title: Toward onset prevention of cognitive decline in adults with Down syndrome (the TOP-COG study): study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Early-onset dementia is common in Down syndrome adults, who have trisomy 21. The amyloid precursor protein gene is on chromosome 21, and so is over-expressed in Down syndrome, leading to amyloid β (Aβ) over-production, a major upstream pathway leading to Alzheimer disease (AD). Statins (microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), have pleiotropic effects including potentially increasing brain amyloid clearance, making them plausible agents to reduce AD risk. Animal models, human observational studies, and small scale trials support this rationale, however, there are no AD primary prevention trials in Down syndrome adults. In this study we study aim to inform the design of a full-scale primary prevention trial.
  
  
  METHODS
  TOP-COG is a feasibility and pilot double-blind randomized controlled trial (RCT), with a nested qualitative study, conducted in the general community. About 60 Down syndrome adults, aged ≥50 will be included. The intervention is oral simvastatin 40 mg at night for 12 months, versus placebo. The primary endpoint is recruitment and retention rates. Secondary endpoints are (1) tolerability and safety; (2) detection of the most sensitive neurocognitive instruments; (3) perceptions of Down syndrome adults and caregivers on whether to participate, and assessment experiences; (4) distributions of cognitive decline, adaptive behavior, general health/quality of life, service use, caregiver strain, and sample size implications; (5) whether Aβ42/Aβ40 is a cognitive decline biomarker. We will describe percentages recruited from each source, the number of contacts to achieve this, plus recruitment rate by general population size. We will calculate summary statistics with 90% confidence limits where appropriate, for each study outcome as a whole, by treatment group and in relation to baseline age, cognitive function, cholesterol and other characteristics. Changes over time will be summarized graphically. The sample size for a definitive RCT will be estimated under alternative assumptions.
  
  
  CONCLUSIONS
  This study is important, as AD is a major problem for Down syndrome adults, for whom there are currently no effective preventions or treatments. It will also delineate the most suitable assessment instruments for this population. Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN Register ID: ISRCTN67338640 (17 November 2011).
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Mental Health and Wellbeing Unit, Gartnavel Royal Hospital, Administrative Building, 1055, Great Western Road, Glasgow G12 0XH, UK. Sally-Ann.Cooper@glasgow.ac.uk.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Cooper
authors.forename: Muriel
authors.initials: M
authors.lastname: Caslake
authors.forename: Jonathan
authors.initials: J
authors.lastname: Evans
authors.forename: Angela
authors.initials: A
authors.lastname: Hassiotis
authors.forename: Andrew
authors.initials: A
authors.lastname: Jahoda
authors.forename: Alex
authors.initials: A
authors.lastname: McConnachie
authors.forename: Jill
authors.initials: J
authors.lastname: Morrison
authors.forename: Howard
authors.initials: H
authors.lastname: Ring
authors.forename: John
authors.initials: J
authors.lastname: Starr
authors.forename: Ciara
authors.initials: C
authors.lastname: Stiles
authors.forename: Frank
authors.initials: F
authors.lastname: Sullivan
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D004314:Down Syndrome / Q000150:complications* / Q000188:drug therapy*; D005240:Feasibility Studies; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009483:Neuropsychological Tests; D010865:Pilot Projects; D011322:Primary Prevention / Q000379:methods; D036301:Qualitative Research; D012107:Research Design; D019821:Simvastatin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000960:Hypolipidemic Agents; D019821:Simvastatin