Trond Riise’s research while affiliated with University of Bergen and other places

Background People with multiple sclerosis (MS) have an increased risk of migraine. However, little is known about migraine and other headaches during the prodromal phase (before MS symptom onset). Our objective was to study the risk of migraine in women with MS before MS onset. Methods A nationwide, prospective cohort study of women participating in the Norwegian Mother, Father, and Child cohort study 1999–2008. The women reported the occurrence of migraine and other headaches prior to or during pregnancy. We identified women who later developed MS through data linkage with national health registries in 2018. We excluded women with an established MS diagnosis (n = 125) and women who had experienced their first clinical symptom of MS, but not yet received an MS diagnosis (n = 91). The reference group comprised all other women in the cohort (n = 85,292). We used logistic regression to estimate adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs). Results Two hundred and forty-six women developed MS during follow-up. Of these, 116 women had MS symptom onset after 1–5 years, 92 after 6–10 years, and 38 after 10 years. Migraine was more common among women who developed MS compared to the reference group, 18% vs 11%, aOR 1.6 (1.2–2.3), adjusted for age, smoking, socioeconomic status and overweight. The risk of other headaches was similar for women who developed MS compared to the reference group, 29% vs 27%, aOR 1.1 (0.8–1.4). Migraine was reported by 21 of 116 (18%) women with $\le$ 5 years until MS symptom onset (aOR 1.7 [1.1–2.8]) and 19 of 92 (21%) women with 6–10 years until MS symptom onset (aOR 1.9 [1.1–2.8]. Only three of 38 (8%) women with > 10 years until MS symptom onset reported migraine, aOR 0.7 (0.2–2.2). Conclusions Women with MS have increased risk of migraine, but not other headaches, up to a decade before the onset of classical MS symptoms. This supports that migraine can be a symptom of the MS prodrome. Special attention in people with migraine may lead to earlier recognition of MS.

Background We aimed to assess whether exposure to risk factors in early life from conception to puberty continue to contribute to lung function decline later in life by using a pooled cohort comprising approx. 11,000 adults followed for more than 20 years and with up to three lung function measurements. Methods Participants (20–68 years) in the ECRHS and NFBC1966 cohort studies followed in the periods 1991–2013 and 1997–2013, respectively, were included. Mean annual decline in maximum forced expired volume in 1 s (FEV1) and forced vital capacity (FVC) were main outcomes. Associations between early life risk factors and change in lung function were estimated using mixed effects linear models adjusted for sex, age, FEV1, FVC and height at baseline, accounting for personal smoking. Findings Decline in lung function was accelerated in participants with mothers that smoked during pregnancy (FEV1 2.3 ml/year; 95% CI: 0.7, 3.8) (FVC 2.2 ml/year; 0.2, 4.2), with asthmatic mothers (FEV1 2.6 ml/year; 0.9, 4.4) (FEV1/FVC 0.04 per year; 0.04, 0.7) and asthmatic fathers (FVC 2.7 ml/year; 0.5, 5.0), and in women with early menarche (FVC 2.4 ml/year; 0.4, 4.4). Personal smoking of 10 pack-years contributed to a decline of 2.1 ml/year for FEV1 (1.8, 2.4) and 1.7 ml/year for FVC (1.3, 2.1). Severe respiratory infections in early childhood were associated with accelerated decline among ever-smokers. No effect-modification by personal smoking, asthma symptoms, sex or cohort was found. Interpretation Mothers’ smoking during pregnancy, parental asthma and early menarche may contribute to a decline of FEV1 and FVC later in life comparable to smoking 10 pack-years. Funding 10.13039/501100007601European Union's Horizon 2020; 10.13039/501100005416Research Council of Norway; 10.13039/501100002341Academy of Finland; University Hospital Oulu; 10.13039/501100008530European Regional Development Fund; 10.13039/501100004837Spanish Ministry of Science and Innovation; 10.13039/501100002809Generalitat de Catalunya.

