Speech metrics, general disability, brain imaging and quality of life in multiple sclerosis.

BACKGROUND AND PURPOSE: Objective measurement of speech has shown promising results to monitor disease state in multiple sclerosis. In this study, we characterize the relationship between disease severity and speech metrics through perceptual (listener based) and objective acoustic analysis. We further look at deviations of acoustic metrics in people with no perceivable dysarthria. METHODS: Correlations and regression were calculated between speech measurements and disability scores, brain volume, lesion load and quality of life. Speech measurements were further compared between three subgroups of increasing overall neurological disability: mild (as rated by the Expanded Disability Status Scale ≤2.5), moderate (≥3 and ≤5.5) and severe (≥6). RESULTS: Clinical speech impairment occurred majorly in people with severe disability. An experimental acoustic composite score differentiated mild from moderate (P < 0.001) and moderate from severe subgroups (P = 0.003), and correlated with overall neurological disability (r = 0.6, P < 0.001), quality of life (r = 0.5, P < 0.001), white matter volume (r = 0.3, P = 0.007) and lesion load (r = 0.3, P = 0.008). Acoustic metrics also correlated with disability scores in people with no perceivable dysarthria. CONCLUSIONS: Acoustic analysis offers a valuable insight into the development of speech impairment in multiple sclerosis. These results highlight the potential of automated analysis of speech to assist in monitoring disease progression and treatment response.

Cognitive processing speed deficits in multiple sclerosis: Dissociating sensorial and motor processing changes from cognitive processing speed.

BACKGROUND: The assessment of cognitive information processing speed (IPS) is complicated in MS, with altered performance on tests such as the Symbol Digit Modalities Test (SDMT) potentially representing changes not only within cognitive networks but in the initial sensorial transmission of information to cognitive networks, and/or efferent transmission of the motor response. OBJECTIVE: We aimed to isolate and characterise cognitive IPS deficits in MS using ocular motor tasks; a prosaccade task (used to assess and control for sensorial and motor IPS) which was then used to adjust performance on the Simon task (cognitive IPS). METHODS: All participants (22 MS patients with early disease, 22 healthy controls) completed the ocular motor tasks and the SDMT. The Simon task assessed cognitive IPS by manipulating the relationship between a stimulus location and its associated response direction. Two trial types were interleaved: (1) congruent, where stimulus location = response direction; or (2) incongruent, where stimulus location ≠ response direction. RESULTS MS patients did not perform differently to controls on the SDMT. For OM tasks, when sensorial and motor IPS was controlled, MS patients had significantly slower cognitive IPS (incongruent trials only) and poorer conflict resolution. SDMT performance did not correlate with slower cognitive IPS in MS patients, highlighting the limitation of using SDMT performance to interpret cognitive IPS changes in patients with MS. CONCLUSION: Cognitive IPS deficits in MS patients are dissociable from changes in other processing stages, manifesting as impaired conflict resolution between automatic and non-automatic processes. Importantly, these results raise concerns about the SDMT as an accurate measure of cognitive IPS in MS.

Individual and joint action of environmental factors and risk of MS.

In this review, the evidence for the leading environmental and lifestyle factors thought to play a role in multiple sclerosis (MS) onset, including Epstein-Barr virus, sun exposure or vitamin D, and smoking, will be discussed. The Causal Pie Model is used as a conceptual framework to understand the causation. Given that no single factor leads to the development of MS, the joint action or interaction of these factors, along with genetic factors, most particularly the HLA-DR15*1501 genotype, is a primary focus.

Heterogeneity at the HLA-DRB1 allelic variation locus does not influence multiple sclerosis disease severity, brain atrophy or cognition.

