Clinical relevance of cortical network dynamics in early primary progressive MS.

BACKGROUND: Structural cortical networks (SCNs) reflect the covariance between the cortical thickness of different brain regions, which may share common functions and a common developmental evolution. SCNs appear abnormal in neurodegenerative conditions such as Alzheimer's and Parkinson's diseases, but have never been assessed in primary progressive multiple sclerosis (PPMS). OBJECTIVE: The aim of this study was to test whether SCNs are abnormal in early PPMS and change over 5 years, and correlate with disability worsening. METHODS: A total of 29 PPMS patients and 13 healthy controls underwent clinical and brain magnetic resonance imaging (MRI) assessments for 5 years. Baseline and 5-year follow-up cortical thickness values were obtained and used to build correlation matrices, considered as weighted graphs to obtain network metrics. Bootstrap-based statistics assessed SCN differences between patients and controls and between patients with fast and slow progression. RESULTS: At baseline, patients showed features of lower connectivity (p = 0.02) and efficiency (p < 0.001) than controls. Over 5 years, patients, especially those with fastest clinical progression, showed significant changes suggesting an increase in network connectivity (p < 0.001) and efficiency (p < 0.02), not observed in controls. CONCLUSION: SCNs are abnormal in early PPMS. Longitudinal SCN changes demonstrated a switch from low- to high-efficiency networks especially among fast progressors, indicating their clinical relevance.

Early imaging predictors of long-term outcomes in relapse-onset multiple sclerosis.

The clinical course of relapse-onset multiple sclerosis is highly variable. Demographic factors, clinical features and global brain T2 lesion load have limited value in counselling individual patients. We investigated early MRI predictors of key long-term outcomes including secondary progressive multiple sclerosis, physical disability and cognitive performance, 15 years after a clinically isolated syndrome. A cohort of patients with clinically isolated syndrome (n = 178) was prospectively recruited within 3 months of clinical disease onset and studied with MRI scans of the brain and spinal cord at study entry (baseline) and after 1 and 3 years. MRI measures at each time point included: supratentorial, infratentorial, spinal cord and gadolinium-enhancing lesion number, brain and spinal cord volumetric measures. The patients were followed-up clinically after ∼15 years to determine disease course, and disability was assessed using the Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test. Multivariable logistic regression and multivariable linear regression models identified independent MRI predictors of secondary progressive multiple sclerosis and Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test, respectively. After 15 years, 166 (93%) patients were assessed clinically: 119 (72%) had multiple sclerosis [94 (57%) relapsing-remitting, 25 (15%) secondary progressive], 45 (27%) remained clinically isolated syndrome and two (1%) developed other disorders. Physical disability was overall low in the multiple sclerosis patients (median Expanded Disability Status Scale 2, range 0-10); 71% were untreated. Baseline gadolinium-enhancing (odds ratio 3.16, P < 0.01) and spinal cord lesions (odds ratio 4.71, P < 0.01) were independently associated with secondary progressive multiple sclerosis at 15 years. When considering 1- and 3-year MRI variables, baseline gadolinium-enhancing lesions remained significant and new spinal cord lesions over time were associated with secondary progressive multiple sclerosis. Baseline gadolinium-enhancing (ß = 1.32, P < 0.01) and spinal cord lesions (ß = 1.53, P < 0.01) showed a consistent association with Expanded Disability Status Scale at 15 years. Baseline gadolinium-enhancing lesions was also associated with performance on the Paced Auditory Serial Addition Test (ß = - 0.79, P < 0.01) and Symbol Digit Modalities Test (ß = -0.70, P = 0.02) at 15 years. Our findings suggest that early focal inflammatory disease activity and spinal cord lesions are predictors of very long-term disease outcomes in relapse-onset multiple sclerosis. Established MRI measures, available in routine clinical practice, may be useful in counselling patients with early multiple sclerosis about long-term prognosis, and personalizing treatment plans.

