Genome-wide association study of Alzheimer's disease with psychotic symptoms.

Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.

Muscle disorders: the latest investigations.

Patients with muscle disorders can present a diagnostic challenge to physicians because of the different ways they can present and the large number of different underlying causes. Recognition of the 'myopathic phenotype' coupled with investigations usually including electrodiagnostic and histological investigations have been essential for diagnosing the underlying cause of a myopathy. Despite these standard investigations, some patients can remain undiagnosed. New tests including more specific antibody tests for immune-mediated myopathies and the introduction of next-generation sequencing promise to revolutionise diagnostic approaches for immune and inherited myopathies, but clinical expertise remains essential to choose the most appropriate tests and interpret the results. The aim of this review is to provide an overview of the different presentations to the neuromuscular clinic and the latest investigations that can be helpful in the diagnosis of muscle disorders.

Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease.

Alzheimer's disease (AD) is a complex disease that is likely influenced by many genetic and environmental factors. Citing evidence that iron may play a role in AD pathology, Robson et al. [Robson et al. (2004); J Med Genet 41:261-265] reported that epistatic interaction between rs1049296 (P589S) in the transferrin gene (TF) and rs1800562 (C282Y) in the hemochromatosis gene (HFE) results in significant association with risk for AD. In this study we attempted to replicate their findings in a total of 1,166 cases and 1,404 controls from three European and European American populations. Allele and genotype frequencies were consistent across the three populations. Using synergy factor analysis (SFA) and Logistic Regression analysis we tested each population and the combined sample for interactions between these two SNPs and risk for AD. We observed significant association between bi-carriers of the minor alleles of rs1049296 and rs1800562 in the combined sample using SFA (P = 0.0016, synergy factor = 2.71) and adjusted SFA adjusting for age and presence of the APOE epsilon 4 allele (P = 0.002, OR = 2.4). These results validate those of the previous report and support the hypothesis that iron transport and regulation play a role in AD pathology.

Association analysis of dynamin-binding protein (DNMBP) on chromosome 10q with late onset Alzheimer's disease in a large caucasian UK sample.

A recent scan of single nucleotide polymorphisms (SNPs) in the region 40-107 Mb on chromosome 10q in a large Japanese case-control cohort identified six SNPs in or near the dynamin-binding protein gene (DNMBP) that were associated with late onset Alzheimer's disease (LOAD) in individuals lacking the APOE epsilon4 allele [Kuwano et al. (2006); Hum Mol Genet 15:2170-2182]. We genotyped these six SNPs in 1,212 unrelated Caucasian patients of UK origin with LOAD and 1,389 ethnically, gender and age matched control subjects. We did not observe a statistically significant association with the risk of LOAD for any of the six SNPs in the sample as a whole. When stratifying the sample by APOE one SNP (intergenic SNP rs11190302) was associated with LOAD in individuals lacking the epsilon4 allele (genotypic P = 0.027, allelic P = 0.066). However this association was in the opposite direction to that detected in the Japanese population. It remains to be determined whether DNMBP is associated with LOAD.

Association analysis of 528 intra-genic SNPs in a region of chromosome 10 linked to late onset Alzheimer's disease.

Late-onset Alzheimer's disease (LOAD) is a genetically complex neurodegenerative disorder. Currently, only the epsilon4 allele of the Apolipoprotein E gene has been identified unequivocally as a genetic susceptibility factor for LOAD. Others remain to be found. In 2002 we observed genome-wide significant evidence of linkage to a region on chromosome 10q11.23-q21.3 [Myers et al. (2002) Am J Med Genet 114:235-244]. Our objective in this study was to test every gene within the maximum LOD-1 linkage region, for association with LOAD. We obtained results for 528 SNPs from 67 genes, with an average density of 1 SNP every 10 kb within the genes. We demonstrated nominally significant association with LOAD for 4 SNPs: rs1881747 near DKK1 (P = 0.011, OR = 1.24), rs2279420 in ANK3 (P = 0.022, OR = 0.79), rs2306402 in CTNNA3 (P = 0.024, OR = 1.18), and rs5030882 in CXXC6 (P = 0.046, OR = 1.29) in 1,160 cases and 1,389 controls. These results would not survive correction for multiple testing but warrant attempts at confirmation in independent samples.

Low-dose methotrexate in systemic onset juvenile chronic arthritis.

