Biomedical subjects

Peter R Schofield

Publications and source records attributed to Peter R Schofield.

At least 19 recordsLinked to original sources

PubMed2012

Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Age of Onset↗

PubMed2006

Serotonin transporter gene status predicts caudate nucleus but not amygdala or hippocampal volumes in older persons with major depression.

BACKGROUND: 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. METHODS: 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, hippocampus, caudate and putamen were determined by reliable tracing techniques. RESULTS: In those with depression, the short allele of 5-HTT was associated with smaller caudate nucleus volumes. Although hippocampal 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. LIMITATIONS: The findings are limited by the number of clinical and control participants. CONCLUSIONS: 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.

Aged↗

PubMed2006

Distinct physiological mechanisms underlie altered glycinergic synaptic transmission in the murine mutants spastic, spasmodic, and oscillator.

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) amplitude and frequency were dramatically reduced (>50%) 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 alpha1-containing GlyRs; however, some non-alpha1-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 microM), indicating alpha1 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" alpha1 homomeric GlyRs at extrasynaptic loci.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2006

Djinn Lite: a tool for customised gene transcript modelling, annotation-data enrichment and exploration.

BACKGROUND: 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 diverse 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. RESULTS: 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. CONCLUSION: Gene annotating remains an ongoing and challenging task that will continue as gene structures, gene transcription repertoires, disease loci, protein products and their interactions become more precisely defined. Djinn Lite offers an accessible interface to help accumulate, enrich, and individualize 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.

Alternative Splicing↗

PubMed2006

Differences in regional brain atrophy in genetic forms of Alzheimer's disease.

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 hippocampal 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.

Adult↗

PubMed2006

Mutations in progranulin explain atypical phenotypes with variants in MAPT.

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.

Base Sequence↗

PubMed2006

Life events, first depression onset and the serotonin transporter gene.

BACKGROUND: A relationship between the serotonin transporter gene, adverse events and onset of major depression has been reported. AIMS: To replicate a gene x environment interaction in a cohort with longitudinal data for life events, experience of depression, parental bonding and neuroticism. METHOD: At the 25-year follow-up, genomic DNA was obtained from 127 cohort members (mean age 48 years) to determine the genotype of the serotonin transporter gene-linked promoter region (5-HTTLPR). Associations were investigated between the 5-HTTLPR genotype, positive and adverse life events and the gene x environment interaction, and also between the 5-HTTLPR genotype and risk factors for depression. RESULTS: No relationship was found between 5-HTTLPR genotype and either risk factors for depression or positive life events. Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype. CONCLUSIONS: The 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events. This is one of the more robust findings concerning specific biological risk factors for depression.

Adult↗

PubMed2005

A Western Australian kindred with Dutch cerebral amyloid angiopathy.

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.

Aged↗

PubMed2005

Altered gene expression in mice treated with the mood stabilizer sodium valproate.

Valproate is now the most widely prescribed mood-stabilizing drug and is being used increasingly in the treatment of bipolar disorder. However, the mechanism of action for valproate remains unclear. Microarray analysis was used to identify genes and cellular pathways that are affected in the mouse brain after treatment with valproate at human therapeutic concentrations. This study has identified 11 genes that are differentially expressed by >or=2-fold when compared to control untreated mice. Altered expression of four of these genes was also validated by quantitative PCR analysis. Valproate was found to significantly decrease the expression of zinc finger protein of the cerebellum 1 (ZIC1) and increase the expression of Scm-related gene containing four mbt domains (SFMBT2), structural maintenance of chromosome 4-like 1 (SCM4L1), and prostate apoptosis response-4 (PAR-4). Many of the genes identified are involved in the development and function of the brain. These results indicate that valproate regulates a large number of different functional pathways in the brain. Understanding the molecular and cellular mechanisms by which valproate achieves its therapeutic action represents a valuable step in clarifying the pathophysiology of bipolar disorder.

Animals↗

PubMed2005

Association analysis of transcripts from the bipolar susceptibility locus on chromosome 4q35, exclusion of a pathogenic role for eight positional candidate genes.

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 individuals 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.

Alleles↗

PubMed2005

Pick bodies in a family with presenilin-1 Alzheimer's disease.

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.

Aged↗

PubMed2005

GSK3B polymorphisms alter transcription and splicing in Parkinson's disease.

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 individuals: odds ratio, 1.64; p = 0.007; (H1/H1 individuals: 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.

Aged↗

PubMed2005

Implications of genetic risk information in families with a high density of bipolar disorder: an exploratory study.

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 sample 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 individual 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.

Adolescent↗

PubMed2005

Techniques for the identification of genes involved in psychiatric disorders.

OBJECTIVE: Most psychiatric disorders are complex genetic traits involving both genetic and environmental risk factors. This paper aims to review the gene identification strategies being applied by molecular geneticists in their efforts to elucidate the genetic and molecular basis of psychiatric disorders. Future strategies will also be canvassed. METHOD: The psychiatric genetic literature was reviewed to identify current strategies applied to gene identification, with examples provided where available. The future strategies and applications that will arise from genome projects, including the International Haplotype Mapping Project, are also discussed. RESULTS: Many advances in the techniques of gene discovery, and the increasing resources available, are rapidly being adopted by researchers and applied to the complex problem of identifying susceptibility genes for mental illnesses. Perhaps the single most important advance to date is the Human Genome Project and all that has stemmed from the vast quantity of information that this endeavour has provided. With these technological advances and the massive increase of publicly available genetic resources, several genes have recently been implicated in the susceptibility to psychiatric illnesses including schizophrenia and depression. After many years of fruitless endeavours, these recent reports indicate that the labours of researchers in psychiatric genetics are beginning to show exciting results. CONCLUSIONS: Identification of these susceptibility genes holds great promise, with the unravelling of the molecular and biochemical basis of some conditions now being a more realistic and tangible goal. The increasing number of genes being identified augers well for the future treatment of psychiatric disorders. The genes identified, and the pathways of genes and proteins that they implicate, will provide potential novel targets for new therapeutic drugs. Psychiatric genetics appears to be poised for significant advances in our knowledge and understanding of the molecular genetic basis of mental illness.

Chromosome Mapping↗

PubMed2005

Identification, characterization, and association analysis of novel genes from the bipolar disorder susceptibility locus on chromosome 4q35.

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.

Bipolar Disorder↗

PubMed2004

Mechanisms of channel gating of the ligand-gated ion channel superfamily inferred from protein structure.

The nicotinic-like ligand-gated ion channel superfamily consists of a group of structurally related receptors that activate an ion channel after the binding of extracellular ligand. The recent publications of the crystal structure of an acetylcholine binding protein and a refined electron micrograph structure of the membrane-bound segment of an acetylcholine receptor have led to insights into the molecular determinants of receptor function. Although the structures confirmed much biochemical and electrophysiological data obtained about the receptors, they also provide opportunities to study further the mechanisms that allow channel activation stimulated by ligand-binding. Here we review the mechanisms of channel gating that have been elucidated by information gained from the structures of the acetylcholine binding protein and membrane-bound segment of the acetylcholine receptor.

Acetylcholine↗

PubMed2004

Tau haplotypes regulate transcription and are associated with Parkinson's disease.

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.

Adult↗

PubMed2004

Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies.

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 individuals with clinical features consistent with FTD and other tauopathies were referred over a three year period. There was neuropathological confirmation of disease in 30%. Individuals 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.

Adult↗