title: Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study): A pilot randomised controlled trial.
abstract: Dementia is very common in Down syndrome (trisomy 21) adults. Statins may slow brain amyloid β (Aβ, coded on chromosome 21) deposition and, therefore, delay Alzheimer disease onset. One prospective cohort study with Down syndrome adults found participants on statins had reduced risk of incident dementia, but there are no randomised controlled trials (RCTs) on this issue. Evidence is sparse on the best instruments to detect longitudinal cognitive decline in older Down syndrome adults.
  
  
  
  TOP-COG was a feasibility/pilot, double-blind RCT of 12 months simvastatin 40 mg versus placebo for the primary prevention of dementia in Alzheimer disease in Down syndrome adults aged 50 years or older. Group allocation was stratified by age, apolipoprotein E (APOE) ε4 allele status, and cholesterol level. Recruitment was from multiple general community sources over 12 months. Adults with dementia, or simvastatin contraindications, were excluded. Main outcomes were recruitment and retention rates. Cognitive decline was measured with a battery of tests; secondary measures were adaptive behaviour skills, general health, and quality of life. Assessments were conducted pre randomisation and at 12 months post randomisation. Blood Aβ40/Aβ42 levels were investigated as a putative biomarker. Results were analysed on an intention-to-treat basis. A qualitative sub-study was conducted and analysed using the Framework Approach to determine recruitment motivators/barriers, and participation experience.
  
  
  
  We identified 181 (78 %) of the likely eligible Down syndrome population, and recruited 21 (11.6 %), from an area with a general population size of 3,135,974. Recruitment was highly labour-intensive. Thirteen (62 %) participants completed the full year. Results favoured the simvastatin group. The most appropriate cognitive instrument (regarding ease of completion and detecting change over time) was the Memory for Objects test from the Neuropsychological Assessment of Dementia in Individuals with Intellectual Disabilities battery. Cognitive testing appeared more sensitive than proxy-rated adaptive behaviour, quality of life, or general health scores. Aβ40 levels changed less for the simvastatin group (not statistically significant). People mostly declined to participate because of not wanting to take medication, and not knowing if they would receive simvastatin or placebo. Participants reported enjoying taking part.
  
  
  
  A full-scale RCT is feasible. It will need 37 % UK population coverage to recruit the required 160 participants. Information/education about the importance of RCT participation is needed for this population.
  
  
  
  ISRCTN67338640 .
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Mental Health and Wellbeing Group, 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.affiliation: Community Learning Disability Psychiatry, The Gatehouse, Inverurie Hospital, Inverurie, AB51 3UL, UK.
authors.forename: Temitope
authors.initials: T
authors.lastname: Ademola
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, McGregor Building, 2nd floor, Western Infirmary, Glasgow, G11 6NT, UK.
authors.forename: Muriel
authors.initials: M
authors.lastname: Caslake
authors.affiliation: Research and Development NHS Greater Glasgow and Clyde, 1st floor Tennent Institute, Western Infirmary Church Street, Glasgow, G11 6NT, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Douglas
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Mental Health and Wellbeing Group, Gartnavel Royal Hospital, Administrative Building, 1055, Great Western Road, Glasgow, G12 0XH, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Evans
authors.affiliation: Robertson Centre for Biostatistics, University of Glasgow, Boyd Orr Building, Glasgow, G12 8QQ, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Greenlaw
authors.affiliation: Robertson Centre for Biostatistics, University of Glasgow, Boyd Orr Building, Glasgow, G12 8QQ, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Haig
authors.affiliation: University College London, Bloomsbury Campus, Charles Bell House, 67-73 Riding House Street, London, W1W 7EY, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Hassiotis
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Mental Health and Wellbeing Group, Gartnavel Royal Hospital, Administrative Building, 1055, Great Western Road, Glasgow, G12 0XH, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jahoda
authors.affiliation: Robertson Centre for Biostatistics, University of Glasgow, Boyd Orr Building, Glasgow, G12 8QQ, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: McConnachie
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, General Practice and Primary Care, 1 Horselethill Road, Glasgow, G12 9LX, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Morrison
authors.affiliation: Department of Psychiatry, University of Cambridge, Douglas House, 18b Trumpington Road, Cambridge, CB2 2AH, UK.
authors.forename: Howard
authors.initials: H
authors.lastname: Ring
authors.affiliation: Alzheimer Scotland Dementia Research Centre, 7 George Square, Edinburgh, EH8 9JZ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Starr
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Mental Health and Wellbeing Group, Gartnavel Royal Hospital, Administrative Building, 1055, Great Western Road, Glasgow, G12 0XH, UK.
authors.forename: Ciara
authors.initials: C
authors.lastname: Stiles
authors.affiliation: Scottish Borders Learning Disability Service, Church Street, Earlson, TD4 6HR, UK.
authors.forename: Chammy
authors.initials: C
authors.lastname: Sirisena
authors.affiliation: Gordon F Cheesbrough Research Chair and Director of UTOPIAN, University of Toronto, North York General Hospital, 4001 Leslie Street, Toronto, ON, M2K 1E1, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Sullivan
mesh_terms: D000328:Adult; D060825:Cognitive Dysfunction / Q000517:prevention & control*; D004311:Double-Blind Method; D004314:Down Syndrome / Q000150:complications*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010865:Pilot Projects; D011446:Prospective Studies; D019821:Simvastatin / Q000627:therapeutic use
chemical_list: D019821:Simvastatin
keywords: Alzheimer disease; Dementia; Down syndrome; Neuropsychology; Primary prevention; Simvastatin; Statin