Genetic Epidemiology of Amyotrophic Lateral Sclerosis in Norway: A 2-Year Population-Based Study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. In Europe, disease-causing genetic variants have been identified in 40-70% of familial ALS patients and approximately 5% of sporadic ALS patients. In Norway, the contribution of genetic variants to ALS has not yet been studied. In light of the potential development of personalized medicine, knowledge of the genetic causes of ALS in a population is becoming increasingly important. The present study provides clinical and genetic data on familial and sporadic ALS patients in a Norwegian population-based cohort. METHODS: Blood samples and clinical information from ALS patients were obtained at all 17 neurological departments throughout Norway during a 2-year period. Genetic analysis of the samples involved expansion analysis of C9orf72 and exome sequencing targeting 30 known ALS-linked genes. The variants were classified using genotype-phenotype correlations and bioinformatics tools. RESULTS: A total of 279 ALS patients were included in the study. Of these, 11.5% had one or several family members affected by ALS, whereas 88.5% had no known family history of ALS. A genetic cause of ALS was identified in 31 individuals (11.1%), among which 18 (58.1%) were familial and 13 (41.9%) were sporadic. The most common genetic cause was the C9orf72 expansion (6.8%), which was identified in 8 familial and 11 sporadic ALS patients. Pathogenic or likely pathogenic variants of SOD1 and TBK1 were identified in 10 familial and 2 sporadic cases. C9orf72 expansions dominated in patients from the Northern and Central regions, whereas SOD1 variants dominated in patients from the South-Eastern region. CONCLUSION: In the present study, we identified several pathogenic gene variants in both familial and sporadic ALS patients. Restricting genetic analysis to only familial cases would miss more than 40 percent of those with a disease-causing genetic variant, indicating the need for genetic analysis in sporadic cases as well.

Association of adverse childhood experiences with the development of multiple sclerosis.

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.

Stroke risk after transient ischemic attack in a Norwegian prospective cohort.

BACKGROUND: Transient ischemic attack (TIA) is a risk factor of stroke. Modern treatment regimens and changing risk factors in the population justify new estimates of stroke risk after TIA, and evaluation of the recommended ABCD2 stroke risk score. METHODS: From October, 2012, to July, 2014, we performed a prospective, multicenter study in Central Norway, enrolling patients with a TIA within the previous 2 weeks. Our aim was to assess stroke risk at 1 week, 3 months and 1 year after TIA, and to determine the predictive value of the dichotomized ABCD2 score (0-3 vs 4-7) at each time point. We used data obtained by telephone follow-up and registry data from the Norwegian Stroke Register. RESULTS: Five hundred and seventy-seven patients with TIA were enrolled of which 85% were examined by a stroke specialist within 24 h after symptom onset. The cumulative incidence of stroke within 1 week, 3 months and 1 year of TIA was 0.9% (95% CI, 0.37-2.0), 3.3% (95% CI, 2.1-5.1) and 5.4% (95% CI, 3.9-7.6), respectively. The accuracy of the ABCD2 score provided by c-statistics at 7 days, 3 months and 1 year was 0.62 (95% CI, 0.39-0.85), 0.62 (95% CI, 0.51-0.74) and 0.64 (95% CI, 0.54-0.75), respectively. CONCLUSIONS: We found a lower stroke risk after TIA than reported in earlier studies. The ABCD2 score did not reliably discriminate between low and high risk patients, suggesting that it may be less useful in populations with a low risk of stroke after TIA. TRIAL REGISTRATION: Unique identifier: NCT02038725 (retrospectively registered, January 16, 2014).

Lyme neuroborreliosis: do we treat according to guidelines?

Evidence-based guidelines, published in 2010, equate the efficacy of oral and intravenous antibiotics and recommend treatment duration of 2 weeks in early Lyme neuroborreliosis (LNB) without encephalitis or myelitis. Further, the Norwegian health authorities give a general advice to choose oral rather than intravenous administration when proven effective, due to lower costs, fewer risks, and reduced patient inconvenience. In this study we aimed to chart LNB treatment practice in Norway and compare it to these recommendations. Adult patients diagnosed with definite LNB between 2007 and 2013 in 11 different hospitals in the four health regions in Norway were invited to answer a questionnaire regarding duration and administration of antibiotic treatment. A total of 253 patients answered. Median age at diagnosis was 59 years (range 19-83), and 125 (49%) were women. Duration of treatment was 1 week in 7 (3%) patients, 2 weeks in 81 (32%), 3 weeks in 62 (25%), 4 weeks in 48 (19%), 5 weeks in 12 (5%), ≥6 weeks in 29 (12%), and unknown in 14 (6%). Treatment was given orally in 77 (30%) patients, intravenously in 110 (44%), both orally and intravenously in 65 (26%), and unknown in one. Treatment practices differed between the health regions (p = 0.002). During the study period, there were no significant time trend neither with respect to proportion of patients treated for only 2 weeks (OR 0.899, p = 0.109) nor with respect to proportion of patients treated exclusively with oral antibiotics (OR 1.131, p = 0.074). In conclusion, there seem to be a gap between evidence-based recommendations and treatment practice of LNB in Norway.

Hospital differences in motor activity early after stroke: a comparison of 11 Norwegian stroke units.