Positive impact of cladribine on quality of life in people with relapsing multiple sclerosis.

BACKGROUND: A number of elements of the pivotal 'cladribine tablets treating multiple sclerosis orally' (CLARITY) trial have remained unpublished. OBJECTIVE: To report the impact of cladribine on health-related quality of life (QoL) in people with relapsing multiple sclerosis (pwRMS). METHODS: QoL data from the phase III trial of two different doses (3.5 and 5.25 mg/kg) of oral cladribine in pwRMS were acquired from the European Medicines Agency through Freedom of Information. Spearman's rank correlation was used to analyse the relationship between baseline QoL scores and baseline Expanded Disability Status Scale (EDSS) scores. Responses of the Euro Quality of Life 5 Dimensions (EQ-5D) and Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaires were compared between treatment and control groups using univariate analyses of covariance. RESULTS: In total, n = 5148 EQ-5D responses and n = 894 MSQOL-54 physical, mental health and dimension scores were extracted. Baseline EQ-5D indices correlated with EDSS scores. After 2 years, pwRMS taking 3.5 ( p = .001) and 5.25 mg/kg ( p = .022) reported significantly improved EQ-5D index scores compared with placebo. Positive, yet non-significant, differences were detected in MSQOL-54 scores between cladribine and placebo. CONCLUSION: Analysis of the CLARITY dataset suggests that, over and above its established clinical efficacy, cladribine leads to improved QoL over 96 weeks. ClinicalTrials.gov identifier: NCT00213135.

Evidence for early neurodegeneration in the cervical cord of patients with primary progressive multiple sclerosis.

Spinal neurodegeneration is an important determinant of disability progression in patients with primary progressive multiple sclerosis. Advanced imaging techniques, such as single-voxel (1)H-magnetic resonance spectroscopy and q-space imaging, have increased pathological specificity for neurodegeneration, but are challenging to implement in the spinal cord and have yet to be applied in early primary progressive multiple sclerosis. By combining these imaging techniques with new clinical measures, which reflect spinal cord pathology more closely than conventional clinical tests, we explored the potential for spinal magnetic resonance spectroscopy and q-space imaging to detect early spinal neurodegeneration that may be responsible for clinical disability. Data from 21 patients with primary progressive multiple sclerosis within 6 years of disease onset, and 24 control subjects were analysed. Patients were clinically assessed on grip strength, vibration perception thresholds and postural stability, in addition to the Expanded Disability Status Scale, Nine Hole Peg Test, Timed 25-Foot Walk Test, Multiple Sclerosis Walking Scale-12, and Modified Ashworth Scale. All subjects underwent magnetic resonance spectroscopy and q-space imaging of the cervical cord and conventional brain and spinal magnetic resonance imaging at 3 T. Multivariate analyses and multiple regression models were used to assess the differences in imaging measures between groups and the relationship between magnetic resonance imaging measures and clinical scores, correcting for age, gender, spinal cord cross-sectional area, brain T2 lesion volume, and brain white matter and grey matter volume fractions. Although patients did not show significant cord atrophy when compared with healthy controls, they had significantly lower total N-acetyl-aspartate (mean 4.01 versus 5.31 mmol/l, P = 0.020) and glutamate-glutamine (mean 4.65 versus 5.93 mmol/l, P = 0.043) than controls. Patients showed an increase in q-space imaging-derived indices of perpendicular diffusivity in both the whole cord and major columns compared with controls (P < 0.05 for all indices). Lower total N-acetyl-aspartate was associated with higher disability, as assessed by the Expanded Disability Status Scale (coefficient = -0.41, 0.01 < P < 0.05), Modified Ashworth Scale (coefficient = -3.78, 0.01 < P < 0.05), vibration perception thresholds (coefficient = -4.37, P = 0.021) and postural sway (P < 0.001). Lower glutamate-glutamine predicted increased postural sway (P = 0.017). Increased perpendicular diffusivity in the whole cord and columns was associated with increased scores on the Modified Ashworth Scale, vibration perception thresholds and postural sway (P < 0.05 in all cases). These imaging findings indicate reduced structural integrity of neurons, demyelination, and abnormalities in the glutamatergic pathways in the cervical cord of early primary progressive multiple sclerosis, in the absence of extensive spinal cord atrophy. The observed relationship between imaging measures and disability suggests that early spinal neurodegeneration may underlie clinical impairment, and should be targeted in future clinical trials with neuroprotective agents to prevent the development of progressive disability.

