Publications by authors named "Marianna Cortese"

19 Publications

  • Page 1 of 1

The human gut microbiota in people with amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Nov 2:1-9. Epub 2020 Nov 2.

Sean M. Healey and AMG Center for ALS, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

Objective: To characterize the gut microbiota in people with amyotrophic lateral sclerosis (ALS) relative to controls and to test the hypothesis that butyrate-producing bacteria are less abundant in the gastrointestinal tracts of people with ALS (PALS). We conducted a case-control study at Massachusetts General Hospital to compare the gut microbiota in people with ALS to that in controls. Metagenomic shotgun sequencing was performed on DNA extracted from stool samples of 66 people with ALS (PALS), 61 healthy controls (HC), and 12 neurodegenerative controls (NDC). Taxonomic metagenomic profiles were analyzed for shifts in the microbial community structure between the comparator groups using per-feature univariate and multivariate association tests. The relative abundance of the dominant butyrate-producing bacteria and was significantly lower in ALS patients compared to HC. Adjustment for age, sex, and constipation did not materially change the results. The total abundance of 8 dominant species capable of producing butyrate was also significantly lower in ALS compared to HC (p < 0.001). The levels of several butyrate-producing bacteria, which are important for gut integrity and regulation of inflammation, were lower in people with ALS compared to controls. These findings lend support to the inference that the gut microbiota could be a risk factor for ALS. Further investigations are warranted, preferably earlier in the disease with corresponding dietary collection and a longitudinal design.
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http://dx.doi.org/10.1080/21678421.2020.1828475DOI Listing
November 2020

Pre-diagnostic plasma lipid levels and the risk of amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Sep 28:1-11. Epub 2020 Sep 28.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Objective: To assess whether pre-diagnostic lipid levels are associated with Amyotrophic lateral sclerosis (ALS) risk. We conducted a matched case-control study nested in five large prospective US cohorts (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the Women's Health Initiative), and identified 275 individuals who developed ALS during follow-up and had provided blood samples before disease diagnosis. For each ALS case, we randomly selected two controls who were alive at the time of the case diagnosis and matched on cohort, birth year (±1 year), sex, race/ethnicity, fasting status, and time of blood draw. We measured total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels in the plasma samples, and used conditional logistic regression to estimate associations between lipid levels and ALS risk. Higher levels of HDL-C were associated with higher ALS risk in an analysis adjusted for the matching factors (risk ratio [RR] Q4 vs. Q1: 1.78, 95% confidence interval [CI]: 1.18-2.69, trend: 0.007). The estimate remained similar in a multivariable analysis additionally adjusted for body mass index, physical activity, smoking, alcohol intake, plasma urate levels, and use of cholesterol-lowering drugs (RR Q4 vs. Q1: 1.71, 95% CI: 1.07-2.73, trend: 0.02). Plasma levels of TC, LDL-C, and TG were not associated with ALS risk. Higher pre-diagnostic HDL-C levels, but not levels of other lipids, were associated with a higher risk of ALS.
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http://dx.doi.org/10.1080/21678421.2020.1822411DOI Listing
September 2020

Vitamin D, smoking, EBV, and long-term cognitive performance in MS: 11-year follow-up of BENEFIT.

Neurology 2020 05 16;94(18):e1950-e1960. Epub 2020 Apr 16.

