (BMI) in healthy in iduals. We examined this possibility in 481 adults (age range 18–82 years) without significant medical or psychiatric history. After adjusting for gender, analysis of covariance showed that persons with the Met-Met genotype had a lower BMI than those with the Val-Met/Val-Val genotypes (22.28 ± 3.77 vs. 24.72 ± 4.81). A similar, though nonsignificant, trend emerged when comparing all three genotypes separately. These findings suggest a possible relationship between Val66Met polymorphism and BMI in healthy adults. Further work is needed to clarify possible mechanisms for this relationship.
Molecular cloning and expression of a chloride ion channel of cell nuclei
Publisher: Elsevier BV
Date: 05-1997
Predicted structure of the extracellular region of ligand-gated ion-channel receptors shows SH2-like and SH3-like domains forming the ligand-binding site
Publisher: Wiley
Date: 05-1997
Abstract: Fast synaptic neurotransmission is mediated by ligand-gated ion-channel (LGIC) receptors, which include receptors for acetylcholine, serotonin, GABA, glycine, and glutamate. LGICs are pentamers with extracellular ligand-binding domains and form integral membrane ion channels that are selective for cations (acetylcholine and serotonin 5HT3 receptors) or anions (GABAA and glycine receptors and the invertebrate glutamate-binding chloride channel). They form a protein superfamily with no sequence similarity to any protein of known structure. Using a 1D-3D structure mapping approach, we have modeled the extracellular ligand-binding domain based on a significant match with the SH2 and SH3 domains of the biotin repressor structure. Refinement of the model based on knowledge of the large family of SH2 and SH3 structures, sequence alignments, and use of structure templates for loop building, allows the prediction of both monomer and pentamer models. These are consistent with medium-resolution electron microscopy structures and with experimental structure/function data from ligand-binding, antibody-binding, mutagenesis, protein-labeling and subunit-linking studies, and glycosylation sites. Also, the predicted polarity of the channel pore calculated from electrostatic potential maps of pentamer models of superfamily members is consistent with known ion selectivities. Using the glycine receptor alpha 1 subunit, which forms homopentamers, the monomeric and pentameric models define the agonist and antagonist (strychnine) binding sites to a deep crevice formed by an extended loop, which includes the invariant disulfide bridge, between the SH2 and SH3 domains. A detailed binding site for strychnine is reported that is in strong agreement with known structure/function data. A site for interaction of the extracellular ligand-binding domain with the activation of the M2 transmembrane helix is also suggested.
Renin-Angiotensin system genetic polymorphisms and brain white matter lesions in older australians.
Publisher: Oxford University Press (OUP)
Date: 12-03-2014
DOI: 10.1093/AJH/HPU035
Abstract: White matter lesions (WMLs), seen as hyperintensities on T2-weighted magnetic resonance imaging brain scans, are common in the brains of healthy older in iduals. They are thought to be related to cerebral small vessel disease and to have a genetic component to their aetiology, and hypertension is thought to be an important risk factor. Genetic polymorphisms in hypertension-related genes may therefore be associated with the formation of WMLs. In this study, a s le of 445 Australians aged 60-65 years was drawn from a larger longitudinal epidemiological study, the Personality and Total Health Through Life Project. The associations of single nucleotide polymorphisms (SNPs) in the genes encoding angiotensinogen (AGT, rs699), angiotensin-converting enzyme (ACE, rs4362), and angiotensin II receptor type 1 (AGTR1, rs5182) with WMLs were examined. No in idual SNPs showed a significant association with WMLs for the whole s le. When the cohort was stratified by sex, ACE rs4362 and AGT rs699 showed significant associations with WMLs in men only (P = 0.01 and P = 0.03, respectively), and remained significant after controlling for hypertension. Although the AGTR1 SNP did not show any association with WMLs, the interaction of the AGT rs699 and AGTR1 rs5182 SNPs with WMLs was significant before (P = 0.03) and after adjustment for hypertension (P = 0.045). The results provide evidence for association of polymorphisms in the renin-angiotensin system genes with WMLs, independent of hypertension. Male-only associations with WMLs were found for the AGT rs699 and ACE rs362 polymorphisms. Moreover, for the entire s le an interaction between AGT and AGTR1 rs5182 genotypes on WMLs was observed.
Identifying Environmental Determinants Relevant to Health and Wellbeing in Remote Australian Indigenous Communities: A Scoping Review of Grey Literature
Publisher: MDPI AG
Date: 15-04-2021
Abstract: The high prevalence of preventable infectious and chronic diseases in Australian Indigenous populations is a major public health concern. Existing research has rarely examined the role of built and socio-political environmental factors relating to remote Indigenous health and wellbeing. This research identified built and socio-political environmental indicators from publicly available grey literature documents locally-relevant to remote Indigenous communities in the Northern Territory (NT), Australia. Existing planning documents with evidence of community input were used to reduce the response burden on Indigenous communities. A scoping review of community-focused planning documents resulted in the identification of 1120 built and 2215 socio-political environmental indicators. Indicators were systematically classified using an Indigenous indicator classification system (IICS). Applying the IICS yielded indicators prominently featuring the “community infrastructure” domain within the built environment, and the “community capacity” domain within the socio-political environment. This research demonstrates the utility of utilizing existing planning documents and a culturally appropriate systematic classification system to consolidate environmental determinants that influence health and disease occurrence. The findings also support understanding of which features of community-level built and socio-political environments amenable to public health and social policy actions might be targeted to help reduce the prevalence of infectious and chronic diseases in Indigenous communities.
Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)
Publisher: Elsevier BV
Date: 12-2016
Analysis of shared heritability in common disorders of the brain
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-06-2018
Abstract: Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric and neurologic disorders share relatively little common genetic risk. However, different and independent pathways can result in similar clinical manifestations (e.g., psychosis, which occurs in both schizophrenia and Alzheimer's disease). Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn's disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Science , this issue p. eaap8757
Specific and common genes implicated across major mental disorders: A review of meta-analysis studies
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.JPSYCHIRES.2014.09.014
Abstract: Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for in idual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress.
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