Upper cervical cord area in early relapsing-remitting multiple sclerosis: cross-sectional study of factors influencing cord size.

PURPOSE: To determine whether the upper cervical cord area (UCCA) is influenced by disease effect in early relapsing-remitting multiple sclerosis (MS), using statistical modeling to account for potential covariates. MATERIALS AND METHODS: A cohort of 39 patients were studied cross-sectionally within three years of first symptom onset (median disease duration = 1.6 years) and compared with 26 healthy controls. The UCCA was measured from axial reconstructions of three-dimensional T1-weighted scans with automated detection of the edge of the cord. Statistical analysis adjusted for factors such as total intracranial volume (TICV) and gender. Clinical correlations, in particular those thought likely to be related to cord pathology, were also investigated. RESULTS: No significant disease effect was noted on UCCA (P = 0.685), although there was borderline evidence of a lower UCCA in patients with symptoms of bowel or bladder disturbance (P = 0.043). A strong association was noted between UCCA and TICV (r = 0.558; P < or = 0.001), and there was a trend for females to have a smaller UCCA (P = 0.062). The latter finding appeared to reflect a gender-related difference in TICV (P < or = 0.001). CONCLUSION: Atrophy of the upper cervical cord is not readily apparent in most patients early in the course of relapsing-remitting MS. In evaluations of disease-related changes in the UCCA in cross-sectional studies, TICV and gender should be considered as potentially confounding covariates.

The global burden of disease attributable to low consumption of fruit and vegetables: implications for the global strategy on diet.

OBJECTIVE: We estimated the global burden of disease attributable to low consumption of fruit and vegetables, an increasingly recognized risk factor for cardiovascular disease and cancer, and compared its impact with that of other major risk factors for disease. METHODS: The burden of disease attributable to suboptimal intake of fruit and vegetables was estimated using information on fruit and vegetable consumption in the population, and on its association with six health outcomes (ischaemic heart disease, stroke, stomach, oesophageal, colorectal and lung cancer). Data from both sources were stratified by sex, age and by 14 geographical regions. FINDINGS: The total worldwide mortality currently attributable to inadequate consumption of fruit and vegetables is estimated to be up to 2.635 million deaths per year. Increasing individual fruit and vegetable consumption to up to 600 g per day (the baseline of choice) could reduce the total worldwide burden of disease by 1.8%, and reduce the burden of ischaemic heart disease and ischaemic stroke by 31% and 19% respectively. For stomach, oesophageal, lung and colorectal cancer, the potential reductions were 19%, 20%, 12% and 2%, respectively. CONCLUSION: This study shows the potentially large impact that increasing fruit and vegetable intake could have in reducing many noncommunicable diseases. It highlights the need for much greater emphasis on dietary risk factors in public health policy in order to tackle the rise in noncommunicable diseases worldwide, and suggests that the proposed intersectoral WHO/FAO fruit and vegetable promotion initiative is a crucial component in any global diet strategy.

Polymorphisms and circulating levels in the insulin-like growth factor system and risk of breast cancer: a systematic review.