From the Department of Nutrition (M.C., K.L.M, A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Global Public Health and Primary Care (M.C.), University of Bergen, Bergen, Norway; Department of Neurology (E.H.M.-L.), Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Departments of Medicine, Biomedicine and Clinical Research (C.B., L.K., J.K.), Neurologic Clinic and Policlinic, University Hospital Basel, University of Basel, Basel, Switzerland; CHU Hôpital Pontchaillou (G.E.), Rennes, France; University of Ottawa and Ottawa Hospital Research Institute (M.S.F.), Ottawa, Canada; Department of Neurology (H.-P.H.), Medical Faculty, Heinrich-Heine Universität, Düsseldorf, Germany; St. Michael's Hospital (X.M.), University of Toronto, Canada and Multiple Sclerosis Center of Catalonia (Cemcat) (X.M.), Vall d'Hebron University Hospital, Barcelona, Spain; Ferkauf Graduate School of Psychology (F.W.F.), Yeshiva University, New York, NY; Department of Neurology (I.K.P.), Medical Faculty, Heinrich-Heine Universität, Düsseldorf and COGITO Center for Applied Neurocognition and Neuropsychological Research (I.K.P.), Düsseldorf, Germany; Technical University of Munich (B.H.), School of Medicine and Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Central Texas Neurology Consultants (E.J.F.), Round Rock, TX; Neuroimmunology and Multiple Sclerosis Research (S.S.), Department of Neurology, University Hospital Zurich, University of Zurich and Center for Neuroscience Zurich (S.S.), Federal Institute of Technology (ETH), Zurich, Switzerland; Bayer AG (E.-M.W.), Berlin, Germany; Department of Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA and Channing Division of Network Medicine (A.A.); and Department of Medicine (A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objective: To investigate whether vitamin D, smoking, and anti-Epstein-Barr virus (EBV) antibody concentrations predict long-term cognitive status and neuroaxonal injury in multiple sclerosis (MS).

Methods: This study was conducted among 278 patients with clinically isolated syndrome who participated in the clinical trial BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) and completed the 11-year assessment (BENEFIT-11). We measured serum 25-hydroxyvitamin-D (25(OH)D), cotinine (smoking biomarker), and anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) at baseline and at months 6, 12, and 24 and examined whether these biomarkers contributed to predict Paced Auditory Serial Addition Test (PASAT)-3 scores and serum neurofilament light chain (NfL) concentrations at 11 years. Linear and logistic regression models were adjusted for sex, baseline age, treatment allocation, steroid treatment, multifocal symptoms, T2 lesions, and body mass index.

Results: Higher vitamin D predicted better, whereas smoking predicted worse cognitive performance. A 50-nmol/L higher mean 25(OH)D in the first 2 years was related to 65% lower odds of poorer PASAT performance at year 11 (95% confidence intervals [95% CIs]: 0.14-0.89). Standardized PASAT scores were lower in smokers and heavy smokers than nonsmokers ( = 0.026). Baseline anti-EBNA-1 IgG levels did not predict cognitive performance ( = 0.88). Associations with NfL concentrations at year 11 corroborated these findings-a 50-nmol/L higher mean 25(OH)D in the first 2 years was associated with 20% lower NfL (95% CI: -36% to 0%), whereas smokers had 20% higher NfL levels than nonsmokers (95% CI: 2%-40%). Anti-EBNA-1 antibodies were not associated with NfL.

Conclusions: Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS.
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http://dx.doi.org/10.1212/WNL.0000000000009371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274920PMC
May 2020

Ultra-processed food consumption during childhood and asthma in adolescence: Data from the 2004 Pelotas birth cohort study.

Pediatr Allergy Immunol 2020 01 8;31(1):27-37. Epub 2019 Oct 8.

Post-graduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.

Background: Diet has been of interest for asthma; however, it remains unknown whether the consumption of ultra-processed food (UPF) increases the risk of the disease. Our objective was to investigate whether UPF consumption during childhood was associated with wheeze, asthma, and severe asthma in adolescence.

Methods: We included 2190 11-year-old children from the 2004 Pelotas Birth Cohort Study, without asthma at the age of 6 years. Consumption of UPF was assessed by Food Frequency Questionnaires at 6- and 11-year follow-ups. Wheeze, asthma, and severe asthma data were assessed at 11-year follow-up. We classified foods according to the processing degree in ultra-processed food. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (CIs), for the association between UPF consumption and the asthma outcomes.

Results: Cumulative incidence of wheeze and asthma between 6 and 11 years was 12.7% and 23.2%, respectively. In prospective analyses, comparing children in the highest and the lowest quintile of UPF consumption at age 6, we found no association with wheeze (OR = 0.85; 95% CI = 0.54-1.34), asthma (OR = 0.84; 95% CI = 0.58-1.21), or severe asthma (OR = 1.12; 95% CI = 0.62-2.03) in early adolescence. In cross-sectional analyses, comparing adolescents in the highest and lowest quintile of UPF consumption at 11 years, we found no association with wheeze (OR = 1.12; 95% CI = 0.72-1.75), asthma (OR = 1.00; 95% CI = 0.7-1.44), or severe asthma (OR = 1.05; 95% CI = 0.59-1.86).