BACKGROUND: HLA-DRB1*1501 (DR15) and other HLA class II alleles increase the risk of developing multiple sclerosis (MS). However, the contribution of genetic heterogeneity to the clinical course of MS remains controversial. We examined the influence of DR15 and other common DRB1 alleles (DRB1*01 (DR1), DRB1*03 (DR3) and DRB1*04 (DR4) on MS severity in a large, Australian, population-based cohort. METHODS: We studied the association between common HLA-DRB1 alleles and genotypes and age of onset as well as three clinical disease severity descriptors: Multiple Sclerosis Severity Score, progression index), and the interval between the first and second attack in 978 patients with relapsing remitting MS and secondary progressive MS. We assessed cognition using the Symbol Digit Modalities Test in 811 patients and brain atrophy using the linear magnetic resonance imaging marker, the intercaudate ratio, in 745 patients. RESULTS: Carrying DR15 significantly decreased the age of MS onset by 3.2 years in homozygotes and 1.3 years in heterozygotes. Carrying the HLA-DR15, -DR1, -DR3 or -DR4 alone or in combination did not affect clinical disease severity, cognition or cerebral atrophy. CONCLUSIONS: This study confirms that heterogeneity of HLA-DRB1 does not influence disease outcome in relapsing MS patients, with the exception of a younger age of onset in HLA-DR15 carriers.

Associations between the genetic polymorphisms of MTHFR and outcomes of methotrexate treatment in rheumatoid arthritis.

OBJECTIVES: To determine whether 5, 10-methylenetetrahydrofolate reductase (MTHFR) rs1801133C/T, rs1801131A/C, rs2274976A/G, rs2066462C/T genetic polymorphisms are associated with clinical response and adverse effects (AEs) of methotrexate (MTX) treatment in Chinese Han patients with rheumatoid arthritis (RA). METHODS: One hundred and ten RA patients defined by the American College of Rheumatology (ACR) 1987 revised criteria were involved in this study. All patients were treated with low-dose MTX (10-15 mg/week) without concomitant uses of other DMARDs. Clinical response (using ACR20 criteria) and AEs were evaluated at 0, 4, 12, 16 and 24 weeks. The genotypes of MTHFR rs1801133C/T, rs1801131A/C, rs2274976A/G and rs2066462C/T were detected by real-time fluorescent quantitative PCR. RESULTS: The allele frequency of rs1801131C in the clinical response group was higher than in the non-response group (21.0% vs. 8.1%, p<0.05), and the patients with CC or AC genotype had greater clinical response than those with AA genotype. The allele frequencies of rs1801133T and rs2274976A were higher in the group with AEs than that without AEs (56.4% vs. 37.5% and 14.9% vs. 4.2%, respectively, both p<0.05). The patients with CT or TT genotype in rs1801133 had higher risks of AEs than those with CC genotype. CONCLUSIONS: While rs1801131A/C genetic polymorphism is associated with the clinical response, rs1801133C/T and rs2274976A/G genetic polymorphisms are associated with MTX-related AEs in the treatment of RA. This suggests individualisation is necessary to achieve optimal outcomes in MTX therapy of RA.

Apolipoprotein genotype does not influence MS severity, cognition, or brain atrophy.

BACKGROUND: The influence of APOE allelic heterogeneity on multiple sclerosis (MS) disease severity has been reported in multiple datasets with conflicting results. Several studies have reported an unfavorable association of APOE epsilon4 with more severe clinical disease course while, in contrast, APOE epsilon2 has been associated with a more benign disease course. In this study, we examine the influence of heterogeneity of the APOE gene on disease severity in a large, Australian, population-based MS cohort. METHODS: Associations between APOE allele status, 2 promoter region single nucleotide polymorphisms (-219 G/T and +113 C/G), and 4 measures of disease severity were tested in 1,006 patients with relapsing-remitting MS and secondary progressive MS: 1) Multiple Sclerosis Severity Score; 2) Progression Index (Expanded Disability Status Scale/disease duration); 3) age at first symptom; and 4) interval between the first and second attack. The Symbol Digit Modalities Test was used as a single cognitive marker in 889 patients. Brain atrophy was measured in 792 patients using the intercaudate ratio. APOE epsilon4 and epsilon3 carriers were stratified by -219 G/T or +113 C/G to investigate haplotypic heterogeneity in the APOE gene region. RESULTS: In this MS study, neither APOE allele status nor promoter region heterogeneity at positions -219 G/T or +113 C/G influenced the clinical disease severity, cognition, or cerebral atrophy. CONCLUSIONS: Allelic and haplotypic heterogeneity of the APOE gene region does not influence multiple sclerosis disease course in this well-defined Australian multiple sclerosis cohort.

