Publications by authors named "Kjetil Bjornevik"

37 Publications

Prediagnostic Neurofilament Light Chain Levels in Amyotrophic Lateral Sclerosis.

Neurology 2021 Aug 11. Epub 2021 Aug 11.

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

Objective: To assess whether plasma neurofilament light chain (NfL) levels are elevated before ALS diagnosis and to evaluate whether pre-diagnostic NfL levels are associated with metabolic alterations.

Methods: We conducted a matched case-control study nested in three large prospective US cohorts (the Nurses' Health Study, the Health Professionals Follow-up Study, and the Multiethnic Cohort Study), and identified 84 individuals who developed ALS during follow-up and had available plasma samples prior to disease diagnosis. For each ALS case, we randomly selected controls from those who were alive at the time of the case diagnosis and matched on birth year, sex, race/ethnicity, fasting status, cohort, and time of blood draw. We measured NfL in the plasma samples and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for ALS, adjusting for body mass index, smoking, physical activity, and urate levels.

Results: Higher NfL levels were associated with a higher ALS risk in plasma samples collected within 5 years of the ALS diagnosis (RR per 1 standard deviation [SD] increase: 2.68, 95% CI: 1.18-6.08), but not in samples collected further away from the diagnosis (RR per 1 SD increase 1.16, 95% CI: 0.78-1.73). A total of 21 metabolites were correlated with pre-diagnostic NfL levels in ALS cases (p < 0.05), but none of these remained significant after multiple comparison adjustments.

Conclusions: Plasma NfL levels were elevated in pre-diagnostic ALS cases, indicating that NfL may be a useful biomarker already in the earliest stages of the disease.

Classification Of Evidence: This study provides Class II evidence that plasma NfL levels are elevated in pre-diagnostic ALS patients.
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http://dx.doi.org/10.1212/WNL.0000000000012632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575132PMC
August 2021

Aging with multiple sclerosis: A longitudinal study of physical function, mental health, and memory in two cohorts of US women.

Mult Scler 2021 Apr 16:13524585211007739. Epub 2021 Apr 16.

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

Background: It is unknown how individuals with multiple sclerosis (MS) age compared to unaffected peers.

Objectives: The objective of the study is to describe the impact of MS on health and functioning in aging women.

Methods: We used 10-item Physical Functioning Scale (PF10) scores (from the Short Form-36 (SF-36)) and other indicators of general, physical, mental health, and memory collected repeatedly over 25 years with self-administered questionnaires among participants in the Nurses' Health Study ( = 121,700 recruited at ages 30-55) and Nurses' Health Study II ( = 116,429 recruited at ages 25-42) to compare women with MS ( = 733) to unaffected peers in their health and disability, and describe/quantify the burden of aging with MS.

Results: Women with MS had a consistently lower PF10 by 0.9-1.7 standard deviations with greater overall variability than unaffected women. PF10-scores gradually decreased with increasing age in both groups, but MS cases declined 3-4 times faster in midlife, while decline was similar in old age. The physical function score of 45-year-old women with MS was comparable to that of 75-year-old unaffected women; 70-year-old women with MS scored similarly to 85-year-old unaffected women. MS cases also reported worse health/more disability throughout adulthood on the other indicators.

Conclusion: The age-related decline in physical health is accelerated by 15-30 years in MS patients compared to unaffected peers.
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http://dx.doi.org/10.1177/13524585211007739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521558PMC
April 2021

Low vitamin D, but not tobacco use or high BMI, is associated with long-term disability progression in multiple sclerosis.

Mult Scler Relat Disord 2021 May 28;50:102801. Epub 2021 Jan 28.

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

Background: Low vitamin D levels, tobacco use and high body mass index (BMI) have been linked to adverse disease outcomes in multiple sclerosis (MS), but their influence on long-term disability progression remains unclear. Therefore, we explored whether these modifiable lifestyle factors were associated with 10-year clinical disability progression in patients with MS.

Methods: In this prospective study, a cohort of 88 patients with relapsing-remitting MS completed a randomized controlled study on ω-3 fatty acids between 2004 and 2008. During 24 months, serum 25-hydroxyvitamin D (25(OH)D), serum cotinine (nicotine metabolite), and BMI were repeatedly measured. In 2017, a follow-up study was conducted among 80 of the participants, including disability assessment by the Expanded Disability Status Scale (EDSS). Linear regression was used to explore associations between the lifestyle factors and the EDSS change over 10 years.