We reviewed all English-language articles on associations among circulating levels of the insulin-like growth factors (IGF) and their binding proteins (IGFBP), polymorphisms in their genes, and breast cancer risk. In premenopausal women, five of eight IGF-I studies and four of six IGFBP-3 studies of circulating levels found that women in the highest quantile had more than twice the risk of developing breast cancer of those in the lowest, although in some this effect was only apparent at young ages. In postmenopausal women, however, there was no consistent effect. A simple sequence length polymorphism 1 kb 5' to IGF-I was examined in relation to circulating levels of IGF-I (12 studies) or breast cancer risk (4 studies), but there was no convincing evidence of any effect. For an A/C polymorphism 5' to IGFBP-3, all three studies were consistent with a modest effect on circulating levels, but no evidence of a direct effect on breast cancer risk was seen in the only relevant study. Variation within the reference range of IGF-I and IGFBP-3 may confer only modest increases in breast cancer risk, and any single polymorphism may only account for a small proportion of that variation. Nevertheless, population attributable fractions for high circulating levels of IGF-I and IGFBP-3 and for common genetic variants could be substantial. Further large studies, or combined analysis of data from existing studies, are needed to quantify these effects more precisely.

Mortality in England and Wales attributable to any drinking, drinking above sensible limits and drinking above lowest-risk level.

AIMS: To quantify mortality attributable to any alcohol consumption, and mortality attributable to consumption above different levels. DESIGN: We related all-cause mortality to alcohol consumption using cause-specific mortality models from a systematic review and using the distribution of alcohol consumption and causes of death by age and sex in England and Wales in 1997. We estimated the deaths and person-years of life lost to age 65 that were attributable: to any drinking; to drinking above the nadir (the level of alcohol consumption carrying the lowest risk); and to drinking more than the British Royal Colleges' recommended limits of 21 units/week in men and 14 units/week in women. FINDINGS: Ischaemic heart disease deaths prevented by alcohol consumption (11 276 in men, 4050 in women) roughly balanced other deaths attributable to alcohol consumption (9246 in men, 4216 in women). Overall, 0.8% of all deaths in men were prevented by alcohol consumption (95% confidence interval, 0.2% to 1.3%), while 0.1% of all deaths in women were attributable to alcohol consumption (95% confidence interval, - 0.3% to 0.4%); 2.1% (1.9-2.3%) of all deaths in men and 0.8% (0.6-1.0%) of all deaths in women were attributable to drinking more than the recommended limits, while 2.8% and 1.2% of deaths, respectively, were attributable to drinking above the nadir. Of all person-years of life lost to age 65, 10.3% in men and 5.6% in women were attributable to any drinking; 8.5% and 4.0% were attributable to drinking above the recommended limits; and 12.6% and 6.0% were attributable to drinking above the nadir. CONCLUSIONS: Although overall mortality risks and benefits of alcohol consumption appear roughly equal, drinking above recommended limits remains responsible for many deaths and a large loss of person-years of life.

The challenge of measuring global fruit and vegetable intake.

The WHO recently conducted, within its Global Burden of Disease 2000 Study, a Comparative Risk Assessment (CRA) to estimate the global health effect of low fruit and vegetable intake. This paper summarizes the methods used to obtain exposure data for the CRA and provides estimates of worldwide fruit and vegetable intakes. Intakes were derived from 26 national population-based surveys, complemented with food supply statistics. Estimates were stratified by 14 subregions, 8 age groups, and gender. Subregions were categorized on the bases of child mortality under age 5 y and 15- to 59-y-old male mortality (A: very low child and adult mortality; B: low child and adult mortality; C: low child, high adult mortality; D: high child and adult mortality; E: high child, very high adult mortality). Mean intakes were highest in Europe A [median = 449 g/(person.d)] and the Western Pacific Region A. They were lowest in America B [median = 192 g/(person.d)], and low in Europe C, the South East Asian Regions B and D, and Africa E. Children and elderly individuals generally had lower intakes than middle-aged adults. SDs varied considerably by region, gender, and age [overall median = 223 g/(person.d)]. Assessing exposure levels for the CRA had major methodological limitations, particularly due to the lack of nationally representative intake data. The results showed mean intakes generally lower than current recommendations, with large variations among subregions. If the burden of disease attributable to dietary factors is to be assessed more accurately, more countries will have to assess the dietary intake of their populations using comparable methods.

Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes.

While brain atrophy occurs early in the clinical course of multiple sclerosis, exactly how early, which tissues are affected and the rate at which early atrophy occurs are unclear. Regional brain atrophy was investigated in 58 patients recruited within 3 months of onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis, who were followed-up for 3 years. At 3 years, 31 subjects had developed multiple sclerosis as defined by the McDonald criteria, while 27 had not (13 had MRI-visible brain lesions and 14 did not). In those who developed multiple sclerosis, the mean decrease in grey matter fractional volume (GMF, as a fraction of total intracranial volume) was -0.017 (-3.3%) and was significantly larger than in the combined lesion-positive and lesion-negative CIS subjects [-0.005 (-1.1%), P = 0.001]. No decrease in white matter fractional volumes (WMF) was seen. Change in GMF correlated only modestly with the change in T2 lesion volume from baseline to year 3 (r = -0.428, P = 0.004). These results suggest that progressive grey matter, but not white matter, atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis, and this is only moderately related to lesion accumulation. Longer-term follow-up is required to determine whether early grey matter atrophy is associated with subsequent disability or cognitive impairment.

Alcohol consumption and mortality: modelling risks for men and women at different ages.

OBJECTIVE: To estimate the relation between alcohol consumption and risk of death, the level of alcohol consumption at which risk is least, and how these vary with age and sex. DESIGN: Analysis using published systematic reviews and population data. SETTING: England and Wales in 1997. MAIN OUTCOME MEASURES: Death from any of the following causes: cancer of lip, oral cavity, pharynx, oesophagus, colon, rectum, liver, larynx, and breast, essential hypertension, coronary heart disease, stroke, cirrhosis, non-cirrhotic chronic liver disease, chronic pancreatitis, and injuries. RESULTS: A direct dose-response relation exists between alcohol consumption and risk of death in women aged 16-54 and in men aged 16-34. At older ages the relation is U shaped. The level at which the risk is lowest increases with age, reaching 3 units a week in women aged over 65 and 8 units a week in men aged over 65. The level at which the risk is increased by 5% above this minimum is 8 units a week in women aged 16-24 and 5 units a week in men aged 16-24, increasing to 20 and 34 units a week in women and men aged over 65, respectively. CONCLUSIONS: Substantially increased risks of all cause mortality can occur even in people drinking lower than recommended limits, and especially among younger people.

Socio-demographic determinants of intrauterine device use and failure in China.

BACKGROUND: This study examines social, demographic and family planning programme factors influencing intrauterine device (IUD) use, failure and subsequent resolution ('use dynamics') in the 1988 Chinese National Survey of Fertility and Contraceptive Prevalence. METHOD: A time-to-failure model was used to identify independent determinants of IUD failure. Logistic regression was used to identify independent predictors of abortion in women after failure. RESULTS: Being younger at IUD fitting [<25 versus > or = 35 years, hazard ratio 5.9, 95% confidence interval (CI) 4.3, 7.7] and having a larger number of living children (> or = 3 versus <2 children, hazard ratio 1.2, 95% CI 1.1, 1.4) predict higher risk of IUD failure when controlled for each other; but in women with IUD failure, being older and having fewer children predict a much higher chance of resulting abortion. Contraceptive history and social/regional factors were also associated with higher IUD failure risk, in particular, use before 1984 (hazard ratio 1.3, 95% CI 1.2,1.4); and some of these factors were also predictive of abortion following failure. CONCLUSIONS: The determinants of IUD use dynamics suggest two main possible mechanisms. Some determinants may reflect effects of the Chinese family planning programme; some may indicate women's physiological and biological reactions to IUD. Health implications and relevant policy recommendations are discussed.