Past environmental sun exposure and risk of multiple sclerosis: a role for the Cdx-2 Vitamin D receptor variant in this interaction.

Multiple studies have provided evidence for an association between reduced sun exposure and increased risk of multiple sclerosis (MS), an association likely to be mediated, at least in part, by the vitamin D hormonal pathway. Herein, we examine whether the vitamin D receptor (VDR), an integral component of this pathway, influences MS risk in a population-based sample where winter sun exposure in early childhood has been found to be an important determinant of MS risk. Three polymorphisms within the VDR gene were genotyped in 136 MS cases and 235 controls, and associations with MS and past sun exposure were examined by logistic regression. No significant univariate associations between the polymorphisms, rs11574010 (Cdx-2A > G), rs10735810 (Fok1T > C), or rs731236 (Taq1C > T) and MS risk were observed. However, a significant interaction was observed between winter sun exposure during childhood, genotype at rs11574010, and MS risk (P = 0.012), with the 'G' allele conferring an increased risk of MS in the low sun exposure group (

HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis.

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease (n = 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk (P = 7 x 10(-45)), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 (P = 5 x 10(-7)). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.

Melanocortin 1 receptor genotype, past environmental sun exposure, and risk of multiple sclerosis.

OBJECTIVE: Low past sun exposure, fair skin type, and polymorphisms of the MC1R gene have been associated with multiple sclerosis (MS) risk. We aimed to investigate the interplay between melanocortin 1 receptor gene variants, red hair/fair skin phenotype, and past environmental sun exposure in MS. METHODS: Population-based case-control study in Tasmania, Australia, involving 136 cases with MS and 272 controls randomly drawn from the community and matched on sex and year of birth. Measures included past sun exposure by calendar and questionnaire, spectrophotometric skin type, and MC1R genotype, with any MC1R Arg151Cys, Arg160Trp, or Asp294His alleles present denoted as red hair color (RHC) variant. RESULTS: The association between RHC variant genotype and MS was more evident for women (odds ratio 2.02 [1.15-3.54]) than for men (odds ratio 0.65 [0.27-1.57]) (difference in effect, p = 0.03). The RHC variant genotype was associated with behavioral sun avoidance. In addition, increasing summer sun exposure at ages 6 through 10 years was associated with reduced MS risk among those with no RHC variant (p = 0.03), but not among those with RHC variant genotype (p = 0.15; difference in effect, p = 0.02). Similar findings were evident for other past sun exposure measures and when the sample was restricted to women only. CONCLUSION: The interplay between red hair color variant genotype, red hair/fair skin phenotype, and multiple sclerosis (MS) is complex. The modification of past sun exposure by MC1R genotype provides further support that ultraviolet radiation or derivatives such as vitamin D may be causally related to a reduced MS risk.

Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians.

A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of 'true' association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P=3 x 10(-8)) evidence of an association between KIAA0350 and risk of disease.

SNP mapping and candidate gene sequencing in the class I region of the HLA complex: searching for multiple sclerosis susceptibility genes in Tasmanians.

