Search PubMed⌕ Search

Biomedical subjects

S Lovestone

Publications and source records attributed to S Lovestone.

At least 73 records · Page 4Linked to original sources
PubMed1998

Abnormalities of Wnt signalling in schizophrenia--evidence for neurodevelopmental abnormality.

The Wnt signalling pathway is central to normal brain development in vertebrates and invertebrates and mediates cell fate determination, cell adhesion and cell proliferation. However, its relevance to disorders of cerebral development in man is untested. We evaluated the potential involvement of the Wnt signalling pathway in schizophrenia, a disorder of neurodevelopment origin in which alterations in neuronal lamination and orientation have been described. Using immunohistochemistry and semi-quantitative rating scales, we examined the distribution of two components of the Wnt signalling pathway, beta-catenin and gamma-catenin in the hippocampus and subiculum of 12 schizophrenic (DSMIIR criteria) and 14 control subjects. Both catenins were distributed as intraneuronal diffuse and/or ring shaped forms. The diffuse staining of both forms catenin were reduced in the CA3 and beta-catenin was also reduced in the CA4 hippocampal subregion among schizophrenic subjects. These alternations may represent the basis of the developmental brain abnormalities found in schizophrenia and would have functionally important consequences in the adult.

Adult↗
PubMed1998

Apolipoprotein E: depressive illness, depressive symptoms, and Alzheimer's disease.

BACKGROUND: The apolipoprotein E (ApoE) epsilon 4 and epsilon 2 alleles may influence the age of onset of depressive illness. Depressive illness of late onset is also a risk factor for Alzheimer's disease (AD), and there is some evidence that the ApoE epsilon 2 allele is associated with depressive symptomatology in AD. Depressive symptomatology in AD may thus share common genetic risk factors with late-onset depressive illness. METHODS: The frequency of the epsilon 2 and epsilon 4 alleles of ApoE and their effects on age of onset of disease in three independent groups of subjects, with depressive illness, with AD, and controls, were compared in a defined population from Southeast London. RESULTS: The frequency of the ApoE epsilon 2 allele was significantly lower in the depressive illness group compared with the control group and was associated with a later mean age at onset. Subjects with depressive symptomatology in AD had a higher frequency of the ApoE epsilon 2 allele and had a significantly later age of onset of depressive illness compared with the nondepressed AD group. CONCLUSIONS: The presence of the ApoE epsilon 2 allele in AD is found to be highly associated with depressive symptomatology, and it is proposed that this subgroup represents the presence of delayed depressive illness and that there are common genetic risk factors between AD and depressive illness.

Age of Onset↗
PubMed1998

Clinical predictors of aggressive behaviour in Alzheimer's disease.

OBJECTIVES: To examine the level and clinical correlates of aggressive behaviour in Alzheimer's disease (AD). METHOD: Seventy patients with probable AD were rated using validated assessment instruments including the Rating Scale for Aggressive Behaviour in the Elderly (RAGE). RESULTS: Thirty-one subjects were rated as at least mildly aggressive during the 3-day period prior to assessment. RAGE scores correlated significantly with delusions and activity disturbance scores. Aggressive behaviour was not associated with age, sex, dementia severity, hallucinations or depression. CONCLUSIONS: Aggressive behaviour occurs frequently in patients with AD. Our results confirm the findings of previous studies that the presence of delusions increases the risk of aggression in this population.

Aged↗
PubMed1998

5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease.

The psychopathology of Alzheimer's disease (AD) is varied and includes both behavioural and psychological symptoms. Behavioural and psychological symptoms are common and contribute to the difficulties experienced by carers. However, the mechanism whereby these symptoms occur in some individuals with AD is not understood. We hypothesized that common genetic polymorphisms in neurotransmitter systems are risk factors for these symptoms in the course of AD. A total of 211 subjects from a population-based prospective study of psychopathology within late-onset AD were genotyped for the 5-HT2A receptor polymorphism 102-T/C and the 5-HT2C receptor polymorphism Cys23Ser. Associations were found between the presence of the C102 allele and the presence of visual (Fisher's exact test, one-tailed, P = 0.003) and auditory hallucinations (Fisher's exact test, one-tailed, P = 0.004) and between the presence of the Ser23 allele and visual hallucinations (chi2 = 7.5, df = 1, P = 0.006) (P = 0.03, 0.04 and 0.06, respectively, after Bonferroni correction). In addition, there was an association between the Cys23Ser polymorphism and hyperphagia (chi2 = 6.7, df = 2, P = 0.03) (P = 0.3 after Bonferroni correction). We conclude that common 5-HT2A and 5-HT2C genetic polymorphisms previously showing only weak associations with psychotic illness are associated with psychotic symptoms in AD but are clinically silent until the onset of the neurodegenerative process.

Age of Onset↗
PubMed1998

Isolation and chromosomal mapping of human glycogen synthase kinase-3 alpha and -3 beta encoding genes.

Glycogen synthase kinase-3 (GSK-3) is a serine-threonine kinase that exists as two isoforms, alpha and beta, encoded by separate genes. Phosphorylation targets include a variety of cytoplasmic and nuclear proteins. Recent studies found that neurofilaments, amyloid precursor protein, and tau proteins are substrates of GSK-3 and that aberrant phosphorylation of these proteins is implicated in pathologies of the nervous system. To analyse the organisation of these two genes, a YAC library was screened by polymerase chain reaction, using primers specific for human GSK-3 alpha and GSK-3 beta cDNA. Two clones, 220 and 285 kb in size, containing the complete GSK-3 alpha coding sequence, and two clones, 365 and 285 kb in size, containing the 5' coding sequence of GSK-3 beta, were isolated. By somatic cell hybrid panel DNA amplification and radiation hybrid mapping, GSK-3 alpha was found to be located at 19q13.2. On the other hand, by somatic cell hybrid panel DNA amplification and fluorescence in situ hybridisation using the 285-kb YAC clone, GSK-3 beta was mapped to 3q13.3.