Results: Higher seasonally adjusted 25(OH)D levels were associated with lower 10-year EDSS progression (change in EDSS per 1 SD increase in 25(OH)D in a model adjusted for sex, age and baseline EDSS: -0.45 point, 95% CI: -0.75 to -0.16, p=0.003). Further adjustments for potential confounders related to lifestyle and disease status gave similar results. The association was mainly driven by low 25(OH)D levels during spring, as well as seasonally adjusted levels below 80 nmol/L. No clear association was found for BMI and cotinine.

Conclusion: Lower 25(OH)D levels, but apparently not tobacco use or higher BMI, were significantly associated with worse long-term disability progression in MS.
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http://dx.doi.org/10.1016/j.msard.2021.102801DOI Listing
May 2021

MRI Lesion State Modulates the Relationship Between Serum Neurofilament Light and Age in Multiple Sclerosis.

J Neuroimaging 2021 03 21;31(2):388-393. Epub 2021 Jan 21.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background And Purpose: Serum neurofilament light (sNfL) has been studied as a biomarker of disease activity in multiple sclerosis (MS). Several factors, including age, can influence its dynamics, and several studies have shown that sNfL increases with age in controls. Our objective was to explore the relationship of sNfL and age at different MS disease stages, including remission and after a gadolinium-enhancing (Gad+) lesion.

Methods: We included 94 patients with MS with annual sNfL measurements performed with a single-molecule array assay. We used multivariable linear mixed-effects models with random intercept to test the association between age and sNfL during remission and after a Gad+ lesion (ie, within 90 days after the Gad+ lesion). The model was adjusted for medication use and sex.

Results: We report a positive association between sNfL level and age during remission (adjusted estimate = 1.18% yearly increase, 95% CI = .34-2.03%, P = .008). In contrast, a negative interaction between age and Gad+ lesion status was observed (adjusted estimate = -1.73%, 95% CI = -2.85 to -.58%, P = .004).

Conclusion: We propose that younger patients experience a greater elevation in sNfL than older patients in response to Gad+ lesions. Our study provides potential insights into the effects of aging on neuroinflammation in MS.
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http://dx.doi.org/10.1111/jon.12826DOI Listing
March 2021

The human gut microbiota in people with amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 2;22(3-4):186-194. 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
May 2021

Tenofovir as a treatment option for multiple sclerosis.

Mult Scler Relat Disord 2020 Nov 7;46:102569. Epub 2020 Oct 7.

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

Some antiretroviral medications are also inhibitors of EBV. We describe a patient with highly active MS who was infected with HIV and started HIV-treatment containing tenofovir alafenamide (TAF), a potent inhibitor of EBV lytic reactivation. Her MS was in complete remission during this treatment, and she had new radiological disease activity again after switching to tenofovir disoproxil fumarate, a HIV drug with less potent activity against EBV replication. Based on the recently detected mechanism of TDF and TAF, we suggest that further studies on these drugs in MS are warranted.
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http://dx.doi.org/10.1016/j.msard.2020.102569DOI Listing
November 2020

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

Amyotroph Lateral Scler Frontotemporal Degener 2021 02 28;22(1-2):133-143. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004541PMC
February 2021

Intake of carbohydrates and SFA and risk of CHD in middle-age adults: the Hordaland Health Study (HUSK).

Public Health Nutr 2020 Sep 10:1-15. Epub 2020 Sep 10.

Department of Global Public Health and Primary Care, University of Bergen, Årstadveien 17, 5009Bergen, Norway.

Objective: Limiting SFA intake may minimise the risk of CHD. However, such reduction often leads to increased intake of carbohydrates. We aimed to evaluate associations and the interplay of carbohydrate and SFA intake on CHD risk.

Design: Prospective cohort study.

Setting: We followed participants in the Hordaland Health Study, Norway from 1997-1999 through 2009. Information on carbohydrate and SFA intake was obtained from a FFQ and analysed as continuous and categorical (quartiles) variables. Multivariable Cox regression estimated hazard ratios (HR) and 95 % CI. Theoretical substitution analyses modelled the substitution of carbohydrates with other nutrients. CHD was defined as fatal or non-fatal CHD (ICD9 codes 410-414 and ICD10 codes I20-I25).

Participants: 2995 men and women, aged 46-49 years.