This study is an extension to previously published work that has linked variation in the human leukocyte antigen (HLA) class I region with susceptibility to multiple sclerosis (MS) in Australians from the Island State of Tasmania. Single nucleotide polymorphism (SNP) mapping was performed on an 865-kb candidate region (D6S1683-D6S265) in 166 Tasmanian MS families, and seven candidate genes [ubiquitin D (UBD), olfactory receptor 2H3 (OR2H3), gamma-aminobutyric acid B receptor 1 (GABBR1), myelin oligodendrocyte glycoprotein (MOG), HLA-F, HLA complex group 4 (HCG4) and HLA-G] were resequenced. SNPs tagging the extended MS susceptibility haplotype were genotyped in an independent sample of 356 Australian MS trios and SNPs in the MOG gene were significantly over-transmitted to MS cases. We identified significant effects on MS susceptibility of HLA-A*2 (OR: 0.51; P = 0.05) and A*3 (OR: 2.85; P = 0.005), and two coding polymorphisms in the MOG gene (V145I: P = 0.01, OR: 2.2; V142L: P = 0.04, OR: 0.45) after full conditioning on HLA-DRB1. We have therefore identified plausible candidates for the causal MS susceptibility allele, and although not conclusive at this stage, our data provide suggestive evidence for multiple class I MS susceptibility genes.

Measuring environmental factors can enhance the search for disease causing genes?

The value of the concurrent measurement of environmental factors in studies aimed at the discovery of disease causing genes has been questioned on the grounds that such an approach fails to increase study power. This report discusses the issue and shows with examples from the recent literature that the examination of a gene disease association within an environmental subgroup can provide enhanced opportunities for detecting gene effects. The concurrent collection of environmental as well as genetic factors in studies of disease aetiology may enhance study informativeness and validity in several ways, including an increase in the power of the study to detect gene disease associations.

Trends in diabetes management practices of patients from an Australian insulin-treated diabetes register.

AIMS: To compare diabetes management practices in 2001 among individuals from Tasmania, Australia, with a previous management survey conducted in 1995-7. METHODS: Subjects were ascertained through the Tasmanian Insulin-Treated Diabetes Register. General demographic data were collected by telephone interview, and participants mailed a questionnaire on their diabetes management practices. RESULTS: The response rate in 2001 was 80.8% (n=1336). There was a trend to more frequent blood glucose self-monitoring, notably in those less than 25 years (P<0.001 for monitoring >2 times/day), together with continued uptake of the pen system of insulin administration. More intensive shared management by general practitioner and diabetes specialist was noted, including a greater proportion visiting their doctor more than five times per year (P=0.006 for those <50 years). Most patients continue to be appropriately screened for hypertension and retinopathy. Dietitian visits declined overall (P=0.03 for at least annual visits), and there appeared to be an inadequate level of foot examination by patients and doctors. CONCLUSIONS: The survey indicated that most patients were taking greater responsibility for their metabolic control, and intensive management practices and more convenient methods of administration may be contributors. Two areas of possible concern are access to dietitian services, and patient and health provider education on appropriate foot care.

Investigation of chromosome 2q in osteoarthritis of the hand: no significant linkage in a Tasmanian population.

BACKGROUND: Previous studies have suggested a strong genetic component to osteoarthritis (OA), especially that of the hand, and three linkage studies have suggested the existence of susceptibility loci in disparate regions of chromosome 2q. OBJECTIVE: To examine for linkage to 2q in a Tasmanian population of women and men with familial hand OA. METHODS: Hand OA (distal interphalangeal, carpometacarpal, and Heberden's nodes) was assessed by a combination of hand photographs and radiographs. A non-parametric linkage (NPL) analysis was performed on chromosome 2q of 69 members in 22 families with severe distal interphalangeal joint OA using Genehunter. A quantitative trait linkage analysis of a larger group of 456 members in 68 families was also performed using SOLAR. RESULTS: The maximum non-parametric linkage score was 1.05 (p=0.15) at marker IL1R1, close to the centromere. All components of hand OA scores had significant heritability in this dataset (28%-35%, all p<0.001). Despite this, the quantitative trait analysis (after adjustment for age and, where appropriate, sex) yielded maximum LOD scores of 0.90 for Heberden's nodes (both sexes combined), and 1.19 for carpometacarpal OA score (women only). CONCLUSIONS: These results do not provide confirmation of linkage on chromosome 2q in the larger white population with hand OA. They suggest that there are regional variations in the genetic cause of hand OA and that other loci not on 2q may be important in this disease.

