Repeat expansions in AR, ATXN1, ATXN2 and HTT in Norwegian patients diagnosed with amyotrophic lateral sclerosis.

Genetic repeat expansions cause neuronal degeneration in amyotrophic lateral sclerosis as well as other neurodegenerative disorders such as spinocerebellar ataxia, Huntington's disease and Kennedy's disease. Repeat expansions in the same gene can cause multiple clinical phenotypes. We aimed to characterize repeat expansions in a Norwegian amyotrophic lateral sclerosis cohort. Norwegian amyotrophic lateral sclerosis patients (n = 414) and neurologically healthy controls adjusted for age and gender (n = 713) were investigated for repeat expansions in AR, ATXN1, ATXN2 and HTT using short read exome sequencing and the ExpansionHunter software. Five amyotrophic lateral sclerosis patients (1.2%) and two controls (0.3%) carried ≥36 repeats in HTT (P = 0.032), and seven amyotrophic lateral sclerosis patients (1.7%) and three controls (0.4%) carried ≥29 repeats in ATXN2 (P = 0.038). One male diagnosed with amyotrophic lateral sclerosis carried a pathogenic repeat expansion in AR, and his diagnosis was revised to Kennedy's disease. In ATXN1, 50 amyotrophic lateral sclerosis patients (12.1%) and 96 controls (13.5%) carried ≥33 repeats (P = 0.753). None of the patients with repeat expansions in ATXN2 or HTT had signs of Huntington's disease or spinocerebellar ataxia type 2, based on a re-evaluation of medical records. The diagnosis of amyotrophic lateral sclerosis was confirmed in all patients, with the exception of one patient who had primary lateral sclerosis. Our findings indicate that repeat expansions in HTT and ATXN2 are associated with increased likelihood of developing amyotrophic lateral sclerosis. Further studies are required to investigate the potential relationship between HTT repeat expansions and amyotrophic lateral sclerosis.

Serum neurofilament as a predictor of 10-year grey matter atrophy and clinical disability in multiple sclerosis: a longitudinal study.

BACKGROUND: The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear. OBJECTIVE: Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years. METHODS: 85 patients, originally enrolled in a multicentre, randomised trial of ω-3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer. RESULTS: Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (ß=-0.399, p=0.040) and deep (ß=-0.556, p=0.010) GM volume, lower mean cortical thickness (ß=-0.581, p=0.010) and higher T2 lesion count (ß=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (ß=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression. CONCLUSION: Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions.

The Effect of Smoking on Long-term Gray Matter Atrophy and Clinical Disability in Patients with Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS). METHODS: We included 85 treatment-naive patients with RRMS with recent inflammatory disease activity who participated in a 10-year follow-up visit after a multicenter clinical trial of 24 months. Smoking status was decided for each patient by 2 separate definitions: by serum cotinine levels measured regularly for the first 2 years of the follow-up (during the clinical trial) and by retrospective patient self-reporting. At the 10-year follow-up visit, clinical tests were repeated, and brain atrophy measures were obtained from MRI using FreeSurfer. Differences in clinical and MRI measurements at the 10-year follow-up between smokers and nonsmokers were investigated by 2-sample t tests or Mann-Whitney tests and linear mixed-effect regression models. All analyses were conducted separately for each definition of smoking status. RESULTS: After 10 years, smoking (defined by serum cotinine levels) was associated with lower total white matter volume (ß = -21.74, p = 0.039) and higher logT2 lesion volume (ß = 0.22, p = 0.011). When defining smoking status by patient self-reporting, the repeated analyses found an additional association with lower deep gray matter volume (ß = -2.35, p = 0.049), and smoking was also associated with a higher score (higher walking impairment) on the log timed 25-foot walk test (ß = 0.050, p = 0.039) after 10 years and a larger decrease in paced auditory serial addition test (attention) scores (ß = -3.58, p = 0.029). DISCUSSION: Smoking was associated with brain atrophy and disability progression 10 years later in patients with RRMS. The findings imply that patients should be advised and offered aid in smoking cessation shortly after diagnosis, to prevent long-term disability progression.

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.

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

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.

ω-3 fatty acid treatment in multiple sclerosis (OFAMS Study): a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To investigate whether ω-3 fatty acids reduce magnetic resonance imaging (MRI) and clinical disease activity in patients with multiple sclerosis, both as monotherapy and in combination with interferon beta-1a treatment. DESIGN: Multicenter, randomized, double-blind, placebo-controlled clinical trial conducted from 2004 to 2008. SETTING: Thirteen public neurology departments in Norway. PARTICIPANTS: Patients aged 18 to 55 years with active relapsing-remitting multiple sclerosis, with a disability score equivalent to 5.0 or less on the Kurtzke Expanded Disability Status Scale. Ninety-two patients were randomized to ω-3 fatty acids (n = 46) or placebo capsules (n = 46). INTERVENTIONS: Administration of 1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily or placebo. After 6 months, all patients in addition received subcutaneously 44 µg of interferon beta-1a 3 times per week for another 18 months. MAIN OUTCOME MEASURE: The primary outcome measure was MRI disease activity as measured by the number of new T1-weighted gadolinium-enhancing lesions during the first 6 months. Secondary outcome measures included MRI disease activity after 9 months and 24 months, relapse rate, disability progression, fatigue, quality of life, and safety. RESULTS: The cumulative number of gadolinium-enhancing MRI lesions during the first 6 months were similar in the ω-3 fatty acids and placebo groups (median difference, 1; 95% CI, 0 to 3; P = .09). No difference in relapse rate was detected after 6 (median difference, 0; 95% CI, 0 to 0; P = .54) or 24 (median difference, 0; 95% CI, 0 to 0; P = .72) months. The proportion of patients without disability progression was 70% in both groups (P > .99). No differences were detected in fatigue or quality-of-life scores, and no safety concerns appeared. Serum analyses of fatty acids showed an increase in ω-3 fatty acids (mean difference, 7.60; 95% CI, 5.57 to 7.91; P < .001) in the patients treated with ω-3 fatty acids compared with the placebo group. CONCLUSION: No beneficial effects on disease activity were detected from ω-3 fatty acids when compared with placebo as monotherapy or in combination with interferon beta-1a. Magnetic resonance imaging disease activity was reduced as expected by interferon beta-1a. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00360906.