Results: Adjusting for age, sex, energy intake, physical activity and smoking, SFA was associated with lower risk (HRQ4 v. Q1 0·44, 95 % CI 0·26, 0·76, Ptrend = 0·002). For carbohydrates, the opposite pattern was observed (HRQ4 v. Q1 2·10, 95 % CI 1·22, 3·63, Ptrend = 0·003). SFA from cheese was associated with lower CHD risk (HRQ4 v. Q1 0·44, 95 % CI 0·24, 0·83, Ptrend = 0·006), while there were no associations between SFA from other food items and CHD. A 5 E% substitution of carbohydrates with total fat, but not SFA, was associated with lower CHD risk (HR 0·75, 95 % CI 0·62, 0·90).

Conclusions: Higher intake of predominantly high glycaemic carbohydrates and lower intake of SFA, specifically lower intake from cheese, were associated with higher CHD risk. Substituting carbohydrates with total fat, but not SFA, was associated with significantly lower risk of CHD.
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http://dx.doi.org/10.1017/S1368980020003043DOI Listing
September 2020

Diet pattern and prodromal features of Parkinson disease.

Neurology 2020 10 19;95(15):e2095-e2108. Epub 2020 Aug 19.

From the Population Health Sciences Program (S.M.), Harvard University, Cambridge; Departments of Nutrition (K.B., K.C.H., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health; Partners Multiple Sclerosis Center (B.H.), Brigham and Women's Hospital; Department of Neurology (M.S.), Massachusetts General Hospital; and Channing Division of Network Medicine (A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objective: To assess the relationship between diet pattern and prodromal Parkinson disease (PD) features.

Methods: These analyses include 47,679 participants from the Nurses' Health Study and the Health Professionals Follow-up Study. Since 1986, both cohorts have collected dietary information every 4 years and calculated scores for adherence to different diet patterns, including the alternate Mediterranean diet (aMED) and the Alternative Healthy Eating Index (AHEI). In 2012, participants responded to questions regarding constipation and probable REM sleep behavior disorder. For a subset of 17,400 respondents to the 2012 questionnaire, 5 additional prodromal features of PD were assessed in 2014 to 2015. We used multinomial logistic regression to estimate the association between baseline (1986) diet pattern score quintiles and number of prodromal features (0, 1, 2, or ≥3) in 2012 to 2015. Additional analyses investigated the association between long-term adherence to these dietary patterns over 20 years and prodromal features suggestive of PD.

Results: In a comparison of extreme aMED diet quintiles, the odds ratio for ≥3 vs 0 features was 0.82 (95% confidence interval [CI] 0.68-1.00, false discovery rate [FDR]-adjusted = 0.03) at baseline and 0.67 (95% CI 0.54-0.83, FDR- < 0.001) for long-term diet; results were equally strong for the association with AHEI scores. Higher adherence to these diets was inversely associated with individual features, including constipation, excessive daytime sleepiness, and depression.

Conclusions: The inverse association between these diet patterns and prodromal PD features is consistent with previous findings and suggests that adherence to a healthy diet may reduce the occurrence of nonmotor symptoms that often precede PD diagnosis.
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http://dx.doi.org/10.1212/WNL.0000000000010523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713746PMC
October 2020

Temporal association of sNfL and gad-enhancing lesions in multiple sclerosis.

Ann Clin Transl Neurol 2020 06 25;7(6):945-955. Epub 2020 May 25.

Harvard Medical School, Boston, Massachusetts, 02115, USA.

Objective: Multiple sclerosis (MS) is an autoimmune demyelinating disorder, which is characterized by relapses and remissions. Serum neurofilament light chain (sNfL) is an emerging biomarker of disease activity but its clinical use is still limited. In this study, we aim to characterize the temporal association between sNfL and new clinical relapses and new gadolinium-enhancing (Gd+) lesions.

Methods: Annual sNfL levels were measured with a single-molecule array (SIMOA) assay in 94 patients with MS enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study. We used a multivariable linear mixed-effects model to test the temporal association of sNfL with clinical relapses and/or new Gd+ lesions. We adjusted this model for age, disease duration, sex, and disease-modifying therapies (DMTs) use.

Results: In the 3 months after a Gd+ lesion, we observed an average 35% elevation in sNfL (P < 0.0001) compared to remission samples. We also observed an average 32.3% elevation in sNfL at the time of or prior to a Gd+ lesion (P = 0.002) compared to remission. We observed a significant elevation in sNfL after a clinical relapse only when associated with a Gd+ lesion.

Interpretation: Our findings support sNfL as a marker of clinical relapses and Gd+ lesions. sNfL peaks in a 3-month window around Gd+ lesions. sNfL shows promise as a biomarker of neurological inflammation and possibly of simultaneous Gd+ lesions during a clinical relapse.
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http://dx.doi.org/10.1002/acn3.51060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318095PMC
June 2020

Plasma Metabolomic Markers of Insulin Resistance and Diabetes and Rate of Incident Parkinson's Disease.