Conclusion: Our study provided evidence that UPF consumption during childhood or adolescence is not associated with asthma or wheeze among adolescents.
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http://dx.doi.org/10.1111/pai.13126DOI Listing
January 2020

Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis.

JAMA Neurol 2020 01;77(1):58-64

Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Importance: Unrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease.

Objective: To assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset.

Design, Setting, And Participants: Nested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding.

Exposures: Serum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa).

Main Outcomes And Measurements: Log-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models.

Results: Mean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for ≥5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009).

Conclusions And Relevance: The levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.
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http://dx.doi.org/10.1001/jamaneurol.2019.3238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745051PMC
January 2020

Epstein-barr virus and multiple sclerosis risk in the finnish maternity cohort.

Ann Neurol 2019 09 3;86(3):436-442. Epub 2019 Jul 3.

Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA.

Objective: To determine whether maternal Epstein-Barr virus (EBV) IgG antibody levels are associated with risk of multiple sclerosis (MS) in the offspring.

Methods: We conducted a prospective nested case-control study in the Finnish Maternity Cohort (FMC) with serum samples from >800,000 women collected during pregnancy since 1983. Cases of MS among offspring born between 1983 and 1991 were identified via hospital and prescription registries; 176 cases were matched to up to 3 controls (n = 326) on region and dates of birth, sample collection, and mother's birth. We used conditional logistic regression to estimate relative risks (RRs) and adjusted models for sex of the child, gestational age at sample collection, and maternal serum 25-hydroxyvitamin D and cotinine levels. Similar analyses were conducted among 1,049 women with MS and 1,867 matched controls in the FMC.

Results: Maternal viral capsid antigen IgG levels during pregnancy were associated with an increased MS risk among offspring (RR = 2.44, 95% confidence interval [CI] = 1.20-5.00, p trend = 0.004); no associations were found between maternal EBV nuclear antigen 1 (EBNA-1), diffuse early antigen, or cytomegalovirus IgG levels and offspring MS risk. Among women in the FMC, those in the highest versus lowest quintile of EBNA-1 IgG levels had a 3-fold higher risk of MS (RR = 3.21, 95% CI = 2.37-4.35, p trend <1.11e-16). These associations were not confounded or modified by 25-hydroxyvitamin D.

Interpretation: Offspring of mothers with high viral capsid antigen IgG during pregnancy appear to have an increased risk of MS. The increase in MS risk among women with elevated prediagnostic EBNA-1 IgG levels is consistent with previous results. ANN NEUROL 2019;86:436-442.
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http://dx.doi.org/10.1002/ana.25532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839107PMC
September 2019

Total intake of different minerals and the risk of multiple sclerosis.

Neurology 2019 04 3;92(18):e2127-e2135. Epub 2019 Apr 3.

From the Departments of Nutrition (M.C., A.A., K.L.M.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Global Public Health and Primary Care (M.C.), University of Bergen, Norway; and Partners Multiple Sclerosis Center (T.C.) and Channing Division of Network Medicine, Department of Medicine (A.A.), Brigham and Women's Hospital, Boston, MA.

Objective: To investigate the association between mineral intake (potassium, magnesium, calcium, phosphorus, iron, zinc, manganese, copper) and multiple sclerosis (MS) risk.

Methods: In a prospective cohort study, we assessed dietary and supplemental mineral intake by a validated food frequency questionnaire administered every 4 years to 80,920 nurses in the Nurses' Health Study (1984-2002) and 94,511 in the Nurses' Health Study II (1991-2007). There were 479 new MS cases during follow-up. We estimated hazard ratios and 95% confidence intervals for the association of energy-adjusted mineral intake with MS risk using Cox regression, adjusting for age, residence latitude at age 15, ancestry, body mass index at age 18, supplemental vitamin D, smoking, and total energy intake.

Results: We did not find any association between the minerals and MS risk, either for baseline or cumulative intake during follow-up. The associations were null comparing women with highest to those with lowest intakes in quintiles or deciles and there was no significant trend for higher intakes ( across baseline quintiles: potassium 0.35, magnesium 0.13, calcium 0.22, phosphorus 0.97, iron 0.85, zinc 0.67, manganese 0.48, copper 0.59).