BACKGROUND: Activity levels in patients early after stroke vary across the world. The primary aim of this study was to assess the variation in motor activity in patients admitted to multiple Norwegian stroke units and to identify factors which explained the variation between hospitals. METHODS: Eligible patients were those less than 14 days after stroke, more than 18 years, not receiving palliative care. Activity levels, people present, and location were recorded by the use of a standard method of observation between 8 am and 5 pm. Hospital policy on serving meals in communal areas was also registered. Mixed general binomial model was used to analyze, which factors explained variation in activity levels between hospitals, after adjusting for age and stroke severity. RESULTS: A total of 393 patients from 11 stroke units were included. The patients spent 44.1% of the day in bed, 43.2% sitting out of bed, and 8.3% in higher motor activities (4.4% were not observed). Increased physical activity was associated with spending more time with a physical therapist, odds ratio (OR), 1.05 (95% confidence interval [CI], 1.03-1.08, P < .001) and admitted to a hospital serving the meals in communal areas, OR, 1.46 (95% CI, 1.09-1.95, P = .011). CONCLUSIONS: Despite variation between the hospitals, patients admitted to Norwegian stroke units spend most of the day out of bed. Time spent with a physical therapist and hospitals having a policy of serving meals in communal areas explained most of the variation in activity between hospitals.

Benefit of phosphodiesterase 4 inhibitors as supplemental therapy after lung transplantation concerning their antiproliferative effects: an experimental study using a heterotopic rodent model.

BACKGROUND: Recent advances in the understanding of immunomodulatory properties of phosphodiesterase 4 (PDE4) inhibitors recommend these drugs for immunosuppressive therapy after lung transplantation. The potency of three PDE4 inhibitors was tested using an established model of heterotopic tracheal transplantation in rats. METHODS: Five allogenic groups were investigated and treated with the PDE4 inhibitors: rolipram, cilomilast (Ariflo, SB-207499, SmithKline Beecham, Munich, Germany), roflumilast (Altana Pharmacia, Bad Homburg, Germany) or cyclosporine A (CsA), or left without immunosuppression. The grafts were quantitatively analyzed for epithelial integrity, monocyte/macrophage content, cell proliferation, and tracheal obliteration by histology/immunohistochemistry (days 1, 5, 7, 21, 28; n=4-7). RESULTS: In animals treated with the PDE4 inhibitors, the epithelium was completely lost until day 21. The epithelium was partially preserved in the rats receiving CsA until day 28. In the acute phase (days 5 and 7) the infiltration of monocytes and macrophages was significantly inhibited similarly (cilomilast) or less effective (rolipram, roflumilast) as in CsA-treated rats. In the chronic phase (day 28) the significant increase of monocytes and macrophages after CsA-treatment was not found in PDE4 inhibitor-treated rats. The PDE4 inhibitors showed lower (rolipram) or higher (cilomilast, roflumilast) potency as CsA to inhibit the cell proliferation. Only treatment with PDE4 inhibitor (Ariflo) significantly inhibited the obliteration, but to a lesser degree as CsA. CONCLUSION: The PDE4 inhibitors tested in our study are not suitable on their own for immunosuppressive therapy after lung transplantation because of the limited protection against the epithelial disturbance, infiltration of immune cells, and luminal obliteration. The strong anti-proliferative effect of the second-generation PDE4 inhibitors, cilomilast and roflumilast, suggest a benefit for the effective inhibition of immune cell and fibroblast proliferation contributing to the development of obliterative bronchiolitis.

Human inward rectifier potassium channels in chronic and postoperative atrial fibrillation.

OBJECTIVE: We showed recently that the 825T allele of the G-protein beta 3-subunit C825T polymorphism is associated with large inward rectifier K(+) currents I(K1) but low acetylcholine-activated K(+) current I(K,ACh) amplitudes. During chronic atrial fibrillation (AF), I(K1) and I(K,ACh) current densities were increased when compared to sinus rhythm (SR). It is unknown whether chronic AF and G beta 3 gene status are independent contributors to atrial K(+) current activity. We measured I(K1) and I(K,ACh) in tissue from AF patients with different G beta 3 genotypes and assessed the relation between the I(K1) and I(K,ACh) amplitudes and the incidence of postoperative AF. METHODS: We measured the amplitudes of I(K1) and I(K,ACh) in atrial myocytes from 26 patients with sinus rhythm (SR) and from 16 patients with chronic AF (>6 months). The K(+) currents were measured with standard patch-clamp techniques. The G beta 3 gene status of the patients was determined by PCR and restriction analysis. RESULTS: At -100 mV, the amplitude of I(K1) was larger in AF (10.9+/-1.0 pA/pF, n=49/16, cells/patients) than in SR (6.3+/-0.6 pA/pF, n=68/26, P<0.05), whereas the amplitude of I(K,ACh) was smaller in chronic AF (2.9+/-0.7 pA/pF, n=49/16) than in SR (6.3+/-0.7 pA/pF, n=68/26, P<0.05). These changes were independent of the patient G beta 3 gene status. Eight patients out of 26 in the SR group (31%) developed postoperative AF. When analysed based on incidence of postoperative AF, current amplitudes did not differ significantly. CONCLUSION: We provide evidence for up-regulation of I(K1) but down-regulation of I(K,ACh) in chronic AF which are independent of G beta 3 gene status. Atrial myocytes from patients who are in SR but later develop postoperative AF have no manifestation of altered I(K1) and I(K,ACh) at the time of cardiac surgery. Our results suggest that the AF-related changes of I(K1) and I(K,ACh) may be a consequence of or a contributory factor to chronic AF.