J Parkinsons Dis 2020 ;10(3):1011-1021

Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

Background: Although there is evidence of shared dysregulated pathways between diabetes and Parkinson's disease, epidemiologic research on an association between the two diseases has produced inconsistent results.

Objective: We aimed to assess whether known metabolomic markers of insulin resistance and diabetes are also associated with Parkinson's disease development.

Methods: We conducted a nested case-control study among Nurses' Health Study and Health Professionals Follow-up Study participants who had provided blood samples up to twenty years prior to Parkinson's diagnosis. Cases were matched to risk-set sampled controls by age, sex, fasting status, and time of blood collection. Participants provided covariate information via regularly collected cohort questionnaires. We used conditional logistic regression models to assess whether plasma levels of branched chain amino acids, acylcarnitines, glutamate, or glutamine were associated with incident development of Parkinson's disease.

Results: A total of 349 case-control pairs were included in this analysis. In the primary analyses, none of the metabolites of interest were associated with Parkinson's disease development. In investigations of the association between each metabolite and Parkinson's disease at different time intervals prior to diagnosis, some metabolites showed marginally significant association but, after correction for multiple testing, only C18 : 2 acylcarnitine was significantly associated with Parkinson's disease among subjects for whom blood was collected less than 60 months prior to case diagnosis.

Conclusions: Plasma levels of diabetes-related metabolites did not contribute to predict risk of Parkinson's disease. Further investigation of the relationship between pre-diagnostic levels of diabetes-related metabolites and Parkinson's disease in other populations is needed to confirm these findings.
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http://dx.doi.org/10.3233/JPD-191896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034435PMC
August 2021

Big health data and Parkinson's disease epidemiology: Challenges and opportunities.

Parkinsonism Relat Disord 2020 02 7;71:58-59. Epub 2020 Jan 7.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.parkreldis.2020.01.001DOI Listing
February 2020

Prediagnostic plasma polyunsaturated fatty acids and the risk of amyotrophic lateral sclerosis.

Neurology 2020 02 3;94(8):e811-e819. Epub 2019 Dec 3.

From the Departments of Nutrition (É.J.O., K.B., J.D.F., A.A.) and Epidemiology (J.E.M., A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; School of Public Health (É.J.O.), College of Medicine, University College Cork, Ireland; Epidemiology Program (L.N.K., L.L.M.), University of Hawaii Cancer Center, Honolulu; Behavioral and Epidemiology Research Group (M.L.M., V.L.S.), American Cancer Society, Atlanta, GA; Family Medicine and Public Health (A.H.S.), School of Medicine, University of California San Diego; Department of Epidemiology (L.S.), College of Public Health, University of Iowa, Iowa City; and Department of Medicine (J.E.M.) and Channing Division of Network Medicine (J.E.M., A.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objective: To examine the association between prediagnostic plasma polyunsaturated fatty acids levels (PUFA) and amyotrophic lateral sclerosis (ALS).

Methods: We identified 275 individuals who developed ALS while enrolled in 5 US prospective cohorts, and randomly selected 2 controls, alive at the time of the case diagnosis, matched on cohort, birth year, sex, ethnicity, fasting status, and time of blood draw. We measured PUFA, expressed as percentages of total fatty acids, using gas liquid chromatography and used conditional logistic regression to estimate risk ratios (RR) and 95% confidence intervals (CI) for the association between PUFA and ALS.

Results: There was no association between total, n-3, and n-6 PUFA, eicosapentaenoic acid, or docosapentaenoic acid levels and ALS. Higher plasma α-linolenic acid (ALA) in men was associated with lower risk of ALS in age- and matching factor-adjusted analyses (top vs bottom quartile: RR = 0.21 [95% CI 0.07, 0.58], for trend = 0.004). In women, higher plasma arachidonic acid was associated with higher risk (top vs bottom quartile: RR = 1.65 [95% CI 0.99, 2.76], for trend = 0.052). Multivariable adjustment, including correlated PUFA, did not change the findings for ALA and arachidonic acid. In men and women combined, higher plasma docosahexaenoic acid (DHA) was associated with higher risk of ALS (top vs bottom quartile: RR = 1.56 [95% CI 1.01, 2.41], for trend = 0.054), but in multivariable models the association was only evident in men.

