title: Novel Statistically-Derived Composite Measures for Assessing the Efficacy of Disease-Modifying Therapies in Prodromal Alzheimer's Disease Trials: An AIBL Study.
abstract: BACKGROUND
  There is a growing consensus that disease-modifying therapies must be given at the prodromal or preclinical stages of Alzheimer's disease (AD) to be effective. A major unmet need is to develop and validate sensitive measures to track disease progression in these populations.
  
  
  OBJECTIVE
  To generate novel statistically-derived composites from standard scores, which have increased sensitivity in the assessment of change from baseline in prodromal AD.
  
  
  METHODS
  An empirically based method was employed to generate domain specific, global, and cognitive-functional novel composites. The novel composites were compared and contrasted with each other, as well as standard scores for their ability to track change from baseline. The longitudinal characteristics and power to detect decline of the measures were evaluated. Data from participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study characterized as mild cognitively impaired with high neocortical amyloid-β burden were utilized for the study.
  
  
  RESULTS
  The best performing standard scores were CDR Sum-of-Boxes and MMSE. The statistically-derived novel composites performed better than the standard scores from which they were derived. The domain-specific composites generally did not perform as well as the global composites or the cognitive-functional composites.
  
  
  CONCLUSIONS
  A systematic method was employed to generate novel statistically-derived composite measures from standard scores. Composites comprised of measures including function and multiple cognitive domains appeared to best capture change from baseline. These composites may be useful to assess progression or lack thereof in prodromal AD. However, the results should be replicated and validated using an independent clinical sample before implementation in a clinical trial.
authors.affiliation: CSIRO Digital Productivity Flagship, Floreat, WA, Australia.
authors.forename: Samantha C
authors.initials: SC
authors.lastname: Burnham
authors.affiliation: Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Raghavan
authors.affiliation: CSIRO Digital Productivity Flagship, North Ryde, NSW, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Wilson
authors.affiliation: Janssen Research and Development, Titusville, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.affiliation: Janssen Research and Development, Fremont, CA, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ropacki
authors.affiliation: Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Novak
authors.affiliation: Academic Unit for Psychiatry of Old Age, Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia.|National Ageing Research Institute, Parkville, VIC, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Ames
authors.affiliation: Academic Unit for Psychiatry of Old Age, Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Ellis
authors.affiliation: Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia.|Sir James McCusker Alzheimer's Disease Research Unit (Hollywood Private Hospital), Perth, WA, Australia.
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
authors.affiliation: Cogstate, Melbourne, VIC, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Maruff
authors.affiliation: Mental Health Research Institute (MHRI), The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Romano
authors.affiliation: Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia.|Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Rowe
authors.affiliation: ARC Centre of Excellence in Cognition and its Disorders, and Department of Psychology, Macquarie University, Sydney, NSW, Australia.
authors.forename: Greg
authors.initials: G
authors.lastname: Savage
authors.affiliation: CSIRO Food and Nutrition Flagship, Melbourne, VIC, Australia.
authors.forename: S Lance
authors.initials: SL
authors.lastname: Macaulay
authors.affiliation: Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Vaibhav A
authors.initials: VA
authors.lastname: Narayan
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics / Q000523:psychology / Q000628:therapy; D000814:Aniline Compounds / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D001315:Australia; D015415:Biomarkers / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D008019:Life Style; D008137:Longitudinal Studies; D008297:Male; D008609:Mental Status Schedule; D059906:Neuroimaging / Q000379:methods*; D009483:Neuropsychological Tests; D062706:Prodromal Symptoms; D015203:Reproducibility of Results; D013844:Thiazoles / Q000378:metabolism
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000814:Aniline Compounds; D001057:Apolipoproteins E; D015415:Biomarkers; D013844:Thiazoles
keywords: Alzheimer’s disease; clinical marker; clinical trial; mild cognitive impairment; prodromal stage