Brain substrates of learning and retention in mild cognitive impairment diagnosis and progression to Alzheimer's disease

Abstract

Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer's disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c) examining their underlying brain morphometric correlates. A total of 607 participants were assigned to three MCI groups (high learning-low retention; low learning-high retention; low learning-low retention) and one control group (high learning-high retention) based on scores above or below a 1.5 SD cutoff on learning and retention indices of the Rey Auditory Verbal Learning Test. Our results demonstrated that MCI individuals with predominantly a learning deficit showed a widespread pattern of gray matter loss at baseline, whereas individuals with a retention deficit showed more focal gray matter loss. Moreover, either learning or retention measures provided good predictive value for longitudinal clinical outcome over two years, although impaired learning had modestly better predictive power than impaired retention. As expected, impairments in both measures provided the best predictive power. Thus, the conventional practice of relying solely on the use of delayed recall or retention measures in studies of amnestic MCI misses an important subset of older adults at risk of developing AD. Overall, our results highlight the importance of including learning measures in addition to retention measures when making a diagnosis of MCI and for predicting clinical outcome.

Keywords: Amnestic MCI; Early detection; Episodic memory; Longitudinal outcome; MR morphometry.

Figure 1

Bar chart showing MR values for hippocampal volume and thickness for selected regions for the four groups. All values are standardized residuals (z-score) after the effects of age and gender have been regressed out. The hippocampal volumes are also controlled for the effect of eTIV. Error bars = standard error of the mean. Hippo = hippocampus; Entorh = entorhinal cortex; Parahi = parahippocampal gyrus; MTG = middle temporal gyrus; PCC = posterior cingulate cortices; IPL = inferior parietal lobule; RMF = rostral middle frontal; MOF = medial orbitofrontal gyrus; F pole = frontal pole.

Figure 2

Reconstructed cortical surface maps representing the average mean difference in thickness (mm, p < .002) for the three groups with learning and/or retention impairment relative to memory intact group (top three rows), and the LL-LR group relative to the HL-LR group (bottom row), after controlling for the effects of age and gender. Blue and cyan indicate thinning whereas red and yellow indicate thickening. Relative to the HL-HR group, the two groups with impaired learning ability showed a more widespread pattern of cortical thinning, involving temporal, frontal regions, and PCC. In contrast, the low retention group (the HL-LR group) demonstrated significantly thinner gray matter in medial temporal areas and PCC relative to the HL-HR group.

Figure 3

Bar chart of AD conversion rate over two years for the four groups (left) as well as for the combined low learning/ retention groups (right).