Conclusions: The majority of individual PUFAs were not associated with ALS. In men, ALA was inversely and DHA was positively related to risk of ALS, while in women arachidonic acid was positively related. These findings warrant confirmation in future studies.
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http://dx.doi.org/10.1212/WNL.0000000000008676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136057PMC
February 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

Prediagnostic plasma metabolomics and the risk of amyotrophic lateral sclerosis.

Neurology 2019 04 29;92(18):e2089-e2100. Epub 2019 Mar 29.

From the Departments of Nutrition (K.B., Z.Z., É.J.O., D.D.W., A.A.) and Epidemiology (L.L., J.E.M., A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; School of Public Health (É.J.O.), College of Medicine, University College Cork, Ireland; Department of Neurology (J.D.B., M.A.S.), Massachusetts General Hospital, Boston; Metabolomics Platform (C.B.C., A.D., S.J., K.A.P.), Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA; Department of Oncology (I.K.), Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI; Channing Division of Network Medicine (R.S.K., A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Epidemiology Program (L.N.K., L.L.M.), University of Hawaii Cancer Center, Honolulu; Behavioral and Epidemiology Research Group (M.L.M.), American Cancer Society, Atlanta, GA; Department of Physical Medicine and Rehabilitation (S.P.), Spaulding Rehabilitation Hospital and Massachusetts General Hospital; Harvard Medical School (S.P., M.A.S.), Boston, MA; Family Medicine and Public Health (A.H.S.), School of Medicine, University of California San Diego; Epidemiology and Environmental Health, Public Health and Health Professions (J.W.-W.), University at Buffalo, NY; Behavioral and Epidemiology Research Group (Y.W.), American Cancer Society, Atlanta, GA; and Department of Medicine (J.E.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objective: To identify prediagnostic plasma metabolomic biomarkers associated with amyotrophic lateral sclerosis (ALS).

Methods: We conducted a global metabolomic study using a nested case-control study design within 5 prospective cohorts and identified 275 individuals who developed ALS during follow-up. We profiled plasma metabolites using liquid chromatography-mass spectrometry and identified 404 known metabolites. We used conditional logistic regression to evaluate the associations between metabolites and ALS risk. Further, we used machine learning analyses to determine whether the prediagnostic metabolomic profile could discriminate ALS cases from controls.

Results: A total of 31 out of 404 identified metabolites were associated with ALS risk ( < 0.05). We observed inverse associations (n = 27) with plasma levels of diacylglycerides and triacylglycerides, urate, purine nucleosides, and some organic acids and derivatives, while we found positive associations for a cholesteryl ester, 2 phosphatidylcholines, and a sphingomyelin. The number of significant associations increased to 67 (63 inverse) in analyses restricted to cases with blood samples collected within 5 years of onset. None of these associations remained significant after multiple comparison adjustment. Further, we were not able to reliably distinguish individuals who became cases from controls based on their metabolomic profile using partial least squares discriminant analysis, elastic net regression, random forest, support vector machine, or weighted correlation network analyses.

Conclusions: Although the metabolomic profile in blood samples collected years before ALS diagnosis did not reliably separate presymptomatic ALS cases from controls, our results suggest that ALS is preceded by a broad, but poorly defined, metabolic dysregulation years before the disease onset.
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http://dx.doi.org/10.1212/WNL.0000000000007401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512888PMC
April 2019

Shedding light on the link between early life sun exposure and risk of multiple sclerosis: results from the EnvIMS Study.

Int J Epidemiol 2019 08;48(4):1073-1082

Neuroepidemiology Research Unit, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Background: Lower levels of sun exposure in childhood have been suggested to be associated with increased risk of multiple sclerosis (MS). In this paper we extend previous work, using two novel analytical strategies.

Methods: Data collected in the Environmental risk factors In MS (EnvIMS) study, a case-control study with MS cases and population-based controls from Canada, Italy and Norway, were used. Participants reported on sun exposure behaviours for 5-year age intervals from birth; we focused on the first three age intervals (≤15 years). We compared two life course epidemiology conceptual models, the critical period and the accumulation model. We also used latent class analysis to estimate MS risk for different latent sun exposure behaviour groups.

Results: The analyses included 2251 cases and 4028 controls. The accumulation model was found to be the best model, which demonstrated a nearly 50% increased risk of MS comparing lowest reported summer sun exposure with highest [risk ratio (RR) = 1.47 (1.24, 1.74)]. The latent sun exposure behaviour group, characterized by low sun exposure during summer and winter and high sun protection use, had the highest risk of MS; a 76% increased risk as compared with the group with high sun exposure and low sun protection use [RR = 1.76 (1.27, 2.46)].

