title: Preclinical disease activity in multiple sclerosis: A prospective study of cognitive performance prior to first symptom.
abstract: To prospectively investigate potential signs of preclinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort.
  
  
  
  We linked the cognitive performance of all Norwegian men born 1950-1995 who underwent conscription examination at age 18 to 19 years to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study, cognitive test scores were available for 924 male cases and 19,530 male controls. We estimated mean score differences among cases and controls (Student t test) and the risk of developing MS comparing lower to higher scores (Cox regression) in strata of years to clinical onset.
  
  
  
  Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ = 0.80, p = 0.0095), corresponding to a 6 intelligence quotient (IQ)-point difference. Those scoring lowest, that is, >1 standard deviation below the controls' mean, had an increased MS risk during the 2 following years (relative risk = 2.81, 95% confidence interval = 1.52-5.20). Whereas results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored a significant 4.6 to 6.9 IQ points lower than controls up to 20 years prior to first progressive symptoms.
  
  
  
  RRMS may start years prior to clinical presentation, and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease. Ann Neurol 2016;80:616-624.
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway. Marianna.Cortese@uib.no.|Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. Marianna.Cortese@uib.no.|Norwegian MS Competence Center, Haukeland University Hospital, Bergen, Norway. Marianna.Cortese@uib.no.
authors.forename: Marianna
authors.initials: M
authors.lastname: Cortese
authors.affiliation: Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.|Norwegian MS Competence Center, Haukeland University Hospital, Bergen, Norway.
authors.forename: Trond
authors.initials: T
authors.lastname: Riise
authors.affiliation: Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.|Norwegian MS Competence Center, Haukeland University Hospital, Bergen, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Bjørnevik
authors.affiliation: Department of Neurology, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Alok
authors.initials: A
authors.lastname: Bhan
authors.affiliation: Department of Neurology, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Farbu
authors.affiliation: Norwegian MS Competence Center, Haukeland University Hospital, Bergen, Norway.|Kristian Gerhard Jebsen Center for MS Research, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Nina
authors.initials: N
authors.lastname: Grytten
authors.affiliation: Department of Neurology, Haugesund Hospital, Haugesund, Norway.
authors.forename: Ineke
authors.initials: I
authors.lastname: Hogenesch
authors.affiliation: Department of Neurology, Molde Hospital, Molde, Norway.|Unit for Applied Clinical Research, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Rune
authors.initials: R
authors.lastname: Midgard
authors.affiliation: Department of Neurology, Drammen Hospital, Drammen, Norway.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Smith Simonsen
authors.affiliation: Department of Neurology, Førde Hospital, Førde, Norway.
authors.forename: Wenche
authors.initials: W
authors.lastname: Telstad
authors.affiliation: Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA.|Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA.|Channing Division of Network Medicine of the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ascherio
authors.affiliation: Norwegian MS Competence Center, Haukeland University Hospital, Bergen, Norway.|Kristian Gerhard Jebsen Center for MS Research, Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Norwegian MS Registry and Biobank, Haukeland University Hospital, Bergen, Norway.
authors.forename: Kjell-Morten
authors.initials: KM
authors.lastname: Myhr
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D060825:Cognitive Dysfunction / Q000175:diagnosis* / Q000209:etiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000150:complications*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000150:complications*; D009664:Norway; D062706:Prodromal Symptoms; D011446:Prospective Studies; D012042:Registries; D055815:Young Adult