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.
Highlights
Despite intensive efforts, pharmacological strategies aimed at disrupting the underlying pathology of Alzheimer’s disease (AD)have far failed to translate into therapies for patients
In this study we demonstrate a significant relationship between hippocampal atrophy rates and amyloid load in cognitively normal individuals, and show that this is independent of increasing age
We provide sample size estimates for therapeutic trials seeking to assess disease-modification effects using rates of hippocampal atrophy as outcome measures in asymptomatic amyloid-positive individuals who may be at risk of AD
Summary
Pharmacological strategies aimed at disrupting the underlying pathology of Alzheimer’s disease (AD)have far failed to translate into therapies for patients. Recent CSF [9] and amyloid PET [10,11,12,13] studies have shown that around a third of cognitively normal individuals in their 70 s have significant amyloid deposition Whilst it is not yet known whether all individuals with ‘‘asymptomatic amyloidosis’’ will develop AD if they live long enough, on a group level some [14], if not all [15] studies have shown that these individuals have worse cognition, increased cognitive decline [16,17], with some early evidence for a higher risk of subsequent conversion to MCI or AD [16,18]. We aimed to assess whether using amyloid PET as an inclusion criteria, and atrophy measured from serial MRI as an outcome measure, might be a feasible means of helping to determine disease modifying effects in AD secondary prevention studies
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