Conclusions: Our analyses provide novel insights into the link between sun exposure and MS. We demonstrate that more time indoors during childhood and early adolescence is linked with MS risk, and that sun protection behaviours in those who spend most time indoors may play a key role in increasing risk.
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http://dx.doi.org/10.1093/ije/dyy269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693814PMC
August 2019

Prediagnostic plasma branched-chain amino acids and the risk of amyotrophic lateral sclerosis.

Neurology 2019 04 14;92(18):e2081-e2088. Epub 2018 Nov 14.

From the Departments of Nutrition (K.B., É.J.O., Z.Z., A.A.) and Epidemiology (J.E.M., A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; School of Public Health (É.J.O.), College of Medicine, University College Cork, Ireland; Department of Neurology (J.D.B., M.A.S.), Massachusetts General Hospital (S.P.), Boston; Metabolomics Platform (C.B.C., S.J.), Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge; Department of Oncology (I.K.), Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI; Epidemiology Program (L.N.K., L.L.M.), University of Hawaii Cancer Center, Honolulu; Epidemiology Research Program (M.L.M.), American Cancer Society, Atlanta, GA; Department of Physical Medicine and Rehabilitation (S.P.), Spaulding Rehabilitation Hospital, Charlestown; Harvard Medical School (S.P., M.A.S.), Boston, MA; Department of Epidemiology (E.O.T.), Graduate School of Public Health, University of Pittsburgh, PA; Department of Epidemiology (R.B.W.), College of Public Health, University of Iowa, Iowa City; and Department of Medicine (J.E.M.) and Channing Division of Network Medicine (A.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objective: To assess whether prediagnostic levels of plasma branched-chain amino acids (BCAAs) are associated with amyotrophic lateral sclerosis (ALS) risk.

Methods: We included participants from 5 large cohort studies-The Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition, the Multiethnic Cohort Study, and the Women's Health Initiative-and identified 275 individuals who developed ALS during follow-up. Two controls were randomly selected for each case, matched on cohort, age, sex, fasting status, and time of blood draw. We measured metabolites using liquid chromatography-mass spectrometry and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for the association of individual BCAAs with ALS risk.

Results: None of the 3 BCAAs was associated with a higher ALS risk. The risk estimates were similar for leucine (RR top vs bottom quartile: 0.87, 95% CI 0.57-1.33), isoleucine (RR top vs bottom quartile: 0.81, 95% CI 0.52-1.24), and valine (RR top vs bottom quartile: 0.80, 95% CI 0.52-1.23) in a multivariable analysis adjusted for body mass index, smoking, level of education, and physical activity. The estimates did not vary significantly by sex, fasting status, or time interval between blood draw and disease onset.

Conclusion: The results from this study do not support the hypothesis that BCAAs are risk factors for ALS.
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http://dx.doi.org/10.1212/WNL.0000000000006669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512885PMC
April 2019

Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System.

Mult Scler 2019 10 19;25(12):1633-1640. Epub 2018 Sep 19.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.

Background: Drug-induced liver injury (DILI) has been observed in patients with multiple sclerosis (MS), raising concerns on the liver safety of MS drugs.

Objective: To describe DILI events with MS drugs by analyzing the FDA Adverse Event Reporting System.

Methods: DILI reports were extracted and classified in overall liver injury (OLI), including asymptomatic elevation of liver enzymes, and severe liver injury (SLI). We performed disproportionality analysis by calculating adjusted reporting odds ratios (RORs) with 95% confidence interval (CI) and case-by-case evaluation for concomitant drugs with hepatotoxic potential.

Results: Fampridine showed statistically significant ROR for both OLI and SLI, whereas teriflunomide and fingolimod generated solid disproportionality (ROR > 2) only for OLI (ROR, 2.31; 95% CI, 2.12-2.52; and 2.53; 2.40-2.66, respectively). Among monoclonal antibodies, only alemtuzumab generated higher-than-expected ROR for OLI (1.34; 1.09-1.65). We also detected the expected hepatotoxic potential of beta interferon and mitoxantrone. Concomitant reporting of hepatotoxic drugs ranged from 26% (dimethyl fumarate) to 90% (mitoxantrone).

Conclusion: These real-world pharmacovigilance findings suggest that DILI might be a common feature of MS drugs and call for (1) formal population-based study to verify the risk of fampridine and (2) awareness by clinicians, who should assess the possible responsibility of MS drugs when they diagnose DILI.
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http://dx.doi.org/10.1177/1352458518799598DOI Listing
October 2019

Multiple sclerosis as an adverse drug reaction: clues from the FDA Adverse Event Reporting System.