Twelve children with severe systemic juvenile chronic arthritis, all requiring high dose corticosteroids, have been admitted to a pilot study to evaluate the effect of low-dose methotrexate (mean dose: 8.5 mg/M2) on disease activity over a 6 month period. Definite improvement occurred in 4 children, allowing reduction of the steroid dose in 2 cases. Two children showed an acute flare of disease activity during the treatment period and in three, steroids had to be increased. Overall, side effects were rare with a rise in transaminases only occurring once. MTX blood levels taken on 14 occasions in 8 children documented absorption in all cases with a mean level of 3.45 x 10(-7) mol/l on a mean dose of 9 mg/M2. Low-dose MTX appears to be a safe drug in the short term treatment of severe systemic JCA with beneficial effect in about a third of patients. Long-term controlled trials will be needed to evaluate its role in the treatment of systemic disease as well as side effects.

The British version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

We report herein the results of the cross-cultural adaptation and validation into the British language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. A total of 440 subjects were enrolled: 219 patients with JIA (17% systemic onset, 41% polyarticular onset, 33% extended oligoarticular subtype, and 9% persistent oligoarticular subtype) and 221 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the British version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

The painful swollen sterno-clavicular joint.

Thirteen patients with isolated pain and swelling of a sterno-clavicular clavicular joint have been reviewed. Three groups were identified. Group 1 comprised four patients, all of whom had a short history of less than six weeks and suffered a pyarthrosis or malignant disease; group 2, four patients who were shown to have features of condensing osteitis of the clavicle (Cone et al, 1983); and group 3, five patients, had degenerative arthritis of a sterno-clavicular joint. The only difference between groups 2 and 3 were that patients in group 3 had a rather longer history, both articular surfaces were involved and showed a possible increase in the incidence of degenerative joint disease elsewhere. It is suggested that condensing osteitis is but a part of a spectrum of degenerative disease of the sterno-clavicular joints, akin to discogenic vertebral body sclerosis (McCarthy & Dorfman, 1982).

Steps towards a situational ethic.

PIP: The Australian Royal Commission on Human Relationships summarized the problems of adolescents and family planning by declaring there is a level of teenage sexual activity that cannot be ignored. Young single people have a low rate of effective contraception. Teenagers suffer a very high proportion of unwanted pregnancies and abortions. Placing the ethical questions in a contemporary social context enables society to face the issues in a practical, realistic fashion. Historically preserved traditions, like the taboo against premarital sex, are and will continue to be important in the bonding of families, individuals, and societies. A situational ethic applies to changes in the social fabric and addresses them. Society has changed from rural to urban, from agrarian to technological, from literacy to mass media, from superstitious knowledge of reproduction to scientific methods of birth control. The realities of change should be faced with a sense of ethics that is grounded in tradition and adjusted to the needs of the actual situation which is that too many teenagers have too many unwanted pregnancies. They can be helped.^ieng

No consistent evidence for association between mtDNA variants and Alzheimer disease.

OBJECTIVE: Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain. METHODS: We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis. RESULTS: In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD. CONCLUSION: The current evidence linking common mtDNA variations with AD is not compelling.

A Multiple Indicators Multiple Causes (MIMIC) model of Behavioural and Psychological Symptoms in Dementia (BPSD).

INTRODUCTION: Although there is evidence for distinct behavioural sub-phenotypes in Alzheimer's disease (AD), their inter-relationships and the effect of clinical variables on their expression have been little investigated. METHODS: We have analysed a sample of 1850 probable AD patients from the UK and Greece with 10 item Neuropsychiatric Inventory (NPI) data. We applied a Multiple Indicators Multiple Causes (MIMIC) approach to investigate the effect of MMSE, disease duration, gender, age and age of onset on the structure of a four-factor model consisting of "psychosis", "moods", "agitation" and "behavioural dyscontrol". RESULTS: Specific clinical variables predicted the expression of individual factors. When the inter-relationship of factors is modelled, some previously significant associations are lost. For example, lower MMSE scores predict psychosis, agitation and behavioural dyscontrol factors, but psychosis and mood predict the agitation factor. Taking these associations into account MMSE scores did not predict agitation. CONCLUSIONS: The complexity of the inter-relations between symptoms, factors and clinical variables is efficiently captured by this MIMIC model.

Evidence that variation in the oligodendrocyte lineage transcription factor 2 (OLIG2) gene is associated with psychosis in Alzheimer's disease.

