Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI

Abstract

The vitamin E and donepezil trial for the treatment of amnestic mild cognitive impairment (MCI) was conducted at 69 centers in North America; 24 centers participated in an MRI sub study. The objective of this study was to evaluate the effect of treatment on MRI atrophy rates; and validate rate measures from serial MRI as indicators of disease progression in multi center therapeutic trials for MCI. Annual percent change (APC) from baseline to follow-up was measured for hippocampus, entorhinal cortex, whole brain, and ventricle in the 131 subjects who remained in the treatment study and completed technically satisfactory baseline and follow-up scans. Although a non-significant trend toward slowing of hippocampal atrophy rates was seen in APOE ∈4 carriers treated with donepezil; no treatment effect was confirmed for any MRI measure in either treatment group. For each of the four brain atrophy rate measures, APCs were greater in subjects who converted to AD than non-converters, and were greater in APOE ∈4 carriers than non-carriers. MRI APCs and changes Disclosure Statement for AuthorsThe authors have no conflicts of interest to disclose. The industry sponsors had no role in the analysis or interpretation of these data nor in the content of the paper. Appropriate approval procedures were used concerning human subjects. NIH Public Access IntroductionThe vitamin E and donepezil clinical trial for the treatment of mild cognitive impairment (MCI) was conducted in 769 subjects at 69 centers in North America . The study was designed to determine whether the antioxidant vitamin E or donepezil, the only cholinesterase inhibitor available at the time the study was designed, would be effective at delaying the clinical progression of subjects with the amnestic form of MCI to the clinical diagnosis of Alzheimer's disease (AD). While vitamin E had no beneficial effect, donepezil reduced the risk of progression from amnestic MCI to clinically possible or probable AD for up to 12 months. This treatment effect was extended to 24 months in carriers of the apolipoprotein E ∈4 (APOE e4) allele. Twenty-four of the recruiting sites voluntarily participated in a Magnetic Resonance Imaging (MRI) sub study which was grafted onto the existing clinical therapeutic study design. The purpose of the MRI sub study was to determine if a therapeutic effect of either vitamin E or donepezil could be detected on rates of brain atrophy from serial MRI studies. Four different brain atrophy brain measures were assessed; the hippocampus, entorhinal cortex (ERC), whole brain, and ventricular volume. Each of these MRI measurements has figured prominently in anatomic MRI based studies of MCI, AD, and normal aging (Jack et al., 1992;Fox et al., 1996;Jack et al., 1997;Fox et al., 1999;Killiany 2000;Dickerson et al., 2001;Killiany et al., 2002;Du et al., 2003). A primary objective of this analysis was to test the hypothesis that vitamin E or donepezil slowed the rate of brain atrophy relative to placebo in subjects with amnestic MCI (Petersen 1995;Pe...

Basal forebrain atrophy is a presymptomatic marker for Alzheimer's disease

“…Most research on the prodromal phase of AD has focused on alterations in the hippocampus and related structures (36,(51)(52)(53)(54)(55)(56)(57), and prospective studies have found that hippocampal atrophy in presymptomatic individuals was highly predictive of AD (5,58,59). Individuals with MCI, an early manifestation of AD (60), have alterations in multiple cortical and subcortical areas, including the parietotemporal and prefrontal cortices, posterior cingulate gyrus (61-64), insula, mammillary bodies, and thalamus (43,65).…”

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