Animals↗
PubMed1997

Arylsulphatase A pseudodeficiency in vascular dementia and Alzheimer's disease.

The carrier rates of a genetic marker for arylsulphatase A pseudodeficiency (ASA-PD) were determined in three series of patients with vascular dementia (VaD) or Alzheimer's disease (AD). In the first community-based sample, the 1524 + 95A-->G mutation, which is known to be associated with ASA-PD, was present in 35% of VaD cases and none of the AD cases. In a second sample of cases drawn from a Dementia Register, the mutation rates were 18% (VaD) and 16% (AD). Brain DNA from a post-mortem sample revealed the ASA-PD mutation in 60% of VaD cases and 34% of AD cases. These rates are higher than previous studies of culturally similar populations and suggest that ASA-PD may be a risk factor for dementia.

Adenine↗
PubMed1997

Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimer's disease.

We examined a deletion/insertion promoter polymorphism of the serotonin transporter gene, which confers an approximately 40% reduction in expression of the protein, in 196 subjects with late onset Alzheimer's disease (AD) and 271 controls. The frequency of the 484 bp low activity allele was elevated in the subjects with AD (p = 0.004), and an excess of the low activity genotype (30%) was also found in comparison with the controls (20%) (chi 2 = 7.16; p = 0.03). This association was unrelated to the age of the subjects or controls, or to epsilon 4 alleles of the ApoE gene. The odds ratio for the effect of the homozygous low activity genotype was 1.7 (95% CI 1.08-2.67), with a population attributable risk of 33% (95% CI 5-54%). These findings indicate that the low activity allele of the serotonin transporter is a risk factor for late onset AD.

Age of Onset↗
PubMed1996

Association between a PS-1 intronic polymorphism and late onset Alzheimer's disease.

Previous work suggests an association between allele 1 and the 1-1 genotype of an intronic polymorphism in the presenilin-1 (PS-1) gene and late onset Alzheimer's disease. We found an excess of the 1-1 genotype in our late onset clinical sample (p = 0.006, one-tailed) but not in our postmortem confirmed sample, which instead exhibited an excess of allele 1 (p = 0.02, one-tailed). No interaction between PS-1 and ApoE genotype was detected and the findings remained significant when the effects of ApoE were taken into account (p = 0.03, one-tailed). These results suggest that the PS-1 polymorphism, or a locus in linkage disequilibrium with it, acts as a risk factor for late onset AD.

Age of Onset↗
PubMed1996

The intracellular fate of apolipoprotein E is tau dependent and apoe allele-specific.

The apolipoprotein E (apoE) gene has been identified as a susceptibility gene for Alzheimer's disease, although the mechanism whereby apoE exerts this effect has not been determined. The aim of this study was to examine the intracellular fate of apoE and we demonstrate that in mammalian cells-transiently expressing tau and the low density lipoprotein receptor, apoE is taken up from cerebrospinal fluid (CSF) and apoE3, but not apoE4, reaches the cytoplasm. This isoform difference in the intracellular distribution of apoE is dependent upon tau expression and, although tau phosphorylation was not affected by apoE, these results suggest that apoE interactions with the cytoskeleton might be important in the molecular pathogenesis of Alzheimer's disease.

Alleles↗
PubMed1996

Phosphorylation of tau by glycogen synthase kinase-3 beta in intact mammalian cells: the effects on the organization and stability of microtubules.

The phosphorylation state of tau changes during neurodevelopment and highly phosphorylated tau accumulates in the paired helical filaments found in Alzheimer's disease. In non-neuronal mammalian cells transiently expressed tau is predominantly not phosphorylated at sites known to be phosphorylated in paired helical filaments. However this pattern of phosphorylation is induced by both glycogen synthase kinase-3 alpha and -3 beta and here we show that this results in a change in the intracellular properties of tau. Within cells tau is bound to cytoskeletal structures and causes changes in cellular cytoarchitecture with the induction of thick and stable microtubule bundles. This morphology is lost when tau is co-expressed with glycogen synthase kinase-3 beta; microtubules become less stable and are not bound by tau. Independently of any direct or indirect effects on tau, glycogen synthase kinase-3 beta induces some but relatively slight changes in microtubule organization with the loss of a prominent centrosomal microtubular origin. The cytoskeleton is critical to cell function and within post-mitotic neurons has a highly specialized structure induced, in part, by the neuronal-specific microtubule-associated proteins such as tau. In vitro studies have suggested that the properties of tau are regulated by phosphorylation as highly phosphorylated tau does not promote tubulin polymer assembly. We have demonstrated, in intact cells, that tau highly phosphorylated in the presence of glycogen synthase kinase-3 beta loses the properties of microtubule binding and stabilization, suggesting that regulation of tau phosphorylation by this enzyme might be an important mechanism whereby cytoskeletal function is modulated during neurodevelopment and lost in neurodegeneration.

Animals↗
PubMed1996

Familial psychiatric presentation of Huntington's disease.

Symptoms of schizophrenia may be encountered in Huntington's disease (HD) but usually when the full clinical syndrome is apparent; prechoreic psychosis is relatively uncommon. We describe a family where all four members affected with HD presented first with a severe psychiatric syndrome, which in three cases was schizophreniform in nature. Two other living members with no current signs of motor disorder have received psychiatric treatment, one for schizophrenia. Concurrence of psychosis and Huntington's disease in this family is unlikely to have occurred by chance, suggesting that there is some feature in this family which gives rise to the psychotic presentation. Families such as this may contribute to the investigation of genetic factors associated with psychiatric illnesses.

Adult↗