Syndrome X in 8-y-old Australian children: stronger associations with current body fatness than with infant size or growth.

OBJECTIVE: Syndrome X (clustering of insulin resistance, dyslipidaemia and hypertension) in adults with central obesity has been suggested to be a consequence of poor foetal development. We investigated clustering of syndrome X factors in a sample of 8-y-old Australian children, and whether the clusters were associated with size at birth and childhood obesity. DESIGN: Longitudinal, 1997 follow-up of children enrolled as singleton-born neonates in 1989. SUBJECTS: A total of 298 healthy Australian children (208 boys, 90 girls, age range 7.4-8.9 y). MEASUREMENTS: Anthropometry at birth and at 4 weeks. In 1997, at 8 y of age: fasting insulin and glucose, total and HDL-cholesterol, triglycerides and blood pressure. RESULTS: Adverse levels of insulin and glucose, cholesterol and triglycerides co-existed more often than expected by chance (P<0.01). Three factors were identified in factor analysis: one loading on systolic and diastolic blood pressure ('blood pressure'); a second loading on insulin and glucose ('insulin resistance'); and a third loading negatively on HDL-cholesterol and positively on triglycerides ('dyslipidaemia'). The blood pressure factor was correlated with fatness at age 8 y (eg fat mass estimated from skin folds, r=0.11) and, after adjustment for current size, with birth weight (r=-0.15). Fat mass was also correlated with both 'insulin resistance' (r=0.24) and 'dyslipidaemia' (r=0.19). The increase in 'insulin resistance' (P=0.03) and 'dyslipidaemia' (P<0.01) per category of fat mass was greatest for subjects with higher-than-median subscapular-to-triceps ratio of skin folds. Neither 'insulin resistance' nor 'dyslipidaemia' was associated with anthropometry at birth. CONCLUSIONS: The Syndrome X risk variables clustered among children who had a tendency to deposit fat on the trunk. There was no evidence in this sample that infant size predicts development of the insulin resistance or dyslipidaemic components of the syndrome by age 8.

Interactions between Two Spherical Particles with Nonuniform Surface Potentials: The Linearized Poisson-Boltzmann Theory.

Using the linearized Poisson-Boltzmann theory, electrical double layer interactions are calculated between two nonuniform spherical colloidal particles with mean potential zero. Most results are for the case of surface potentials modeled by a single spherical harmonic and aligned relative to each other. As previously observed for flat surfaces, interactions decay more rapidly as a function of separation between spheres with such periodic, "single-mode" potentials than between spheres with uniform potentials. The Deryaguin approximation for single-mode spheres is tested and calculations are made of the force and torque that particles in a doublet exert on one another. Many of the concepts developed from models of flat plates with periodic aligned surface potentials are shown to be useful in this more general case. Attempts to explain recent differential electrophoresis experiments on the basis of nonuniform double layers fail in that the maximum restraining torques produced under plausible assumptions about the amplitude of nonuniformity are an order of magnitude smaller than those implied by the measurements. The main reason for this is that the torques are too small at the separations characteristic of a secondary minimum. The effect of misalignment of single-mode spheres is assessed by calculating the distribution of interaction energies over a set of relative orientations generated by quasi-random sampling. Finally, a method for generating spheres with "random" surface potentials is devised and potentials of mean force are calculated for pairs of spheres with such surface potentials. Comparison with the single-mode case is kept at a qualitative level, in the absence of detailed knowledge of how realistic such "random" surfaces are. Copyright 1999 Academic Press.