Expert Opin Drug Saf 2018 Sep 11;17(9):869-874. Epub 2018 Aug 11.

a Department of Medical and Surgical Sciences , Alma Mater Studiorum, University of Bologna , Bologna , Italy.

Background: Possible relationship between drug exposure and multiple sclerosis (MS) development is insufficiently investigated, and further challenged by the incomplete understanding of MS etiopathogenesis. The study aims to investigate whether drug exposure could contribute to MS, by analyzing worldwide spontaneous reporting archives of adverse drug reaction (ADRs).

Research Design And Methods: We retrieved information from the US Food and Drug Administration Adverse Event Reporting System (FAERS) over a 13-year period. Reporting odds ratio (ROR) for MS was calculated for each single substance. Disproportionality signals were considered when at least 10 cases were retrieved with a lower limit of the 95% confidence interval (CI) >1.

Results: After a customized data-mining process, 3,226 reports of MS were retrieved. 'Antineoplastic and immunomodulating drugs' (33% of total reports) were the most frequently reported, with 10 disproportionality signals, including etanercept (445 cases; ROR: 2.48; 95% Cl: 2.24-2.74), adalimumab (329; 2.05; 1.83-2.30), and infliximab (119; 2.25; 1.87-2.70). We also observed signals for drugs acting on hormone balance, bone density, and central nervous system.

Conclusion: Our findings suggest that immunomodulatory drugs increase the risk of MS and point out that some other drug classes should be further investigated for this risk.
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http://dx.doi.org/10.1080/14740338.2018.1506763DOI Listing
September 2018

α-Linolenic acid is associated with MRI activity in a prospective cohort of multiple sclerosis patients.

Mult Scler 2019 06 4;25(7):987-993. Epub 2018 Jun 4.

The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Background: The plant-based ω-3 fatty acid α-linolenic acid (ALA) has been associated with lower MS risk. It is currently unknown whether ALA affects disease activity.

Objective: To investigate the association between ALA levels and disease activity.

Methods: We conducted a cohort study including 87 multiple sclerosis (MS)-patients who originally participated in a randomized trial of ω-3 fatty acids (the OFAMS study). We measured serum levels of ALA during follow-up and used random intercept logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association between ALA levels, new magnetic resonance imaging (MRI) lesions, Expanded Disability Status Scale (EDSS) progression and new relapses adjusting for age at inclusion, sex, and use of interferon beta-1a.

Results: In continuous (per 1-SD increase) multivariable-adjusted analyses, higher ALA levels were significantly associated with lower odds of new T2-lesions (OR: 0.59, 95% CI: 0.37-0.95) during follow-up. The effect estimates were similar for new T1Gd + lesions (OR: 0.73, 95% CI: 0.48-1.11), EDSS-progression (OR: 0.62, 95% CI: 0.34-1.16) and new relapses (OR: 0.49, 95% CI: 0.22-1.10), but these estimates did not reach statistical significance. Further adjustment for vitamin D and tobacco use did not materially change the results.

Conclusion: We found that higher levels of ALA were associated with lower disease activity in MS-patients.
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http://dx.doi.org/10.1177/1352458518779925DOI Listing
June 2019

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

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

Amyotroph Lateral Scler Frontotemporal Degener 2018 05 26;19(3-4):194-200. Epub 2017 Dec 26.

b Department of Nutrition , Harvard TH Chan School of Public Health , Boston , MA , USA.

Objective: To prospectively examine for the first time the association between plasma urate levels measured in healthy participants and future amyotrophic lateral sclerosis (ALS) risk.

Methods: A pooled case-control study nested in five US prospective cohorts comprising 319,617 participants who provided blood, of which 275 had ALS during follow-up. Pre-diagnostic plasma urate was determined for all participants using a clinical colorimetric enzyme assay. Gender-specific multivariable-adjusted rate ratios (RR) of ALS incidence or death estimated by conditional logistic regression and pooled using inverse-variance weighting.

Results: In age- and matching factor-adjusted analyses, a 1 mg/dL increase in urate concentration was associated with RR = 0.88 (95% CI: [0.78, 0.997] p = 0.044). After adjustment for BMI, a strong predictor of ALS and urate levels, and other potential covariates, the RR = 0.89 (95% CI: [0.78, 1.02]; p = 0.08 for 1mg/dL increase in urate).

Conclusion: Elevation of plasma urate was modestly inversely associated with the risk of ALS and warrants further study for a potential role in this disease.
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http://dx.doi.org/10.1080/21678421.2017.1418005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423442PMC
May 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

Neurofilament light chain predicts disease activity in relapsing-remitting MS.