Psychotic symptoms are common in individuals with Alzheimer's disease (AD), and define a phenotype associated with more rapid cognitive and functional decline. Evidence suggests that psychotic symptoms may be influenced by genetic factors, and recent studies in schizophrenia, bipolar affective disorder (BPAD) and Alzheimer's disease with psychosis (AD+P) suggest that psychosis susceptibility or modifier genes may act across diseases. We hypothesised that oligodendrocyte lineage transcription factor 2 (OLIG2), a regulator of white matter development and a candidate gene for schizophrenia, may also be associated with psychotic symptoms in AD. We genotyped 11 SNPs in OLIG2 previously tested for association with schizophrenia [L. Georgieva, V. Moskvina, T. Peirce, N. Norton, N.J. Bray, L. Jones, P. Holmans, S. Macgregor, S. Zammit, J. Wilkinson, H. Williams, I. Nikolov, N. Williams, D. Ivanov, K.L. Davis, V. Haroutunian, J.D. Buxbaum, N. Craddock, G. Kirov, M.J. Owen, M.C. O'Donovan, Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia, Proc. Natl. Acad. Sci. U.S.A. 103 (33) (2006) 12469-12474] and tested these for association with AD and AD+P. Significant evidence for association of psychotic symptoms within cases was identified for two SNPs, rs762237 (allelic P=0.002, OR=1.42, corrected P=0.019) and rs2834072 (allelic P=0.004, OR=1.41, corrected P=0.05).

Increased familial risk and genomewide significant linkage for Alzheimer's disease with psychosis.

Psychotic symptoms are common in Alzheimer's disease (AD) and are associated with increased cognitive impairment and earlier institutionalization. One study has suggested that they are genetically modified and two genome screens have been performed to search for susceptibility loci for AD with psychosis (AD + P). The aim of this study was to further investigate the familial aggregation of AD + P and perform a genome screen for AD, conditioning on the presence or absence of psychotic symptoms. Samples from the UK and US were combined, providing data from 374 families in which at least two members met criteria for AD and had complete data regarding psychotic symptoms. Generalized estimating equations (GEE) were used to assess the relationship of psychotic symptoms between siblings. A total of 321 affected relative pairs (ARPs) were genotyped for linkage. There was a significant association between proband psychosis status and the occurrence of AD + P in siblings in the UK (OR = 4.17, P = 0.002) and US (OR = 3.2, P < 0.001) samples. Chromosomewide and genomewide significant linkage peaks were observed on chromosomes 7 (LOD = 2.84) and 15 (LOD = 3.16), respectively, with the strongest evidence coming from pairs concordant for AD without psychosis. A LOD score of 2.98 was observed close to a previously reported AD + P linkage region on chromosome 6, however the increase in LOD attributable to psychosis was not significant. These findings support the hypothesis that psychotic symptoms in AD are genetically modified and that a gene/s implicated in their aetiology may be located on chromosome 7 and 15.

Association studies of 23 positional/functional candidate genes on chromosome 10 in late-onset Alzheimer's disease.

Late-onset Alzheimer's disease (LOAD) is a common neurodegenerative disorder, with a complex etiology. APOE is the only confirmed susceptibility gene for LOAD. Others remain yet to be found. Evidence from linkage studies suggests that a gene (or genes) conferring susceptibility for LOAD resides on chromosome 10. We studied 23 positional/functional candidate genes from our linkage region on chromosome 10 (APBB1IP, ALOX5, AD037, SLC18A3, DKK1, ZWINT, ANK3, UBE2D1, CDC2, SIRT1, JDP1, NET7, SUPV3L1, NEN3, SAR1, SGPL1, SEC24C, CAMK2G, PP3CB, SNCG, CH25H, PLCE1, ANXV111) in the MRC genetic resource for LOAD. These candidates were screened for sequence polymorphisms in a sample of 14 LOAD subjects and detected polymorphisms tested for association with LOAD in a three-stage design involving two stages of genotyping pooled DNA samples followed by a third stage in which markers showing evidence for association in the first stages were subjected to individual genotyping. One hundred and twenty polymorphisms were identified and tested in stage 1 (4 case + 4 control pools totaling 366 case and 366 control individuals). Single nucleotide polymorphisms (SNPs) showing evidence of association with LOAD were then studied in stage 2 (8 case + 4 control pools totaling 1,001 case and 1,001 control individuals). Five SNPs, in four genes, showed evidence for association (P < 0.1) at stage 2 and were individually genotyped in the complete dataset, comprising 1,160 LOAD cases and 1,389 normal controls. Two SNPs in SGPL1 demonstrated marginal evidence of association, with uncorrected P values of 0.042 and 0.056, suggesting that variation in SGPL1 may confer susceptibility to LOAD.