title: Atrophy rates in asymptomatic amyloidosis: implications for Alzheimer prevention trials.
abstract: There is considerable interest in designing therapeutic studies of individuals at risk of Alzheimer disease (AD) to prevent the onset of symptoms. Cortical β-amyloid plaques, the first stage of AD pathology, can be detected in vivo using positron emission tomography (PET), and several studies have shown that ~1/3 of healthy elderly have significant β-amyloid deposition. Here we assessed whether asymptomatic amyloid-PET-positive controls have increased rates of brain atrophy, which could be harnessed as an outcome measure for AD prevention trials. We assessed 66 control subjects (age = 73.5±7.3 yrs; MMSE = 29±1.3) from the Australian Imaging Biomarkers & Lifestyle study who had a baseline Pittsburgh Compound B (PiB) PET scan and two 3T MRI scans ~18-months apart. We calculated PET standard uptake value ratios (SUVR), and classified individuals as amyloid-positive/negative. Baseline and 18-month MRI scans were registered, and brain, hippocampal, and ventricular volumes and annualized volume changes calculated. Increasing baseline PiB-PET measures of β-amyloid load correlated with hippocampal atrophy rate independent of age (p = 0.014). Twenty-two (1/3) were PiB-positive (SUVR>1.40), the remaining 44 PiB-negative (SUVR≤1.31). Compared to PiB-negatives, PiB-positive individuals were older (76.8±7.5 vs. 71.7±7.5, p<0.05) and more were APOE4 positive (63.6% vs. 19.2%, p<0.01) but there were no differences in baseline brain, ventricle or hippocampal volumes, either with or without correction for total intracranial volume, once age and gender were accounted for. The PiB-positive group had greater total hippocampal loss (0.06±0.08 vs. 0.02±0.05 ml/yr, p = 0.02), independent of age and gender, with non-significantly higher rates of whole brain (7.1±9.4 vs. 4.7±5.5 ml/yr) and ventricular (2.0±3.0 vs. 1.1±1.0 ml/yr) change. Based on the observed effect size, recruiting 384 (95%CI 195-1080) amyloid-positive subjects/arm will provide 80% power to detect 25% absolute slowing of hippocampal atrophy rate in an 18-month treatment trial. We conclude that hippocampal atrophy may be a feasible outcome measure for secondary prevention studies in asymptomatic amyloidosis.
authors.affiliation: Dementia Research Centre, University College London, London, United Kingdom. a.andrews@ucl.ac.uk
authors.forename: K Abigail
authors.initials: KA
authors.lastname: Andrews
authors.forename: Marc
authors.initials: M
authors.lastname: Modat
authors.forename: Kate E
authors.initials: KE
authors.lastname: Macdonald
authors.forename: Tom
authors.initials: T
authors.lastname: Yeatman
authors.forename: M Jorge
authors.initials: MJ
authors.lastname: Cardoso
authors.forename: Kelvin K
authors.initials: KK
authors.lastname: Leung
authors.forename: Josephine
authors.initials: J
authors.lastname: Barnes
authors.forename: Victor L
authors.initials: VL
authors.lastname: Villemagne
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Rowe
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.forename: Sebastien
authors.initials: S
authors.lastname: Ourselin
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000517:prevention & control; D000686:Amyloidosis / Q000175:diagnosis*; D001057:Apolipoproteins E / Q000235:genetics; D001284:Atrophy; D001921:Brain / Q000473:pathology; D060825:Cognitive Dysfunction; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size; D058225:Plaque, Amyloid; D049268:Positron-Emission Tomography
chemical_list: D001057:Apolipoproteins E
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