Neurol Neuroimmunol Neuroinflamm 2018 Jan 28;5(1):e422. Epub 2017 Nov 28.

Department of Neurology (K.N.V., K.B., K.-M.M., Ø.T., S.W., L.A.B., C.V.), Haukeland University Hospital; Department of Clinical Medicine (K.N.V., K.-M.M., Ø.T., S.W., L.A.B., C.V.), University of Bergen, Norway; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Clinical Research and Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Global Public Health and Primary Care (K.B.), University of Bergen, Norway; and Norwegian MS-Registry & Biobank (K.-M.M.).

Objective: To investigate whether serum neurofilament light chain (NF-L) and chitinase 3-like 1 (CHI3L1) predict disease activity in relapsing-remitting MS (RRMS).

Methods: A cohort of 85 patients with RRMS were followed for 2 years (6 months without disease-modifying treatment and 18 months with interferon-beta 1a [IFNB-1a]). Expanded Disability Status Scale was scored at baseline and every 6 months thereafter. MRI was performed at baseline and monthly for 9 months and then at months 12 and 24. Serum samples were collected at baseline and months 3, 6, 12, and 24. We analyzed the serum levels of NF-L using a single-molecule array assay and CHI3L1 by ELISA and estimated the association with clinical and MRI disease activity using mixed-effects models.

Results: NF-L levels were significantly higher in patients with new T1 gadolinium-enhancing lesions (37.3 pg/mL, interquartile range [IQR] 25.9-52.4) and new T2 lesions (37.3 pg/mL, IQR 25.1-48.5) compared with those without (28.0 pg/mL, IQR 21.9-36.4, β = 1.258, < 0.001 and 27.7 pg/mL, IQR 21.8-35.1, β = 1.251, < 0.001, respectively). NF-L levels were associated with the presence of T1 gadolinium-enhanced lesions up to 2 months before ( < 0.001) and 1 month after ( = 0.009) the time of biomarker measurement. NF-L levels fell after initiation of IFNB-1a treatment ( < 0.001). Changes in CHI3L1 were not associated with clinical or MRI disease activity or interferon-beta 1a treatment.

Conclusion: Serum NF-L could be a promising biomarker for subclinical MRI activity and treatment response in RRMS. In clinically stable patients, serum NF-L may offer an alternative to MRI monitoring for subclinical disease activity.

Clinicaltrialsgov Identifier: NCT00360906.
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http://dx.doi.org/10.1212/NXI.0000000000000422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707445PMC
January 2018

β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease.

Science 2017 09;357(6354):891-898

Neurogenomics Laboratory and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.

Copy number mutations implicate excess production of α-synuclein as a possibly causative factor in Parkinson's disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the β2-adrenoreceptor (β2AR) is a regulator of the α-synuclein gene (). β2AR ligands modulate transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the β2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a β2AR antagonist correlated with increased risk. β2AR activation protected model mice and patient-derived cells. Thus, β2AR is linked to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.
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http://dx.doi.org/10.1126/science.aaf3934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761666PMC
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

Polyunsaturated fatty acids and the risk of multiple sclerosis.

Mult Scler 2017 Dec 3;23(14):1830-1838. Epub 2017 Feb 3.

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

Background: Results from previous studies on polyunsaturated fatty acid (PUFA) intake and multiple sclerosis (MS) risk are conflicting.

Objective: To prospectively investigate the association between dietary intake of PUFA and MS risk.

Methods: We followed 80,920 women from Nurses' Health Study (1984-2004) and 94,511 women from Nurses' Health Study II (1991-2009) who reported on diet using a validated food frequency questionnaire every 4 years and identified 479 incident MS cases during follow-up. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), for the effect of PUFA intake on MS risk adjusting for age, latitude of residence at age 15, ancestry, cigarette smoking, supplemental vitamin D intake, body mass index, and total energy intake.

Results: Higher intake of total PUFA at baseline was associated with a lower risk of MS (HR top vs bottom quintile: 0.67, 95% CI: 0.49-0.90, p trend = 0.01). Among the specific types of PUFA, only α-linolenic acid (ALA) was inversely associated with MS risk (HR top vs bottom quintile: 0.61, 95% CI: 0.45-0.83, p trend = 0.001). The long-chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not associated with MS risk.

Conclusion: Low dietary PUFA intake may be another modifiable risk factor for MS.
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http://dx.doi.org/10.1177/1352458517691150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494026PMC
December 2017

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
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