Conclusions: Our findings suggest that mineral intake is not an important determinant of MS risk.
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http://dx.doi.org/10.1212/WNL.0000000000006800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512881PMC
April 2019

Diet quality and risk of multiple sclerosis in two cohorts of US women.

Mult Scler 2019 11 23;25(13):1773-1780. Epub 2018 Oct 23.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Objective: To determine the association between measures of overall diet quality (dietary indices/patterns) and risk of multiple sclerosis (MS).

Methods: Over 185,000 women in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) completed semiquantitative food frequency questionnaires every 4 years. There were 480 MS incident cases. Diet quality was assessed using the Alternative Healthy Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet (aMED) index, and Dietary Approaches to Stop Hypertension (DASH) index. Principal component analysis was used to determine major dietary patterns. We calculated the hazard ratio (HR) of MS with Cox multivariate models adjusted for age, latitude of residence at age 15, body mass index at age 18, supplemental vitamin D intake, and cigarette smoking.

Results: None of the dietary indices, AHEI-2010, aMED, or DASH, at baseline was statistically significantly related to the risk of MS. The principal component analysis identified "Western" and "prudent" dietary patterns, neither of which was associated with MS risk (HR, top vs bottom quintile: Western, 0.81 ( = 0.31) and prudent, 0.96 ( = 0.94)). When the analysis was repeated using cumulative average dietary pattern scores, the results were unchanged.

Conclusion: There was no evidence of an association between overall diet quality and risk of developing MS among women.
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http://dx.doi.org/10.1177/1352458518807061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478561PMC
November 2019

When Intuition Invites the Analytical Mind to Dance-The Essential Role of Creativity in Science.

Epidemiology 2018 11;29(6):753-755

Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.

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http://dx.doi.org/10.1097/EDE.0000000000000913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193552PMC
November 2018

Urate and the risk of Parkinson's disease in men and women.

Parkinsonism Relat Disord 2018 07 28;52:76-82. Epub 2018 Mar 28.

Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. Electronic address:

Introduction: High urate levels have consistently been associated with lower Parkinson's disease (PD) risk among men, but the association is less clear among women. In this study we prospectively investigated the association between high uric acid levels and PD, evaluating potential differences by sex and age.

Methods: This historical cohort study included the entire Norwegian population alive and at least 18 years old on 01/01/2004. We retrieved use of urate-lowering drugs, a marker of high urate levels/gout, from the Norwegian Prescription Database, and followed individuals from 01/01/2005 to PD onset, emigration, death, or end of follow-up on 31/12/2013. We identified 4523 incident PD cases during follow-up, and used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for sex, age, and level of education. We also tested for effect modification by sex and age.

Results: Exposure to urate-lowering drugs was associated with a significantly lower PD risk (HR = 0.80, 95% CI: 0.68-0.95). The association was more marked in men (HR = 0.77, 95% CI: 0.63-0.94), compared to women (HR = 0.89, 95% CI: 0.65-1.22), but the difference was not significant (p for effect modification = 0.61). The association varied significantly by age among women (p = 0.01) with a protective effect suggested only at higher age (above 70 years) when urate levels are higher than premenopausally (HR = 0.65, 95% CI: 0.41-1.03), but not in men (p = 0.61).

Conclusion: These findings suggest that urate may be protective against PD in both men and women.
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http://dx.doi.org/10.1016/j.parkreldis.2018.03.026DOI Listing
July 2018

Diabetes is associated with decreased migraine risk: A nationwide cohort study.

Cephalalgia 2018 10 17;38(11):1759-1764. Epub 2017 Dec 17.