Background: Associations between phenotypic traits, environmental exposures, and Parkinson’s disease have largely been evaluated one-by-one, piecemeal, and pre-selections. A comprehensive picture of comorbidities, phenotypes, exposures, and polypharmacy characterizing the complexity and heterogeneity of real-world patients presenting to academic movement disorders clinics in the US is missing. Objectives: To portrait the complexity of features associated with patients with Parkinson’s disease in a study of 933 cases and 291 controls enrolled in the Harvard Biomarkers Study. Methods: The primary analysis evaluated 64 health features for associations with Parkinson’s using logistic regression adjusting for age and sex. We adjusted for multiple testing using the false discovery rate (FDR) with £ 0.05 indicating statistical significance. Exploratory analyses examined feature correlation clusters and feature combinations. Results: Depression (OR = 3.11, 95% CI 2.1 to 4.71), anxiety (OR = 3.31, 95% CI 2.01-5.75), sleep apnea (OR 2.58, 95% CI 1.47-4.92), and restless leg syndrome (RLS; OR 4.12, 95% CI 1.81-12.1) were significantly more common in patients with Parkinson’s than in controls adjusting for age and sex with FDR £ 0.05. The prevalence of depression, anxiety, sleep apnea, and RLS were correlated, and these diseases formed part of a larger cluster of mood traits and sleep traits linked to PD. Exposures to pesticides (OR 1.87, 95% CI 1.37-2.6), head trauma (OR 2.33, 95% CI 1.51-3.73), and smoking (OR 0.57, 95% CI 0.43-0.75) were significantly associated with the disease consistent with previous studies. Vitamin supplementation with cholecalciferol (OR 2.18, 95% CI 1.4-3.45) and coenzyme Q10 (OR 2.98, 95% CI 1.89-4.92) was more commonly used by patients than controls. Cumulatively, 43% (398 of 933) of Parkinson’s patients had at least one psychiatric or sleep disorder, compared to 21% (60 of 291) of healthy controls. Conclusions: 43% of Parkinson’s patients seen at Harvard-affiliated teaching hospitals have depression, anxiety, and disordered sleep. This syndromic cluster of mood and sleep traits may be pathophysiologically linked and clinically important.

Background and objectives The incidence rate of Parkinson’s disease (PD) has been increasing rapidly during the last years. Yet, no treatments exist to prevent or slow the progression of the disease. Moreover, we are unable to detect early disease stages during which intervention with disease-modifying therapies is most likely to succeed. The objective of this study was to perform an agnostic drug-wide association study (DWAS) estimating the association between use of any of the drugs prescribed in Norway and the subsequent risk of PD. Methods This registry-based cohort study use data from the entire Norwegian population between 2004–2019 linked to the Norwegian Prescription Registry, with more than 600 million individual prescriptions. Drug classes were screened according to ATC codes at level 2, corresponding to therapeutic subgroups. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for the associations between drug classes and PD risk. All p-values were corrected for multiple testing using the false discovery rate. Additionally, we conducted sensitivity analyses of exposure definition, as well as time-lag and dose-response analyses. Results The study population comprised 3,223,672 individuals, 15,849 of whom developed PD during the follow-up. We identified thirty-one drug classes that were statistically significantly associated with PD risk in Norway during the follow-up. Drugs acting on the renin-angiotensin system (HR = 0.92, 95% CI: 0.89–0.95), corticosteroids for systemic use (0.88, 95% CI: 0.84–0.93), and vaccines (0.89, 95% CI: 0.82–0.96) were associated with a decreased risk of PD even up to 10 years prior to PD onset. Drug classes used to treat symptoms related to prodromal signs of PD such as constipation, urological issues, and depression were associated with an increased risk of subsequent diagnosis of PD with HRs of 1.6 (95% CI: 1.49–1.73), 1.48 (1.42–1.53), and 1.94 (1.87–2.01), respectively. Discussion This drug-wide study identified thirty-one drug classes that were associated with the PD risk change. It reveals links of renin-angiotensin system medications, vaccines, and corticosteroids with PD risk and suggests that monitoring drug usage using pharmacoepidemiology may allow identifying individuals with prodromal PD.

Background: Caesarean section (CS) may affect the risk of developing multiple sclerosis (MS) in the offspring, possibly through changes in gut microbiota composition, but findings from previous studies are inconsistent. We investigated whether birth by CS was associated with the risk of adult-onset MS. Methods: We conducted a prospective population-based cohort study, including all individuals born in Norway between 1967 and 2003, using the Medical Birth Registry of Norway linked with the Norwegian Multiple Sclerosis Registry and Biobank. The follow-up was until 2021. We used multivariable Cox models to estimate HRs for MS risk with 95% CIs. Results: Among 2 046 637 individuals in the cohort, 4954 MS cases were identified. Being born by CS was associated with a modest increase in MS risk (HR=1.18, 95% CI 1.05 to 1.32). In the sibling-matched analysis, we found no association between CS and MS risk. We found an interaction between CS and gestational age (p=0.03): CS was associated with an increased risk of MS in individuals born preterm (HR=1.62, 95% CI 1.18 to 2.24), whereas there was no association in individuals born at term (HR=1.13, 95% CI 0.99 to 1.27). In a subgroup analysis of individuals born in 1988 and onwards, emergency CS was related to an elevated MS risk (HR=1.40, 95% CI 1.07 to 1.83), whereas planned CS was not (HR: 1.10, 95% CI 0.77 to 1.58). Conclusions: CS was associated with a modestly higher risk of developing MS. However, the stronger associations seen in subgroups who likely experienced a more complicated pregnancy/delivery may point to confounding underlying these associations.

