title: White matter lesion progression in LADIS: frequency, clinical effects, and sample size calculations.
abstract: OBJECTIVE
  White matter lesion (WML) progression has been advocated as a surrogate marker in intervention trials on cerebral small vessel disease. We assessed the rate of visually rated WML progression, studied correlations between lesion progression and cognition, and estimated sample sizes for clinical trials with pure WML progression vs combined WML progression-cognitive outcomes.
  
  
  METHODS
  Those 394 participants of the Leukoaraiosis and Disability Study (LADIS) study with magnetic resonance imaging scanning at baseline and 3-year follow-up were analyzed. WML progression rating relied on the modified Rotterdam Progression Scale. The Vascular Dementia Assessment Scale global score and a composite score of specific executive function tests assessed longitudinal change in cognition. Sample size calculations were based on the assumption that treatment reduces WML progression by 1 grade on the Rotterdam Progression Scale.
  
  
  RESULTS
  WML progression related to deterioration in cognitive functioning. This relationship was less pronounced in subjects with early confluent and confluent lesions. Consequently, studies in which the outcome is cognitive change resulting from treatment effects on lesion progression will need between 1809 subjects per treatment arm when using executive tests and up to 18 853 subjects when using the Vascular Dementia Assessment Scale score. Studies having WML progression as the sole outcome will need only 58 or 70 individuals per treatment arm.
  
  
  CONCLUSIONS
  WML progression is an interesting outcome for proof-of-concept studies in cerebral small vessel disease. If cognitive outcome measures are added to protocols, then sample size estimates increase substantially. Our data support the use of an executive test battery rather than the Vascular Dementia Assessment Scale as the primary cognitive outcome measure.
authors.affiliation: Department of Neurology, Statistics and Documentation Medical University Graz, Austria. reinhold.schmidt@medunigraz.at
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schmidt
authors.forename: Andrea
authors.initials: A
authors.lastname: Berghold
authors.forename: Hanna
authors.initials: H
authors.lastname: Jokinen
authors.forename: Alida A
authors.initials: AA
authors.lastname: Gouw
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.forename: Katja
authors.initials: K
authors.lastname: Petrovic
authors.forename: Sofia
authors.initials: S
authors.lastname: Madureira
authors.forename: Ana
authors.initials: A
authors.lastname: Verdelho
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ferro
authors.forename: Gunhild
authors.initials: G
authors.lastname: Waldemar
authors.forename: Anders
authors.initials: A
authors.lastname: Wallin
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Wahlund
authors.forename: Anna
authors.initials: A
authors.lastname: Poggesi
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pantoni
authors.forename: Domenico
authors.initials: D
authors.lastname: Inzitari
authors.forename: Franz
authors.initials: F
authors.lastname: Fazekas
authors.forename: Timo
authors.initials: T
authors.lastname: Erkinjuntti
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003072:Cognition Disorders / Q000175:diagnosis / Q000453:epidemiology*; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D049292:Leukoaraiosis / Q000175:diagnosis / Q000473:pathology*; D056784:Leukoencephalopathies / Q000175:diagnosis / Q000473:pathology*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D017063:Outcome Assessment, Health Care; D015995:Prevalence; D011379:Prognosis; D018401:Sample Size