1 Department of Global Public Health and Primary Care, University of Bergen, Norway.

Background Results from studies on diabetes and migraine risk are conflicting, which may be due to methodological limitations. Prospective studies with long follow-up could increase our understanding of the relationship between the two diseases. Method We performed a cohort study including the whole Norwegian population alive on 01.01.2004, using prescriptions registered in the Norwegian prescription database to identify individuals developing type 1 diabetes, type 2 diabetes and migraine during follow-up (10 years). We used Cox proportional hazards regression to estimate rate ratios with corresponding 95% confidence intervals for the effect of diabetes on migraine risk, adjusting for age, sex, and educational level. Result We identified 7,883 type 1 diabetes patients and 93,600 type 2 patients during the study period. Type 1 diabetes was significantly associated with a subsequent decreased migraine risk during follow-up in the age- and sex-adjusted analyses (0.74; 0.61-0.89). Type 2 diabetes was also associated with a significantly lower migraine risk (0.89; 0.83-0.95). Further adjustment for educational level yielded similar results for both diabetes. Conclusion Both type 1 and type 2 diabetes were significantly associated with a decreased risk of migraine. This suggests that diabetes or diabetes treatment may have a protective effect on the development of migraine.
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http://dx.doi.org/10.1177/0333102417748573DOI Listing
October 2018

No association between dietary sodium intake and the risk of multiple sclerosis.

Neurology 2017 Sep 25;89(13):1322-1329. Epub 2017 Aug 25.

From the Departments of Clinical Medicine and Global Public Health and Primary Care (M.C.), University of Bergen; The Norwegian Multiple Sclerosis Competence Center (M.C.), Haukeland University Hospital, Bergen, Norway; Departments of Nutrition (M.C., C.Y., A.A., K.L.M.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health; Partners Multiple Sclerosis Center (T.C.), Brigham and Women's Hospital; and Channing Division of Network Medicine, Department of Medicine (A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objective: To prospectively investigate the association between dietary sodium intake and multiple sclerosis (MS) risk.

Methods: In this cohort study, we assessed dietary sodium intake by a validated food frequency questionnaire administered every 4 years to 80,920 nurses in the Nurses' Health Study (NHS) (1984-2002) and to 94,511 in the Nurses' Health Study II (NHSII) (1991-2007), and calibrated it using data from a validation study. There were 479 new MS cases during follow-up. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the effect of energy-adjusted dietary sodium on MS risk, adjusting also for age, latitude of residence at age 15, ancestry, body mass index at age 18, supplemental vitamin D intake, cigarette smoking, and total energy intake in each cohort. The results in both cohorts were pooled using fixed effects models.

Results: Total dietary intake of sodium at baseline was not associated with MS risk (highest [medians: 3.2 g/d NHS; 3.5 g/d NHSII] vs lowest [medians: 2.5 g/d NHS; 2.8 g/d NHSII] quintile: HR 0.98, 95% CI 0.74-1.30, for trend = 0.75). Cumulative average sodium intake during follow-up was also not associated with MS risk (highest [medians: 3.3 g/d NHS; 3.4 g/d NHSII] vs lowest [medians: 2.7 g/d NHS; 2.8 g/d NHSII] quintile: HR 1.02, 95% CI 0.76-1.37, for trend = 0.76). Comparing more extreme sodium intake in deciles yielded similar results ( for trend = 0.95).

Conclusions: Our findings suggest that higher dietary sodium intake does not increase the risk of developing MS.
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http://dx.doi.org/10.1212/WNL.0000000000004417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649760PMC
September 2017

Body size and physical exercise, and the risk of multiple sclerosis.

Mult Scler 2018 03 13;24(3):270-278. Epub 2017 Mar 13.

The Norwegian MS Registry and Biobank and The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway/The KG Jebsen Centre for MS-Research, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Background: Whether large body size increases multiple sclerosis (MS) risk in men is not well understood. Concurrently, physical exercise could be an independent protective factor.

Objective: To prospectively investigate the association between body mass index (BMI) and aerobic fitness, indicators of body size and exercise, and MS risk in men.

Methods: We performed a population-based nested case-control study within the historical cohort of all Norwegian men, born in 1950-1975, undergoing mandatory conscription at the age of 19 years. 1016 cases were identified through linkage to the Norwegian MS registry, while 19,230 controls were randomly selected from the cohort. We estimated the effect of BMI and fitness at conscription on MS risk using Cox regression.