Introduction: There is limited information on how the association between Parkinson's disease and the use of beta2-adrenoreceptor (β2AR) agonists varies among groups of short-, long-, and ultra-long-acting β2AR agonists (SABA, LABA and ultraLABA). Methods: In this prospective study of the Norwegian population, we estimated the incidence of Parkinson's disease according to exposure to β2AR agonists as a time-dependent variable by means of Cox regression. We adjusted for educational level, comorbidity and performed a sensitivity analysis excluding individuals with chronic obstructive pulmonary disease (COPD), all factors associated with smoking. Anticholinergics and corticosteroids as drugs with the same indication were analyzed for comparison. Results: In the follow-up period from 2005 to 2019, 15,807 incident Parkinson's cases were identified. After adjustments for sex, education and age as the timescale, SABA (Hazard ratio (HR) = 0.84; 95%CI: 0.79, 0.89; p < 0.001), LABA (HR = 0.85; 95%CI: 0.81, 0.90; p < 0.001) and ultraLABA (HR = 0.6; 95%CI: 0.49, 0.73; p < 0.001) were all associated with a lower risk of Parkinson's disease. After exclusion of COPD patients, corticosteroids and anticholinergics were no longer inversely associated, whereas β2AR agonists remained associated. Conclusion: Of drugs with the same indication of use, only β2AR agonists remained inversely associated with PD risk after all adjustments, with ultraLABA displaying the overall strongest association. Although the precision of the estimate is limited by the modest number of exposed PD cases without COPD, the association is intriguing and suggest that longer-acting, more lipophilic, and thus likely more brain-penetrant β2AR agonists could be prioritized for further studies.

Objective To study whether exposure to childhood emotional, sexual or physical abuse is associated with subsequent multiple sclerosis (MS) development. Methods A nationwide, prospective cohort study based on participants in the Norwegian Mother, Father and Child cohort study. Enrolment took place 1999–2008, with follow-up until 31 December 2018. Childhood abuse before age 18 years was obtained from self-completed questionnaires. We identified MS diagnoses through data-linkage with national health registries and hospital records. The Cox model was used to estimate HRs for MS with 95% CIs, adjusting for confounders and mediators. Results In this prospective cohort study, 14 477 women were exposed to childhood abuse and 63 520 were unexposed. 300 women developed MS during the follow-up period. 71 of these (24%) reported a history of childhood abuse, compared with 14 406 of 77 697 (19%) women that did not develop MS. Sexual abuse (HR 1.65, 95% CI 1.13 to 2.39) and emotional abuse (HR 1.40, 95% CI 1.03 to 1.90) in childhood were both associated with an increased risk of developing MS. The HR of MS after exposure to physical abuse was 1.31 (95% CI 0.83 to 2.06). The risk of MS was further increased if exposed to two (HR 1.66, 95% CI 1.04 to 2.67) or all three abuse categories (HR 1.93, 95% CI 1.02 to 3.67). Interpretation Childhood sexual and emotional abuse were associated with an increased risk of developing MS. The risk was higher when exposed to several abuse categories, indicating a dose–response relationship. Further studies are needed to identify underlying mechanisms.

Background and Objectives Many studies have examined the relation between PD and environmental variables serially --- one candidate association at a time. In the real world however, both environmental exposures and patients are much more complex, including correlated environmental exposures, polypharmacy, and complex comorbidities. Here we begin to characterize a holistic view of environmental, health, and pharmacological traits linked to patients with PD. Methods The Harvard Biomarkers Study (HBS) is a large case-control study of PD patients and healthy controls that includes an extensive questionnaire covering past medical and social history data and is thus well-suited for such an exploratory study. Sixty-four environmental, pharmacological, and clinical features were evaluated for associations with PD using logistic regression analysis with backward elimination. Results Male gender, coronary artery disease, depression, anxiety, restless leg syndrome, head trauma, ibuprofen use, co-enzyme Q10 use, and vitamin D supplementation were significantly positively associated with PD. By contrast, asthma/chronic obstructive pulmonary disease (COPD), naproxen, ezetimibe, and smoking were significantly negatively associated with PD. Discussion This study shows that unbiased, data-rich exploration of the Parkinson phenome has the promise to uncover, prioritize, and clarify associations between environment, multi-system health phenotypes, and PD in a patient-centric manner. Associations with coronary artery disease, mood disorders, and the cholesterol-absorption inhibitor ezetimibe were revealed that have been largely neglected in traditional hypothesis-driven investigations. Interestingly, asthma/COPD was inversely associated with PD, and this was independent of smoking history. Furthermore, well-established associations were confirmed for male gender, smoking, head trauma, and restless legs syndrome.