Results: Higher BMI (≥25 vs 18.5-<25 kg/m) was significantly associated with increased MS risk (adjusted relative risk (RR) = 1.36, 95% confidence interval (CI): 1.05-1.76). We also found a significant inverse association between aerobic fitness (high vs low) and MS risk independent of BMI (RR = 0.69, 95% CI: 0.55-0.88, p-trend = 0.003), remaining similar when men with MS onset within 10 years from conscription were excluded ( p-trend = 0.03).

Conclusion: These findings add weight to evidence linking being overweight to an increased MS risk in men. Furthermore, they suggest that exercise may be an additional modifiable protective factor for MS.
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http://dx.doi.org/10.1177/1352458517699289DOI Listing
March 2018

Physical activity is associated with a decreased multiple sclerosis risk: The EnvIMS study.

Mult Scler 2018 02 1;24(2):150-157. Epub 2017 Feb 1.

Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway/The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: The lifestyle factors smoking and obesity have been associated with the risk of multiple sclerosis (MS). Physical activity (PA) may also be of importance.

Objective: To examine the association between PA and MS risk in Italy, Norway, and Sweden and to evaluate the possible influence by established risk factors.

Methods: In this case-control study, 1904 cases and 3694 controls were asked to report their average weekly amounts of light and vigorous PA during adolescence on a scale ranging from none to more than 3 hours activity. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and adjusted for potential confounders.

Results: Vigorous PA was inversely associated with MS risk in the pooled analysis ( p-trend < 0.001) with an age- and sex-adjusted OR of 0.74 (95% CI: 0.63-0.87) when comparing the highest and lowest levels. Adjusting for outdoor activity, infectious mononucleosis, body size, and smoking yielded similar results. The association was present in all countries and was not affected by exclusion of patients with early disease onset. Light PA was not associated with the risk of MS.

Conclusion: Our findings suggest that vigorous PA can modify the risk of developing MS independent of established risk factors.
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http://dx.doi.org/10.1177/1352458517694088DOI Listing
February 2018

Negative interaction between smoking and EBV in the risk of multiple sclerosis: The EnvIMS study.

Mult Scler 2017 Jun 23;23(7):1018-1024. Epub 2016 Sep 23.

The Kristian Gerhard Jebsen Centre for MS-Research, Department of Clinical Medicine, University of Bergen, Bergen, Norway/The Norwegian Multiple Sclerosis Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: Results from previous studies on a possible interaction between smoking and Epstein-Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting.

Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS.

Methods: Within the case-control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale.

Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis ( p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66-1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): -0.98, 95% CI: -2.05-0.15, p = 0.09).

Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.
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http://dx.doi.org/10.1177/1352458516671028DOI Listing
June 2017

Preclinical disease activity in multiple sclerosis: A prospective study of cognitive performance prior to first symptom.

Ann Neurol 2016 10;80(4):616-24

Norwegian MS Competence Center, Haukeland University Hospital, Bergen, Norway.

Objective: To prospectively investigate potential signs of preclinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort.

Methods: We linked the cognitive performance of all Norwegian men born 1950-1995 who underwent conscription examination at age 18 to 19 years to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study, cognitive test scores were available for 924 male cases and 19,530 male controls. We estimated mean score differences among cases and controls (Student t test) and the risk of developing MS comparing lower to higher scores (Cox regression) in strata of years to clinical onset.

Results: Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ = 0.80, p = 0.0095), corresponding to a 6 intelligence quotient (IQ)-point difference. Those scoring lowest, that is, >1 standard deviation below the controls' mean, had an increased MS risk during the 2 following years (relative risk = 2.81, 95% confidence interval = 1.52-5.20). Whereas results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored a significant 4.6 to 6.9 IQ points lower than controls up to 20 years prior to first progressive symptoms.

Interpretation: RRMS may start years prior to clinical presentation, and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease. Ann Neurol 2016;80:616-624.
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http://dx.doi.org/10.1002/ana.24769DOI Listing
October 2016

Level of education and multiple sclerosis risk after adjustment for known risk factors: The EnvIMS study.

Mult Scler 2016 Jan 26;22(1):104-11. Epub 2015 May 26.

Department of Global Public Health and Primary Care, University of Bergen, Norway/Department of Clinical and Experimental Medicine, University of Sassari, Italy/Division of Medicine, McGill University, Canada.

Background: Several recent studies have found a higher risk of multiple sclerosis (MS) among people with a low level of education. This has been suggested to reflect an effect of smoking and lower vitamin D status in the social class associated with lower levels of education.

Objective: The objective of this paper is to investigate the association between level of education and MS risk adjusting for the known risk factors smoking, infectious mononucleosis, indicators of vitamin D levels and body size.

Methods: Within the case-control study on Environmental Factors In MS (EnvIMS), 953 MS patients and 1717 healthy controls from Norway reported educational level and history of exposure to putative environmental risk factors.

Results: Higher level of education were associated with decreased MS risk (p trend = 0.001) with an OR of 0.53 (95% CI 0.41-0.68) when comparing those with the highest and lowest level of education. This association was only moderately reduced after adjusting for known risk factors (OR 0.61, 95% CI 0.44-0.83). The estimates remained similar when cases with disease onset before age 28 were excluded.

Conclusion: These findings suggest that factors related to lower socioeconomic status other than established risk factors are associated with MS risk.
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http://dx.doi.org/10.1177/1352458515579444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702243PMC
January 2016

Timing of use of cod liver oil, a vitamin D source, and multiple sclerosis risk: The EnvIMS study.

Mult Scler 2015 Dec 6;21(14):1856-64. Epub 2015 May 6.

The KG Jebsen Centre for MS-Research, Department of Clinical Medicine, University of Bergen, Norway/The Norwegian Multiple Sclerosis Competence Center, Department of Neurology, Haukeland University Hospital, Norway.

Background: Low vitamin D levels have been associated with an increased risk of multiple sclerosis (MS), although it remains unknown whether this relationship varies by age.

Objective: The objective of this paper is to investigate the association between vitamin D3 supplementation through cod liver oil at different postnatal ages and MS risk.

Methods: In the Norwegian component of the multinational case-control study Environmental Factors In Multiple Sclerosis (EnvIMS), a total of 953 MS patients with maximum disease duration of 10 years and 1717 controls reported their cod liver oil use from childhood to adulthood.

Results: Self-reported supplement use at ages 13-18 was associated with a reduced risk of MS (OR 0.67, 95% CI 0.52-0.86), whereas supplementation during childhood was not found to alter MS risk (OR 1.01, 95% CI 0.81-1.26), each compared to non-use during the respective period. An inverse association was found between MS risk and the dose of cod liver oil during adolescence, suggesting a dose-response relationship (p trend = 0.001) with the strongest effect for an estimated vitamin D3 intake of 600-800 IU/d (OR 0.46, 95% CI 0.31-0.70).

Conclusions: These findings not only support the hypothesis relating to low vitamin D as a risk factor for MS, but further point to adolescence as an important susceptibility period for adult-onset MS.
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http://dx.doi.org/10.1177/1352458515578770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657387PMC
December 2015

Concentration effect relationship of CYP3A inhibition by ritonavir in humans.

Eur J Clin Pharmacol 2013 Oct 9;69(10):1795-800. Epub 2013 Jun 9.

Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Purpose: To investigate the dose and concentration dependency of CYP3A inhibition by ritonavir using the established limited sampling strategy with midazolam for CYP3A activity.

Methods: An open, fixed-sequence study was carried out in 12 healthy subjects. Single ascending doses of ritonavir (0.1-300 mg) were evaluated for CYP3A inhibition in two cohorts using midazolam as a marker substance.

Results: Ritonavir administered as a single oral dose produced a dose-dependent CYP3A inhibition with an ID50 of 3.4 mg. Using the measured ritonavir concentrations an exposure-inhibition effect curve was established with an IC50 of 600 h pmol/L (AUC2-4). Over the ritonavir dose range studied non-linear exposure of ritonavir was observed.

Conclusions: Ritonavir shows a dose and concentration effect relationship of CYP3A inhibition. In addition, a proposed auto-inhibition of ritonavir metabolism resulted in a non-linear exposure of ritonavir with sub-proportional concentrations at low doses. A time-dependent CYP3A activity may result when inhibitors of CYP3A with short elimination half-lives are used.
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http://dx.doi.org/10.1007/s00228-013-1530-8DOI Listing
October 2013